The Respiratory Epithelial Barrier as an Immunopharmacological Rheostat: From Homeostatic Sentinel to Therapeutic Target in Chronic Lung Disease

ABSTRACT

The respiratory epithelium is a dynamic immunopharmacological interface that transcends its traditional role as a passive barrier to become a central coordinator of pulmonary immunity. This review introduces and elaborates on the paradigm of the “Epithelial Immunopharmacological Rheostat,” a conceptual framework that posits the epithelium as a dynamic, multidimensional signal processor that continuously calibrates the threshold of immune activation. Distinct from static models of barrier dysfunction or isolated alarmin biology, this rheostat operates through four hierarchically interacting axes: barrier integrity, alarmin/type 2, senescence/repair, and tolerogenic programming. We critically dissect how dysregulation of specific axes—alone or in combination—initiates and perpetuates the pathology of chronic respiratory diseases, including asthma, COPD, and idiopathic pulmonary fibrosis. A rigorous, pharmacology‐centric analysis deconstructs the molecular circuitry of epithelial–immune crosstalk, evaluating the druggability of targets from tight junction complexes and pattern recognition receptors to the alarmin (TSLP, IL‐33, IL‐25) signaling cascades and their downstream JAK‐STAT, NF‐κB, and MAPK effectors. Beyond cataloguing mechanisms, this review provides a comparative and critical appraisal of emerging therapeutic strategies, including alarmin‐targeted biologics, barrier‐restorative agents (e.g., postbiotics, short‐chain fatty acids), kinase inhibitors, senotherapeutics, and frontier cell‐based therapies. A dedicated synthesis addresses pivotal pharmacokinetic hurdles, biomarker‐driven stratification, and the imperative of precision endotyping. Finally, we forecast how advanced human organoid models are catalyzing the shift toward personalized interventions designed to reset the defective rheostat. This comprehensive synthesis maps the intricate landscape of epithelial immunopharmacology and identifies critical barriers that must be overcome to translate these insights into transformative clinical outcomes.

This review introduces the “Epithelial Immunopharmacological Rheostat,” a framework where the respiratory epithelium calibrates immune tolerance versus inflammation through four interacting axes. Dysregulation of these axes drives chronic lung diseases, offering a roadmap for precision therapies that reset the rheostat.

Abbreviations

AhR

aryl hydrocarbon receptor

ALI

acute lung injury

AMPK

AMP‐activated protein kinase

ARDS

acute respiratory distress syndrome

AT2

alveolar type II (cells)

CAR‐T

chimeric antigen receptor T cell

CLDN

claudin

COPD

chronic obstructive pulmonary disease

CRS

cytokine release syndrome

CTGF

connective tissue growth factor

DAMP

damage‐associated molecular pattern

DC

dendritic cell

EGFR

Epidermal growth factor receptor

ERK

extracellular signal‐regulated kinase

EV

extracellular vesicle

FeNO

fractional exhaled nitric oxide

G‐CSF

granulocyte colony‐stimulating factor

GEMM

genetically engineered mouse model

GPCR

G protein‐coupled receptor

HDAC

histone deacetylase

HMGB1

high mobility group box 1

Hv1

voltage‐gated proton channel

IgA

immunoglobulin A

IgE

immunoglobulin E

ILC2

group 2 innate lymphoid cell

IL

interleukin

IPF

idiopathic pulmonary fibrosis

JAK

Janus kinase

JAM

junctional adhesion molecule

LPS

lipopolysaccharide

MAPK

mitogen‐activated protein kinase

MMP

matrix metalloproteinase

MSC

mesenchymal stromal cell

mTOR

mammalian target of rapamycin

MUC1

mucin 1

MyD88

myeloid differentiation primary response 88

NADPH

nicotinamide adenine dinucleotide phosphate

NF‐κB

nuclear factor kappa‐light‐chain‐enhancer of activated B cells

NLRP3

NLR family pyrin domain containing 3

NOD2

nucleotide‐binding oligomerization domain‐containing protein 2

OCLN

occludin

PAINS

pan‐assay interference compounds

PAMP

pathogen‐associated molecular pattern

PAR‐2

protease‐activated receptor 2

PDGF

platelet‐derived growth factor

PEG

polyethylene glycol

PKC

protein kinase C

PM2.5

particulate matter with diameter ≤ 2.5 µm

PRR

pattern recognition receptor

RCT

randomized controlled trial

SASP

senescence‐associated secretory phenotype

SCFA

short‐chain fatty acid

sST2

soluble ST2

STAT

signal transducer and activator of transcription

ST2

IL‐33 receptor (IL‐1RL1)

T2

type 2

TEER

transepithelial electrical resistance

TGF‐β

transforming growth factor beta

Th2

T helper type 2

TJ

tight junction

TLR

toll‐like receptor

Treg

regulatory T cell

TSLP

thymic stromal lymphopoietin

ZO

zonula occludens

1. Introduction

Chronic respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF), represent a leading cause of global morbidity and mortality. These conditions are characterized by persistent inflammation, irreversible tissue remodeling, and often suboptimal responses to conventional therapies [1]. This unmet clinical need underscores the urgency for novel therapeutic strategies anchored in a precise, mechanistic understanding of disease pathogenesis. A profound paradigm shift has redefined the respiratory epithelium from a simple structural lining to an active immunopharmacological hub [2, 3]. Strategically positioned at the host‐environment interface, the pseudostratified epithelium executes a triad of critical functions: it forms a selective physical barrier via intercellular junctions, provides innate chemical defense through mucociliary clearance and antimicrobial peptides, and performs active immunological surveillance via an array of pattern recognition receptors (PRRs) [2, 4]. Compelling evidence now positions epithelial dysfunction as a primary pathogenic driver, rather than a secondary consequence, in many chronic lung conditions [4]. Indeed, asthma research is entering an “epithelium era”, recognizing the altered airway epithelium as the initiator and principal regulator of the inflammatory cascade [5].

