The Role of HMGB1, a Nuclear Damage-Associated Molecular Pattern Molecule, in the Pathogenesis of Lung Diseases

Mao Wang; Alex Gauthier; LeeAnne Daley; Katelyn Dial; Jiaqi Wu; Joanna Woo; Mosi Lin; Charles Ashby; Lin L Mantell

doi:10.1089/ars.2019.7818

. 2019 Sep 26;31(13):954–993. doi: 10.1089/ars.2019.7818

The Role of HMGB1, a Nuclear Damage-Associated Molecular Pattern Molecule, in the Pathogenesis of Lung Diseases

Mao Wang ^1,,^*, Alex Gauthier ^1,,^*, LeeAnne Daley ¹, Katelyn Dial ¹, Jiaqi Wu ¹, Joanna Woo ¹, Mosi Lin ¹, Charles Ashby ¹, Lin L Mantell ^1,,^2,^✉

PMCID: PMC6765066 PMID: 31184204

Abstract

Significance: High-mobility group protein box 1 (HMGB1), a ubiquitous nuclear protein, regulates chromatin structure and modulates the expression of many genes involved in the pathogenesis of lung cancer and many other lung diseases, including those that regulate cell cycle control, cell death, and DNA replication and repair. Extracellular HMGB1, whether passively released or actively secreted, is a danger signal that elicits proinflammatory responses, impairs macrophage phagocytosis and efferocytosis, and alters vascular remodeling. This can result in excessive pulmonary inflammation and compromised host defense against lung infections, causing a deleterious feedback cycle.

Recent Advances: HMGB1 has been identified as a biomarker and mediator of the pathogenesis of numerous lung disorders. In addition, post-translational modifications of HMGB1, including acetylation, phosphorylation, and oxidation, have been postulated to affect its localization and physiological and pathophysiological effects, such as the initiation and progression of lung diseases.

Critical Issues: The molecular mechanisms underlying how HMGB1 drives the pathogenesis of different lung diseases and novel therapeutic approaches targeting HMGB1 remain to be elucidated.

Future Directions: Additional research is needed to identify the roles and functions of modified HMGB1 produced by different post-translational modifications and their significance in the pathogenesis of lung diseases. Such studies will provide information for novel approaches targeting HMGB1 as a treatment for lung diseases.

Keywords: HMGB1, inflammatory lung injury, pulmonary infection, pulmonary vascular remodeling, fibrosis, cancer

Introduction

High-mobility group protein box 1 (HMGB1) was first identified in 1973 as a nonhistone chromosomal nuclear protein (107). It was isolated from calf thymus chromatin and was categorized as a “high-mobility group” protein by its defining characteristic of rapid migration in polyacrylamide gel electrophoresis systems, without any signs of aggregation (107). In 1999, it was reported that extracellular HMGB1 was significantly increased in animal models of sepsis and in septic patients (336). Circulating HMGB1 can produce significant proinflammatory effects and cause lethal sepsis shock (336, 337). Over the last two decades, HMGB1 has been described as a damage-associated molecular pattern (DAMP) molecule or an alarmin that plays a role in the pathogenesis of an increasing number of diseases, including, but not limited to, sepsis, autoimmune diseases, cancer, liver diseases, and lung diseases (69, 145, 218, 262).

A number of reviews have been published in this journal that have discussed the (i) post-translational modifications of HMGB1 that occur during inflammatory responses; (ii) role of HMGB1 receptors in oxidative and inflammatory tissue injury; (iii) the involvement of HMGB1 in cardiovascular diseases, including pulmonary hypertension; and (iv) targeting HMGB1 for the treatment of various metabolic disorders resulting from sterile inflammation (44, 96, 289). In this review, we focus on recent studies regarding the potential cellular and molecular mechanisms underlying the roles of HMGB1, especially in the pathogenesis of lung diseases where it could represent a biomarker for disease prognosis and a target for therapeutic strategies in treating lung diseases.

HMGB1 Structure and Its Function in the Nucleus

HMGB1 is a 215 amino acid nuclear protein, weighing 25 kDa (123a). The gene that encodes for HMGB1 is located on chromosome 13q12.3 and was sequenced in 1996 (91). The primary structure of HMGB1 is well conserved across species and shares high sequence homology among species such as yeast, Drosophila, Chironomidae, bacteria, plants, and fish (101, 175, 282, 331, 347, 351, 354). Furthermore, mouse and rat HMGB1 shares 100% homology, while human and rodent HMGB1 has 99% homology (45, 91, 98, 271, 344).

The binding of nuclear HMGB1 in the minor groove of DNA can facilitate DNA bending, producing higher transcription factor activity, DNA repair, and remodeling of the chromatin (34, 208, 250, 264). As illustrated in Figure 1, HMGB1 binds to DNA via two unique binding domains, the A-box (amino acid residues 9–79) and the B-box (amino acid residues 95–163), which share high sequence similarity with each other (11, 32). The A-Box and B-Box are separated by a short interlinking peptide sequence (32, 264, 265). The C-terminal of HMGB1 (amino acid residues 186–215) is composed of a highly acidic tail containing aspartic and glutamic acid residues (22, 34). The acidic C-terminal tail of HMGB1, which is not required for binding, regulates its effects on transcriptional activity, as it is required for DNA bending (119, 300, 332). The C-terminal plays an essential role in the binding of protein p53 to DNA to regulate cell cycle and death pathways (6, 22).

FIG. 1. — **The structure and function determining sequence of HMGB1.** Human HMGB1 is a protein with 215 amino acids, encoded by the gene located at chromosome 13q12.3. HMGB1 contains two DNA-binding domains: the A Box (amino acids 9–79) and B-Box (amino acids 95–163), and a C-terminal tail (amino acids 186–215), which is involved in promoting the interaction of A and B box with DNA. HMGB1 contains two NLS, which are located at amino acids 28–44 (NLS1) and 179–185 (NLS2), responsible for the nuclear localization of HMGB1 and for regulating HMGB1's translocation between the nucleus and the cytoplasm on post-translational modifications, such as phosphorylation and acetylation. There are three critical cysteines (C23, C45, and C106) subject to redox modifications, which determine whether HMGB1 functions as a cytokine, a chemokine, or an inactive protein. HMGB1 also has a heparin binding site (amino acids 6–12), a TLR4 binding site (amino acids 89–108), and an RAGE binding site (amino acids 150–183). HMGB1, high-mobility group protein box 1; NLS, nuclear localization signals; RAGE, receptor for advanced glycation end products; TLR, toll-like receptor.

HMGB1 Localization and Lung Diseases

Wang et al. reported in 1999 that treatment of cultured macrophages with endotoxin lipopolysaccharide (LPS) caused a significant release of nuclear HMGB1 into cell culture media. They further demonstrated that extracellular HMGB1 in the serum of subjects with sepsis can act as a late mediator of inflammation for septic shock mice (336). Since then, excessive accumulation of extracellular HMGB1, especially airway and sputum HMGB1, has been reported in many studies of a variety of lung diseases, such as cystic fibrosis (CF), asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis, pneumonia, tuberculosis (TB), pulmonary arterial hypertension (PAH), and lung cancer (Table 1). Thus, blocking the accumulation of extracellular HMGB1 has been postulated in the treatment of these disorders.

Table 1.

Levels and Modifications of High-Mobility Group Protein Box 1 in Biological Samples in Lung Diseases

Lung disease	Sample (origin)	Fold increase compared to control	HMGB1 modification	References
Asthma	Sputum	5	Reduced and disulfide	(71)
COPD	Sputum	37	—	(128)
	Plasma	3.83	—	(128)
	Serum	4.0	—	(366)
ALI/ARDS	BAL	10–17	Oxidized, reduced, and disulfide	(377)
PF	Serum	1.97–5.66	—	(296)
CF	Serum	5.11	—	(57)
	Sputum	4.64
	BAL	20.11	—	(86)
Pneumonia	BAL	4	—	(378)
TB	Plasma	1.68	—	(368)
TB	Sputum	1.82	—	(368)
Lung cancer	Serum	1.8–8.2	—	(343)
PAH	Serum	2.47	—	(366)

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ALI, acute lung injury; ARDS, acute respiratory distress syndrome; BAL, bronchoalveolar lavage; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; HMGB1, high-mobility group protein box 1; PAH, pulmonary arterial hypertension; PF, pulmonary fibrosis; TB, tuberculosis.

Under normal physiological conditions, HMGB1 is localized in the nucleus, due to its two nuclear localization signals (NLS), located at amino acids 28–44 (NLS1) and 179–185 (NLS2) (Fig. 2) (138, 253, 278). However, HMGB1 can be readily shuttled between the nucleus and the cytoplasm by modifications of NLS1 and NLS2 via acetylation and deacetylation (Fig. 2) (138, 280, 363). Acetylation and deacetylation of HMGB1 are mediated by histone acetyltransferase (HAT) family proteins and histone deacetylase, thus regulating its translocation between the nucleus and the cytoplasm (37, 201, 363).

FIG. 2. — **Regulation of HMGB1 localization.** HMGB1 is a nuclear nonhistone binding protein that can shuttle between the nucleus and the cytosol through nuclear pores. HMGB1 contains two nuclear localization sequences (NSL1 and NLS2). These NLS are post-translationally modified by hyperacetylating lysine residues within NLS1 and NLS2. Hyperacetylation of NLS by HAT (p300, PCAF, CBP) is required to induce nucleocytoplasmic translocation. Also, the phosphorylation of cytoplasmic HMGB1 by PKC can cause HMGB1 to bind with karyopherin-α-1 and importin-β-1, which can block its nuclear import, keeping it in the cytoplasm. In addition, the methylation of lysine-42 at NLS1 alters HMGB1 conformation, which can result in its decreased ability to bind with DNA and causing HMGB1's passive diffusion to the cytoplasm. Under conditions of oxidative stress, HMGB1 translocates from the nucleus to the cytoplasm through nuclear export factor 1 (CRM1). Cytoplasmic HMGB1 can then be secreted from the cell in secretory vesicle-mediated exocytosis. Alternatively, HMGB1 can be passively secreted from injured or necrotic cells. Whether passively or actively secreted, HMGB1 then can accumulate in extracellular spaces such as the airways and circulating blood. Extracellular HMGB1 also is subjected to redox modifications of three critical cysteine residues (C23, C45, and C106). When HMGB1 fully reduces it can function as a cytokine and when HMGB1 is oxidized it forms a disulfide bond between C23 and C45, which imparts chemokine and cytokine activity. HMGB1 can be terminally oxidized (sulfonic acid) at all three cysteines, which inactivates all activity. CRM1, chromosome region maintenance 1; HAT, histone acetyltransferase; PCAF, p300/CBP-associated factor; PKC, protein kinase C.

Under cellular stress, the translocation of HMGB1 from the nucleus to the cytoplasm can be favored by post-translational modifications of nuclear HMGB1, such as hyperacetylation, phosphorylation, methylation, and oxidation (37, 68, 99, 139, 166, 238, 314). The accumulation of HMGB1 in the cytoplasm can lead to active HMGB1 release from cells into the extracellular milieu by secretory lysosomes (37, 97, 238).

The translocation of HMGB1 from the nucleus to the cytoplasm was first shown in HMGB1 with hyperacetylated lysine residues in NLS1 and NLS2 (37, 201, 363). It was found that the acetylation of HMGB1 is primarily regulated by the HAT family protein p300/CBP and p300/CBP-associated factor (PCAF) (37, 362). In addition, under oxidative conditions, HMGB1 can form a complex with chromosome region maintenance 1 (CRM1), a nuclear export factor (NEF), and is readily translocated to the cytoplasm on acetylation (314). Hyperacetylated HMGB1 was found in cells or animals subjected to oxidative stress under conditions of exposure to hyperoxia or proinflammatory stimuli (66, 301).

Interestingly, it was recently discovered that oxidation of the critical cysteine residues of HMGB1 (Fig. 1) can directly affect its subcellular location (166). HMGB1 has three critical cysteine residues at amino acids C23, C45, and C106 (Fig. 1). Intracellular HMGB1 is present in the fully reduced state (85). In a recent study, Kwak et al. demonstrated that hydrogen peroxide generated in macrophages on exposure to LPS can facilitate the intramolecular disulfide formation between cysteines C23 and C45. Such oxidation of HMGB1 cysteines can stimulate its nucleocytoplasmic translocation and release from macrophages (166).

