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1
Brune, Kieran, James Frank, Andreas Schwingshackl, James Finigan, and Venkataramana K. Sidhaye. "Pulmonary epithelial barrier function: some new players and mechanisms." American Journal of Physiology-Lung Cellular and Molecular Physiology 308, no. 8 (April 15, 2015): L731—L745. http://dx.doi.org/10.1152/ajplung.00309.2014.
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The pulmonary epithelium serves as a barrier to prevent access of the inspired luminal contents to the subepithelium. In addition, the epithelium dictates the initial responses of the lung to both infectious and noninfectious stimuli. One mechanism by which the epithelium does this is by coordinating transport of diffusible molecules across the epithelial barrier, both through the cell and between cells. In this review, we will discuss a few emerging paradigms of permeability changes through altered ion transport and paracellular regulation by which the epithelium gates its response to potentially detrimental luminal stimuli. This review is a summary of talks presented during a symposium in Experimental Biology geared toward novel and less recognized methods of epithelial barrier regulation. First, we will discuss mechanisms of dynamic regulation of cell-cell contacts in the context of repetitive exposure to inhaled infectious and noninfectious insults. In the second section, we will briefly discuss mechanisms of transcellular ion homeostasis specifically focused on the role of claudins and paracellular ion-channel regulation in chronic barrier dysfunction. In the next section, we will address transcellular ion transport and highlight the role of Trek-1 in epithelial responses to lung injury. In the final section, we will outline the role of epithelial growth receptor in barrier regulation in baseline, acute lung injury, and airway disease. We will then end with a summary of mechanisms of epithelial control as well as discuss emerging paradigms of the epithelium role in shifting between a structural element that maintains tight cell-cell adhesion to a cell that initiates and participates in immune responses.
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Aghapour, Mahyar, Alexander H. V. Remels, Simon D. Pouwels, Dunja Bruder, Pieter S. Hiemstra, Suzanne M. Cloonan, and Irene H. Heijink. "Mitochondria: at the crossroads of regulating lung epithelial cell function in chronic obstructive pulmonary disease." American Journal of Physiology-Lung Cellular and Molecular Physiology 318, no. 1 (January 1, 2020): L149—L164. http://dx.doi.org/10.1152/ajplung.00329.2019.
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Disturbances in mitochondrial structure and function in lung epithelial cells have been implicated in the pathogenesis of various lung diseases, including chronic obstructive pulmonary disease (COPD). Such disturbances affect not only cellular energy metabolism but also alter a range of indispensable cellular homeostatic functions in which mitochondria are known to be involved. These range from cellular differentiation, cell death pathways, and cellular remodeling to physical barrier function and innate immunity, all of which are known to be impacted by exposure to cigarette smoke and have been linked to COPD pathogenesis. Next to their well-established role as the first physical frontline against external insults, lung epithelial cells are immunologically active. Malfunctioning epithelial cells with defective mitochondria are unable to maintain homeostasis and respond adequately to further stress or injury, which may ultimately shape the phenotype of lung diseases. In this review, we provide a comprehensive overview of the impact of cigarette smoke on the development of mitochondrial dysfunction in the lung epithelium and highlight the consequences for cell function, innate immune responses, epithelial remodeling, and epithelial barrier function in COPD. We also discuss the applicability and potential therapeutic value of recently proposed strategies for the restoration of mitochondrial function in the treatment of COPD.
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Hollenhorst, Monika I., Katrin Richter, and Martin Fronius. "Ion Transport by Pulmonary Epithelia." Journal of Biomedicine and Biotechnology 2011 (2011): 1–16. http://dx.doi.org/10.1155/2011/174306.
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The lung surface of air-breathing vertebrates is formed by a continuous epithelium that is covered by a fluid layer. In the airways, this epithelium is largely pseudostratified consisting of diverse cell types such as ciliated cells, goblet cells, and undifferentiated basal cells, whereas the alveolar epithelium consists of alveolar type I and alveolar type II cells. Regulation and maintenance of the volume and viscosity of the fluid layer covering the epithelium is one of the most important functions of the epithelial barrier that forms the outer surface area of the lungs. Therefore, the epithelial cells are equipped with a wide variety of ion transport proteins, among which Na+, Cl−, and K+channels have been identified to play a role in the regulation of the fluid layer. Malfunctions of pulmonary epithelial ion transport processes and, thus, impairment of the liquid balance in our lungs is associated with severe diseases, such as cystic fibrosis and pulmonary oedema. Due to the important role of pulmonary epithelial ion transport processes for proper lung function, the present paper summarizes the recent findings about composition, function, and ion transport properties of the airway epithelium as well as of the alveolar epithelium.
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Herrero, Raquel, Mishie Tanino, Lincoln S. Smith, Osamu Kajikawa, Venus A. Wong, Steve Mongovin, Gustavo Matute-Bello, and Thomas R. Martin. "The Fas/FasL pathway impairs the alveolar fluid clearance in mouse lungs." American Journal of Physiology-Lung Cellular and Molecular Physiology 305, no. 5 (September 1, 2013): L377—L388. http://dx.doi.org/10.1152/ajplung.00271.2012.
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Alveolar epithelial damage is a critical event that leads to protein-rich edema in acute lung injury (ALI), but the mechanisms leading to epithelial damage are not completely understood. Cell death by necrosis and apoptosis occurs in alveolar epithelial cells in the lungs of patients with ALI. Fas activation induces apoptosis of alveolar epithelial cells, but its role in the formation of lung edema is unclear. The main goal of this study was to determine whether activation of the Fas/Fas ligand pathway in the lungs could alter the function of the lung epithelium, and the mechanisms involved. The results show that Fas activation alters the alveolar barrier integrity and impairs the ability of the lung alveolar epithelium to reabsorb fluid from the air spaces. This result was dependent on the presence of a normal Fas receptor and was not affected by inflammation induced by Fas activation. Alteration of the fluid transport properties of the alveolar epithelium was partially restored by β-adrenergic stimulation. Fas activation also caused apoptosis of alveolar endothelial cells, but this effect was less pronounced than the effect on the alveolar epithelium. Thus, activation of the Fas pathway impairs alveolar epithelial function in mouse lungs by mechanisms involving caspase-dependent apoptosis, suggesting that targeting apoptotic pathways could reduce the formation of lung edema in ALI.
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Kim, Kwang-Jin, and Asrar B. Malik. "Protein transport across the lung epithelial barrier." American Journal of Physiology-Lung Cellular and Molecular Physiology 284, no. 2 (February 1, 2003): L247—L259. http://dx.doi.org/10.1152/ajplung.00235.2002.
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Alveolar lining fluid normally contains proteins of important physiological, antioxidant, and mucosal defense functions [such as albumin, immunoglobulin G (IgG), secretory IgA, transferrin, and ceruloplasmin]. Because concentrations of plasma proteins in alveolar fluid can increase in injured lungs (such as with permeability edema and inflammation), understanding how alveolar epithelium handles protein transport is needed to develop therapeutic measures to restore alveolar homeostasis. This review provides an update on recent findings on protein transport across the alveolar epithelial barrier. The use of primary cultured rat alveolar epithelial cell monolayers (that exhibit phenotypic and morphological traits of in vivo alveolar epithelial type I cells) has shown that albumin and IgG are absorbed via saturable processes at rates greater than those predicted by passive diffusional mechanisms. In contrast, secretory component, the extracellular portion of the polymeric immunoglobulin receptor, is secreted into alveolar fluid. Transcytosis involving caveolae and clathrin-coated pits is likely the main route of alveolar epithelial protein transport, although relative contributions of these internalization steps to overall protein handling of alveolar epithelium remain to be determined. The specific pathways and regulatory mechanisms responsible for translocation of proteins across lung alveolar epithelium and regulation of the cognate receptors (e.g., 60-kDa albumin binding protein and IgG binding FcRn) expressed in alveolar epithelium need to be elucidated.
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Bao, Shenying, and Daren L. Knoell. "Zinc modulates cytokine-induced lung epithelial cell barrier permeability." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 6 (December 2006): L1132—L1141. http://dx.doi.org/10.1152/ajplung.00207.2006.
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Apoptosis plays a causative role in acute lung injury in part due to epithelial cell loss. We recently reported that zinc protects the lung epithelium during inflammatory stress whereas depletion of intracellular zinc enhances extrinsic apoptosis. In this investigation, we evaluated the relationship between zinc, caspase-3, and cell-to-cell contact via proteins that form the adherens junction complex. Cell adhesion proteins are directly responsible for formation of the mechanical barrier of the lung epithelium. We hypothesized that exposure to inflammatory cytokines, in conjunction with zinc deprivation, would induce caspase-3, leading to degradation of junction proteins, loss of cell-to-cell contact, and compromised barrier function. Primary human upper airway and type I/II alveolar epithelial cultures were obtained from multiple donors and exposed to inflammatory stimuli that provoke extrinsic apoptosis in addition to depletion of intracellular zinc. We observed that zinc deprivation combined with tumor necrosis factor-α, interferon-γ, and Fas receptor ligation accelerates caspase-3 activation, proteolysis of E-cadherin and β-catenin, and cellular apoptosis, leading to increased paracellular leak across monolayers of both upper airway and alveolar lung epithelial cultures. Zinc supplementation inhibited apoptosis and paracellular leak, whereas caspase inhibition was less effective. We conclude that zinc is a vital factor in the lung epithelium that protects against death receptor-mediated apoptosis and barrier dysfunction. Furthermore, our findings suggest that although caspase-3 inhibition reduces lung epithelial apoptosis it does not prevent mechanical dysfunction. These findings facilitate future studies aimed at developing therapeutic strategies to prevent acute lung injury.