This review advances the unifying concept of the “Epithelial Immunopharmacological Rheostat.” This framework posits the respiratory epithelium as a dynamic, multidimensional signal processor that integrates environmental and endogenous cues to continuously calibrate the threshold of pulmonary immune activation. Distinct from traditional models that focus on static structural compromise (barrier dysfunction) or isolated initiating signals (alarmin biology), the rheostat model is defined by three core properties. First, the rheostat operates through axial integration of four mechanistically distinct yet hierarchically interacting axes: the barrier integrity axis (tight junction complexes and paracellular permeability), the alarmin/type 2 axis (TSLP, IL‐33, IL‐25, and downstream type 2 immunity), the senescence/repair axis (cellular senescence, SASP, aberrant regeneration), and the Tolerogenic Programming axis (constitutive anti‐inflammatory signals, Treg induction). These axes do not function in isolation; compromise of the barrier integrity axis facilitates allergen penetration and potentiates alarmin release, thereby cranking the alarmin/type 2 axis, while persistent alarmin/type 2 activation (via IL‐4, IL‐13) further degrades barrier function, creating a pathological positive feedback loop. Senescent epithelial cells, through the senescence‐associated secretory phenotype (SASP), simultaneously undermine barrier integrity, fuel chronic inflammation, and alter the tissue microenvironment—dysregulating multiple axes in tandem. Second, the rheostat enables dynamic threshold setting: under homeostasis, the four axes are balanced, maintaining a high activation threshold that favors immune tolerance to innocuous environmental antigens. Environmental insults (allergens, pathogens, pollutants, cigarette smoke) or genetic predispositions “turn the dial” by perturbing specific axes, lowering this threshold, and permitting graded, context‐appropriate inflammatory responses. The output is not a binary switch but a continuous spectrum. Third, the rheostat produces a quantifiable output that ranges from profound tolerance to overt inflammation, determined by the integrated state of all four axes. A modest decrease in barrier integrity combined with low‐level alarmin release produces a different output (e.g., subclinical eosinophilia) than profound senescence alone (e.g., fibrotic remodeling). Distinct disease endotypes correspond to specific patterns (“fingerprints”) of rheostat maladjustment: hyper‐responsive alarmin axis in type 2‐high asthma, jammed senescence program in COPD/IPF, or combinatorial dysregulation.

Herein, we provide a comprehensive and critical synthesis of this paradigm through an explicitly pharmacological lens. Our objectives are threefold: first, to elucidate the core molecular mechanisms (“dials”) constituting the epithelial rheostat and their pharmacological susceptibility; second, to analyze how specific dysregulations define disease endotypes and create actionable therapeutic windows; and third, to conduct a systematic evaluation of current and emerging therapeutic strategies aimed at repairing, resetting, or modulating this rheostat, with a focused critique on their mechanistic rationale, clinical pharmacodynamics, and translational challenges. We conclude by exploring how cutting‐edge technologies are paving the way for personalized epithelial immunopharmacology.

2. Core Mechanisms of the Epithelial Rheostat: Structure, Signaling, and Pharmacological Nodes

The epithelium maintains immune homeostasis through an integrated network of structural, chemical, and cellular mechanisms [6]. Each mechanism represents a cluster of druggable targets that collectively constitute the rheostat.

2.1. The Structural Dynamic: Barrier Integrity Axis and Cellular Heterogeneity

The physical barrier is governed by a sophisticated, signal‐responsive protein network. Claudins (notably CLDN1, CLDN3, CLDN4, CLDN7) form the primary seal, creating charge‐ and size‐selective pores. Occludin and junctional adhesion molecules (JAMs) contribute to dynamic stability and can regulate leukocyte transmigration [7, 8]. Intracellularly, these transmembrane proteins are anchored and organized by zonula occludens (ZO) proteins, which link them to the perijunctional actin‐myosin ring, a contractile apparatus that allows for rapid, signal‐dependent modulation of permeability [9].

This architecture is dynamically regulated by several factors. Among the most potent negative regulators are the Th2 cytokines IL‐4 and IL‐13, which signal through the shared IL‐4 receptor alpha (IL‐4Rα) and STAT6 pathway to downregulate key claudins (e.g., CLDN18, CLDN4) and promote endocytosis of junctional proteins [10]. This mechanism is a critical early step in allergic sensitization and a validated target for dupliumab [11]. Conversely, cytokines such as IL‐22 and IL‐17 can enhance barrier integrity via STAT3 activation, promoting epithelial repair and antimicrobial defense [11, 12]. Environmental insults also act as pharmacological disruptors: proteases from common allergens (e.g., Der p 1 from house dust mites) can directly cleave tight junction proteins or activate protease‐activated receptor‐2 (PAR‐2), triggering PKC/ERK pathways that disrupt ZO‐1 localization [13]. Cigarette smoke extract induces oxidative stress, causing tyrosine phosphorylation and internalization of occludin [14, 15]. Particulate matter (PM2.5) can act via the aryl hydrocarbon receptor (AhR) pathway to disrupt barrier integrity, linking environmental exposure to epithelial‐driven inflammation [16, 17, 18].