In addition to NLS acetylation-dependent subcellular localization, the phosphorylation of serine residues of NLS1 and NLS2 is another modification that regulates the shuttling of HMGB1 from the nucleus to the cytoplasm (99, 363). The phosphorylation of specific serine residues in HMGB1 is mediated by protein kinase C (PKC). Compounds that are specific PKC inhibitors (i.e., okadaic acid and baicalein) can cause a concentration-dependent reduction in HMGB1 phosphorylation (363), whereas activators of PKC (e.g., 12-O-tetradecanoylphorbol-13-acetate [PMA] and bryostatin-1) increase HMGB1 phosphorylation and its secretion (238). On phosphorylation, HMGB1 can bind to karyopherin-α1, a member of the importin-α family, which induces the sequestration of HMGB1 in the cytoplasm by blocking its translocation to the nucleus (Fig. 2) (363).

Nuclear HMGB1 can also be methylated at Lys42, which can alter HMGB1 protein conformation, decreasing HMGB1-DNA binding activity (139, 349). Decreased binding of HMGB1 to DNA increases its passive diffusion out of the nucleus and into the cytoplasm (139, 149, 280). This has been reported in neutrophils under chronic inflammatory conditions (139). Moreover, the secretion of HMGB1 from macrophages can be facilitated when HMGB1 is poly(ADP-ribosyl)ated, a post-translational modification produced by poly(ADP)-ribose polymerase (PARP)-1 (68, 360).

In summary, many post-translational modifications regulate HMGB1's translocation from the nucleus to the cytoplasm and the subsequent active release from cells (Fig. 2) (37, 68, 99, 139, 238, 314). Because of the critical role of extracellular HMGB1 in the pathogenesis of numerous lung diseases, blocking the release of HMGB1 has been postulated for therapeutic approaches. In fact, inhibiting PARP-1, either genetically or pharmacologically, has been shown to effectively attenuate LPS-stimulated HMGB1 release, suggesting its therapeutic application in treating lung disorders caused by bacterial infections (68). Other studies have shown that ascorbic acid and GTS-21, a partial agonist of α7 nicotinic acetylcholine receptors, can effectively attenuate ALI and enhance host defense against pulmonary infections by inhibiting HMGB1 hyperacetylation (247, 301). These studies are discussed further in this review.

HMGB1 can also be passively released by leaking necrotic cells, a process that can induce inflammation (37, 280). Interestingly, HMGB1 is not easily released by cells undergoing apoptosis due to its high affinity to chromatin and the low levels of NLS acetylation (280). The significant difference in HMGB1-induced clinical outcomes, by HMGB1 released from cells undergoing either necrosis or apoptosis, was elegantly demonstrated in a recent study by Rafikov et al. (258). In this study, the authors show that HMGB1 released from necrotic cells was in a reduced redox status, exhibiting a more potent and sustained inflammatory ability than HMGB1 released from apoptotic cells. The redox regulation of HMGB1 activities is further discussed in this review.

HMGB1 Signaling in Pathophysiology of Lung Diseases

Extracellular HMGB1, as a DAMP through similar pathways, can play a critical role in activating signaling pathways leading to inflammatory responses, vascular remodeling, and fibrotic progression in several lung diseases. Figure 3 illustrates these HMGB1-elicited signaling events mediated by HMGB1 receptors.

FIG. 3. — **The role of HMGB1 in the pathogenesis of lung diseases.** In the studies reviewed in this article, elevated extracellular HMGB1, whether it is in the airways, serum, or other extracellular milieu, can signal as a DAMP through similar pathways that lead to the pathogenesis of different lung diseases. The binding of extracellular HMGB1 to its receptors, such as TLR2, TLR4, TLR9, and RAGE, can initiate innate immune responses by increasing NF-κB and MAPK activities. The activation of NF-κB is responsible for the increased secretion of numerous proinflammatory mediators, including the active release of HMGB1 into the airways. Proinflammatory mediators can induce the infiltration of leukocytes into the lungs and airways, leading to lung inflammation. This further causes an elevation in the levels of proteases and ROS, which feeds back and contributes to increased NF-κB activity. A significant elevation in ROS can damage and cause dysfunction, injury, and death to lung cells, including macrophages and endothelial and epithelial cells. Both ROS and extracellular HMGB1 can directly disrupt epithelial and endothelial intercellular tight junctions, reduce their barrier integrity, and result in increased alveolar permeability. Macrophage injury reduces efferocytosis, which contributes to the higher leukocyte counts, as well as impairs the phagocytosis of invading bacteria, resulting in increased susceptibility to infections. Pulmonary infections and damage to the lung cells further increase the accumulation of extracellular HMGB1, establishing a negative feedback cycle. In addition, the binding of HMGB1 to RAGE receptors increases MAPK activity, altering cell proliferation and inducing vascular remodeling. Overall, HMGB1-induced inflammatory lung cell damage, in combination with vascular remodeling, can significantly compromise lung functions and cause lung diseases. DAMP, damage-associated molecular pattern; MAPK, mitogen-activated protein kinase; NF-κβ, nuclear factor kappa-light-chain-enhancer of activated B cells; ROS, reactive oxygen species.

Extracellular HMGB1 can function as a DAMP molecule that can activate immune cells via the pattern recognition receptors, including toll-like receptors (TLRs), TLR2, TLR4, TLR9, and receptor for advanced glycation end products (RAGE). The binding of HMGB1 to these cell surface receptors can elicit inflammatory responses by activating nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK)/p38 pathways (Fig. 3) (56, 117, 193, 239, 334, 366). It has been shown that extracellular HMGB1 has high affinity for the TLR2, TLR4, and RAGE, on pneumocytes and leukocytes (137, 245).

Binding of extracellular HMGB1 to TLR2/4/9 receptors can activate the canonical pathway of NF-κB. Following the activation of TLR2 and TLR4 receptors, the phosphorylation of the inhibitory IκB-α protein by IκB kinase (IKK) causes the NF-κB subunit complex (p65 [NF-kappa-B p65 subunit/transcription factor p65] and p50) to translocate to the nucleus after p65 phosphorylation (17, 18, 58, 169, 170). On entering the nucleus, NF-κB upregulates the expression of more than 150 proteins (41, 195, 292). On HMGB1 binding to RAGE, it can activate the MAPK pathway to phosphorylate extracellular signal-regulated kinase (ERK) and p38, which also can activate NF-κB (188).

HMGB1-induced activation of canonical NF-κB pathways can induce the synthesis secretion and secretion of proinflammatory mediators, including interleukin (IL)-1β, IL-8, tumor necrosis factor-α (TNF-α), interferon (IFN)-γ, and monocyte chemoattractant protein-1 (MCP-1), which are involved in the recruitment of leukocytes and lymphocytes to the lung, and contribute to furthering lung inflammation (56, 59, 67, 106, 114, 334). The chemokine activity of HMGB1 was revealed following the pharmacological inhibition of α-chemokine receptors, which resulted in the attenuation of the HMGB1-induced increase in airway levels of infiltrated neutrophils, subsequent lung injury, or even death of the animals (192).

During pulmonary bacterial infection, pathogen-associated molecular pattern (PAMP) molecules, including bacterial components such as LPS, peptidoglycan, and lipoteichoic acid, can activate airway cells, including alveolar macrophages and epithelial cells, through surface receptor PRRs, TLR2, TLR4, TLR9, and RAGE (324, 376). The activation of these receptors can increase HMGB1 expression and induce the translocation and release of HMGB1 into the extracellular milieu (338, 376). Together, PAMPs and HMGB1 can cause synergetic effects on activating immune cells, producing exacerbated inflammatory lung injury (8, 130, 256). The binding of HMGB1 to RAGE, TLR2, and TLR9 receptors has been shown to increase the production of chemokines and cytokines that are critical in the host defense against TB, demonstrated in TB-infected TLR2 and TLR9 knockout mice and TLR2/9 double knockout mice (95, 116).

Although inflammation is essential for host defense against pulmonary infection, activated leukocytes in the lung can release myeloperoxidase (MPO), matrix metalloproteinase 9 (MMP9), proteases, and reactive oxygen species (ROS) (52, 270, 272). In addition, neutrophils undergoing cell death release various DAMPs (e.g., HMGB1, chemokine ligand 8 [CXCL8], IL-8, TNF-α, and IL-1β). When airway epithelial cells are exposed to these DAMPs, epithelial cells can release the potent chemotactic protein, CXCL8 (120, 205). CXCL8 can increase the infiltration of more neutrophils, thereby augmenting neutrophil-induced damage (120, 163, 205, 281). It has been reported that in epithelial cells exposed to necrotic neutrophil DAMPs, the pharmacological inhibition of TLR2, TLR4, and RAGE can significantly decrease CXCL8 levels (120).

The activation of HMGB1-mediated RAGE can compromise endothelial cell/cell junctions and increase endothelial barrier permeability (287, 348). The binding of HMGB1 to RAGE primarily activates the MAPK/p38 pathway (87, 160, 348). One of the downstream targets of MAPK/p38 activation catalyzes the phosphorylation of heat shock protein 27 (Hsp27), an actin binding protein (145, 313, 348). The phosphorylation of Hsp27 produces actin stress fiber formation, actin cytoskeletal disorganization, and cell/cell junction dissociation (108, 148, 348). These changes increase the permeability of endothelial cells, which contributes to decreased lung function (348).

The increase in ROS levels and extracellular HMGB1 can directly disrupt epithelial and endothelial intercellular tight junctions, damage alveolar architecture, and stimulate further upregulation of proinflammatory mediators and the release of HMGB1 into the airways, establishing a vicious feedback loop (156, 204). Thus, neutrophil-derived ROS and protease secretion can promote cell injury and death, disrupting the distribution of junction proteins, resulting in the loss of epithelial/endothelial barrier integrity, which contributes to poorer lung function, airway obstruction, and the progression of many lung diseases, including COPD, ALI/ARDS, PAH, and pneumonia (1, 103, 131, 302, 366).

In addition, extracellular HMGB1 can directly induce macrophage injury, causing reduced efferocytosis, which contributes to an increased number of leukocytes, and impairing the phagocytosis of invading bacteria, resulting in increased susceptibility to infections (86, 194, 248). Pulmonary infections and resulting damage to lung cells can further increase the accumulation of extracellular HMGB1, establishing a positive feedback cycle. Moreover, HMGB1 has been reported to mediate the recruitment of inflammatory cells in subjects with asthma, thereby exacerbating oxidative stress-mediated asthma pathology (126, 206). Therefore, blocking HMGB1 activities using neutralizing anti-HMGB1 antibodies could effectively enhance host defense against bacterial infections and attenuate lung injuries, as demonstrated in mouse models of ventilator-associated pneumonia (VAP) and CF (86, 248).

In addition, HMGB1-induced activation of MAPK pathways via binding to RAGE can lead to vascular remodeling by enhancing endothelial and epithelial cell proliferation (Fig. 3). HMGB1 has also been shown to directly increase the proliferation of primary arterial endothelial cells and pulmonary arterial smooth muscle cells, as evidenced by activation of MAPK/ERK/p38 and activator protein 1 (AP-1; c-fos/c-jun) (366). Silencing the expression of c-jun significantly decreased the HMGB1-induced proliferation of endothelial and epithelial cells (366).

HMGB1-mediated activation of NF-κB can also induce the upregulation of α-smooth muscle actin (α-sma) and transforming growth factor-β (TGF-β) (340). As a mediator of vascular remodeling, TGF-β1 can induce phosphorylation of SMAD2 and SMAD3, which can phosphorylate the transcription factor signal transducer and activator of transcription 3 (STAT-3) (251, 316). Activated STAT-3 can induce cell proliferation and TGF-β-dependent myofibroblast differentiation (56, 251, 340). TGF-β-induced proliferation is STAT-3 dependent and inhibition of STAT-3 decreased α-sma, collagen deposition, total airway leukocytes, and the transition of fibroblasts to myofibroblasts (251, 316). Zhang et al. also reported that the exposure of alveolar epithelial cells to TGF-β1 promoted HMGB1 expression and epithelial to mesenchymal transition (EMT), as well as decreased RAGE expression (372).

EMT is stimulated by abnormal cell proliferation and differentiation and is characterized by a reversible alteration in the phenotype of epithelial cells to motile mesenchymal cells (117, 181, 305). During this process, epithelial cells are transformed into myofibroblasts, which secrete extracellular matrix (ECM) components and collagen (305, 315). During EMT, cell/cell junction dissolution occurs and fibroblasts and myofibroblasts accumulate, producing profibrotic factors, fibroblast growth factor 2 (FGF2) and platelet-derived growth factor (PDGF), in addition to α-sma, collagen, and ECM proteins (239, 340). The accumulation of ECM proteins can further promote airway remodeling, through which ECM components are cleaved causing ECM dysregulation, resulting in increased collagen deposition and tissue stiffening (117, 305). Lung stiffening and increased deposition of collagen and ECM promote fibrosis of lung tissue (305).

