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. 2018 Jan 4;8:1644. doi: 10.3389/fimmu.2017.01644

Table 2.

Impact of different factors on the alveolar–capillary barrier.

Mediator Impact on pulmonary barrier function Mechanism of action
Alveolar epithelium
TGFβ1 −

  • Decreases lung epithelial barrier function (203–205)

  • Increases the permeability of pulmonary endothelial monolayers (206)

  • Increases the permeability of alveolar epithelial monolayers (206)
Tumor necrosis factor (TNF) −

  • Causes alveolar epithelial dysfunction (207)
Lectin-like domain of TNF +

  • Increases occludin expression, and improved gas–blood barrier function (7)
TNF-related apoptosis-inducing ligand (TRAIL) −

  • Disruption of alveolar epithelial barrier (199, 208, 209)
Interleukin-1β (IL-1β) +

  • Augments in vitro alveolar epithelial repair (139)
Protein kinase D3 −

  • Dysfunction of airway epithelial barrier through downregulation of a key tight junctional protein claudin-1 (210)
Claudin-3 −

  • Decreases alveolar epithelial barrier function (211)
Claudin-4 +

  • Improves the barrier function of pulmonary epithelial barrier by promoting pulmonary fluid–clearance function (211, 212)
Transient receptor potential vanilloid 4 (TRPV4) −

  • Disruption of alveolar type I epithelial cells leading to lung vascular leak and alveolar edema (213)
Ethanol −

  • Disruption of alveolar epithelial barrier function by activation of macrophage-derived TGFβ1 (214)
Acetoin (butter), diacetyl, pentanedione, maltol (malt), ortho-vanillin (vanilla), coumarin, and cinnamaldehyde −

  • Impairment of epithelial barrier function in human bronchial epithelial cells (215)
Asbestos −

  • Increases lung epithelial permeability through increasing epithelial fibrinolytic activity (216)
Pneumolysin (PLY) −

  • Impairs epithelial barrier (217)
Fas-ligand system −

  • Causes alveolar epithelial injury in humans with ALI or ARDS (218)

  • Impairs alveolar epithelial function in mouse lungs by mechanisms involving caspase-dependent apoptosis (219)

  • Inducing apoptosis of cells of the distal pulmonary epithelium during ALI (57)
CO −

  • Enhances pulmonary epithelial permeability (220, 221)
Tight junctions (TJ)
Purinergic receptor +

  • Preserving integrity of endothelial cell (EC)-cell junctions (222)
Na+/K+ ATPase +

  • Formation of TJs through RhoA GTPase and stress fibers (223)

  • Gene transfer of β1-Na+, K+-ATPase upregulates TJs formation by enhancing expression of TJ protein zona occludins-1 and occludin and reducing pre-existing increase of lung permeability (224)
+
Nitric oxide (NO) −

  • Decreases expression and mistargeting of TJ proteins in lung (225)
Influenza A virus (IAV) −

  • Disruption epithelial cell TJs (226)
Caveolin-1 +

  • Regulates the expression of TJ proteins during hyperoxia-induced pulmonary epithelial barrier breakdown (227)
IL-4 −

  • Causes TJ disassembly and epithelial barrier permeability alteration via an EGFR-dependent MAPK/ERK1/2-pathway (228)

  • Reduce protein density at the TJ without causing major changes in cldn1, cldn2, cldn3, and occludin protein levels (229)
IL-13 −

  • Reduction of protein density at the TJ without causing major changes in cldn1, cldn2, cldn3, and occludin protein levels (229)
TNF −

  • Causes TJ permeability (230)
Interferon-gamma (IFN-γ) −/+

  • Disorganization of the TJ and an increase in paracellular permeability (231)

  • Promotes epithelial restitution by enhancing barrier function and wound healing (232)

  • It can also reverse IL-4- and IL-13-induced barrier disruption (232)
Trypsin −

  • Destroys the TJs which lead to airway leakage
Cigaret smoke −

  • Causes disassembly of TJs, modulated through the EGFR–ERK1/2 signaling pathway (233)
Cadmium −

  • Causes disruption of TJ integrity in human ALI airway cultures both through occludin hyperphosphorylation via kinase activation and by direct disruption of the junction-interacting complex (234)
Capillary endothelium
TGFβ 1 −

  • Induces endothelial barrier dysfunction via Smad2-dependent p38 activation (235)
TNF −

  • Disruption of the lung vascular barrier (236, 237)

  • Augmenting endothelial permeability (67, 238)

  • Apoptosis of lung microvascular ECs (39, 239, 240)
Lectin-like domain of TNF +

  • Strengthens barrier function or increasing endothelial barrier tightness (9)

  • Protective effect in PLY-Induced endothelial barrier dysfunction (9)

  • Can reduce PLY-induced RhoA/Rac-1 balance impairment and MLC phosphorylation (10)

  • Protects from listeriolysin-induced hyperpermeability in human pulmonary microvascular ECs (241)

  • Reducing vascular permeability (196)

  • Increases in membrane conductance in primary lung microvascular ECs (242)
IFN-γ −

  • Increases vascular permeability (243)
Interleukin-1β (IL-1β) −

  • Given intratracheally, IL-1β increased endothelial permeability and lung leak (244–247)

  • Increases vascular permeability (243)
Interleukin-2 (IL-2) −

  • Increases vascular permeability (248)
Interleukin-6 (IL-6) −

  • Increases endothelial permeability (249)
Interleukin-8 (IL-8) −

  • Increases endothelial permeability (250)
Interleukin -12 (IL-12) −

  • Upregulate the release of the vascular permeability factor which is a lymphokine derived from LN peripheral blood mononuclear cells (251)
Neutrophils −

  • Inducing endothelial barrier disruption through secretion of leukotrienes or heparin-binding protein, direct signaling into the EC via adhesion-dependent mechanisms and production of ROS (252)
ENaC +

  • ENaC-α can strengthen capillary barrier function (9)
TRPV4 −

  • Increases in vascular permeability thus promoting protein and fluid leak (253)

  • Applying TRPV4 inhibitors exhibits vasculoprotective effects, inhibiting vascular leakage, and improving blood oxygenation (254)
Thrombin −

  • Increase in endothelial permeability (255)
Platelet-activating factor −

  • Increase in endothelial permeability (256)
Hydrogen peroxide −

  • Increase vascular permeability through enhancing vascular endothelial growth factor expression (257)
Integrin αvβ5 −

  • Increases pulmonary vascular permeability (258)
T-cadherin −

  • Causes enhancement of endothelial permeability (259)
Myosin light chain kinase −

  • Vascular hyperpermeability (260)
Lipopolysaccharide (LPS) −

  • Induces lung endothelial barrier dysfunction (261)
PLY −

  • Impairs endothelial barrier (10, 262)
P2Y receptors +

  • Regulators of lung endothelial barrier integrity (263)
CO −

  • Enhances pulmonary epithelial permeability (221)
Soluble receptor for advanced glycation end products −

  • Increase in alveolar–capillary barrier permeability (264)
EC adhesion
Podocalyxin +

  • Decreases vascular permeability of ECs by altering EC adhesion (265)
NLRP3 +

  • Protects alveolar barrier integrity by an inflammasome-independent increase of epithelial cell adherence (266)