In contrast, microbiome‐derived metabolites serve as barrier enhancers. Short‐chain fatty acids (SCFAs) like butyrate and propionate, derived from commensal microbiota, act as endogenous histone deacetylase (HDAC) inhibitors. By increasing histone acetylation at promoters of tight junction genes, they upregulate expression and strengthen the barrier, presenting a novel indirect pharmacological strategy via prebiotic, probiotic, or postbiotic interventions targeting the gut–lung axis [19, 20, 21, 22].

Critically, the barrier integrity axis both regulates and is regulated by other rheostatic axes. The Th2 cytokines IL‐4 and IL‐13, central effectors of the alarmin/type 2 axis, are potent downregulators of tight junction protein—establishing a critical link where alarmin release leads to barrier disruption, which in turn facilitates further allergen exposure and alarmin release. Moreover, components of the SASP from senescent epithelial cells (senescence/repair axis), such as specific MMPs and reactive oxygen species, can directly degrade junctional proteins or disrupt their cytoskeletal anchorage. Therefore, therapeutic restoration of barrier function may require concurrent modulation of interconnected axes to achieve durable efficacy.

2.2. The Chemical Signaling Dial: The Alarmin Triad and Steady‐State Immunomodulation

Upon damage, epithelial cells release a trio of potent cytokines—thymic stromal lymphopoietin (TSLP), interleukin‐33 (IL‐33), and interleukin‐25 (IL‐25)—collectively termed “alarmins” [23]. These act as master upstream switches that potently activate type 2 immunity. TSLP binds to a heterodimeric receptor complex (TSLPR/IL‐7Rα) primarily on dendritic cells and mast cells, activating JAK1/JAK2 and STAT5 transcription factors, thereby programming dendritic cells to prime naïve T cells toward a Th2 phenotype [24, 25, 26]. IL‐33, constitutively stored in the nucleus, is released upon cellular necrosis; it signals through its receptor ST2 (IL‐1RL1) in complex with IL‐1RAcP, recruiting the adaptor MyD88 to activate NF‐κB and MAPK pathways in group 2 innate lymphoid cells (ILC2s) and memory Th2 cells, driving production of IL‐5 and IL‐13 [27, 28]. IL‐25 (IL‐17E) engages a receptor complex of IL‐17RA and IL‐17RB, activating NF‐κB via the adaptor Act1 and TRAF6; it is particularly implicated in amplifying ILC2 responses and in steroid‐resistant, severe asthma endotypes [29].

The alarmin axis represents a premier target for upstream immunomodulation. Blocking these pathways (e.g., with tezepelumab against TSLP) aims to suppress multiple downstream inflammatory arms simultaneously [30]. However, significant redundancy exists among alarmins, which may limit the efficacy of monotherapies and inform future combination strategies [31]. In some allergic sensitization models, TSLP acts as a master upstream switch, essential for initiating the inflammatory cascade. In established disease or steroid‐resistant states, IL‐33 and IL‐25 may play more dominant or compensatory roles. Understanding the dominant alarmin axis in specific patient endotypes is thus a key goal for precision medicine.

2.3. The Cellular Behavior Dial: Senescence, Metabolism, and Vesicular Communication

Beyond acute signaling, the epithelium's long‐term behavioral state is a critical rheostatic component. Chronic or repetitive injury can induce a state of irreversible growth arrest known as cellular senescence. Senescent epithelial cells remain metabolically active and secrete a plethora of pro‐inflammatory cytokines, chemokines, growth factors, and proteases—the senescence‐associated secretory phenotype (SASP) [32]. The SASP creates a perpetually inflammatory microenvironment that drives tissue remodeling, fibroblast activation, and immune dysfunction, “jamming” the rheostat in a pro‐inflammatory state characteristic of COPD and IPF [33, 34, 35]. Importantly, the SASP also impairs neighboring epithelial cells (weakening barrier integrity) and lowers the threshold for alarmin activation, making senescent cells a high‐value therapeutic target.

Epithelial cell metabolic pathways (e.g., glycolysis, oxidative phosphorylation, fatty acid oxidation) are intricately linked to their immune function [36]. Metabolic shifts can influence the production of inflammatory mediators and response to damage [37]. In chronic inflammatory settings and cancer, metabolic reprogramming of epithelial cells can alter the local microenvironment [38]. For example, in lung adenocarcinoma‐to‐squamous transdifferentiation (AST), dysregulated epithelial signaling drives neutrophil infiltration; these neutrophils can transfer lipids to tumor cells, fueling tumor plasticity and growth [39]. This exemplifies how the metabolic dial, when corrupted, contributes to pathological outcomes beyond classic inflammation. Pharmacologically targeting metabolic checkpoints (e.g., AMPK, mTOR, or lipid metabolism enzymes) presents an emerging strategy [40, 41].

Epithelial cells constitutively release extracellular vesicles (exosomes, microvesicles) containing miRNAs, mRNAs, proteins, and lipids [42]. Under homeostasis, their vesicles mediate tolerogenic communication with immune cells; under stress, their cargo shifts to promote inflammation or repair, making vesicle biogenesis a potential therapeutic target [43].

2.4. Epithelium‐Driven Immune Tolerance: Active Pharmacological Dampening

A critical, pharmacologically targetable function of the healthy epithelium is the active maintenance of immunological tolerance in the steady state. This tolerogenic programming prevents inappropriate responses to innocuous environmental antigens and is mediated by secreted mediators (e.g., G‐CSF, kynurenines, lactate) and cell‐surface molecules. Epithelial‐derived G‐CSF promotes expression of TGF‐β, IL‐10, and the inhibitory receptor CD200R on lung macrophages, raising the activation threshold [44, 45]. Dendritic cells intimately interact with the epithelium, extending dendrites through tight junctions to sample luminal antigens in a noninflammatory manner, promoting regulatory T cell (Treg) induction [46].