It has been reported that COPD patients have not only increased levels of HMGB1 in cigarette smoke-exposed neutrophils but also an increase in neutrophil autophagy, which can induce excessive levels of intracellular ROS, incite the release of neutrophil elastase, and increase airway obstruction (120, 205, 297). Excessive levels of neutrophil MPO and MMP9 can damage lung elastic fibers and the ECM, which impairs vascular remodeling (59, 302). Thus, HMGB1 may play a role in vascular remodeling and airway obstruction in COPD.

Overall, data suggest that decreasing the accumulation of extracellular HMGB1 and attenuating its downstream signaling with TLRs and RAGE may decrease inflammation, vascular remodeling, and fibrotic lung injury. Therefore, compounds targeting HMGB1 signaling pathways have been postulated to treat patients with lung diseases. Reagents, such as anti-HMGB1 antibodies, thrombomodulin, pulmonary rehabilitation mixture, and ethyl pyruvate, have been tested in animal models of lung diseases and are discussed further in this review.

Redox Regulation of HMGB1 Pathophysiology

On its secretion into the extracellular milieu, HMGB1 is subject to redox modifications at three critical cysteine residues: C23, C45, and C106 (149, 276, 328). Redox modification of these cysteine residues determines whether HMGB1 will function as a cytokine, chemokine, or an inactive protein (118, 159, 359). The oxidation of HMGB1 can form disulfide (C23 and C45) or fully oxidized isoforms, such as sulfonic acid (276, 359). Redox-modified HMGB1 has been shown to present in bronchoalveolar lavage fluids (BALF) of mouse models of ALI (85, 301). Redox regulation of HMGB1 has also been shown to play an essential role in the gender differences in PAH (258).

HMGB1, whether in the fully reduced or disulfide isoform, produces cytokine activity (203, 358, 359). However, on terminal oxidation (i.e., the sulfonic acid isoform), HMGB1's cytokine activity is abrogated, further demonstrating the significant role of redox modifications on the functions of HMGB1 (141, 359). When all three critical cysteines of HMGB1 are fully reduced, HMGB1 retains chemoattractant activity (213, 328).

Reduced HMGB1 with cytokine activity can induce inflammatory responses following binding to its receptors, such as the receptor for RAGE at HMGB1 150–183 residues (Fig. 1), by stimulating the expression and secretion of TNF-α by macrophages (13, 125, 178, 280, 310). Reduced HMGB1 can also bind to TLR4 and TLR2 at the 89–108 residues to stimulate the expression and secretion of proinflammatory mediators such as IL-8, IL-6, and TNF-α (358). The cysteine present at residue 106 (Fig. 1) is critical for the binding of HMGB1 to TLR4 (178, 358).

Interestingly, the heparin-binding domain of HMGB1, located in the A-box at amino acid residues 6–12 (Fig. 1), also regulates its binding to cell surface receptors (140, 217, 333, 355). When heparin is bound to HMGB1, the binding affinity of HMGB1 to RAGE is significantly decreased, indicating a unique mechanism for modulating HMGB1 activity (140, 217, 303, 375). Studies in our laboratory using 2-O,3-O desulfated heparin (ODSH), a modified heparin, demonstrated that blocking HMGB1 binding to its receptors could effectively attenuate bacterial infection-induced lung injury (291).

The clinical relevance of redox regulation of HMGB1 in the pathophysiology was demonstrated in the gender differences between female and male patients with PAH (258). In this study, the authors showed that cells from males are more likely to die by necrosis, while cells from females more likely die by apoptosis. During necrotic cell death, many thiols were released into the extracellular milieu, creating a reduced environment for extracellular HMGB1. Reduced HMGB1 elicits further inflammation, prolonging the stimulation of downstream inflammatory pathways. On the contrary, extracellular HMGB1 is more oxidized in an inflammatory environment in females with the influx of thiols from necrotic cells, thus losing the ability to bind to PRRs and triggering further inflammatory responses (258). Thus, redox regulation of HMGB1 may provide another approach to modulate the impact of extracellular HMGB1 on the pathogenesis of lung diseases.

Asthma

Globally, 300 million people suffer from asthma (244, 249, 277, 322). More than 80% of asthma deaths occur in low-income to lower middle-income countries, and in 2015, it was estimated that 383,000 deaths occurred from asthma globally (244, 345). Although asthma has a relatively low fatality rate compared with other chronic diseases, many asthmatics have symptoms that can significantly reduce their quality of life (80, 237, 244, 249). Asthma is often underdiagnosed and undertreated, creating a substantial burden to individuals that can restrict various activities for the remainder of their lives (244, 249). Recurrent asthma symptoms frequently cause sleeplessness, daytime fatigue, reduced activity levels, and school and work absenteeism (237, 244, 249).

Asthma is typically characterized by reversible airway obstruction, airway remodeling, airway hyperresponsiveness, and inflammation (71, 123). Airway irritants, such as pollution, dust, pollen, cold air, tobacco smoke, and chemical irritants, may trigger asthmatic reactions (26, 244, 249, 322, 345). Airway smooth muscle in asthmatic patients is hyperresponsive to certain stimuli such as environmental allergens, resulting in airway constriction and obstruction (236, 254). In addition, there is an increase in inflammatory mediator release and the smooth muscle mass of the lungs (80, 123, 126, 171, 206, 323). Furthermore, asthma airflow obstruction and airway remodeling can be triggered by inflammatory mediators (80, 105, 123, 228, 277, 279).

Extracellular HMGB1 has been shown to be involved in mediating certain inflammatory responses in asthma (Fig. 4) (145, 180). Indeed, HMGB1 levels are significantly increased in the airways of asthmatic patients and in animal models of asthma (71, 126, 206, 295, 315). Di Candia et al. reported that sputum concentrations of HMGB1 and HMGB1 expression in smooth muscle were significantly increased in patients with severe asthma (71). An increase in the airway levels of HMGB1 has been shown to occur in tandem with increased inflammation in neutrophilic sputum, increased blood neutrophil counts, and increased levels of MMP, chemokines, and cytokines in severe asthmatic patients (123, 126).

The use of anti-HMGB1 antibodies has provided information about the role of HMGB1 in the pathogenesis of asthma. In mouse models of asthma, generated by exposing animals to compounds such as toluene 2,6-diisocyanate (TDI) or ovalbumin, the treatment of these animals with anti-HMGB1 antibody significantly attenuated elevated airway levels of MMP9, cytokines, cell counts, collagen levels, and leukocyte infiltration (126, 206, 369). In addition, airway hyperresponsiveness, inflammatory responses, and airway remodeling were significantly decreased in mice administered anti-HMGB1 antibodies (126, 206).

Moreover, in a mouse model of ovalbumin-induced airway hypersensitivity that produces some of the pathogenic characteristics of asthma, an antibody to HMGB1 significantly (i) inhibited lung HMGB1 expression; (ii) suppressed HMGB1-induced infiltration of neutrophils in the airways; (iii) decreased IL-23 levels and airway hyperresponsiveness; and (iv) attenuated T helper cell type 17 (Th17) secretion of IL-17, IL-4, and IFN-γ (369). Furthermore, eosinophilic airway inflammation, nonspecific airway resistance, and airway responsiveness were also significantly decreased in these animals (295).

Data obtained from mouse models of asthma indicate that HMGB1 stimulates the secretion of proinflammatory mediators such as TNF-α, IL-17, IL-6, IL-8, IL-1β, IL-4, and IL-5 (126, 295, 369). Moreover, HMGB1 mediates the recruitment of inflammatory cells, thereby exacerbating oxidative stress-mediated asthma pathology (126, 206). Indeed, fully reduced HMGB1 significantly increased intracellular ROS levels in the smooth muscles of nonasthmatics (71). The induction of oxidative stress by activation of the HMGB1/TLR4 pathway can subsequently oxidize HMGB1, thereby attenuating inflammatory responses as oxidized HMGB1 is less effective than reduced HMGB1 in eliciting inflammation (258). Although it is not clear how an oxidative environment affects the pathology of asthma, it may facilitate asthmatic airway remodeling of smooth muscle cells (71).

In patients with severe asthma, airway remodeling involves the accumulation of ECM proteins such as fibulin-1 and collagen (193). HMGB1 has been implicated in the increased deposition of ECM proteins suggesting a potential role in the airway remodeling that occurs in asthma (126, 239). HMGB1's role in airway remodeling is, in part, due to the upregulation of several proteases (i.e., MMPs), other enzymes, and growth-related proteins such as vascular endothelial growth factor (VEGF) (76, 188). MMP9 and α-sma are involved in the remodeling of airway smooth muscle (89, 126, 171, 172). In mice with ovalbumin-induced airway hypersensitivity similar to asthma, HMGB1 can upregulate α-sma expression and increase MMP9 expression in the airways and interstitial lung tissue (126).

Excessive levels of airway HMGB1 in subjects with asthma are associated with increased lung levels of α-sma, increased number of fibroblasts (as a result of increased migratory activity), higher secretion of VEGF, TGF-β, higher collagen content, and airway hyperresponsiveness (126). In these mice, high levels of extracellular HMGB1 increased the hyperplasia of mucus secreting goblet cells, increasing mucus secretion (206). This is supported by findings showing that HMGB1 upregulates MUC5AC and MUC5B messenger RNA (mRNA) and protein in human bronchial epithelial cells via HMGB1-RAGE signaling (165).These changes were significantly attenuated by the systemic administration of an anti-HMGB1 antibody (206).

The HMGB1-induced increase in mucus could potentially contribute to the severity of rhinorrhea, airway hyperreactivity, and reversible airway obstruction in asthmatic patients. Overall, these studies suggest that HMGB1 may play a role in mediating inflammation and remodeling in asthmatic subjects. Thus, HMGB1 represents a potential therapeutic target for the treatment of asthma.

Studies using reagents that inhibit the release of HMGB1 or attenuate its downstream signaling pathways provide further support for the critical role of HMGB1 in the pathogenesis of asthma. In ovalbumin-induced asthmatic mice, the intravenous (via tail vein) administration of vitamin D significantly decreased airway resistance, inflammatory response, and inflammatory cytokine secretion, and increased the secretion of the anti-inflammatory cytokine, IL-10 (370). Importantly, attenuation of these effects was correlated with a significant decrease in HMGB1 levels and HMGB1 translocation from the nucleus to cytoplasm (370). In addition, 10–100 mg/kg of ethyl pyruvate interperitoneally administered to mice with TDI-induced asthma significantly decreased the number of immune, cells including macrophages, neutrophils, eosinophils, and lymphocytes, and significantly decreased the levels of extracellular HMGB1 (315).

Overall, there are data suggesting that in asthma, HMGB1 plays a deleterious role in disease progression and severity by inducing inflammation and airway remodeling. Therefore, HMGB1 may be a potential therapeutic target in the treatment of asthmatic patients.

Chronic Obstructive Pulmonary Disease

COPD (Fig. 5) is a major cause of morbidity and mortality worldwide. As of 2010, estimates suggest that ∼328 million people suffer from COPD (198). Approximately 3 million people die each year from COPD, making it the fourth largest cause of death since the year 2000 (198). About 70% of all cases of COPD are caused by cigarette smoking or chronic inhalation of environmental and occupational air pollutants (198, 335). COPD is characterized by emphysema and chronic bronchitis (112, 162, 207). Decreased airflow in the lungs of COPD patients is a symptom caused by fixed airway obstruction and increased pulmonary inflammation (112, 162, 207). Repeated injury to the respiratory system from cigarette smoke or air pollutants in patients with COPD can result in alveolar tissue destruction (i.e., emphysema), hypersecretion of mucus (i.e., chronic bronchitis), and fibrosis, which can hasten disease progression (112, 162, 207).

Recently, studies in both patients and animal models have implicated the role of HMGB1 in the pathogenesis of COPD. First, HMGB1 levels in the lung tissue of COPD patients were either 17-fold (smokers) or 10-fold (nonsmokers) greater than those of healthy controls (158). In addition, the increase in the airway levels of HMGB1 is negatively correlated with a 60% (smokers with COPD) and 40% (nonsmokers with COPD) decrease in the forced expiratory volume 1% (FEV1%) (90, 144). Furthermore, BALF samples from 14 healthy nonsmokers, 13 smokers without COPD, and 30 smokers with COPD were analyzed, and the levels of peripheral (alveolus and bronchioles) airway HMGB1 were significantly increased in COPD patients. This increase was positively correlated with a significant decrease in the FEV1% score (90). The mean HMGB1 levels in the peripheral BALF of smokers with COPD, smokers without COPD, and healthy controls were 1496, 816, and 250 ng/mL, respectively. Thus, both smokers with COPD and nonsmokers with COPD had significantly higher (p < 0.01) levels of peripheral airway HMGB1 compared with healthy controls (144).