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Wu, Huijuan, and Nan Tang. "Stem cells in pulmonary alveolar regeneration." Development 148, no. 2 (January 15, 2021): dev193458. http://dx.doi.org/10.1242/dev.193458.
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ABSTRACTThe lungs are constantly exposed to the external environment and are therefore vulnerable to insults that can cause infection and injury. Maintaining the integrity and barrier function of the lung epithelium requires complex interactions of multiple cell lineages. Elucidating the cellular players and their regulation mechanisms provides fundamental information to deepen understanding about the responses and contributions of lung stem cells. This Review focuses on advances in our understanding of mammalian alveolar epithelial stem cell subpopulations and discusses insights about the regeneration-specific cell status of alveolar epithelial stem cells. We also consider how these advances can inform our understanding of post-injury lung repair processes and lung diseases.
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Overgaard, Christian E., Barbara Schlingmann, StevenClaude Dorsainvil White, Christina Ward, Xian Fan, Snehasikta Swarnakar, Lou Ann S. Brown, David M. Guidot, and Michael Koval. "The relative balance of GM-CSF and TGF-β1 regulates lung epithelial barrier function." American Journal of Physiology-Lung Cellular and Molecular Physiology 308, no. 12 (June 15, 2015): L1212—L1223. http://dx.doi.org/10.1152/ajplung.00042.2014.
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Lung barrier dysfunction is a cardinal feature of the acute respiratory distress syndrome (ARDS). Alcohol abuse, which increases the risk of ARDS two- to fourfold, induces transforming growth factor (TGF)-β1, which increases epithelial permeability and impairs granulocyte/macrophage colony-stimulating factor (GM-CSF)-dependent barrier integrity in experimental models. We hypothesized that the relative balance of GM-CSF and TGF-β1 signaling regulates lung epithelial barrier function. GM-CSF and TGF-β1 were tested separately and simultaneously for their effects on lung epithelial cell barrier function in vitro. TGF-β1 alone caused an ∼25% decrease in transepithelial resistance (TER), increased paracellular flux, and was associated with projections perpendicular to tight junctions (“spikes”) containing claudin-18 that colocalized with F-actin. In contrast, GM-CSF treatment induced an ∼20% increase in TER, decreased paracellular flux, and showed decreased colocalization of spike-associated claudin-18 with F-actin. When simultaneously administered to lung epithelial cells, GM-CSF antagonized the effects of TGF-β1 on epithelial barrier function in cultured cells. Given this, GM-CSF and TGF-β1 levels were measured in bronchoalveolar lavage (BAL) fluid from patients with ventilator-associated pneumonia and correlated with markers for pulmonary edema and patient outcome. In patient BAL fluid, protein markers of lung barrier dysfunction, serum α2-macroglobulin, and IgM levels were increased at lower ratios of GM-CSF/TGF-β1. Critically, patients who survived had significantly higher GM-CSF/TGF-β1 ratios than nonsurviving patients. This study provides experimental and clinical evidence that the relative balance between GM-CSF and TGF-β1 signaling is a key regulator of lung epithelial barrier function. The GM-CSF/TGF-β1 ratio in BAL fluid may provide a concentration-independent biomarker that can predict patient outcomes in ARDS.
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Mitchell, Leslie A., Christian E. Overgaard, Christina Ward, Susan S. Margulies, and Michael Koval. "Differential effects of claudin-3 and claudin-4 on alveolar epithelial barrier function." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 1 (July 2011): L40—L49. http://dx.doi.org/10.1152/ajplung.00299.2010.
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Alveolar barrier function depends critically on the claudin family tight junction proteins. Of the major claudins expressed by alveolar epithelial cells, claudin (Cldn)-3 and Cldn-4 are the most closely related by amino acid homology, yet they differ dramatically in the pattern of expression. Previously published reports have shown that Cldn-3 is predominantly expressed by type II alveolar epithelial cells; Cldn-4 is expressed throughout the alveolar epithelium and is specifically upregulated in response to acute lung injury. Using primary rat alveolar epithelial cells transduced with yellow fluorescent protein-tagged claudin constructs, we have identified roles for Cldn-3 and Cldn-4 in alveolar epithelial barrier function. Surprisingly, increasing expression of Cldn-3 decreased alveolar epithelial barrier function, as assessed by transepithelial resistance and dye flux measurements. Conversely, increasing Cldn-4 expression improved alveolar epithelial transepithelial resistance compared with control cells. Other alveolar epithelial tight junction proteins were largely unaffected by increased expression of Cldn-3 and Cldn-4. Taken together, these results demonstrate that, in the context of the alveolar epithelium, Cldn-3 and Cldn-4 have different effects on paracellular permeability, despite significant homology in their extracellular loop domains.
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Ishii, Mitsutoshi, Tomoshi Tsuchiya, Ryoichiro Doi, Yoichi Morofuji, Takashi Fujimoto, Hideki Muto, Takashi Suematsu, et al. "Increased In Vitro Intercellular Barrier Function of Lung Epithelial Cells Using Adipose-Derived Mesenchymal Stem/Stromal Cells." Pharmaceutics 13, no. 8 (August 16, 2021): 1264. http://dx.doi.org/10.3390/pharmaceutics13081264.
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With the emergence of coronavirus disease-2019, researchers have gained interest in the therapeutic efficacy of mesenchymal stem/stromal cells (MSCs) in acute respiratory distress syndrome; however, the mechanisms of the therapeutic effects of MSCs are unclear. We have previously reported that adipose-derived MSCs (AD-MSCs) strengthen the barrier function of the pulmonary vessels in scaffold-based bioengineered rat lungs. In this study, we evaluated whether AD-MSCs could enhance the intercellular barrier function of lung epithelial cells in vitro using a transwell coculture system. Transepithelial electrical resistance (TEER) measurements revealed that the peak TEER value was significantly higher in the AD-MSC coculture group than in the AD-MSC non-coculture group. Similarly, the permeability coefficient was significantly decreased in the AD-MSC coculture group compared to that in the AD-MSC non-coculture group. Immunostaining of insert membranes showed that zonula occuldens-1 expression was significantly high at cell junctions in the AD-MSC coculture group. Moreover, cell junction-related gene profiling showed that the expression of some claudin genes, including claudin-4, was upregulated in the AD-MSC coculture group. Taken together, these results showed that AD-MSCs enhanced the barrier function between lung epithelial cells, suggesting that both direct adhesion and indirect paracrine effects strengthened the barrier function of lung alveolar epithelium in vitro.
11
Pelaez, Andres, Rabih I. Bechara, Pratibha C. Joshi, Lou Ann S. Brown, and David M. Guidot. "Granulocyte/macrophage colony-stimulating factor treatment improves alveolar epithelial barrier function in alcoholic rat lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 286, no. 1 (January 2004): L106—L111. http://dx.doi.org/10.1152/ajplung.00148.2003.
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Chronic alcohol abuse increases the risk of developing acute lung injury approximately threefold in septic patients, and ethanol ingestion for 6 wk in rats impairs alveolar epithelial barrier function both in vitro and in vivo. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a trophic factor for the alveolar epithelium, and a recent phase II clinical study suggests that GM-CSF therapy decreases sepsis-mediated lung injury. Therefore, we hypothesized that GM-CSF treatment could improve ethanol-mediated defects in the alveolar epithelium during acute stresses such as endotoxemia. In this study, we determined that recombinant rat GM-CSF improved lung liquid clearance (as reflected by lung tissue wet:dry ratios) in ethanol-fed rats anesthetized and then challenged with 2 ml of saline via a tracheostomy tube. Furthermore, GM-CSF treatment improved lung liquid clearance and decreased epithelial protein leak in both control-fed and ethanol-fed rats after 6 h of endotoxemia induced by Salmonella typhimurium lipopolysaccharide given intraperitoneally, but with the greater net effect seen in the ethanol-fed rats. Our previous studies indicate that chronic ethanol ingestion decreases lung liquid clearance by increasing intercellular permeability. Consistent with this, GM-CSF treatment in vitro decreased permeability of alveolar epithelial monolayers derived from both control-fed and ethanol-fed rats. As in the endotoxemia model in vivo, the effect of GM-CSF was most dramatic in the ethanol group. Together, these results indicate that GM-CSF treatment has previously unrecognized effects in promoting alveolar epithelial barrier integrity and that these salutary effects may be particularly relevant in the setting of chronic alcohol abuse.