This constitutive “dampening” signal represents a foundational setting of the rheostat toward tolerance. Pharmacologically, “toleromimetic” therapies aimed at amplifying these endogenous pathways—such as cell‐permeable kynurenine analogs or small molecules potentiating downstream mediators—represent a novel strategy. The challenge lies in achieving context‐specific activation without generalized immunosuppression, underscoring the need for inhalation‐based delivery. Table 1 compares the key features of PAMPs and DAMPs in the context of epithelial immunity.

TABLE 1.

Comparative characteristics of pathogen‐associated molecular patterns (PAMPs) and damage‐associated molecular patterns (DAMPs) in the context of epithelial immunity.

Feature dimension	Pathogen‐associated molecular patterns (PAMPs)	Damage‐associated molecular patterns (DAMPs)	References
Nature	Conserved molecular structures of pathogens (non‐self)	Self‐components released or altered following host cell stress/damage	[47]
Primary source	Invading microorganisms (bacteria, viruses, fungi, etc.)	Damaged/necrotic/stressed host cells	[48]
Representative molecules	Lipopolysaccharide (LPS), flagellin, viral RNA/DNA	HMGB1, ATP, mitochondrial DNA, uric acid crystals, S100 proteins	[49]
Core PRRs	TLR4, TLR3, TLR9, etc.	NLRP3, cGAS, TLR4, RAGE, etc.	[50]
Role in epithelial immunity	Trigger of infectious inflammation	Amplifier of sterile and infectious inflammation	[ 51 ]
Relationship with barrier	Breaching intact barrier causes infection	Both consequence and cause of barrier dysfunction	[52]

2.5. A Note on Multifactorial Integration: The Epithelium as a Critical Node

While this review focuses on the epithelium as the principal rheostat, the final output of pulmonary immunity is an emergent property of a multicellular ecosystem. Immune cells (tissue‐resident memory T cells, ILCs, alveolar macrophages) possess intrinsic programs that can be triggered independently of epithelial alarmins. Fibroblasts and endothelial cells contribute significantly to tissue remodeling, angiogenesis, and leukocyte recruitment, particularly in late‐stage disease. Neuronal circuits (e.g., vagal reflexes) can rapidly modulate immune tone via neuropeptides. Systemic factors (circulating hormones, microbiome‐derived metabolites) and the local lung microbiome constantly modulate epithelial set‐points. Therefore, the epithelial rheostat is best viewed as a highly influential but not exclusive node in a distributed control system. Effective therapeutic restoration of homeostasis may require combining epithelial‐directed strategies with those targeting other nodes, depending on disease stage and endotype.

3. Maladjusted Rheostasis: Defining Pharmacologically Distinct Disease Endotypes

Chronic lung diseases arise from specific, often overlapping, failures of the epithelial rheostat. Understanding these endotypes is essential for targeted pharmacotherapy.

3.1. Allergic Asthma: Dominant Hyperactivation of the Alarmin/Type 2 Axis

In the prototypic type 2 (T2)‐high endotype (approximately 50% of severe asthmatics), the rheostat fails primarily via hyperactivation of the Alarmin/type 2 axis. Allergen proteases and pollutants compromise barrier integrity, facilitating allergen penetration [53]. Damaged epithelial cells release TSLP, IL‐33, and IL‐25, which collectively drive ILC2/Th2 activation, eosinophilia, IgE production, goblet cell metaplasia, and airway hyperresponsiveness (Figure 1) [54]. Disease severity and steroid responsiveness may correlate with the relative dominance of one alarmin pathway (e.g., IL‐25‐high severe asthma) [54].

FIGURE 1.

Pathological mechanism of Th2‐driven airway epithelial barrier dysfunction. Environmental triggering and epithelial sensing airway epithelial cells—including basal, goblet, and ciliated cells—are exposed to exogenous stimuli such as pathogens (viruses, bacteria), allergens, particulate matter, and immune components (e.g., IgA, antimicrobial peptides). Alarmin release and Th2 cell activation stimulated epithelial cells to secrete alarmins (TSLP, IL‐25, IL‐33), which in turn activate Th2 lymphocytes. Th2 polarization and downstream effects activated Th2 cells produce signature cytokines (IL‐4, IL‐5, IL‐9, IL‐13) that: promote plasma cell differentiation and antibody production; drive eosinophil expansion and recruitment; induce airway hyperresponsiveness. Epithelial barrier injury and impaired repair eosinophil and mast cell degranulation disrupt epithelial tight junctions (TJs) and adherens junctions (AJs): loss of epithelial cell adhesion; increased barrier permeability; enhanced goblet cell metaplasia; delayed epithelial repair.

Endotypic heterogeneity must be acknowledged. The T2‐high fingerprint does not account for all asthma. In T2‐low endotypes (neutrophilic or paucigranulocytic asthma), the rheostat may instead be dominated by a jammed senescence/repair axis or a barrier integrity defect driven by non‐type 2 mechanisms (e.g., IFN‐γ, IL‐17), leading to steroid resistance and a distinct therapeutic landscape [55]. Recognizing such heterogeneity is essential for precise targeting of the correct rheostat dial.