In addition, in the subset of patients with COPD who also have other lung diseases, such as idiopathic pulmonary arterial hypertension (COPD+IPAH), serum HMGB1 levels are further increased compared with healthy patients (366). The serum levels of HMGB1 from COPD+IPAH patients were 4.2 and 2.6 ng/mL for patients with only COPD, compared with 1.05 ng/mL in healthy volunteers (366). A study in 36 COPD patients reported a significant increase in serum HMGB1 compared with healthy controls. Increased HMGB1 levels were positively correlated with significant decreases in FEV1% and oxygen saturation (302). Interestingly, recent genome-wide association studies reported that HMGB1 is the top differentially expressed gene (p = 5.40 × 10⁻¹⁰) that is significantly correlated with decreased lung function (FEV1%) in COPD patients (224). Based on these results, it has been hypothesized that HMGB1 is involved in the pathogenesis of COPD (144, 224, 302, 366).

Numerous studies in animal models of COPD provide further compelling evidence for the role of HMGB1 in COPD pathology (31, 56, 366). While it is currently unknown whether HMGB1 accumulation in the lungs of COPD patients is due to disease progression or from direct injury to the lungs, it has been found that cigarette smoke induces the accumulation of HMGB1 in the airways of mice. The exposure of mice to five cigarettes four times a day for 3 days significantly increased HMGB1 accumulation in the airways and significantly upregulated TLR4 expression (56). Long-term exposure of mice to cigarette smoke can induce higher levels of HMGB1 in lung tissues (31). In addition, HMGB1 expression is increased in the lung tissue in animal models of COPD (59, 334). Furthermore, studies in in vitro models of COPD have revealed that hydrogen peroxide can induce the nuclear to cytoplasmic translocation of HMGB1, subsequently releasing significantly high levels of HMGB1 into the cell culture media (127).

Numerous studies indicate that excessive lung inflammation can also contribute to airway obstruction and exacerbation of COPD (59, 90, 158, 302, 366). It has been reported that in COPD patients, platelet-activating factor receptor (PAFR) levels are increased compared with nonsmoking healthy controls (297). The activation of PAFRs in COPD can elicit inflammatory cell recruitment, proinflammatory cytokine production, oncogenic cell growth, angiogenesis, and tumor growth and exacerbate inflammation (56, 205, 290, 297). HMGB1 levels are significantly increased in cigarette smoke-exposed neutrophils, which have an upregulated expression of PAFR (120, 297). In addition, the JNK, p38, and NF-κB pathways were activated by smoke exposure, and this effect was augmented by exogenous HMGB1 (56).

In TLR4-knockout mice exposed to cigarette smoke or in mice treated with an HMGB1 polyclonal antibody, the airway levels of IL-1β, TNF-α, IL-6, IFN-γ, IL-8, and MCP-1 were significantly decreased (56). In fact, in myeloid differentiation primary response 88 (MyD88) knockout mice exposed to cigarette smoke and exogenous HMGB1, there was no significant activation of JNK and p38, and phosphorylation of NF-κB inhibitor (IκB-α) (56). Ethyl pyruvate (20 mg/kg administered concomitantly with cigarette smoke), an inhibitor of NF-κB activation (56), significantly decreased cigarette smoke-induced HMGB1 airway accumulation. These studies in mouse models of COPD suggest that airway HMGB1 can activate NF-κB and JNK/p38 pathways by TLR4- and MyD88-mediated pathways (56). The inflammation in COPD caused by cigarette smoke has been shown to induce neutrophil infiltration into the lung (56, 120, 205). Interestingly, continuous exposure of airway neutrophils to cigarette smoke induced a shift from neutrophil apoptosis to necrosis (120, 162, 205). Neutrophil-derived ROS and protease secretion can promote the progression of COPD (1, 77, 93, 259).

Moreover, the binding of HMGB1 to RAGE activates MAPK/p38 pathways in mouse models of COPD to induce vascular remodeling, which occurs in the lungs of COPD patients (173, 334). Overall, these data suggest that (i) HMGB1 may play a role in vascular remodeling and airway obstruction, and (ii) oxidative stress, generated after exposure to smoke, can induce the accumulation of extracellular HMGB1 in animals, activating its downstream pathways, leading to the COPD pathologies (127). Thus, while it is unclear whether HMGB1 induces COPD or is secondary to COPD initiation, it is evident that HMGB1 plays an essential role in the pathogenesis of emphysema and chronic bronchitis in COPD.

Acute Lung Injury/Acute Respiratory Distress Syndrome

ALI and ARDS (Fig. 6) are major concerns for patients in intensive care units (ICUs) (29, 134, 227). A recent international study of 50 countries indicated that 10% of all admitted ICU patients were diagnosed with ALI/ARDS (29). Patients diagnosed with ALI/ARDS can develop respiratory failure and hypoxemia, and, currently, the only supportive measure is invasive mechanical ventilation (MV) with hyperoxia, which has been shown to exacerbate ALI and ARDS (29, 161, 227). The clinical outcomes for patients with ARDS are problematic, with mortality rates as high as 75% (367). ALI/ARDS is primarily caused by infection, sepsis, trauma, shock, and inhalation of toxicants, including particulate matter or other substances (161, 246, 252, 269). In addition, it is well known that animal models of ALI can be induced or exacerbated by prolonged exposure to hyperoxia (85, 115, 269, 319).

ALI is characterized by excessive lung inflammation with neutrophil/monocyte infiltration and dysfunction of the alveolar endothelial/epithelial barrier, leading to increased alveolar capillary permeability, subsequent lung cell dysfunction, and pulmonary edema (43, 85, 113, 269). A major pathological feature of ALI/ARDS is increased levels of cytokines/chemokines in the airways and plasma, such as TNF-α, IL-1β, MCP-1, IL-6, and IL-8 (13, 106, 185). Proinflammatory cytokines, such as IL-1β and TNF-α, are early mediators of inflammation and are present primarily at the onset of ALI/ARDS (16).

After the first report of HMGB1's role as a late mediator of inflammation during septic shock, it was postulated that HMGB1 could be a major mediator of lung inflammation in endotoxin-induced lung injury (336). The intratracheal administration of HMGB1 can induce a concentration-dependent increase in the infiltration of interstitial/intra-alveolar neutrophils, alveolar red blood cells, levels of MPO and lung edema, similar to endotoxin-induced ALI. This suggests that HMGB1 may play a role in mediating inflammatory lung injury in ALI/ARDS (3, 326).

The level of HMGB1 in the airways of postsurgical patients who required MV for several days was 10-fold higher compared with patients who were ventilated for 5 h (377). However, the levels of airway HMGB1 in patients ventilated for 5 h were not significantly different from healthy controls. In addition, patients who developed postsurgery VAP had a 17-fold higher level of airway HMGB1 compared with healthy controls. These data suggest that prolonged exposure to MV is required to induce the accumulation of HMGB1 in the airways (377).

The role of HMGB1 in the pathogenesis of ALI has been further confirmed in mouse models. For example, the intratracheal administration of anti-HMGB1 antibodies (360 μg anti-HMGB1 antibody/mouse) ameliorated the development of lung injury and increased survival rates (3, 85, 248). In addition, airway HMGB1 can attenuate the phagocytosis of invading bacteria and apoptotic neutrophils by alveolar macrophages, exacerbating inflammatory lung injury (86, 94, 109, 248). Moreover, the HMGB1 box A protein, an antagonist of HMGB1 binding to the RAGE receptor, can significantly attenuate lung injury by decreasing airway inflammation, further suggesting that HMGB1 is involved in the initiation and progression of ALI/ARDS (103).

One major pathological feature of ALI/ARDS is the presence of excessive lung inflammation (191, 214, 342). The accumulation of airway HMGB1 has been reported to produce excessive lung inflammation (3, 13, 85). Extracellular HMGB1, on binding to pneumocytes, neutrophils, and macrophages, can produce potent proinflammatory effects that induce the release of other proinflammatory cytokines, such as TNF-α, IL-1β, IL-8, MCP-1, and IL-6 (13, 178). Consequently, lung cells are injured, cell/cell junctions are damaged, and endothelial/epithelial barrier permeability is increased, causing lung injury and loss of lung function (43, 85, 113, 269, 348).

The other major pathological feature of ALI/ARDS is the presence of lung edema, in part, mediated by an increase in the permeability of the endothelial/epithelial barrier (33, 78, 219, 346). The binding of extracellular HMGB1 to TLR2, TLR4, and RAGE can compromise endothelial cell/cell junction and increase endothelial barrier permeability (348). While the binding to TLR receptors can cause inflammatory damage to lung cells, HMGB1 can also affect the permeability of endothelial cells by activation of RAGE-mediated pathway (287), as illustrated in Figure 3. Several mechanisms have been implicated in the accumulation of HMGB1 in the airways during lung injury. Various biomolecules, such as endotoxins, TNF-α, IFN-β, and hydrogen peroxide, as well as hyperoxia, can induce hyperacetylation and release of HMGB1 from lung cells (85, 201, 248, 314, 336). These results suggest that HMGB1 is one of the mediators that induce the loss of endothelial barrier integrity, causing inflammatory lung injury in patients with ALI/ARDS.

Pulmonary Fibrosis

Pulmonary fibrosis (PF) is an interstitial lung disease that is often irreversible and lethal (153, 157, 284, 341). The median survival of PF is 3 years, and it affects 50,000 individuals annually in the United States (283, 341). Between 1988 and 2005, the estimated incidence of PF increased from 6.8 to 17.4 per 100,000 people in the United States (230). PF is characterized by lung scarring and the formation of fibroids, inflammation, vascular leakage, myofibroblast recruitment, and deposition of elevated amounts of ECM proteins (157, 180, 283). Lung tissue scarring impairs the diffusion of oxygen through alveolar walls into the bloodstream (5, 174, 284).

Patients with PF experience shortness of breath and dry cough (84, 157, 284). PF can increase susceptibility to other conditions such as pneumonia, pneumothorax, pulmonary hypertension, pulmonary embolism, and eventually, respiratory and heart failure (135, 284, 304). While individuals can be genetically predisposed to PF, exposure to hazardous materials (e.g., asbestos, pollutants, and cigarettes) and comorbidities such as autoimmune diseases, sarcoidosis, COPD, and viral infections can increase the risk of PF (157, 284, 294). Genetics can account for up to 30% of the risk of developing PF (7, 146, 284, 286, 360). Mutations in surfactant protein A2 and C, and mutations affecting telomere length are all associated with an increased risk of PF (7, 360).

In patients and subjects with PF, decreased survival has been associated with increased levels of serum and airway HMGB1 (84, 114, 296, 372). In addition, in a mouse model of bleomycin-induced PF, the administration of anti-HMGB1 antibody significantly attenuated the thickening of alveolar walls, decreased collagen content in lung homogenate, and lowered the number of total immune cells present in the airways (114). These studies suggest that HMGB1 plays a role in PF pathogenesis and the degree of disease severity.

HMGB1 plays a role in mediating fibrosis and airway remodeling in PF. HMGB1 can stimulate ROS production, increase α-sma, collagen deposition, and TGF-β, induce the differentiation of fibroblasts to myofibroblasts, and increase the gene expression of MUC8, a mucin that denotes aberrant alveolar epithelia common in PF (154, 340). Zhang et al. also reported that in a model of PF, collagen fibers in the lung tissue of rats were significantly increased in bleomycin-treated rats compared with animals treated with vehicle (373).

The HMGB1-RAGE axis also plays a role in the inflammatory pathology of PF. In a bleomycin-induced PF model, 29% of wild-type mice survived after 14 days of bleomycin administration, while 100% of RAGE knockout mice survived (117). Furthermore, in this PF model, RAGE knockout mice had lower levels of fibrotic deposition and decreased airway levels of TGF-β1. However, total leukocyte, lymphocyte, macrophage, and neutrophil infiltration into the lung, and airway levels of HMGB1 were not reduced, suggesting that HMGB1 inflammatory signaling in PF may be more complicated than RAGE signaling alone (117). Treatment of animals with an anti-RAGE antibody and pharmacological inhibition of ERK1/2 significantly decreased epithelial barrier disruption and permeability associated with inflammation (117, 133). Furthermore, direct inhibition of NF-κB by pyrrolidinedithiocarbamate (PDTC) or upstream inhibition by targeting TLR2 in bleomycin-induced PF reduces edema, histological markers of inflammation in lung tissue, HMGB1-induced TGF-β1 release, collagen-1 levels, and α-sma expression (177, 340).