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Boland, Sonja, Oliver Brookes, Dorian Miremont, René Lai Kuen, Alice Eon-Bertho, and Armelle Baeza-Squiban. "100 Co-Culture of Human type I and type II Pneumocyte Cell Lines as a Model of Alveolar Epithelium for Toxicity Testing." Annals of Work Exposures and Health 67, Supplement_1 (May 1, 2023): i85. http://dx.doi.org/10.1093/annweh/wxac087.206.
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Abstract The epithelial tissues of the distal lung are continuously exposed to inhaled air, and are thus of research interest in studying respiratory exposure to therapeutic and hazardous materials such as plastic particles which represent a new threat for human health. There is a need therefore to develop sophisticated models of the human alveolar epithelium, which better represent the different cell types present in the native lung. Our aim was to develop an air-liquid interface model of the alveolar epithelium by incorporating human cell-lines which bear features of type I (hAELVi) and type II (NCI-H441) epithelial cells. Working both in monotypic cultures and cocultures, we compared the morphology of single cells and the structure of cell layers of the two cell-lines using light and electron microscopy. We measured barrier function by trans-epithelial electrical resistance (TEER). We assessed expression of a panel of relevant genes that play important roles in barrier function and differentiation. We demonstrated that barrier properties can be maintained for 30 days. The coculture model was observed to form a stable barrier akin to that seen in hAELVi, while expressing surfactant protein C, and having a profile of expression of claudins and aquaporins appropriate for the distal lung (Brookes (2021) PLoSONE 16(9):e0248798). In summary, our results support the coculture of these two cell-lines to produce a model which better represents the breadth of functions seen in native alveolar epithelium. Funding: From the European Union’s Horizon 2020 research and innovation programme under grant agreement No965367 (PlasticsFate)
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Frank, James A. "Claudins and alveolar epithelial barrier function in the lung." Annals of the New York Academy of Sciences 1257, no. 1 (June 2012): 175–83. http://dx.doi.org/10.1111/j.1749-6632.2012.06533.x.
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Langer, Marybeth, Elizabeth Stewart Duggan, John Leland Booth, Vineet Indrajit Patel, Ryan A. Zander, Robert Silasi-Mansat, Vijay Ramani, et al. "Bacillus anthracis Lethal Toxin Reduces Human Alveolar Epithelial Barrier Function." Infection and Immunity 80, no. 12 (October 1, 2012): 4374–87. http://dx.doi.org/10.1128/iai.01011-12.
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ABSTRACTThe lung is the site of entry forBacillus anthracisin inhalation anthrax, the deadliest form of the disease.Bacillus anthracisproduces virulence toxins required for disease. Alveolar macrophages were considered the primary target of theBacillus anthracisvirulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target ofBacillus anthracislethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination ofBacillus anthracisfrom the lung in early disease and promoting edema in late stages of the illness.
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Van Driessche, Willy, James L. Kreindler, Asrar B. Malik, Susan Margulies, Simon A. Lewis, and Kwang-Jin Kim. "Interrelations/cross talk between transcellular transport function and paracellular tight junctional properties in lung epithelial and endothelial barriers." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 3 (September 2007): L520—L524. http://dx.doi.org/10.1152/ajplung.00218.2007.
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In this synopsis of a symposium at EB2007, we start with an overview of noise and impedance analyses that have been applied to various epithelial barriers. Noise analysis yields specific information about ion channels and their regulation in epithelial and endothelial barriers. Impedance analysis can yield information about apical and basolateral membrane conductances and paracellular conductance of both epithelial and endothelial barriers. Using a morphologically based model, impedance analysis has been used to assess changes in apical and basolateral membrane surface areas and dimensions of the lateral intercellular space. Impedance analysis of an in vitro airway epithelial barrier under normal, nucleotide-stimulated, and cigarette smoke-exposed conditions yielded information on how activation and inhibition of secretion occur in airway epithelial cells. Similarly, impedance analysis of primary rat alveolar epithelial cell monolayer model under control and EGTA exposure conditions indicate that EGTA causes decreases in resistances of tight junctional routes as well as apical and basolateral cell membranes without causing much change in cell capacitances. In a stretch-caused injury model of alveolar epithelium, transcellular ion transport function and paracellular permeability of solute transport appear to be differentially regulated. Finally, inhibition of caveolae-mediated transcytosis in lung endothelium led to disruption of paracellular routes, increasing the physical dimension and permeability of tight junctional region. These data together demonstrate the cross talk between transcellular and paracellular transport (function and routes) of lung epithelial and endothelial barriers. Mechanistic (e.g., signaling cascades) information on such cross talk remain to be determined.
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Fan, Xian, Bashar S. Staitieh, J. Spencer Jensen, Kara J. Mould, Jared A. Greenberg, Pratibha C. Joshi, Michael Koval, and David M. Guidot. "Activating the Nrf2-mediated antioxidant response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats." American Journal of Physiology-Lung Cellular and Molecular Physiology 305, no. 3 (August 1, 2013): L267—L277. http://dx.doi.org/10.1152/ajplung.00288.2012.
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The master transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression of antioxidant and phase II-metabolizing enzymes by activating the antioxidant response element (ARE) and thereby protects cells and tissues from oxidative stress. Pulmonary complications remain the leading cause of death in human immunodeficiency virus (HIV)-1-infected individuals, who display systemic oxidative stress and glutathione deficiency that can be modeled in transgenic rats where HIV-1-related viral proteins decrease glutathione levels and cause epithelial barrier dysfunction within the alveolar space by as yet unknown mechanisms. We hypothesized that HIV-1-related proteins inhibit Nrf2-mediated antioxidant defenses and thereby disrupt the normally tight alveolar epithelial barrier. Nrf2 RNA silencing dampened Nrf2/ARE activity, decreased the expression of the tight junction proteins zonula occludens-1, occludin, and claudin-18, increased paracellular permeability of alveolar epithelial monolayers derived from wild-type rats, and therefore reproduced the effects of HIV-1 transgene expression on the epithelial barrier that we had previously described. In contrast, upregulating Nrf2 activity, either by plasmid-mediated overexpression or treatment with the Nrf2 activator sulforaphane, increased the expression of ARE-dependent antioxidants, including NAD(P)H dehydrogenase, quinone 1 and glutathione, improved the expression of tight junction proteins, and restored the ability to form tight barriers in alveolar epithelial cells from HIV-1 transgenic rats. Taken together, these new findings argue that HIV-1-related proteins downregulate Nrf2 expression and/or activity within the alveolar epithelium, which in turn impairs antioxidant defenses and barrier function, thereby rendering the lung susceptible to oxidative stress and injury. Furthermore, this study suggests that activating the Nrf2/ARE pathway with the dietary supplement sulforaphane could augment antioxidant defenses and lung health in HIV-1-infected individuals.
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Hung, Li-Yin, Debasish Sen, Taylor K. Oniskey, Wildaliz Nieves, Anatoly Urisman, Matthew F. Krummel, and DeBroski R. Herbert. "Macrophage-Dependent Regeneration of Pulmonary Epithelia Requires Trefoil Factor 2 for Wnt Expression." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 68.10. http://dx.doi.org/10.4049/jimmunol.196.supp.68.10.
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Abstract Coordination between epithelial and myeloid cell lineages may facilitate tissue repair, but mechanistic evidence is lacking. Independently of Type 2 cytokines (interleukin-4/13), and T, B or ILC populations, lung macrophages promoted epithelial proliferation following injury caused by Nippostrongylus brasiliensis or bleomycin sulfate. Multiple myeloid populations up-regulated Trefoil factor 2 (TFF2) following lung injury and CD11c-driven Tff2 deletion impaired the proliferative expansion of pro-SpC+ distal lung epithelial progenitors. Direct interactions between macrophages and damaged epithelia resulted Wnt production, which accelerated epithelial proliferation, trans-epithelial resistance, and barrier function in a TFF2-dependent manner. In summary, the current study demonstrates that TFF2 is a regenerative cytokine expressed by macrophages to facilitate repair of infectious or non-infectious lung damage.
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Brookes, Oliver, Sonja Boland, René Lai Kuen, Dorian Miremont, Jamileh Movassat, and Armelle Baeza-Squiban. "Co-culture of type I and type II pneumocytes as a model of alveolar epithelium." PLOS ONE 16, no. 9 (September 27, 2021): e0248798. http://dx.doi.org/10.1371/journal.pone.0248798.