3.2. COPD and Idiopathic Pulmonary Fibrosis: The Stuck Senescence and Aberrant Repair Dials

In these diseases, the rheostat is damaged by chronic toxic insults (e.g., cigarette smoke, silica), leading to a state of persistent maladjustment. Repeated injury induces epithelial cell senescence. SASP factors (IL‐6, IL‐8, MMPs, TGF‐β) create a chronic, low‐grade inflammatory milieu that drives further tissue damage, fibroblast activation, and immune cell recruitment, effectively jamming the rheostat in a pro‐inflammatory position [56, 57]. Following injury, the normal reparative program (e.g., Wnt/β‐catenin) becomes dysregulated [58]. In IPF, aberrant Wnt signaling in alveolar type II (AT2) cells promotes a pro‐fibrotic phenotype, failure of normal re‐epithelialization, and sustained fibroblast activation [59]. Importantly, senescent AT2 cells do not merely fail to repair; they actively secrete pro‐fibrotic factors (TGF‐β, PDGF, CTGF) that directly activate adjacent fibroblasts. Conversely, activated myofibroblasts feedback to AT2 cells via paracrine Wnt and hedgehog signals, perpetuating a vicious cycle of impaired re‐epithelialization and relentless fibrosis. This epithelial–mesenchymal trophic unit dysfunction underscores that resetting the rheostat in fibrotic diseases may require simultaneous targeting of both the epithelial senescent dial and the reactive stromal compartment.

In COPD, additional mechanisms contribute to the pathology. Damaged COPD epithelium exhibits impaired production of anti‐microbial peptides and increased release of DAMPs like HMGB1, driving sterile inflammation and a skewed neutrophil‐dominated immune response that contributes to tissue destruction [60, 61, 62].

3.3. Respiratory Infections and Acute Lung Injury (ALI): Overload of the Danger‐Sensing Dials

In severe infection or injury (e.g., ARDS), the system is overwhelmed by a massive influx of PAMPs and DAMPs. Widespread epithelial necrosis leads to a massive release of intracellular DAMPs such as HMGB1, ATP, and mitochondrial DNA, which activate PRRs (e.g., TLR4, NLRP3 inflammasome) on epithelial and immune cells, unleashing a hyperinflammatory “cytokine storm” that can cause fatal collateral tissue damage [63]. While neutrophil recruitment is essential for infection control, its dysregulation is central to ALI pathology. Recent studies reveal a critical role for the Hv1 proton channel in neutrophil migration and NADPH oxidase activity during lung infection; Hv1 inhibition reduces lung injury in models of Pseudomonas aeruginosa pneumonia, identifying a novel pharmacologic target at the immune–epithelial interface [64]. The massive inflammatory cascade overrides steady‐state tolerogenic signals (e.g., IL‐10, TGF‐β). The anti‐inflammatory cytokine IL‐37 plays a crucial protective role here, acting to mitigate virus‐induced hyperinflammation and inhibit excessive viral replication in conditions like influenza and COVID‐19 [65, 66].

3.4. The Inflammation‐Cancer Interface: Epithelial Dysfunction as a Precancerous Nexus

Chronic lung diseases such as COPD and IPF are well‐established risk factors for lung cancer, suggesting a shared underlying disruption of the epithelial rheostat that progresses from chronic inflammation to malignancy. First, the Senescence/SASP axis chronically activated in COPD/IPF creates a pro‐tumorigenic microenvironment rich in growth factors (e.g., TGF‐β, amphiregulin), pro‐inflammatory cytokines (IL‐6, IL‐8), and matrix‐remodeling enzymes (MMPs) that promote genomic instability, angiogenesis, and proliferative signaling in adjacent epithelial cells [67]. Second, barrier dysfunction facilitates the penetration of additional carcinogens (e.g., tobacco smoke) and perpetuates a cycle of injury‐repair; repeated regeneration increases replication errors and oncogenic mutations [68]. Third, immunometabolic reprogramming at this interface—e.g., an epithelial‐derived TET2‐STAT3‐CXCL5 axis recruiting pro‐tumorigenic neutrophils—establishes a feed‐forward loop between dysplastic epithelium and the immune landscape [69]. Therefore, therapeutic strategies aimed at “resetting” the rheostat—senolytics to clear the pro‐tumorigenic SASP, barrier fortificants to reduce mutagen exposure, or inhibitors of specific signaling nodes like STAT3—may hold dual promise in mitigating both chronic inflammation and its oncogenic sequelae [70].

4. Pharmacological Targeting of the Rheostat: From Mechanism to Medicine

The therapeutic landscape is evolving from broad anti‐inflammatories to precise strategies targeting specific rheostat dysfunctions. We categorize these based on their primary point of intervention within the rheostat framework.

4.1. Restoring Barrier Integrity

This strategy aims to fix the foundational defect, raising the immune activation threshold. Short‐chain fatty acids (SCFAs) such as bacterial propionate, gut microbiota‐derived metabolites, are potent HDAC inhibitors that increase histone acetylation at promoters of tight junction genes (e.g., CLDN1, OCLN), thereby enhancing their expression [71]. Postbiotics such as bacterial lysates (e.g., OM‐85/Broncho‐Vaxom) have shown efficacy in reducing COPD and asthma exacerbations in clinical trials, likely through modulating dendritic cell function and enhancing mucosal IgA, thereby strengthening barrier defense [72, 73, 74]. Synthetic peptides mimicking extracellular loops of claudins (e.g., a CLDN1‐derived peptide) can act as competitive inhibitors, blocking adhesion and paracellular translocation of pathogens or allergens; however, peptide stability, bioavailability, and cost remain significant development barriers [75]. Recombinant IL‐22 Fc‐fusion proteins activate STAT3 in epithelial cells, promoting proliferation, antimicrobial peptide production, and mucus barrier enhancement, but the pro‐inflammatory potential of IL‐22 in certain contexts necessitates precise disease endotyping and controlled delivery to avoid paradoxical exacerbation [76]. Similarly, certain phytochemicals (e.g., baicalein, iridoid glycosides) have been reported to attenuate cytokine‐induced barrier disruption by activating the EGFR/Akt signaling pathway, stabilizing ZO‐1 and occludin [77, 78]; however, rigorous assessment of pharmacokinetics and screening for pan‐assay interference compounds (PAINS) is paramount [79]. Table 2 summarizes the pharmacological and interventional strategies for restoring respiratory epithelial barrier integrity.