The role of HMGB1 and the levels of RAGE expression and its signaling pathways are not only limited to lung inflammation but are also associated with remodeling and deposition of fibrotic tissue in PF. Increased levels of RAGE are associated with ameliorated lung injury and decreased apoptosis in alveolar epithelial cells (372). However, in a rat model of PF, RAGE expression was significantly decreased compared with the controls (372). Furthermore, in a model of bleomycin-induced PF, RAGE null mice had less fibrotic injury, such as edematous alveolar thickening, cellular infiltration, fibrosis, and collagen deposition (84, 117). Thus, HMGB1/RAGE interaction and signaling in the profibrotic processes play a role in the development of PF.

HMGB1-mediated activation of NF-κB also plays a role in airway remodeling in PF. HMGB1-mediated activation of NF-κB can induce the upregulation of α-sma and TGF-β1, a mediator of vascular remodeling via SMAD-STAT-3 signaling (84, 180, 251, 316, 373). Activated STAT-3 can increase α-sma, collagen deposition, and total airway leukocytes and can induce cell proliferation and TGF-β-dependent myofibroblast differentiation (251, 316, 340). Zhang et al. also reported that the exposure of alveolar epithelial cells to TGF-β1 promoted HMGB1 expression and decreased RAGE expression (372). These studies suggest that HMGB1 may play a role in EMT via SMAD-STAT signaling.

Compounds targeting RAGE or HMGB1 have been used in PF models; however, the clinical efficacy of these compounds remains to be determined. Anti-HMGB1 antibodies and HMGB1 neutralizing reagents such as thrombomodulin decrease the levels of HMGB1 in animals and attenuate fibrotic lung injury (2, 140, 153, 187). Thrombomodulin binds directly to HMGB1 and cleaves it, degrading it to a less inflammatory form (2, 140, 153, 187). Thrombomodulin improves the survival rate of patients by inactivating coagulant factors and thrombin, as well as by competitively inhibiting the binding of HMGB1 to receptors such as TLR4 and RAGE (153, 180, 296).

Treatments targeting the RAGE-HMGB1 signaling pathway could significantly ameliorate the pathology and symptomatology of PF. Although current treatments, such as prednisone, azathioprine, and N-acetylcysteine, may improve the symptoms of PF, there is a need for PF-specific therapies targeting disease biomarkers such as HMGB1 (124, 211, 306). Overall, data suggest that decreasing the accumulation of HMGB1 and attenuating its downstream signaling with RAGE may decrease inflammation in PF. Thus, HMGB1 may be a novel therapeutic target that has the potential to decrease mortality and severity of symptoms in PF (Fig. 7) (153).

FIG. 7. — **The role of HMGB1 in the pathogenesis of PF.** PF, an interstitial lung disease, is characterized by fibroblast proliferation, EMT, lung inflammation and the formation of fibroids, producing lung scarring. Patients and animals with PF have been shown to have increased levels of airway HMGB1. HMGB1 may be involved in the pathogenesis of PF as it can produce fibroblast differentiation and proliferation, alveolar wall thickening or muscularization thickening, and collagen accumulation. HMGB1 binds to RAGE, TLR2, and TLR4, activating both NF-κB and MAPK/p38/ERK 1/2 pathways. NF-κB activation and the p38 pathway can increase the levels of proinflammatory mediators and TGF-β1. As a mediator of vascular remodeling, TGF-β1 can induce phosphorylation of SMAD2 and SMAD3, which phosphorylate the transcription factor STAT-3. STAT-3, when activated, induces cell proliferation and myofibroblast differentiation. STAT-3 activation promotes EMT, where epithelial cells develop mesenchymal characteristics such as loss of cell/cell adhesion. The increased number of fibroblasts and myofibroblasts can stimulate the formation of fibrotic tissue. TGF-β1 can elicit the release of α-sma, upregulate HMGB1 expression, and induce secretion of the profibrotic factors FGF2 and PDGF. α-sma directly stimulates the EMT process, causing an increased accumulation of ECM proteins, which augments airway remodeling. ECM-mediated remodeling involves the dysregulation of ECM composition, cleavage of ECM components, increased collagen deposition, and stiffening of tissue. In addition to inducing remodeling, the binding of HMGB1 to RAGE and TLR4 stimulates the expression and secretion of TNF-α, MCP-1, IL-8, and IL-1β. These proinflammatory mediators recruit and induce the accumulation of macrophages, neutrophils, and lymphocytes into the airways, increasing the levels of proteases, ROS, and HMGB1, establishing a deleterious feedback loop. The release of these molecules contributes to epithelial and endothelial injury and death, dissolution of cell/cell junctions, and loss of barrier integrity, thereby increasing alveolar permeability. Thus, HMGB1-mediated airway remodeling and inflammation contribute to lung fibrosis, scarring, and decreased lung function. EMT, epithelial to mesenchymal transition; ERK, extracellular signal-regulated kinase; FGF2, fibroblast growth factor 2; PF, pulmonary fibrosis; STAT-3, signal transducer and activator of transcription 3.

Cystic Fibrosis

CF (Fig. 8) is a genetic disease affecting 30,000 people, with ∼1000 new cases diagnosed each year in the United States (64, 81). CF is diagnosed by phenotypic features, including sinopulmonary disease, gastrointestinal and nutritional abnormalities, persistent cough with thick mucus, wheezing, recurrent lung infections, as well as poor weight gain and growth (82, 102, 285). Histopathological studies indicate that neutrophilic inflammation and pulmonary infections occur frequently in CF patients, producing acute pulmonary exacerbation and severe lung dysfunction (21, 35, 50, 57, 83, 102).

The first clinical report on CF was published in 1938 and, until recently, the majority of individuals diagnosed with CF died in infancy or early childhood (10). As a result of improvements in symptomatic management, including the use of anti-inflammatory, antimicrobial drugs and nutritional supplements, more than two decades have been added to the life span of CF patients (82, 240). However, the median survival age is still only around 40 years, and thus, novel therapeutic approaches and biomarkers that are predictive of the development of CF are urgently needed (40, 64, 240).

Studies over the last two decades suggest that HMGB1 may represent a new therapeutic target for CF (86, 320). CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes the CFTR protein (151, 164). Almost 2000 mutations in the CFTR gene have been identified, which are classified into six major classes based on the effects of the mutations on the CFTR protein (28, 82, 164). The mutations alter the secondary and tertiary structure of CFTR protein, a chloride ion channel, resulting in impaired secretion of chloride and an increase in sodium absorption (164). This can cause abnormal levels of chloride, bicarbonate, sodium ions, and water, affecting the epithelial lining in the lungs and digestive system (38, 151).

Levels of HMGB1 are significantly increased in the BALF, sputum, and serum of CF patients (110). The two secondary pathogenic mechanisms of CF in the airway are the recruitment of neutrophils and susceptibility to Pseudomonas aeruginosa (PA) infections, which further increase HMGB1 release into the airways (110). A high load of neutrophil elastase, as a result of neutrophil recruitment, can further induce the in vitro and in vivo release of HMGB1 from macrophages (110). In Scnn1b-transgenic mice, which exhibit obstructed mucus production similar to the CF phenotype, and in CFTR⁻/⁻ CF mouse models, HMGB1 levels are significantly increased in the lungs and airways, subsequently increasing the number of leukocytes in the airways through a CXC-chemokine receptor (CXCR)-dependent mechanism (86, 274). Moreover, an anti-HMGB1 antibody decreases the chemotactic efficacy of HMGB1 in CF patient sputum and in the bronchoalveolar lavage (BAL) of CF Scnn1b-transgenic mice (274). These findings are congruent with studies reporting that the administration of an anti-HMGB1 antibody to CF mice significantly decreased neutrophil infiltration into the airways and attenuated inflammatory lung injury (86, 274). Thus, these studies suggest that HMGB1 plays a role in mediating neutrophilic inflammation in CF.

Pulmonary infections, particularly those due to PA, occur frequently in CF patients, as a result of compromised immunity (42, 64, 86, 142, 167). For example, macrophages from CF patients have a significantly lower phagocytic activity compared with healthy individuals (142). The impaired macrophage phagocytosis compromised by CF patient BALF may be mediated by increased levels of airway HMGB1 as CF BALF-compromised macrophage phagocytic activity was attenuated following the administration of an anti-HMGB1 antibody (86). Furthermore, macrophages from TLR4⁻/⁻ mice do not respond to the HMGB1-mediated impairment of macrophage phagocytosis, suggesting that HMGB1-mediated macrophage dysfunction occurs via HMGB1 activation of TLR4 (86).

HMGB1 can also inhibit neutrophil efferocytosis by macrophages in CF, resulting in the accumulation of apoptotic neutrophils in the airways, which can augment proinflammatory responses (194). Alveolar macrophages in CF are also characterized by the overproduction of sCD14 and inflammatory cytokines, as well as a decreased expression of CD11b and TLR5, leading to an overactive proinflammatory response and nonresolution of infection by CF macrophages (142). Pulmonary infections, such as PA, can further induce the release and subsequent accumulation of airway HMGB1, creating a detrimental feedback cycle between infections and HMGB1 accumulation in the lungs (200). However, PA in CF patients does not significantly alter the expression of HMGB1 mRNA, suggesting that PA induces HMGB1 extracellular accumulation by increasing HMGB1 nucleocytoplasmic translocation and release into the airways in CF (320).

At present, the mechanisms that induce HMGB1 accumulation in the airways of CF patients remain to be elucidated. Montanini et al. reported that HMGB1 expression in the CF epithelial cell line, CFBE41o-, is significantly higher than the normal control 16HBE14o- cells (222). The incubation of 16HBE14o- cells with a CFTR inhibitor (CFTR inh 172) increases HMGB1 expression, suggesting that loss of CFTR function can induce HMGB1 expression (222). In the same study, insulin significantly decreased HMGB1 gene expression in CF epithelial cells, suggesting a correlation between upregulated HMGB1 and the diabetic condition in CF subjects. It was postulated that HMGB1 can serve a potential therapeutic target for the treatment of patients with CF (222).

In conclusion, these studies suggest that HMGB1 can serve as a biomarker in CF. However further studies are needed to determine the sources and mechanisms of extracellular HMGB1 accumulation in CF patients, as well as to verify the role of HMGB1 as a therapeutic target in CF.

Pneumonia

Pneumonia (Fig. 9) is an inflammatory condition of the lung primarily affecting the alveoli. The main cause of pneumonia is infection of the lung parenchyma, and it is symptomatically characterized by productive or dry cough, chest pain, fever, and troubled breathing (325). Pneumonia is a leading cause of hospitalization among adults and children in the United States, and at least 1 million people seek medical care for the disease every year. In the United States, ∼50,000 people die from pneumonia annually (60, 61, 241). Globally, 1 million children younger than the age of 5 die from pneumonia each year, which is greater than the numbers of death by any other infectious disease in children, including HIV, malaria, and TB (47, 197, 209, 330). Pneumonia can be caused by bacteria, viruses, and less commonly, fungi. The risk of pneumonia is increased in patients with other health conditions such as asthma, COPD, diabetes, or compromised host defense due to treatments with drugs (60, 61, 232, 241). Based on the setting in which it develops, pneumonia can be categorized into (i) community-acquired pneumonia (CAP), (ii) hospital-acquired pneumonia, (iii) health care-acquired pneumonia, and (iv) aspiration pneumonia (23, 73, 241, 255, 268).

The levels of HMGB1 in the lung tissues and body fluids are altered in patients with pneumonia. Significantly higher levels of HMGB1 in BALF, sputum, and plasma have been reported in patients with different types of pneumonia compared with healthy individuals (8, 14, 122, 248, 338, 378). Interestingly, Wang et al. reported that plasma levels of HMGB1 are decreased in patients with pneumonia after antibiotic treatments (338). Furthermore, the plasma levels of HMGB1 were positively correlated with the pneumonia severity index (PSI) score, suggesting that HMGB1 levels may be indicative of pneumonia severity, although lack of such correlation was also observed in other studies (14, 122, 338). Such conflicting results may be due to small sample sizes, differences in the causes of pneumonia, and other confounding risk factors during the treatments and hospitalization (8). Nonetheless, these studies indicate that HMGB1 concentrations in plasma/serum were elevated in patients with pneumonia and remained elevated throughout the course of treatments in hospitals. In addition, the level of HMGB1 in the sputum is significantly higher in patients with pneumonia caused by Streptococcus pneumoniae (8). These studies suggest that significantly increased levels of HMGB1 can be a biomarker of pneumonia, but they do not indicate the prognosis of pneumonia. Thus, future research should be conducted under narrower scopes and focus on the role of HMGB1 in pneumonia with more specific settings.