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The epithelial tissues of the distal lung are continuously exposed to inhaled air, and are of research interest in studying respiratory exposure to both hazardous and therapeutic materials. Pharmaco-toxicological research depends on the development of sophisticated models of the alveolar epithelium, which better represent the different cell types present in the native lung and interactions between them. We developed an air-liquid interface (ALI) model of the alveolar epithelium which incorporates cell lines which bear features of type I (hAELVi) and type II (NCI-H441) epithelial cells. We compared morphology of single cells and the structure of cell layers of the two lines using light and electron microscopy. Working both in monotypic cultures and cocultures, we measured barrier function by trans-epithelial electrical resistance (TEER), and demonstrated that barrier properties can be maintained for 30 days. We created a mathematical model of TEER development over time based on these data in order to make inferences about the interactions occurring in these culture systems. We assessed expression of a panel of relevant genes that play important roles in barrier function and differentiation. The coculture model was observed to form a stable barrier akin to that seen in hAELVi, while expressing surfactant protein C, and having a profile of expression of claudins and aquaporins appropriate for the distal lung. We described cavities which arise within stratified cell layers in NCI-H441 and cocultured cells, and present evidence that these cavities represent an aberrant apical surface. In summary, our results support the coculture of these two cell lines to produce a model which better represents the breadth of functions seen in native alveolar epithelium.
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Henry, Olivier Y. F., Remi Villenave, Michael J. Cronce, William D. Leineweber, Maximilian A. Benz, and Donald E. Ingber. "Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance (TEER) measurements of human epithelial barrier function." Lab on a Chip 17, no. 13 (2017): 2264–71. http://dx.doi.org/10.1039/c7lc00155j.
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Boitano, Scott, Zeenat Safdar, Donald G. Welsh, Jahar Bhattacharya, and Michael Koval. "Cell-cell interactions in regulating lung function." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 3 (September 2004): L455—L459. http://dx.doi.org/10.1152/ajplung.00172.2004.
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Tight junction barrier formation and gap junctional communication are two functions directly attributable to cell-cell contact sites. Epithelial and endothelial tight junctions are critical elements of the permeability barrier required to maintain discrete compartments in the lung. On the other hand, gap junctions enable a tissue to act as a cohesive unit by permitting metabolic coupling and enabling the direct transmission of small cytosolic signaling molecules from one cell to another. These components do not act in isolation since other junctional elements, such as adherens junctions, help regulate barrier function and gap junctional communication. Some fundamental elements related to regulation of pulmonary barrier function and gap junctional communication were presented in a Featured Topic session at the 2004 Experimental Biology Conference in Washington, DC, and are reviewed in this summary.
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Kage, Hidenori, Per Flodby, Danping Gao, Yong Ho Kim, Crystal N. Marconett, Lucas DeMaio, Kwang-Jin Kim, Edward D. Crandall, and Zea Borok. "Claudin 4 knockout mice: normal physiological phenotype with increased susceptibility to lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 307, no. 7 (October 1, 2014): L524—L536. http://dx.doi.org/10.1152/ajplung.00077.2014.
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Claudins are tight junction proteins that regulate paracellular ion permeability of epithelium and endothelium. Claudin 4 has been reported to function as a paracellular sodium barrier and is one of three major claudins expressed in lung alveolar epithelial cells (AEC). To directly assess the role of claudin 4 in regulation of alveolar epithelial barrier function and fluid homeostasis in vivo, we generated claudin 4 knockout (Cldn4 KO) mice. Unexpectedly, Cldn4 KO mice exhibited normal physiological phenotype although increased permeability to 5-carboxyfluorescein and decreased alveolar fluid clearance were noted. Cldn4 KO AEC monolayers exhibited unchanged ion permeability, higher solute permeability, and lower short-circuit current compared with monolayers from wild-type mice. Claudin 3 and 18 expression was similar between wild-type and Cldn4 KO alveolar epithelial type II cells. In response to either ventilator-induced lung injury or hyperoxia, claudin 4 expression was markedly upregulated in wild-type mice, whereas Cldn4 KO mice showed greater degrees of lung injury. RNA sequencing, in conjunction with differential expression and upstream analysis after ventilator-induced lung injury, suggested Egr1, Tnf, and Il1b as potential mediators of increased lung injury in Cldn4 KO mice. These results demonstrate that claudin 4 has little effect on normal lung physiology but may function to protect against acute lung injury.
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Schweitzer, Kelly S., Hadi Hatoum, Mary Beth Brown, Mehak Gupta, Matthew J. Justice, Besem Beteck, Mary Van Demark, et al. "Mechanisms of lung endothelial barrier disruption induced by cigarette smoke: role of oxidative stress and ceramides." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 6 (December 2011): L836—L846. http://dx.doi.org/10.1152/ajplung.00385.2010.
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The epithelial and endothelial cells lining the alveolus form a barrier essential for the preservation of the lung respiratory function, which is, however, vulnerable to excessive oxidative, inflammatory, and apoptotic insults. Whereas profound breaches in this barrier function cause pulmonary edema, more subtle changes may contribute to inflammation. The mechanisms by which cigarette smoke (CS) exposure induce lung inflammation are not fully understood, but an early alteration in the epithelial barrier function has been documented. We sought to investigate the occurrence and mechanisms by which soluble components of mainstream CS disrupt the lung endothelial cell barrier function. Using cultured primary rat microvascular cell monolayers, we report that CS induces endothelial cell barrier disruption in a dose- and time-dependent manner of similar magnitude to that of the epithelial cell barrier. CS exposure triggered a mechanism of neutral sphingomyelinase-mediated ceramide upregulation and p38 MAPK and JNK activation that were oxidative stress dependent and that, along with Rho kinase activation, mediated the endothelial barrier dysfunction. The morphological changes in endothelial cell monolayers induced by CS included actin cytoskeletal rearrangement, junctional protein zonula occludens-1 loss, and intercellular gap formation, which were abolished by the glutathione modulator N-acetylcysteine and ameliorated by neutral sphingomyelinase inhibition. The direct application of ceramide recapitulated the effects of CS, by disrupting both endothelial and epithelial cells barrier, by a mechanism that was redox and apoptosis independent and required Rho kinase activation. Furthermore, ceramide induced dose-dependent alterations of alveolar microcirculatory barrier in vivo, measured by two-photon excitation microscopy in the intact rat. In conclusion, soluble components of CS have direct endothelial barrier-disruptive effects that could be ameliorated by glutathione modulators or by inhibitors of neutral sphingomyelinase, p38 MAPK, JNK, and Rho kinase. Amelioration of endothelial permeability may alleviate lung and systemic vascular dysfunction associated with smoking-related chronic obstructive lung diseases.
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Yamaguchi, Eiichiro, Joshua Yao, Allison Aymond, Douglas B. Chrisey, Gary F. Nieman, Jason H. T. Bates, and Donald P. Gaver. "Electric Cell-Substrate Impedance Sensing (ECIS) as a Platform for Evaluating Barrier-Function Susceptibility and Damage from Pulmonary Atelectrauma." Biosensors 12, no. 6 (June 5, 2022): 390. http://dx.doi.org/10.3390/bios12060390.
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Biophysical insults that either reduce barrier function (COVID-19, smoke inhalation, aspiration, and inflammation) or increase mechanical stress (surfactant dysfunction) make the lung more susceptible to atelectrauma. We investigate the susceptibility and time-dependent disruption of barrier function associated with pulmonary atelectrauma of epithelial cells that occurs in acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). This in vitro study was performed using Electric Cell-substrate Impedance Sensing (ECIS) as a noninvasive evaluating technique for repetitive stress stimulus/response on monolayers of the human lung epithelial cell line NCI-H441. Atelectrauma was mimicked through recruitment/derecruitment (RD) of a semi-infinite air bubble to the fluid-occluded micro-channel. We show that a confluent monolayer with a high level of barrier function is nearly impervious to atelectrauma for hundreds of RD events. Nevertheless, barrier function is eventually diminished, and after a critical number of RD insults, the monolayer disintegrates exponentially. Confluent layers with lower initial barrier function are less resilient. These results indicate that the first line of defense from atelectrauma resides with intercellular binding. After disruption, the epithelial layer community protection is diminished and atelectrauma ensues. ECIS may provide a platform for identifying damaging stimuli, ventilation scenarios, or pharmaceuticals that can reduce susceptibility or enhance barrier-function recovery.
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Olsen, Colin E., Andrew E. Liguori, Yue Zong, R. Clark Lantz, Jefferey L. Burgess, and Scott Boitano. "Arsenic upregulates MMP-9 and inhibits wound repair in human airway epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 295, no. 2 (August 2008): L293—L302. http://dx.doi.org/10.1152/ajplung.00134.2007.
Full textAbstract:
As part of the innate immune defense, the polarized conducting lung epithelium acts as a barrier to keep particulates carried in respiration from underlying tissue. Arsenic is a metalloid toxicant that can affect the lung via inhalation or ingestion. We have recently shown that chronic exposure of mice or humans to arsenic (10–50 ppb) in drinking water alters bronchiolar lavage or sputum proteins consistent with reduced epithelial cell migration and wound repair in the airway. In this report, we used an in vitro model to examine effects of acute exposure of arsenic (15–290 ppb) on conducting airway lung epithelium. We found that arsenic at concentrations as low as 30 ppb inhibits reformation of the epithelial monolayer following scrape wounds of monolayer cultures. In an effort to understand functional contributions to epithelial wound repair altered by arsenic, we showed that acute arsenic exposure increases activity and expression of matrix metalloproteinase (MMP)-9, an important protease in lung function. Furthermore, inhibition of MMP-9 in arsenic-treated cells improved wound repair. We propose that arsenic in the airway can alter the airway epithelial barrier by restricting proper wound repair in part through the upregulation of MMP-9 by lung epithelial cells.