TABLE 2.

Pharmacological and interventional strategies for restoring respiratory epithelial barrier integrity.

Strategy category	Representative agents	Proposed molecular mechanism	Evidence stage	Advantages and challenges	References
Tight junction reinforcement	Synthetic claudin‐peptides	Competitive occupancy of pathogen binding sites on TJ loops	Preclinical	High specificity; stability and cost hurdles	[80]
Epigenetic modulators	Short‐chain fatty acids (butyrate, propionate)	HDAC inhibitors, increase TJ genes expression	Preclinical/Clinical	Pleiotropic benefits; achieving lung concentration	[81, 82]
Postbiotics	Bacterial lysates (OM‐85)	PRR agonism, enhanced IgA, Treg induction	Clinical (RCTs).	Multitarget; preventive rather than reparative	[81, 82]
Cytokine‐mediated repair	Recombinant IL‐22 Fc‐	STAT3 activation, proliferation, antimicrobial peptides	Preclinical/Early clinical	Pro‐regenerative; risk of pro‐inflammatory effects	[83, 84]

4.2. Quenching the Alarm: Biologics Against Epithelium‐Derived Cytokines

Blocking the alarmin axis represents a paradigm of upstream, broad‐spectrum immunomodulation. Tezepelumab (anti‐TSLP) binds TSLP, preventing engagement with its receptor; its clinical profile—reducing exacerbations in severe asthma across a range of baseline eosinophil counts—validates TSLP as a master upstream switch influencing multiple inflammatory pathways (T2‐high and some T2‐low) [85]. Anti‐IL‐33/ST2 Biologics (Itepekimab, Astegolimab) show pronounced efficacy in patients with elevated type 2 biomarkers (blood eosinophils, FeNO), and soluble ST2 (sST2) is being investigated as a predictive pharmacodynamic biomarker for patient stratification [86]. A key advantage of alarmin blockade over downstream cytokine targets (e.g., anti‐IL‐5) is the potential to attenuate broader inflammatory networks. However, biological redundancy may explain why a subset of patients does not respond to single‐alarmin blockade, highlighting an area for combination therapy research [87]. Table 3 provides a comparison of monoclonal antibodies targeting the epithelial alarmin axis and downstream type 2 cytokine pathways.

TABLE 3.

Comparison of monoclonal antibodies targeting the epithelial alarmin axis and downstream type 2 cytokine pathways.

Target	Agent(s)	Mechanism	Key clinical findings	Positioning and considerations	References
TSLP	Tezepelumab	Blocks TSLP‐TSLPR interaction	Reduces exacerbations irrespective of baseline eosinophil	Most upstream; broad spectrum	[90]
IL‐33/ST2	Itepekimab, Astegolimab	Neutralizes IL‐33 or blocks ST2	Efficacy in T2‐high patients; sST2 biomarker	Central alarmin; redundancy possible	[91]
IL‐4Rα	Dupilumab	Blocks shared IL‐4 /IL‐13 receptor	Highly effective in T2‐ high phenotypes.	Downstream; well‐established	[92]
IL‐5/IL‐5R	Mepolizumab, Benralizumab	Depletes eosinophils	Dramatic reduction in eosinophilic asthma	Terminal effector; no benefit in noneosinophilic	[80]

Although biologics such as dupilumab (anti‐IL‐4Rα) and mepolizumab (anti‐IL‐5) do not directly bind epithelial receptors, they exert beneficial indirect effects on the epithelial barrier. By neutralizing downstream type 2 cytokines (IL‐4, IL‐13) or depleting eosinophils, these agents alleviate the cytokine‐mediated downregulation of tight junction proteins and reduce eosinophil‐derived epithelial damage. Therefore, their inclusion in this review is justified by their ability to secondarily restore epithelial barrier integrity and reset the rheostat, even though their primary targets are immune cells. Table 3 distinguishes direct epithelial targets (TSLP, IL‐33) from downstream immune targets with indirect epithelial benefits.

4.3. Targeting Anti‐Inflammatory Cytokines: The IL‐10 Delivery Challenge

Interleukin‐10 (IL‐10) is a master regulatorof mucosal tolerance, suppressing pro‐inflammatory cytokine production and macrophage activation. Its clinical translation has been hampered by a short plasma half‐life (1‐2 h) and a narrow therapeutic window; systemic administration can cause transient pro‐inflammatory effects or immunosuppression. To overcome these barriers, several sophisticated delivery strategies are under development. These strategies include protein engineering, such as Fc‐fusion proteins or PEGylated variants to extend circulatory half‐life, as well as targeted nanocarrier systems such as lipid nanoparticles, polymersomes, or exosome‐mimetic vesicles functionalized with ligands for epithelial or immune cell targets, enabling controlled release and localized lung accumulation [88]. Cell‐based approaches have also been developed, including engineering mesenchymal stromal cells (MSCs) or regulatory T cells (Tregs) to constitutively produce IL‐10 at the site of inflammation [89]. The choice of strategy depends on the intended clinical context (e.g., acute exacerbation vs. chronic dampening), and this focus on overcoming the delivery challenges exemplifies the advanced pharmacotechnical considerations essential for translating rheostat‐resetting concepts into medicines.