Studies using anti-HMGB1 antibodies have demonstrated that HMGB1 mediates the pathology of pneumonia (129, 248, 317). In numerous mouse models of pneumonia, targeting HMGB1 with monoclonal antibodies not only attenuated inflammatory lung injury but also decreased bacterial burden in the lungs of mice with VAP, Staphylococcus aureus pneumonia, and pneumonia due to influenza A virus subtypes H5N1 and H1N1 (92, 129, 235, 248). By neutralizing HMGB1 with anti-HMGB1 antibodies in mouse and human adenovirus-infected epithelial cells, HMGB1-mediated inflammation can be significantly reduced, accompanied by a decrease in the expression of HMGB1 receptors, (e.g., TLR4, TLR9, RAGE), and decreased NF-κB activation (317).

PAMPs, including bacterial components such as LPS, peptidoglycan, and lipoteichoic acid, can activate airway cells via PRRs (alveolar macrophages and epithelial cells) to increase HMGB1 expression and induce the translocation and release of HMGB1 into the extracellular milieu (324, 376). Bacteria, including Mycoplasma pneumoniae, S. pneumoniae, S. aureus, and Escherichia coli, have been shown to induce the release of HMGB1 into the airways in mice (4, 74, 260). Viruses, such as human adenovirus and influenza A virus, can evoke HMGB1 release and subsequently induce an HMGB1-mediated inflammatory response via activation of NF-κB (317, 379).

In addition, these pathogens not only promote HMGB1 expression and HMGB1 release by interacting with PRRs such as RAGE but also upregulate the expression of these receptors, exacerbating the downstream cascades that can result in an inflammatory response. Morbini et al. reported that RAGE expression was significantly upregulated in patients with interstitial and postobstructive pneumonia (223). TLR receptors and RAGE are also upregulated during pneumonia caused by M. pneumoniae, S. pneumoniae, human adenovirus, and influenza A virus (74, 317, 379).

HMGB1 can be passively or actively released into the airways by injured cells and immune cells on exposure to respiratory infections, which contributes to the high levels of extracellular HMGB1 accumulation in the lung of patients with pneumonia (199, 248). However, the main source of the circulating HMGB1 in plasma/serum is from activated immune cells rather than injured cells in patients with CAP (8). Airway HMGB1 can function as a DAMP molecule that can activate immune cells via PRRs (e.g., TLR2, TLR4, and TLR9) and RAGE (267). During pulmonary bacterial infection, PRRs can be activated by both PAMPs and DAMPs such as HMGB1, which together can cause synergetic effects in activating immune cells, producing exacerbated inflammatory lung injury (8, 130, 256).

The critical roles that HMGB1 plays in the pathogenesis of pneumonia have also been confirmed by numerous studies using compounds that can either inhibit HMGB1 accumulation in the airways or block its downstream pathways. Compounds such as the α7 nicotinic acetylcholine receptor partial agonist, GTS-21, and the NF-κB inhibitors, BAY 11-7082 and ethacrynic acid, inhibit HMGB1 release by decreasing the post-translational hyperacetylation of HMGB1 (301, 339). Curcumin decreases inflammation-mediated ALI in rats by decreasing the release of both HMGB1 and the expression of its receptor RAGE (55). The heparin derivative ODSH blocks extracellular HMGB1 binding to TLR2 and TLR4 receptors, thereby decreasing TLR-dependent pathways (291). This subsequently attenuates lung injury and decreases bacterial burden in mice with P. aeruginosa pneumonia (291). Ethyl pyruvate can also inhibit HMGB1 release by attenuating NF-κB- and p38 MAPK-mediated signaling cascades without affecting the expression of HMGB1 (327). Ethyl pyruvate decreases the level of circulating HMGB1 in mice with sepsis, as well as in postsepsis pneumonia in mice infected with P. aeruginosa (51, 327). Together, these studies suggest that HMGB1 mediates the pathogenesis of pneumonia.

Tuberculosis

TB is a predominantly airborne disease caused by Mycobacterium tuberculosis (36, 75, 104, 210). Globally, TB (Fig. 10) is one of the leading causes of mortality (36, 104). In 2016, it was estimated that as least 10.4 million people were infected with TB, and 1.7 million died from the disease (36, 75, 104). Multidrug-resistant TB (MDR-TB) is a public health crisis in numerous countries. It was estimated that in 2013, 480,000 people were diagnosed with MDR-TB worldwide (150). A prominent pathological feature of TB is masses of mature immune cells, known as granulomas (210, 215, 242). On inhalation, M. tuberculosis infects alveoli in the lungs and can be phagocytosed (62, 242). This is followed by an early inflammatory response, induced by both bacterial and host factors, which results in the recruitment of leukocytes to the site of infection (62, 210). Individuals with compromised immunity, IFN-γ and IL-12 receptor dysfunction, and those undergoing treatment with TNF-α antibody are more vulnerable to TB infection (36, 70).

Studies indicate that extracellular HMGB1 levels are significantly increased in patients with active TB. In patients with TB, levels of HMGB1 in plasma and sputum were significantly increased compared with healthy subjects (368). Lui et al. reported that the levels of HMGB1 and inflammasome-associated factors were significantly increased in patients with TB (202). In addition, there was a positive correlation between plasma HMGB1 levels, fever duration, and respiratory failure (202).

It has been reported that in animal models of TB, there is a significant increase in the accumulation of HMGB1 in the airways (111, 121). In mice with early- and late-stage TB, anti-HMGB1 antibody treatment decreased lung bacterial burden, decreased the expression of IFN-γ, TNF-α, and IL-17, and increased the expression of the anti-inflammatory cytokine IL-10 (121). Furthermore, the intratracheal administration of recombinant HMGB1 to guinea pigs with TB further increases lung bacterial burden when compared with control TB animals (121). These findings suggest that lowering levels of airway HMGB1 attenuates proinflammatory signaling and reduces lung bacterial load.

The binding of HMGB1 to RAGE, TLR2, and TLR9 receptors can increase the production of chemokines and cytokines that are critical in the host defense against TB. In TB-infected TLR2 and TLR9 knockout mice and TLR2/9 double knockouts, there is a decrease in the secretion of TNF-α, IL-12, and IL-6 (95, 116). The activation of these receptors by HMGB1 can activate NF-κB, which can further increase the synthesis and release of proinflammatory mediators such as TNF-α, IL-8, CXCL8, IL-6, IL-12, IFN-γ, and IFN-α (19, 121, 202, 368). TLR2 primarily mediates the release of TNF-α and IL-6, while TLR9 primarily mediates the secretion of INF-γ and INF-α (19).

The generation of excessive proinflammatory mediators can result in pronounced lung inflammation, which can cause leukocyte-mediated cell injury and compromised lung function, thereby exacerbating TB (263). In TB patients, there is a significant increase in leukocyte, monocyte, and neutrophil counts in blood samples, which may be due to elevated airway levels of HMGB1, and an increase in the chemokine CXCL12 (152, 189, 281, 357, 368). HMGB1-RAGE signaling via CXCL12 and CXCL8 can stimulate chemotaxis and increase the infiltration of immune cells such as macrophages and neutrophils (152, 364). As more immune cells accumulate in the airways, granulomas form, which can promote disease severity (229). As neutrophils accumulate in the airway, they elicit granuloma formation and the generation and accumulation of ROS, proteases (e.g., MMP9), and HMGB1 in the airways (229, 231, 309). These biomolecules exacerbate lung inflammation and can drive a feedback cycle initiated by airway HMGB1. The accumulation of these deleterious biomolecules in combination with the HMGB1 feedback cycle can cause cell/cell junction dysfunction and endothelial damage, and increase the permeability of alveolar barriers (133).

The secretion of IL-8 into the airways can recruit cluster of differentiation (CD) 4 and CD8 lymphocytes, which can enhance the phagocytosis and killing of M. tuberculosis (163). The increased number of helper T cells can attenuate bacterial growth as CD4 helper cells can release IFN-γ (19). Furthermore, HIV patients with a CD4+ cell deficiency are more susceptible to contracting TB when compared with healthy controls (63). In IFN-γ knockout mice, there is a significant increase in necrotic granulomas and lung bacterial burden (63). Granuloma necrosis leads to increased intracellular ROS levels, which can cause the dysfunction of phagocytic cells, suggesting a connection to increased lung bacteria burden (229).

In TB, airway HMGB1 can mediate inflammation by interacting with the cell surface receptors TLR4 and RAGE. Through these interactions, proinflammatory mediators are released and immune cells are recruited, exacerbating lung inflammation. While RAGE is involved in proinflammatory signaling that may enhance disease progression, RAGE signaling is also vital in viral immunity. Lui et al. reported that in TB patients, RAGE expression was upregulated in monocytes and dendritic cells (DCs) (202). In TB-infected RAGE-knockout mice, there was increased pulmonary inflammation and mortality compared with wild-type mice (19, 368). Furthermore, in TB-infected RAGE-knockout mice, there was more lung edema, pleuritis, and increased neutrophil infiltration when compared with wild-type mice. After 3 weeks of TB infection, RAGE-knockout mice also had significantly elevated levels of airway TNF-α, IL-6, IL-1β, IL-4, MIP-2, and lung bacterial burden (380). Therefore, RAGE receptors may play a protective role in chronic TB infection due to the need of a fine-tuned level of inflammation in the lung (380).

Soluble RAGE (sRAGE), an unbound isoform of RAGE, antagonizes RAGE-mediated signaling and downstream inflammation as demonstrated in studies in patients with newly diagnosed active TB (202). These patients have significantly lower levels of sRAGE compared with individuals with latent asymptomatic TB patients, correlating with higher mycobacterial counts, lung inflammation, and significantly higher expression of RAGE and plasma levels of HMGB1 (202).

In a recent study, TB patients were found to have significantly higher levels of sRAGE in their serum when compared with healthy controls (299). In TB patients who were smokers, significantly lower levels of serum sRAGE were found, which correlated with higher mortality rates (299). Thus, sRAGE and RAGE levels in TB patients may be complicated as a result of comorbidities, smoking, age, and whether the infection is active or latent asymptomatic. Further studies are needed to study how the balance between sRAGE/RAGE/HMGB1 at certain time points in TB can be modulated to increase survival rates, decrease bacterial loads, and resolve inflammation (202, 299, 380).

Therefore, HMGB1-mediated inflammation plays a complex role in TB. HMGB1 can cause the secretion of proinflammatory mediators that augment and prolong inflammation, producing cell dysfunction and disease progression. Future studies are needed to (i) clarify HMGB1's role during different stages of TB and (ii) determine how to attenuate severe inflammation without reducing lymphocyte recruitment or impairing the host defense against TB.

Lung Cancer

Lung cancer (Fig. 11) is one of the leading causes of mortality in both men and women in the United States (48, 168, 321). Approximately 541,000 Americans are living with lung cancer and an estimated 154,050 were expected to die from lung cancer in 2018, accounting for ∼25% of all cancer deaths (234, 298). Among all the lung cancer cases, about 80–85% are nonsmall-cell lung cancer (NSCLC) (9).

Increased levels of extracellular HMGB1 in patients diagnosed with lung cancer have been correlated with an unfavorable prognosis. The serum levels of HMGB1 in patients with NSCLC are significantly increased compared with healthy individuals (233, 343, 353). Serum levels of HMGB1 are not only positively correlated with tumor size and the stages of lung cancer progression, but can also be significantly reduced 1 month after tumor removal (288). These studies suggest that elevated serum levels of HMGB1 can be a biomarker for the diagnosis and prognosis of NSCLC. In addition, the expression of HMGB1 in lung tissues from NSCLC patients is significantly higher than in healthy individuals (353). HMGB1 expression, assessed by the levels of mRNA and protein in tumor tissues, increases from stage I to II, whereas HMGB1 mRNA and protein levels are downregulated in stages III and IV (293). The mechanisms underlying the discrepancy in the levels of HMGB1 between serum and tumor tissues at different tumor stages are still unclear but likely due to inconsistency in sample size, therapy methods, and analysis strategies (350).

The increase in HMGB1 levels in the serum by lung cancer could result from an increase in HMGB1 production and release from cancer cells (46). Cell ischemia and necrosis are commonly found in solid tumors, including lung tumors (46, 88, 212). During the early phases of tumor development, rapid cell growth is greater than the limited blood supply and physiological space, resulting in an ischemic environment that induces local necrosis (46, 356). Necrosis is usually found in the core region of tumors and is primarily due to the depletion of oxygen and glucose, which further increases the production and release of HMGB1 (46, 190, 361).