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Bechara, Rabih I., Andres Pelaez, Andres Palacio, Pratibha C. Joshi, C. Michael Hart, Lou Ann S. Brown, Robert Raynor, and David M. Guidot. "Angiotensin II mediates glutathione depletion, transforming growth factor-β1 expression, and epithelial barrier dysfunction in the alcoholic rat lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 289, no. 3 (September 2005): L363—L370. http://dx.doi.org/10.1152/ajplung.00141.2005.
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Alcohol abuse markedly increases the risk of sepsis-mediated acute lung injury. In a rat model, ethanol ingestion alone (in the absence of any other stress) causes pulmonary glutathione depletion, increased expression of transforming growth factor-β1 (TGF-β1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-β1 into the alveolar space where it can exacerbate epithelial barrier dysfunction and lung edema. Ethanol ingestion activates the renin-angiotensin system, and angiotensin II is capable of inducing oxidative stress and TGF-β1 expression. We determined that lisinopril, an angiotensin-converting enzyme inhibitor that decreases angiotensin II formation, limited lung glutathione depletion, and treatment with either lisinopril or losartan, a selective angiotensin II type 1 receptor blocker, normalized TGF-β1 expression. The glutathione precursor procysteine also prevented TGF-β1 expression, suggesting that TGF-β1 may be induced indirectly by angiotensin II-mediated oxidative stress and glutathione depletion. Importantly, lisinopril treatment normalized barrier function in alveolar epithelial cell monolayers from ethanol-fed rats, and treatment with either lisinopril or losartan normalized alveolar epithelial barrier function in ethanol-fed rats in vivo, as reflected by lung liquid clearance of an intratracheal saline challenge, even during endotoxemia. In parallel, lisinopril treatment limited TGF-β1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-β1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.
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Lorenowicz, Magdalena J., Mar Fernandez-Borja, Anne-Marieke D. van Stalborch, Marian A. J. A. van Sterkenburg, Pieter S. Hiemstra, and Peter L. Hordijk. "Microtubule dynamics and Rac-1 signaling independently regulate barrier function in lung epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 5 (November 2007): L1321—L1331. http://dx.doi.org/10.1152/ajplung.00443.2006.
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Cadherin-mediated cell-cell adhesion controls the morphology and function of epithelial cells and is a critical component of the pathology of chronic inflammatory disorders. Dynamic interactions between cadherins and the actin cytoskeleton are required for stable cell-cell contact. Besides actin, microtubules also target intercellular, cadherin-based junctions and contribute to their formation and stability. Here, we studied the role of microtubules in conjunction with Rho-like GTPases in the regulation of lung epithelial barrier function using real-time monitoring of transepithelial electrical resistance. Unexpectedly, we found that disruption of microtubules promotes epithelial cell-cell adhesion. This increase in epithelial barrier function is accompanied by the accumulation of β-catenin at cell-cell junctions, as detected by immunofluorescence. Moreover, we found that the increase in cell-cell contact, induced by microtubule depolymerization, requires signaling through a RhoA/Rho kinase pathway. The Rac-1 GTPase counteracts this pathway, because inhibition of Rac-1 signaling rapidly promotes epithelial barrier function, in a microtubule- and RhoA-independent fashion. Together, our data suggest that microtubule-RhoA-mediated signaling and Rac-1 control lung epithelial integrity through counteracting independent pathways.
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Wray, Charlie, Ying Mao, Jue Pan, Anita Chandrasena, Frank Piasta, and James A. Frank. "Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 297, no. 2 (August 2009): L219—L227. http://dx.doi.org/10.1152/ajplung.00043.2009.
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Intact alveolar barrier function is associated with better outcomes in acute lung injury patients; however, the regulation of alveolar epithelial paracellular transport during lung injury has not been extensively investigated. This study was undertaken to determine whether changes in tight junction claudin expression affect alveolar epithelial barrier properties and to determine the mechanisms of altered expression. In anesthetized mice exposed to ventilator-induced lung injury, claudin-4 was specifically induced among tight junction structural proteins. Real-time PCR showed an eightfold increase in claudin-4 expression in the lung injury model. To examine the role of this protein in barrier regulation, claudin-4 function was inhibited with small interfering RNA (siRNA) and a blocking peptide derived from the binding domain of Clostridium perfringens enterotoxin (CPEBD). Inhibition of claudin-4 decreased transepithelial electrical resistance but did not alter macromolecule permeability in primary rat and human epithelial cells. In mice, CPEBD decreased air space fluid clearance >33% and resulted in pulmonary edema during moderate tidal volume ventilation that did not induce edema in control peptide-treated mice. In vitro phorbol ester induced a ninefold increase in claudin-4 expression that was dependent on PKC activation and the JNK MAPK pathway. These data establish that changes in alveolar epithelial claudin expression influence paracellular transport, alveolar fluid clearance rates, and susceptibility to pulmonary edema. We hypothesize that increased claudin-4 expression early in acute lung injury represents a mechanism to limit pulmonary edema and that the regulation of alveolar epithelial claudin expression may be a novel target for acute lung injury therapy.
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Horndahl, Jenny, Rebecka Svärd, Pia Berntsson, Cecilia Wingren, Jingjing Li, Suado M. Abdillahi, Baishakhi Ghosh, et al. "HDAC6 inhibitor ACY-1083 shows lung epithelial protective features in COPD." PLOS ONE 17, no. 10 (October 12, 2022): e0266310. http://dx.doi.org/10.1371/journal.pone.0266310.
Full textAbstract:
Airway epithelial damage is a common feature in respiratory diseases such as COPD and has been suggested to drive inflammation and progression of disease. These features manifest as remodeling and destruction of lung epithelial characteristics including loss of small airways which contributes to chronic airway inflammation. Histone deacetylase 6 (HDAC6) has been shown to play a role in epithelial function and dysregulation, such as in cilia disassembly, epithelial to mesenchymal transition (EMT) and oxidative stress responses, and has been implicated in several diseases. We thus used ACY-1083, an inhibitor with high selectivity for HDAC6, and characterized its effects on epithelial function including epithelial disruption, cytokine production, remodeling, mucociliary clearance and cell characteristics. Primary lung epithelial air-liquid interface cultures from COPD patients were used and the impacts of TNF, TGF-β, cigarette smoke and bacterial challenges on epithelial function in the presence and absence of ACY-1083 were tested. Each challenge increased the permeability of the epithelial barrier whilst ACY-1083 blocked this effect and even decreased permeability in the absence of challenge. TNF was also shown to increase production of cytokines and mucins, with ACY-1083 reducing the effect. We observed that COPD-relevant stimulations created damage to the epithelium as seen on immunohistochemistry sections and that treatment with ACY-1083 maintained an intact cell layer and preserved mucociliary function. Interestingly, there was no direct effect on ciliary beat frequency or tight junction proteins indicating other mechanisms for the protected epithelium. In summary, ACY-1083 shows protection of the respiratory epithelium during COPD-relevant challenges which indicates a future potential to restore epithelial structure and function to halt disease progression in clinical practice.
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Ghofrani, Hossein Ardeschir, Markus Gerhard Kohstall, Norbert Weissmann, Thomas Schmehl, Ralph Theo Schermuly, Werner Seeger, and Friedrich Grimminger. "Alveolar epithelial barrier functions in ventilated perfused rabbit lungs." American Journal of Physiology-Lung Cellular and Molecular Physiology 280, no. 5 (May 1, 2001): L896—L904. http://dx.doi.org/10.1152/ajplung.2001.280.5.l896.
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We employed ultrasonic nebulization for homogeneous alveolar tracer deposition into ventilated perfused rabbit lungs.22Na and 125I-albumin transit kinetics were monitored on-line with gamma detectors placed around the lung and the perfusate reservoir. [3H]mannitol was measured by repetitive counting of perfusion fluid samples. Volume of the alveolar epithelial lining fluid was estimated with bronchoalveolar lavage with sodium-free isosmolar mannitol solutions. Sodium clearance rate was −2.2 ± 0.3%/min. This rate was significantly reduced by preadministration of ouabain/amiloride and enhanced by pretreatment with aerosolized terbutaline. The 125I-albumin clearance rate was −0.40 ± 0.05%/min. The appearance of [3H]mannitol in the perfusate was not influenced by ouabain/amiloride or terbutaline but was markedly enhanced by pretreatment with aerosolized protamine. An epithelial lining fluid volume of 1.22 ± 0.21 ml was calculated in control lungs. Fluid absorption rate was 1.23 μl · g lung weight−1 · min−1, which was blunted after pretreatment with ouabain/amiloride. We conclude that alveolar tracer loading by aerosolization is a feasible technique to assess alveolar epithelial barrier properties in aerated lungs. Data on active and passive sodium flux, paracellular solute transit, and net fluid absorption correspond well to those in previous studies in fluid-filled lungs; however, albumin clearance rates were markedly higher in the currently investigated aerated lungs.