4.4. Modulating the Cellular Behavior Dial: Kinase Inhibition, Senotherapeutics, and Engineered Cells

Janus kinase (JAK) Inhibitors, such as the inhaled small molecule TD‐8236, aim to block signaling downstream of multiple cytokines involved in epithelial–immune crosstalk (e.g., from TSLP, IL‐4, IL‐13), with inhaled formulations designed to maximize local lung exposure while minimizing systemic side effects [93]. Senotherapeutics targets the jammed senescence dial in COPD and IPF. Senolytics (e.g., dasatinib + quercetin) selectively induce apoptosis in senescent cells [94], whereas senomorphics (e.g., mTOR inhibitors) suppress the pro‐inflammatory SASP without killing the cell [95]. Early‐phase clinical trials are exploring their potential to halt chronic inflammation and progression [96]. However, a critical appraisal is warranted, as first‐generation senolytics have off‐target effects (e.g., dasatinib's broad kinase inhibition), and identifying robust biomarkers of senescence and treatment response remains challenging.

Engineered Cell Therapies as Proof‐of‐Concept for rheostat resetting. Pioneering preclinical studies have demonstrated that a single infusion of IL‐5/IL‐5R‐targeting CAR‐T cells can achieve long‐term remission of eosinophilic airway inflammation in murine models [71]. While representing a conceptual breakthrough toward durable remission, these approaches face formidable translational hurdles: long‐term genotoxicity risks, potential for persistent immunosuppression, cytokine release syndrome, and prohibitive costs. As such, they remain a distant frontier for highly selected, severe refractory patients, but they powerfully validate the principle that resetting a dysregulated epithelial–immune rheostat is therapeutically achievable. Mesenchymal stromal cells (MSCs) exert paracrine anti‐inflammatory, antifibrotic, and pro‐repair effects; although phase I/II trials in COPD and IPF show safety and hints of efficacy, issues of cell heterogeneity, lack of engraftment, and transient effects remain significant hurdles. Table 4 outlines the translational landscape of frontier cell‐based and system‐targeted therapies for chronic lung diseases.

TABLE 4.

Translational landscape of frontier cell‐based and system‐targeted therapies for chronic lung diseases.

Therapy	Target condition/mechanism	Current stage and key evidence	Major translational advantages	Pivotal challenges and open questions	References
IL‐5 CAR‐T Cells	Severe eosinophilic asthma	Preclinical/Phase I	One‐time durable remission	Genotoxicity, CRS, cost	[97]
MSCs	COPD, IPF	Phase I/II	Multifactorial action, low immunogenicity	Modest efficacy, heterogeneity	[98]
Senolytics (D+Q, Fisetin)	COPD, IPF	Early clinical	Targets fundamental aging mechanism	Off‐target effects, biomarker need	[99]
Gut–lung axis modulation	Asthma, COPD	Preclinical/Clinical	Noninvasive, safe, low‐cost	Variable effects, causality difficult	[100, 101]

4.5. Systemic Dials: Gut–Lung Axis Modulation

Interventions with specific probiotics, prebiotics (dietary fiber), or postbiotics aim to correct dysbiosis, increase systemic levels of beneficial metabolites like SCFAs, and thereby remotely strengthen the lung epithelial barrier and dampen inappropriate immune responses [102, 103, 104]. However, effects are highly variable based on individual baseline microbiota, and causality in humans is difficult to prove.

4.6. Synthesis: Cross‐Cutting Pharmacological and Translational Challenges

Several overarching hurdles must be addressed in translating rheostat‐targeting strategies. Optimizing drug delivery (e.g., inhaled biologics, nanoparticle‐encapsulated small molecules) to achieve sufficient local target engagement in the epithelial microenvironment while avoiding systemic toxicity remains a key pharmacokinetic/pharmacodynamic challenge. Biomarker‐driven patient stratification is essential, as variable clinical response to biologics underscores that phenotypic diagnoses (e.g., “severe asthma”) encompass multiple molecular endotypes [96]. Pharmacodynamic biomarkers (e.g., sST2 for IL‐33 pathway activity, periostin for IL‐13 activity) are crucial for patient selection and for understanding mechanisms of secondary nonresponse. Future trial designs—such as enrichment designs (selecting patients based on a predictive biomarker) and basket trials (testing one drug across diseases sharing a target)—will be essential. The greatest benefit from barrier‐restorative or senolytic agents will likely come from early or even preventive intervention in at‐risk individuals, requiring sensitive diagnostic tools. Finally, overcoming biological redundancy will require rational combination therapies (e.g., dual alarmin blockade, alarmin + JAK inhibitor) or targeting convergent nodes (e.g., STAT6) for comprehensive rheostat reset, as illustrated inFigure 2.

FIGURE 2.

Therapeutic modalities targeting the dysregulated epithelial immunopharmacological rheostat. Schematic representation of therapeutic strategies categorized by their primary target axis within the epithelial immunopharmacological rheostat framework. These include: (1) barrier‐restorative agents (e.g., SCFAs, postbiotics, synthetic peptides); (2) alarmin axis inhibitors (biologics against TSLP, IL‐33, IL‐25, and downstream kinase inhibitors); (3) senotherapeutics (senolytics and senomorphics); and (4) tolerogenic therapies (e.g., engineered IL‐10 delivery). This mechanistic categorization facilitates a precision medicine approach by matching therapeutic intervention to the patient‐specific pattern of rheostat dysfunction.