HMGB1 can be actively released following the activation of immune cells, or passively by necrotic and ischemic cells (12, 139, 199, 273). As a nuclear protein, HMGB1 is involved in mediating transcription, replication, DNA repair, and nucleosome assembly (225, 318, 329, 365). The overexpression of HMGB1 within the cells is positively correlated with tumorigenesis and tumor metastasis (352, 353, 356). HMGB1 can alter the expression of genes that play important roles in neoplasm progression and metastasis, including the genes involved in cell cycle and growth regulators, cell adhesion, mobility, and invasion regulators of angiogenesis and cell/cell interaction (53, 65, 145, 182, 216, 266).

The presence of HMGB1 in the extracellular environment can further augment the growth and metastasis of tumors by interacting with cell surface receptors, including TLRs and RAGE. For example, activated TLRs interact with the protein MyD88 to induce the recruitment of interleukin-1 receptor-associated kinase 1 (IRAKs) and tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) that activates mitogen-activated protein kinase kinase kinase 7 (MAP3K7, also known as TAK1) (183, 245). TAK1 phosphorylates IKK subsequently activating the NF-κB pathway, as well as the JNK and p38 pathways, which are prominently involved in tumor progression (183, 245). TLR4 plays a role in mediating tumorigenesis caused by chemically induced pulmonary inflammation (24, 132, 312, 361, 371). Extracellular HMGB1 released from keratinocytes following ultraviolet irradiation induced TLR4-mediated inflammation, which is essential during perivascular invasion and metastasis in melanoma (20).

Interestingly, the binding of RAGE to HMGB1 produces inflammation that appears to mediate mitochondrial ATP production and tumor cell growth in pancreatic cancer cells (145). Extracellular HMGB1's induction of inflammation produces precancerous lesion of NSCLC by activating the RAGE/JNK/NF-κB pathway (349, 350). In addition, HMGB1-RAGE signaling can activate NF-κB, MAPK, and type IV collagenase (MMP2/9) pathways that can elicit cancer cell growth, invasion, and metastasis (310, 311). The incubation of endothelial cells with recombinant HMGB1 increases the expression of TLR4 and RAGE, as well as the endogenous expression of HMGB1, establishing a positive feedback loop (310, 311). Extracellular HMGB1 also activates the NLRP3 inflammasome, producing caspase-1-dependent release of IL-1β and IL-18, creating an inflammatory environment and augmenting tumor cell invasion (27, 30, 356). Overall, these studies suggest that extracellular HMGB1 may play a role in tumor pathogenesis and progression.

HMGB1 has also been suggested to promote drug resistance by regulating autophagy in NSCLC (243). HMGB1 translocation from the nucleus to cytoplasm was observed in lung adenocarcinoma cells treated with docetaxel, which inhibited autophagy and promoted cell resistance to docetaxel. HMGB1 was shown to regulate the formation of autophagosome through activating the mitogen-activated protein kinase (MAPK)-ERK signaling pathway. By suppressing HMGB1 cytosolic translocation, the protection in drug-induced autophagy is diminished, and cells restore sensitivity to docetaxel (243).

These effects of HMGB1 may be due to the cellular environment and its concentration. It has been postulated that cancer is not simply a disease of a specific tissue or organ, but a disease that can result from a dysregulation of the host defense (15). Since HMGB1 regulates innate and adaptive immunity, research related to HMGB1 may offer novel treatments for regulating tumorigenesis, progression, and metastasis. For example, HMGB1 released by dying tumor cells can be utilized to activate host DCs to further process and present tumor antigens (15). Furthermore, the interaction of HMGB1 with TLR4 on DCs contributes to the priming of antitumor T cells (15). Clinically, TLR4 polymorphisms, which can decrease the interaction of HMGB1 with TLRs, are negatively correlated with an early relapse of breast cancer following chemotherapy (15). The increased production of HMGB1 in tissues induced by radiation therapy is positively correlated with a superior clinical outcome in esophageal squamous cell carcinoma due to the role of HMGB1 in promoting DC activation and migration (79, 308). However, the exact mechanism by which HMGB1-TLR4 interactions affect the tumor antigen presentation of DCs in immunogenic tumor cell death remains to be elucidated.

Pulmonary Arterial Hypertension

PAH (Fig. 12) is an inflammatory disease that has a high mortality rate due to right ventricular heart failure (307, 362). The median survival time of patients with PAH is 2.8 years (221). In 2010, the death rate of PAH was 6.5 per 100,000 people (100). A recent report indicates that men diagnosed with PAH typically have higher mortality rates than women, which is partly due to higher rates of vascular cell necrosis (258). Pathologically, PAH is characterized by increased peripheral vascular resistance caused by vasoconstriction and obstruction of the pulmonary arteries, abnormal proliferation of smooth muscle cells and endothelial cells, thrombosis, lung inflammation, and extensive vascular remodeling (25, 136, 221). PAH is likely due to an imbalance in various vasodilating (e.g., prostacyclins and nitric oxide) and vasoconstricting biomolecules (e.g., thromboxaneA2 [TAX2], endothelin-1 [ET-1], and serotonin [5-HT]) (131, 226). The risk of PAH is increased by mutations in the BMPR2 (TGF-β receptor bone morphogenetic protein receptor type 2) gene, elevated 5-HT levels, exposure to various toxins, and the presence of pre-existing diseases, such as HIV, schistosomiasis, sarcoidosis, and scleroderma (72, 100, 257).

Studies in both patients with PAH and animal models of PAH indicate a role for HMGB1 in the pathogenesis of PAH. Patients with idiopathic PAH have significantly greater levels of HMGB1 in the serum and airways compared with healthy subjects (25). This elevation in HMGB1 levels was positively correlated with enhanced vasoconstriction, right ventricular hypertrophy, increased pulmonary arterial pressure, and proliferation of endothelial and smooth muscle cells (39, 54, 275, 362, 366). In addition, the administration of an anti-HMGB1 antibody (2 mg antibody/kg via intraperitoneal injection) to rats with PAH induced by monocrotaline and chronic hypoxia, significantly reduced systolic pressure, thickening of the pulmonary arterial wall, right ventricular hypertrophy, and pulmonary vascular remodeling, and significantly decreased the levels of ET-1 (275). Also, in animals administered an anti-HMGB1 antibody, there was an attenuation of lung inflammation and a greater survival rate (25, 275).

The adverse effects of HMGB1 in PAH may result from its interaction with the transmembrane receptors, TLR4 and RAGE (184). Both TLR4 and RAGE are involved in HMGB1-mediated vascular remodeling (25, 184). In mice with monocrotaline-induced PAH, a deficiency of TLR4 abolished HMGB1-induced PAH, as indicated by a lack of an increase in right ventricular systolic pressure, pulmonary vascular remodeling, and wall thickening (25). In addition, in a hypoxia-induced PAH model, HMGB1 and RAGE levels were significantly correlated with the extent of PAH pathology, indicating a critical role of HMGB1-RAGE signaling pathways in the pathogenesis of PAH (54, 184).

As illustrated in Figure 3, the activation of NF-κB and MAPK pathways can increase the expression of numerous genes, including those that code for various proinflammatory cytokines (e.g., IL-6, IL-1β, TNF-α, CXCL8) and TGF-β, contributing to inflammation and vascular remodeling in PAH (54, 275). In an animal model of monocrotaline-induced PAH, Iκβα-deficient mice or mice treated with an NF-κB inhibitor (pyrrolidine dithiocarbamate) had significantly reduced levels of cytokine production and an attenuated EMT process in vascular remodeling (179, 366). Overall, these data suggest a role for the HMGB1-NF-κB signaling pathways in the pathogenesis of PAH.

A significant increase in the airway levels of proinflammatory mediators, notably HMGB1, MCP-1, CXCL8, IL-6, and TNF-α, is observed in animal models of PAH (39, 54, 184, 275). Increased levels of cytokines and airway HMGB1 can contribute to the toxic environment by exacerbating inflammation, which can increase levels of ROS in PAH, as illustrated in Figure 3. Oxidative environments can further increase the release of HMGB1 into the airway and damage lung cells, such as endothelial cells (127, 258, 313). Interestingly, increased necrosis in the vasculature can induce reductive stress in the extracellular environment in PAH, producing highly reduced HMGB1, augmenting inflammation via TLR4-mediated signaling, establishing a feedback loop, and leading to excessive lung inflammation, cell death, and formation of vascular lesions (85, 127, 258, 313).

Vascular remodeling in PAH has also been correlated with elevated HMGB1 levels. HMGB1-induced TNF-α release can directly stimulate the secretion of ET-1 from endothelial cells, producing increased vasoconstriction of the airways (362). In addition, increased levels of TNF-α and IL-6 are significantly correlated with endothelial cell proliferation, increases in right ventricular systolic and diastolic pressure, and enhanced vascular remodeling in rats (39, 181, 275). HMGB1-TLR4 and RAGE signaling has been postulated to affect vascular remodeling, venous hypertrophy, and wall thickening in pulmonary arteries due to an increase in proliferation of endothelial and smooth muscle cells (143, 257, 340). Furthermore, cell proliferation is accompanied by increased TGF-β levels and the increased deposition of ECM proteins and α-sma (143, 340). These results suggest that HMGB1 may mediate peripheral vascular resistance, ventricular pressures, and vasculature remodeling in PAH.

Overall, these studies suggest that HMGB1 plays a critical role in mediating severe pulmonary hypertension by activating its downstream signaling pathways that can induce pathological changes associated with PAH. These downstream signaling pathways can be abrogated by regulating the environmental redox state (258). Thus, the reduced HMGB1 found in PAH patients may serve as a unique biomarker for disease severity and a pharmacological target in the treatment of PAH.

HMGB1 as a Therapeutic Target

Using anti-HMGB1 antibodies, we and others have demonstrated the critical role of HMGB1 in the pathogenesis of pulmonary diseases (i.e., CF, ALI/ARDS, COPD, pneumonia, TB, PF, PAH, and asthma). Although anti-HMGB1 antibodies are effective in attenuating the pathology associated with many of these lung diseases, other approaches targeting HMGB1 have been investigated (Fig. 13) to attenuate the release and airway accumulation of HMGB1, to neutralize extracellular HMGB1, or mitigate its downstream adverse effects. Certain approaches target the post-translational modifications of HMGB1 to attenuate its active release. Ethyl pyruvate inhibits HMGB1 release by inhibiting or decreasing its hyperacetylation (66, 85).

FIG. 13. — **HMGB1 as a therapeutic target in pulmonary diseases.** Preexisting trauma, exposure to toxicants, PAMPs, or DAMPs can induce the release of HMGB1, either active or passively, and subsequently the accumulation of HMGB1 in the airways of patients with pulmonary diseases. Post-translational modifications such as hyperacetylation and phosphorylation result in the translocation of HMGB1 into the cytoplasm, where HMGB1 can be actively released. The hyperacetylation of HMGB1 can be decreased by silent mating type information regulation 2 homolog 1 (SIRT)-1 activators (*e.g*., resveratrol), NF-κB inhibitors (*e.g*., ethyl pyruvate, GTS-21, naringin, hesperidin, FPS-ZMI), Nrf2 activators (*e.g*., baicalin, glycyrrhizin, hydrogen sulfide gas, resveratrol), and ODSH. Antioxidants (*e.g*., ascorbic acid, sulforaphane), as well as other compounds (*e.g*., vitamin D, insulin), can also inhibit the cytoplasmic translocation of HMGB1. Similar to antibodies, compounds such as ODSH, glycyrrhizin, and thrombomodulin can bind directly to, neutralize, or inactivate extracellular HMGB1, thereby decreasing the binding of HMGB1 to its receptors. Extracellular HMGB1 can bind to TLR2, TLR4, TLR9, and RAGE receptors to activate pathways involved in inflammation, tissue injury, and tissue remodeling. Following the binding of HMGB1 to TLR2 and TLR4, it can activate the NF-κB pathway, which ultimately increases the expression and secretion of proinflammatory mediators and further augments the secretion of HMGB1, creating a deleterious feedback cycle. Also, HMGB1 can bind with RAGE receptors and activate MAPK-dependent pathways that mediate tissue injury and remodeling. MAPK inhibitors (*e.g*., ulinastatin, naringin) can decrease the accumulation of airway HMGB1. The accumulation of airway HMGB1 and proinflammatory mediators increases the levels of ROS, MMP9, heat shock proteins, and certain proteases that produce oxidative stress, inflammation, tissue injury, and vascular remodeling. NF-κB inhibitors (*e.g*., ethyl pyruvate, GTS-21, naringin, hesperidin, FPS-ZMI) can attenuate cytokine and HMGB1 airway accumulation. Antioxidants, PPAR-γ, and Nrf2 activators (*e.g*., vitamin D, glycyrrhizin, baicalin, resveratrol, ethyl pyruvate) can decrease inflammation, lung injury, and remodeling by decreasing oxidative stress induced by the accumulation of HMGB1 in the airways. FPS-ZMI, N-benzyl-4-chloro-N-cyclohexylbenzamide; Nrf2, nuclear factor erythroid 2-related factor 2; PPAR, peroxisome proliferator-activated receptor.