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Oldenburger, Anouk, Wilfred J. Poppinga, Fleur Kos, Harold G. de Bruin, Wolter F. Rijks, Irene H. Heijink, Wim Timens, Herman Meurs, Harm Maarsingh, and Martina Schmidt. "A-kinase anchoring proteins contribute to loss of E-cadherin and bronchial epithelial barrier by cigarette smoke." American Journal of Physiology-Cell Physiology 306, no. 6 (March 15, 2014): C585—C597. http://dx.doi.org/10.1152/ajpcell.00183.2013.
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Airway epithelium, which forms the first barrier towards environmental insults, is disturbed by cigarette smoking, a major risk factor for developing chronic obstructive pulmonary disease (COPD). A-kinase anchoring proteins (AKAP) maintain endothelial barrier function and coordinate subcellular localization of protein kinase A (PKA). However, the role of AKAPs in epithelial barrier function is unknown. We studied the role of AKAPs in regulating human bronchial epithelial (Hogg JC, Timens W. Annu Rev Pathol 4: 435–459, 2009; HBE) barrier. Cigarette smoke extract (CSE) reduced barrier function in 16HBE cells and the expression of the adhesion molecule E-cadherin specifically at the cell membrane. In addition, CSE reduced the protein expression of the AKAP family member AKAP9 at the cell membrane. The expression of AKAP5 and AKAP12 was unaffected by CSE. AKAP9 interacted and colocalized with E-cadherin at the cell membrane, suggesting that the reduction of both proteins may be related. Interestingly, disruption of AKAP-PKA interactions by st-Ht31 prevented the CSE-induced reduction of E-cadherin and AKAP9 protein expression and subsequent loss of barrier function. Silencing of AKAP9 reduced the functional epithelial barrier and prevented the ability of st-Ht31 to restore membrane localization of E-cadherin. Our data suggest the possibility of a specific role for AKAP9 in the maintenance of the epithelial barrier. E-cadherin, but not AKAP9, protein expression was reduced in lung tissue from COPD patients compared with controls. However, AKAP9 mRNA expression was decreased in primary bronchial epithelial cells from current smokers compared with non/ex-smokers. In conclusion, our results indicate that AKAP proteins, most likely AKAP9, maintain the bronchial epithelial barrier by regulating the E-cadherin expression at the cell membrane.
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Rimmer, Clara, Savas Hetelekides, Sophia I. Eliseeva, Steve N. Georas, and Janelle M. Veazey. "Budesonide promotes airway epithelial barrier integrity following double-stranded RNA challenge." PLOS ONE 16, no. 12 (December 6, 2021): e0260706. http://dx.doi.org/10.1371/journal.pone.0260706.
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Airway epithelial barrier dysfunction is increasingly recognized as a key feature of asthma and other lung diseases. Respiratory viruses are responsible for a large fraction of asthma exacerbations, and are particularly potent at disrupting epithelial barrier function through pattern recognition receptor engagement leading to tight junction dysfunction. Although different mechanisms of barrier dysfunction have been described, relatively little is known about whether barrier integrity can be promoted to limit disease. Here, we tested three classes of drugs commonly prescribed to treat asthma for their ability to promote barrier function using a cell culture model of virus-induced airway epithelial barrier disruption. Specifically, we studied the corticosteroid budesonide, the long acting beta-agonist formoterol, and the leukotriene receptor antagonist montelukast for their ability to promote barrier integrity of a monolayer of human bronchial epithelial cells (16HBE) before exposure to the viral mimetic double-stranded RNA. Of the three, only budesonide treatment limited transepithelial electrical resistance and small molecule permeability (4 kDa FITC-dextran flux). Next, we used a mouse model of acute dsRNA challenge that induces transient epithelial barrier disruption in vivo, and studied the effects budesonide when administered prophylactically or therapeutically. We found that budesonide similarly protected against dsRNA-induced airway barrier disruption in the lung, independently of its effects on airway inflammation. Taken together, these data suggest that an under-appreciated effect of inhaled budesonide is to maintain or promote airway epithelial barrier integrity during respiratory viral infections.
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Faber, Samantha C., Nicole A. McNabb, Pablo Ariel, Emily R. Aungst, and Shaun D. McCullough. "Exposure Effects Beyond the Epithelial Barrier: Transepithelial Induction of Oxidative Stress by Diesel Exhaust Particulates in Lung Fibroblasts in an Organotypic Human Airway Model." Toxicological Sciences 177, no. 1 (June 11, 2020): 140–55. http://dx.doi.org/10.1093/toxsci/kfaa085.
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Abstract In vitro bronchial epithelial monoculture models have been pivotal in defining the adverse effects of inhaled toxicant exposures; however, they are only representative of one cellular compartment and may not accurately reflect the effects of exposures on other cell types. Lung fibroblasts exist immediately beneath the bronchial epithelial barrier and play a central role in lung structure and function, as well as disease development and progression. We tested the hypothesis that in vitro exposure of a human bronchial epithelial cell barrier to the model oxidant diesel exhaust particulates caused transepithelial oxidative stress in the underlying lung fibroblasts using a human bronchial epithelial cell and lung fibroblast coculture model. We observed that diesel exhaust particulates caused transepithelial oxidative stress in underlying lung fibroblasts as indicated by intracellular accumulation of the reactive oxygen species hydrogen peroxide, oxidation of the cellular antioxidant glutathione, activation of NRF2, and induction of oxidative stress-responsive genes. Further, targeted antioxidant treatment of lung fibroblasts partially mitigated the oxidative stress response gene expression in adjacent human bronchial epithelial cells during diesel exhaust particulate exposure. This indicates that exposure-induced oxidative stress in the airway extends beyond the bronchial epithelial barrier and that lung fibroblasts are both a target and a mediator of the adverse effects of inhaled chemical exposures despite being separated from the inhaled material by an epithelial barrier. These findings illustrate the value of coculture models and suggest that transepithelial exposure effects should be considered in inhalation toxicology research and testing.
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Peterson, Michael W., and Jennifer Kirschbaum. "Asbestos-induced lung epithelial permeability: potential role of nonoxidant pathways." American Journal of Physiology-Lung Cellular and Molecular Physiology 275, no. 2 (August 1, 1998): L262—L268. http://dx.doi.org/10.1152/ajplung.1998.275.2.l262.
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Asbestos fibers are an important cause of lung fibrosis; however, the biological mechanisms are incompletely understood. The lung epithelium serves an important barrier function in the lung, and disrupting the epithelial barrier can contribute to lung fibrosis. Lung epithelial permeability is increased in patients with asbestosis, and asbestos fibers increase permeability across cultured human lung epithelium. However, the mechanism of this increased permeability is not known. Many of the biological effects of asbestos are postulated to be due to its ability to generate oxidants, and oxidants are known to increase epithelial permeability. However, we previously reported that altering the iron content of asbestos (important in oxidant generation) had no effect on its ability to increase permeability. For that reason, we undertook these studies to determine whether asbestos increases epithelial permeability through nonoxidant pathways. Both extracellular (H2O2) and intracellular (menadione) oxidants increase paracellular permeability across human lung epithelial monolayers. Extracellular catalase but not superoxide dismutase prevented increased permeability after both oxidant exposures. However, catalase offered no protection from asbestos-induced permeability. We next depleted the cells of glutathione or catalase to determine whether depleting normal cellular antioxidants would increase the sensitivity to asbestos. Permeability was the same in control cells and in cells depleted of these antioxidants. In addition to generating oxidants, asbestos also activates signal transduction pathways. Blocking protein kinase C activation did not prevent asbestos-induced permeability; however, blocking tyrosine kinase with tyrophostin A25 did prevent asbestos-induced permeability, and blocking tyrosine phosphatase with sodium vanadate enhanced the effect of asbestos. These data demonstrate that asbestos may increase epithelial permeability through nonoxidant pathways that involve tyrosine kinase activation. This model offers an important system for studying pathways involved in regulating lung epithelial permeability.
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Qu, Huinan, Qiu Jin, and Chengshi Quan. "CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers." International Journal of Molecular Sciences 22, no. 24 (December 14, 2021): 13416. http://dx.doi.org/10.3390/ijms222413416.
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Claudins (CLDNs) are the most important tight junction proteins, which are mainly expressed in endothelial cells or epithelial cells in a tissue-specific manner. As a member of the CLDNs family, CLDN6 is highly expressed in fetal tissues such as the stomach, pancreas, lung, and kidney, but is not expressed in corresponding adult tissues. The expression of CLDN6 is regulated by a variety of factors, including but not limited to stimuli and transcription factors, DNA methylation, and post-translational modifications. CLDN6 has been found to have a key role in the formation of barriers, especially the lung epithelial barrier and the epidermal permeability barrier (EPB). Importantly, the roles of CLDN6 in cancers have gained focus and are being investigated in recent years. Strong evidence indicates that the altered expression of CLDN6 is linked to the development of various cancers. Malignant phenotypes of tumors affected by CLDN6 include proliferation and apoptosis, migration and invasion, and drug resistance, which are regulated by CLDN6-mediated key signaling pathways. Given the important role in tumors and its low or no expression in normal tissues, CLDN6 is an ideal target for tumor therapy. This review aims to provide an overview of the structure and regulation of CLDN6, and its traditional barrier function, with a special emphasis on its emerging roles in cancers, including its impact on the malignant phenotypes, signal-modulating effects, the prognosis of tumor patients, and clinical applications in cancers.