5. Challenges, Future Perspectives, and Concluding Synthesis

5.1. Enabling Technologies for Precision Epithelial Pharmacology

Advanced human model systems are accelerating the field. Patient‐derived air‐liquid interface (ALI) cultures and vascularized lung organoids co‐cultured with immune cells provide human‐relevant, personalized platforms for drug screening, toxicity testing, and efficacy prediction, reducing translational attrition [109]. These models capture the differentiated, pseudostratified epithelium with functional cilia and mucus production. Emerging technologies such as spatial transcriptomics and imaging mass cytometry allow mapping of molecular conversations between epithelial subsets and adjacent immune cells within intact tissue architecture [110]. Artificial intelligence is accelerating target identification and integration of multimodal data, but these tools remain in early stages for epithelial pharmacology and are discussed elsewhere in depth [111].

5.2. Emerging Strategies to Overcome Translational Hurdles

To overcome biological redundancy, next‐generation biologics such as bispecific antibodies (e.g., simultaneously targeting TSLP and IL‐4Rα) or trispecific antibodies are designed to block multiple pathways synergistically. An alternative strategy is targeting critical convergent downstream nodes like specific JAK isoforms or STAT6. Advanced delivery systems, including inhaled nanoparticle formulations, engineered extracellular vesicles, and lung‐tropic viral vectors (e.g., AAV6.2), are being explored to deliver therapeutics (mRNAs, siRNA, proteins) directly to the respiratory epithelium with high efficiency and reduced off‐target effects. Furthermore, integration of spatial multi‐omics on biopsy specimens, liquid biopsy approaches analyzing lung‐derived EVs, and AI‐driven analysis holds promise for identifying dynamic biomarker signatures that can predict treatment response and guide therapy switching. Table 5 summarizes advanced preclinical model systems for studying human respiratory epithelial–immune interactions.

TABLE 5.

Advanced preclinical model systems for studying human respiratory epithelial–immune interactions.

Therapy/Strategy	Core mechanism of action	Key research progress/Evidence	Current stage	References
IL‐5 CAR‐T (Ying's team)	Targets and eliminates IL‐5Rα+ eosinophils	Long‐term remission in animal models; GMP process established; Preclinical safety verified	Clinical trials initiated	[105]
5TIF4 CAR‐T (Peng's team)	Eliminates eosinophils and continuously blocks IL‐4/13 signaling	“Functional cure” achieved in mouse model with single infusion	Preclinical research (animal models)	[106]
MSC therapy for COPD	Immunomodulation, anti‐inflammation, paracrine effects	Phase I safety/feasibility trial in advanced COPD patients	Early‐stage clinical trials	[107]
Gut–lung axis Intervention (e.g., dietary fiber)	Modulates microbiota, increases SCFAs, improves immunity	Shown to enhance efficacy in lung cancer immunotherapy; Basic research supports potential in inflammatory diseases	Basic and translational research/Exploratory adjunct therapy	[108]

5.3. Concluding Synthesis

The respiratory epithelial barrier is far more than a simple wall; it is a dynamic, intelligent, and pharmacologically rich immunoregulatory interface whose dysfunction sits at the core of numerous chronic respiratory diseases. The concept of the “Epithelial Immunopharmacological Rheostat” provides a powerful framework for understanding how this tissue sets and adjusts the threshold for immune activation—integrating barrier integrity, alarmin signaling, senescence programs, and tolerogenic cues into a unified, tunable system.

Our deepening molecular understanding has unveiled a vast landscape of therapeutic opportunities, from junctional complexes and alarmins to senescent cell programs. The therapeutic pipeline is now populated with agents that aim not just to suppress inflammation, but to correct the underlying epithelial defect—to repair the barrier, quench aberrant alarm signals, and clear senescent cells. The journey from bench to bedside, however, is fraught with pharmacological complexities: redundancy, delivery challenges, and patient heterogeneity.

The ultimate goal is evolving: from merely suppressing downstream inflammation to restoring physiological homeostasis by repairing the barrier and resetting the immune rheostat. As we move forward, the field of respiratory medicine will increasingly embrace a paradigm of precision immunopharmacology, where therapies are chosen based on an individual's unique epithelial–immune fingerprint. This approach holds transformative promise for achieving durable disease control and improved quality of life for patients with currently refractory lung diseases.

Author Contributions

Z.B.J. designed the study. F.X.N., J.H., P.S.C., H.H.C., D.H.H., and Z.B.J. wrote the manuscript. D.H.H. and Z.B.J. revised the paper. All authors read and approved the final manuscript.

Funding

This work was supported by the Guangdong Provincial Bureau of Traditional Chinese Medicine (Nos. 20221361, 20251345, 20241290, 20241285) and the Zhuhai Science and Technology Innovation Bureau (Nos. 2320004000290, 2420004000022). Furthermore, this work received support from Zhuhai Hospital of Integrated Traditional Chinese & Western Medicine (No. 202303). This work was also supported by the Guangdong Province‐Provincial Chinese Medicine construction special fund named Traditional Chinese Medicine Inheritance Studio construction project, Guangdong Chinese Medicine Office Letter [2023] 108, and Beijing Chao Enxiang Traditional Chinese Medicine Heritage and Development Foundation 2023 “Towards a New Horizon” Research Project (Project No. 2023CX03).

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Ni F.‐X., Hu J., Chen H.‐H., Huang D.‐H., and Jiang Z.‐B., “The Respiratory Epithelial Barrier as an Immunopharmacological Rheostat: From Homeostatic Sentinel to Therapeutic Target in Chronic Lung Disease.” European Journal of Immunology 56, no. 7 (2026): e70249. 10.1002/eji.70249

Data Availability Statement

The authors have nothing to report.