GTS-21, a partial agonist of α7 nicotinic acetylcholine receptors, significantly decreases the active release of HMGB1 by decreasing its hyperacetylation in macrophages in the presence of a hyperoxic environment (301). The NF-κB inhibitors, BAY 11-7082 and ethacrynic acid, inhibit HMGB1 release by attenuating the post-translational hyperacetylation of HMGB1 (339). Ascorbic acid, in addition to modulating intracellular levels of ROS, inhibits the activation of the NF-κB pathway and subsequently attenuates the oxidative stress-induced HMGB1 translocation from the nucleus to the cytoplasm in hyperoxia-exposed macrophages (247). Similarly, Vitamin D also inhibits HMGB1 translocation by reducing the expression of NF-κB (261, 374). Other compounds, such as resveratrol, a Sirtuin-1 (SIRT-1) activator, can attenuate the active release of HMGB1 into the extracellular milieu (76). As a deacetylase, SIRT-1 activation can block the active release of HMGB1, by decreasing its acetylation, from lung endothelial cells, and attenuating lung epithelial barrier leakage induced by exposure to airway ventilation and LPS (78, 263, 362).

Antioxidants are effective in reducing HMGB1 release in lung cells. For example, the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) attenuates oxidative stress by upregulation of heme oxygenase-1 (HO-1) and downregulation of active HMGB1 release (49, 147, 156). Nrf2 activators, such as hydrogen sulfide gas and resveratrol, significantly decrease the levels of airway HMGB1, restoring epithelial barrier integrity, attenuating lung injury, and increase animal survival after bacterial infections. Other studies have investigated the effects of antioxidants in mediating lung injury by affecting HMGB1 release (76, 155, 156). Antioxidants, such as naringin, a flavanone glycoside, significantly decrease airway accumulation of HMGB1 and ALI by reducing the efficacy of the activation of the NF-κB and MAPK/ERK/p38/JNK pathways (103). The downregulation of these HMGB1-activated pathways decreases the airway accumulation of IL-1β, IL-4, IL-6, and TNF-α, leading to a decrease in airway neutrophil infiltration, edema, and hemorrhage (303). Hesperidin is an antioxidant flavonoid glycoside commonly found in citrus fruits that attenuates LPS-induced ALI by reducing HMGB1 release in mice (196). Hesperidin also attenuates LPS-induced MPO activity and significantly decreases the secretion of TNF-α, IL-6, and MCP-1, as well as lung damage (196). Baicalin and curcumin, compounds derived from plants with antioxidant properties, inhibit the translocation of HMGB1 (55, 56, 344). Therefore, targeting HMGB1 release into the airways by blocking its post-translational modifications of hyperacetylation and oxidation may prove to be an important therapeutic approach to treat lung diseases such as ALI and ARDS.

Other therapeutic strategies include the application of compounds that can neutralize extracellular HMGB1. For example, thrombomodulin, which binds and cleaves HMGB1, reduces HMGB1-mediated proinflammatory responses (2, 140, 153, 186). The heparin derivative ODSH inhibits the binding of extracellular HMGB1 to TLR2, TLR4, and RAGE, attenuating lung injury and bacterial burden in mice infected with P. aeruginosa (291). Glycyrrhizin, which binds to the A and B boxes of HMGB1, can decrease HMGB1-mediated adverse effects (220). Glycyrrhizin also decreases HMGB1 release by activating Nrf2, as previously reported for other Nrf2 activators, such as ethyl pyruvate and vitamin D (155, 176, 362).

Conclusions

HMGB1 has been implicated in various pathological processes in lung diseases, as either a nuclear or an extracellular protein. Thus, it has been postulated not only as a biomarker for pathology but also a therapeutic target for the treatment of lung diseases. As a DAMP molecule, HMGB1 can be released into the extracellular milieu either passively from injured cells, especially those undergoing necrosis, or secreted actively from activated immune cells. Extracellular HMGB1 can accumulate in the airways and/or in the serum and acts as a potent danger signal to neighboring cells. The extracellular levels of HMGB1 in the airway, sputum, and serum positively correlate with the stage or the severity of lung diseases, with often higher levels of accumulation in the local environments such as BAL and sputum than the systemic circulation (Tables 1 and 2).

Table 2.

Sources and Effects of Elevated HMGB1 in Lung Diseases

Disease	Species	HMGB1 (source)	Affected cell/tissue types	References
Asthma	Mice	Elevated in BALF, sputum, lung homogenate	Total lung lysate, bronchial epithelial cells	(71, 126, 206)
COPD	Mice	Elevated in BALF and serum	Epithelial and endothelial cells, neutrophils, lung vasculature	(56, 120, 205, 366)
ALI/ARDS	Mice	Elevated in BALF	Neutrophils, monocytes, macrophages, lung tissue	(85, 301)
PF	Rats	Elevated in BALF and serum	Alveolar/bronchial epithelial cell, fibroblasts, leukocytes	(114, 153)
CF	Mice	Elevated in BALF	Neutrophils, monocytes, macrophages, epithelial cells	(38, 50, 86)
Pneumonia	Mice	Elevated in BALF and serum	Bronchoalveolar cells	(4, 235)
TB	Guinea pigs	Elevated in BALF	Macrophages, epithelial cells, endothelial cells, fibroblasts	(111)
Lung cancer	In vitro	Elevated in cell culture media	Keratinocytes, parenchyma cells	(20, 145)
PAH	Rat	Elevated in BALF	Pulmonary arterial smooth muscle cells, airway epithelial cells	(184, 275, 362)

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BALF, bronchoalveolar lavage fluids.

As a cytokine and an inflammatory mediator, extracellular HMGB1 can bind to its receptors on the neighboring cells and activates signaling pathways to further induce proinflammatory cytokine secretion, to cause dysfunctions of lung cells and cell junctions, to promote cell proliferation, and exacerbate HMGB1 accumulation in the extracellular milieu. Ultimately, these pathways can result in excessive infiltration of immune cells, endothelial/epithelial barrier integrity loss, vascular remodeling, fibrosis, increased susceptibility to infections, and tumorigenesis.

As a transcription factor, nuclear HMGB1 can regulate the transcription of various genes associated with inflammation, tumorigenesis, and metastasis. Herein, these pathological changes drive lung disease progression that can result in lung injury, decreased lung functions, and even mortality. Thus, elevated levels of HMGB1 in different lung diseases share a similar etiology with respect to the initiation of signaling pathways mediated by TLRs and RAGE, leading to activation of several signaling pathways, eliciting an inflammatory response. However, the pathology varies in different lung diseases, which may result from many other compounding factors.

The involvement of other compounding factors, such as genetic backgrounds including CFTR deficiency, exposure to xenobiotics including infectious agents, oxidative or reductive reagents/inducers including cigarette smoke and particulate matter, the use of pro- or anti-inflammatory reagents, could affect the expression levels and post-translational modifications of HMGB1. These factors can contribute to the different microenvironments, including different redox states, which can result in different levels of local HMGB1, different post-translational modifications of HMGB1, which can affect not only its sublocation but also the impact of HMGB1 on the physiology/pathophysiology through its interaction with different types of surrounding cells. Consequently, the outcome of HMGB1 downstream pathology in different lung diseases can be different. Thus, multiple factors, including biochemical modifications of HMGB1, local concentrations of HMGB1, cell types that HMGB1 interacts with, and signaling pathways activated by HMGB1, can drive different pathologies observed in different lung diseases. However, the detailed mechanisms driving these pathologies remain to be further delineated.

Therefore, there are still many questions about how HMGB1 mediates different lung diseases that remain unanswered. This urges future studies with standardized animal models of human lung diseases and better analyses on larger patient populations. Although many studies have been successful in animal models by targeting HMGB1 through modulating its redox modifications, extracellular neutralization, and its downstream effects, it is still not clear whether this can be translated to treating patients with these lung diseases. Future research with more accurate analysis of the time course of HMGB1 release, HMGB1 concentrations at local site and in systemic circulation, as well as post-translational modifications is needed to elucidate the function of HMGB1 on redox modifications, other post-translational modifications, and how these modifications can impact lung disease pathogenesis and outcomes. In addition, research is needed to illustrate signaling pathways, especially RAGE- and TLR-mediated pathways, as well as the cross talk between them. These future studies will no doubt help in the design of novel therapeutic strategies toward targeting HMGB1 as a treatment for lung diseases.

Acknowledgments

This work was supported by grants (L.L.M.) from the National Heart and Blood Institute (HL093708) and St. John's University. The authors thank Susana Solis for her help in editing this work.

Abbreviations Used

α-sma: α-smooth muscle actin
5-HT: serotonin
ALI: acute lung injury
ARDS: acute respiratory distress syndrome
BAL: bronchoalveolar lavage
BALF: bronchoalveolar lavage fluid
CAP: community-acquired pneumonia
CD: cluster of differentiation
CF: cystic fibrosis
CFTR: cystic fibrosis transmembrane conductance regulator
COPD: chronic obstructive pulmonary disease
CXCL8: chemokine ligand 8
DAMP: damage-associated molecular pattern
DC: dendritic cell
ECM: extracellular matrix
EMT: epithelial to mesenchymal transition
ERK: extracellular signal-regulated kinase
ET-1: endothelin-1
FEV: forced expiratory volume
HAT: histone acetyltransferase
HMGB1: high-mobility group protein box 1
Hsp27: heat shock protein 27
ICUs: intensive care units
IFN: interferon
IKK: IκB kinase
IL: interleukin
IPAH: idiopathic pulmonary arterial hypertension
JNK: c-Jun N-terminal kinase
LPS: lipopolysaccharides
MAPK: mitogen-activated protein kinase
MCP-1: monocyte chemoattractant protein-1
MDR-TB: multidrug-resistant TB
MMP9: matrix metalloproteinase 9
MPO: myeloperoxidase
mRNA: messenger RNA
MV: mechanical ventilation
MyD88: myeloid differentiation primary response 88
NF-κβ: nuclear factor kappa-light-chain-enhancer of activated B cells
NLS: nuclear localization signals
Nrf2: nuclear factor erythroid 2-related factor 2
NSCLC: nonsmall-cell lung cancer
ODSH: 2-O,3-O desulfated heparin
p65: NF-kappa-B p65 subunit complex
PA: Pseudomonas aeruginosa
PAFR: platelet-activating factor receptor
PAH: pulmonary arterial hypertension
PAMP: pathogen-associated molecular pattern
PARP: poly(ADP)-ribose polymerase
PF: pulmonary fibrosis
PKC: protein kinase C
RAGE: receptor for advanced glycation end products
ROS: reactive oxygen species
SIRT-1: Sirtuin-1
sRAGE: soluble RAGE
STAT-3: signal transducer and activator of transcription 3
TB: tuberculosis
TDI: toluene 2,6-diisocyanate
TGF-β: transforming growth factor-β
TLR: toll-like receptor
TNF-α: tumor necrosis factor-α
VAP: ventilator-associated pneumonia
VEGF: vascular endothelial growth factor

Author Disclosure Statement

The authors declare no competing financial interest.

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PERMALINK

The Role of HMGB1, a Nuclear Damage-Associated Molecular Pattern Molecule, in the Pathogenesis of Lung Diseases

Mao Wang

Alex Gauthier

LeeAnne Daley

Katelyn Dial

Jiaqi Wu

Joanna Woo

Mosi Lin

Charles Ashby

Lin L Mantell

Abstract

Introduction

HMGB1 Structure and Its Function in the Nucleus

FIG. 1.

HMGB1 Localization and Lung Diseases

Table 1.

FIG. 2.

HMGB1 Signaling in Pathophysiology of Lung Diseases

FIG. 3.

Redox Regulation of HMGB1 Pathophysiology

Asthma

FIG. 4.

Chronic Obstructive Pulmonary Disease

FIG. 5.

Acute Lung Injury/Acute Respiratory Distress Syndrome

FIG. 6.

Pulmonary Fibrosis

FIG. 7.

Cystic Fibrosis

FIG. 8.

Pneumonia

FIG. 9.

Tuberculosis

FIG. 10.

Lung Cancer

FIG. 11.

Pulmonary Arterial Hypertension

FIG. 12.

HMGB1 as a Therapeutic Target

FIG. 13.

Conclusions

Table 2.

Acknowledgments

Abbreviations Used

Author Disclosure Statement

References

ACTIONS

PERMALINK

RESOURCES

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