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Helbing, Thomas, Eva-Maria Herold, Alexandra Hornstein, Stefanie Wintrich, Jennifer Heinke, Sebastian Grundmann, Cam Patterson, Christoph Bode, and Martin Moser. "Inhibition of BMP activity protects epithelial barrier function in lung injury." Journal of Pathology 231, no. 1 (July 10, 2013): 105–16. http://dx.doi.org/10.1002/path.4215.
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Liu, Yuru, Ruxana T. Sadikot, Guy R. Adami, Vladimir V. Kalinichenko, Srikanth Pendyala, Viswanathan Natarajan, You-yang Zhao, and Asrar B. Malik. "FoxM1 mediates the progenitor function of type II epithelial cells in repairing alveolar injury induced by Pseudomonas aeruginosa." Journal of Experimental Medicine 208, no. 7 (June 27, 2011): 1473–84. http://dx.doi.org/10.1084/jem.20102041.
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The alveolar epithelium is composed of the flat type I cells comprising 95% of the gas-exchange surface area and cuboidal type II cells comprising the rest. Type II cells are described as facultative progenitor cells based on their ability to proliferate and trans-differentiate into type I cells. In this study, we observed that pneumonia induced by intratracheal instillation of Pseudomonas aeruginosa (PA) in mice increased the expression of the forkhead transcription factor FoxM1 in type II cells coincidentally with the induction of alveolar epithelial barrier repair. FoxM1 was preferentially expressed in the Sca-1+ subpopulation of progenitor type II cells. In mice lacking FoxM1 specifically in type II cells, type II cells showed decreased proliferation and impaired trans-differentiation into type I cells. Lungs of these mice also displayed defective alveolar barrier repair after injury. Expression of FoxM1 in the knockout mouse lungs partially rescued the defective trans-differentiation phenotype. Thus, expression of FoxM1 in type II cells is essential for their proliferation and transition into type I cells and for restoring alveolar barrier homeostasis after PA-induced lung injury.
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Bigot, Paul, Simon Chesseron, Ahlame Saidi, Damien Sizaret, Christelle Parent, Agnès Petit-Courty, Yves Courty, Fabien Lecaille, and Gilles Lalmanach. "Cleavage of Occludin by Cigarette Smoke-Elicited Cathepsin S Increases Permeability of Lung Epithelial Cells." Antioxidants 12, no. 1 (December 21, 2022): 5. http://dx.doi.org/10.3390/antiox12010005.
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Background. Chronic obstructive pulmonary disease (COPD) is an irreversible disease mainly caused by smoking. COPD is characterized by emphysema and chronic bronchitis associated with enhanced epithelial permeability. Hypothesis. Lung biopsies from smokers revealed a decreased expression level of occludin, which is a protein involved in the cohesion of epithelial tight junctions. Moreover, the occludin level correlated negatively with smoking history (pack-years), COPD grades, and cathepsin S (CatS) activity. Thus, we examined whether CatS could participate in the modulation of the integrity of human lung epithelial barriers. Methods and results. Cigarette smoke extract (CSE) triggered the upregulation of CatS by THP-1 macrophages through the mTOR/TFEB signaling pathway. In a co-culture model, following the exposure of macrophages to CSE, an enhanced level of permeability of lung epithelial (16HBE and NHBE) cells towards FITC-Dextran was observed, which was associated with a decrease in occludin level. Similar results were obtained using 16HBE and NHBE cells cultured at the air–liquid interface. The treatment of THP-1 macrophages by CatS siRNAs or by a pharmacological inhibitor restored the barrier function of epithelial cells, suggesting that cigarette smoke-elicited CatS induced an alteration of epithelial integrity via the proteolytic injury of occludin. Conclusions. Alongside its noteworthy resistance to oxidative stress induced by cigarette smoke oxidants and its deleterious elastin-degrading potency, CatS may also have a detrimental effect on the barrier function of epithelial cells through the cleavage of occludin. The obtained data emphasize the emerging role of CatS in smoking-related lung diseases and strengthen the relevance of targeting CatS in the treatment of emphysema and COPD.
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Hiemstra, Pieter S., Paul B. McCray, and Robert Bals. "The innate immune function of airway epithelial cells in inflammatory lung disease." European Respiratory Journal 45, no. 4 (February 19, 2015): 1150–62. http://dx.doi.org/10.1183/09031936.00141514.
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The airway epithelium is now considered to be central to the orchestration of pulmonary inflammatory and immune responses, and is also key to tissue remodelling. It acts as the first barrier in the defence against a wide range of inhaled challenges, and is critically involved in the regulation of both innate and adaptive immune responses to these challenges. Recent progress in our understanding of the developmental regulation of this tissue, the differentiation pathways, recognition of pathogens and antimicrobial responses is now exploited to help understand how epithelial cell function and dysfunction contributes to the pathogenesis of a variety of inflammatory lung diseases. Herein, advances in our knowledge of the biology of airway epithelium, as well as its role and (dys)function in asthma, chronic obstructive pulmonary fibrosis and cystic fibrosis will be discussed.
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Liu, Mingxing, Qing Wang, Wenda Wu, Min Chen, Pengyun Zhang, Mengru Guo, Huixing Lin, Zhe Ma, Hong Zhou, and Hongjie Fan. "Glaesserella parasuis serotype 5 breaches the porcine respiratory epithelial barrier by inducing autophagy and blocking the cell membrane Claudin-1 replenishment." PLOS Pathogens 18, no. 10 (October 13, 2022): e1010912. http://dx.doi.org/10.1371/journal.ppat.1010912.
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Glaesserella parasuis (G. parasuis), the primary pathogen of Glässer’s disease, colonizes the upper respiratory tract and can break through the epithelial barrier of the respiratory tract, leading to lung infection. However, the underlying mechanisms for this adverse effect remain unclear. The G. parasuis serotype 5 SQ strain (HPS5-SQ) infection decreased the integrity of piglets’ lung Occludin and Claudin-1. Autophagy regulates the function of the epithelial barrier and tight junction proteins (TJs) expression. We tested the hypothesis that HPS5-SQ breaking through the porcine respiratory epithelial barrier was linked to autophagy and Claudin-1 degradation. When HPS5-SQ infected swine tracheal epithelial cells (STEC), autophagosomes encapsulated, and autolysosomes degraded oxidatively stressed mitochondria covered with Claudin-1. Furthermore, we found that autophagosomes encapsulating mitochondria resulted in cell membrane Claudin-1 being unable to be replenished after degradation and damaged the respiratory tract epithelial barrier. In conclusion, G. parasuis serotype 5 breaks through the porcine respiratory epithelial barrier by inducing autophagy and interrupting cell membrane Claudin-1 replenishment, clarifying the mechanism of the G. parasuis infection and providing a new potential target for drug design and vaccine development.
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Samanta, Krishna, and Anant B. Parekh. "Store-operated Ca 2+ channels in airway epithelial cell function and implications for asthma." Philosophical Transactions of the Royal Society B: Biological Sciences 371, no. 1700 (August 5, 2016): 20150424. http://dx.doi.org/10.1098/rstb.2015.0424.
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The epithelial cells of the lung are at the interface of a host and its environment and are therefore directly exposed to the inhaled air-borne particles. Rather than serving as a simple physical barrier, airway epithelia detect allergens and other irritants and then help organize the subsequent immune response through release of a plethora of secreted signals. Many of these signals are generated in response to opening of store-operated Ca 2+ channels in the plasma membrane. In this review, we describe the properties of airway store-operated channels and their role in regulating airway epithelial cell function. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.
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Daugherty, Brandy L., Madalina Mateescu, Anand S. Patel, Kelly Wade, Shioko Kimura, Linda W. Gonzales, Susan Guttentag, Philip L. Ballard, and Michael Koval. "Developmental regulation of claudin localization by fetal alveolar epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 6 (December 2004): L1266—L1273. http://dx.doi.org/10.1152/ajplung.00423.2003.
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Tight junction proteins in the claudin family regulate epithelial barrier function. We examined claudin expression by human fetal lung (HFL) alveolar epithelial cells cultured in medium containing dexamethasone, 8-bromo-cAMP, and isobutylmethylxanthanine (DCI), which promotes alveolar epithelial cell differentiation to a type II phenotype. At the protein level, HFL cells expressed claudin-1, claudin-3, claudin-4, claudin-5, claudin-7, and claudin-18, where levels of expression varied with culture conditions. DCI-treated differentiated HFL cells cultured on permeable supports formed tight transepithelial barriers, with transepithelial resistance (TER) >1,700 ohm/cm2. In contrast, HFL cells cultured in control medium without DCI did not form tight barriers (TER <250 ohm/cm2). Consistent with this difference in barrier function, claudins expressed by HFL cells cultured in DCI medium were tightly localized to the plasma membrane; however, claudins expressed by HFL cells cultured in control medium accumulated in an intracellular compartment and showed discontinuities in claudin plasma membrane localization. In contrast to claudins, localization of other tight junction proteins, zonula occludens (ZO)-1, ZO-2, and occludin, was not sensitive to HFL cell phenotype. Intracellular claudins expressed by undifferentiated HFL cells were localized to a compartment containing early endosome antigen-1, and treatment of HFL cells with the endocytosis inhibitor monodansylcadaverine increased barrier function. This suggests that during differentiation to a type II cell phenotype, fetal alveolar epithelial cells use differential claudin expression and localization to the plasma membrane to help regulate tight junction permeability.
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Abdul-Hafez, Amal, Tarek Mohamed, and Bruce D. Uhal. "Activation of mas restores hyperoxia-induced loss of lung epithelial barrier function through inhibition of apoptosis." Journal of Lung, Pulmonary & Respiratory Research 6, no. 3 (July 18, 2019): 58–62. http://dx.doi.org/10.15406/jlprr.2019.06.00208.
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Background: Neonatal therapy with a high concentration of oxygen (hyperoxia) is a known cause of bronchopulmonary dysplasia (BPD). BPD is characterized by increased pulmonary permeability and diffuse infiltration of various inflammatory cells. Disruption of the epithelial barrier may lead to altered pulmonary permeability and airways fluid accumulation. Mas receptor is a component of the renin angiotensin system and is the receptor for the protective endogenous peptide angiotensin 1-7. The activation of the Mas receptor was previously shown to have protective pulmonary responses. However, the effect of Mas receptor activation on epithelial barrier integrity has not been tested. Objective: To determine the effects of hyperoxia with or without Mas receptor activation on epithelial cell barrier integrity. Design/Methods: Human epithelial cell line A549 was cultured on transwell polycarbonate porous membrane to confluence and treated with 95% oxygen (hyperoxia) for 72 hours with or without the Mas receptor agonist (AVE0991), or the apoptotic inhibitors Z-VAD-FMK or aurintricarboxylic acid. The cells were then challenged with Rhodamine labeled bovine serum albumin (Rh-BSA) on one side of the membrane. Fluorescent quantitation of Rh-BSA (albumin flux) was performed on the media in the other side of the membrane 3 hours later and was compared with 21% oxygen (Normoxia) control group. A549 cells were also cultured with or without AVE0991 in hyperoxia or normoxia and used for nuclear fragmentation apoptosis assay using propidium iodide staining. Results: Hyperoxia induced an increase in albumin flux that was significantly prevented by AVE0991 treatment and by the apoptosis inhibitors. AVE0991 also significantly decreased the hyperoxia-induced nuclear fragmentation. Conclusion: These results suggest that hyperoxia causes a disruption in the epithelial barrier integrity, and that this disruption is inhibited by the Mas receptor agonist AVE0991 through inhibition of epithelial apoptosis. These results reveal a novel potential drug for BPD and pulmonary edema treatment.
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Wagener, Brant M., Ruihan Hu, Songwei Wu, Jean-Francois Pittet, Qiang Ding, and Pulin Che. "The Role of Pseudomonas aeruginosa Virulence Factors in Cytoskeletal Dysregulation and Lung Barrier Dysfunction." Toxins 13, no. 11 (November 2, 2021): 776. http://dx.doi.org/10.3390/toxins13110776.
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Pseudomonas (P.) aeruginosa is an opportunistic pathogen that causes serious infections and hospital-acquired pneumonia in immunocompromised patients. P. aeruginosa accounts for up to 20% of all cases of hospital-acquired pneumonia, with an attributable mortality rate of ~30–40%. The poor clinical outcome of P. aeruginosa-induced pneumonia is ascribed to its ability to disrupt lung barrier integrity, leading to the development of lung edema and bacteremia. Airway epithelial and endothelial cells are important architecture blocks that protect the lung from invading pathogens. P. aeruginosa produces a number of virulence factors that can modulate barrier function, directly or indirectly, through exploiting cytoskeleton networks and intercellular junctional complexes in eukaryotic cells. This review summarizes the current knowledge on P. aeruginosa virulence factors, their effects on the regulation of the cytoskeletal network and associated components, and molecular mechanisms regulating barrier function in airway epithelial and endothelial cells. A better understanding of these processes will help to lay the foundation for new therapeutic approaches against P. aeruginosa-induced pneumonia.
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Clerici, Christine, and Michael A. Matthay. "Transforming growth factor-β1 regulates lung epithelial barrier function and fluid transport." American Journal of Physiology-Lung Cellular and Molecular Physiology 285, no. 6 (December 2003): L1190—L1191. http://dx.doi.org/10.1152/ajplung.00230.2003.
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Jaber, W. S., P. C. Joshi, and D. M. Guidot. "ZINC SUPPLEMENTATION IMPROVES ALVEOLAR EPITHELIAL BARRIER FUNCTION IN THE ALCOHOLIC RAT LUNG." Journal of Investigative Medicine 55, no. 1 (January 2007): S288. http://dx.doi.org/10.1097/00042871-200701010-00764.
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Kawkitinarong, Kamon, Laura Linz-McGillem, Konstantin G. Birukov, and Joe G. N. Garcia. "Differential Regulation of Human Lung Epithelial and Endothelial Barrier Function by Thrombin." American Journal of Respiratory Cell and Molecular Biology 31, no. 5 (November 2004): 517–27. http://dx.doi.org/10.1165/rcmb.2003-0432oc.
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Carlier, François M., Bruno Detry, Marylène Lecocq, Amandine M. Collin, Thomas Planté-Bordeneuve, Ludovic Gérard, Stijn E. Verleden, et al. "The memory of airway epithelium damage in smokers and COPD patients." Life Science Alliance 7, no. 3 (December 29, 2023): e202302341. http://dx.doi.org/10.26508/lsa.202302341.
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Chronic obstructive pulmonary disease (COPD), a devastating and irreversible lung disease, causes structural and functional defects in the bronchial epithelium, the (ir)reversibility of which remains unexplored in vitro. This study aimed to investigate the persistence of COPD-related epithelial defects in long-term airway epithelial cultures derived from non-smokers, smokers, and COPD patients. Barrier function, polarity, cell commitment, epithelial-to-mesenchymal transition, and inflammation were evaluated and compared with native epithelium characteristics. The role of inflammation was explored using cytokines. We show that barrier dysfunction, compromised polarity, and lineage abnormalities observed in smokers and COPD persisted for up to 10 wk. Goblet cell hyperplasia was associated with recent cigarette smoke exposure. Conversely, increased IL-8/CXCL-8 release and abnormal epithelial-to-mesenchymal transition diminished over time. These ex vivo observations matched surgical samples' abnormalities. Cytokine treatment induced COPD-like changes in control cultures and reactivated epithelial-to-mesenchymal transition in COPD cells. In conclusion, these findings suggest that the airway epithelium of smokers and COPD patients retains a multidimensional memory of its original state and previous cigarette smoke-induced injuries, maintaining these abnormalities for extended periods.
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Pasman, Thijs, Danielle Baptista, Sander van Riet, Roman K. Truckenmüller, Pieter S. Hiemstra, Robbert J. Rottier, Naomi M. Hamelmann, Jos M. J. Paulusse, Dimitrios Stamatialis, and André A. Poot. "Development of an In Vitro Airway Epithelial–Endothelial Cell Culture Model on a Flexible Porous Poly(Trimethylene Carbonate) Membrane Based on Calu-3 Airway Epithelial Cells and Lung Microvascular Endothelial Cells." Membranes 11, no. 3 (March 11, 2021): 197. http://dx.doi.org/10.3390/membranes11030197.
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Due to the continuing high impact of lung diseases on society and the emergence of new respiratory viruses, such as SARS-CoV-2, there is a great need for in vitro lung models that more accurately recapitulate the in vivo situation than current models based on lung epithelial cell cultures on stiff membranes. Therefore, we developed an in vitro airway epithelial–endothelial cell culture model based on Calu-3 human lung epithelial cells and human lung microvascular endothelial cells (LMVECs), cultured on opposite sides of flexible porous poly(trimethylene carbonate) (PTMC) membranes. Calu-3 cells, cultured for two weeks at an air–liquid interface (ALI), showed good expression of the tight junction (TJ) protein Zonula Occludens 1 (ZO-1). LMVECs cultured submerged for three weeks were CD31-positive, but the expression was diffuse and not localized at the cell membrane. Barrier functions of the Calu-3 cell cultures and the co-cultures with LMVECs were good, as determined by electrical resistance measurements and fluorescein isothiocyanate-dextran (FITC-dextran) permeability assays. Importantly, the Calu-3/LMVEC co-cultures showed better cell viability and barrier function than mono-cultures. Moreover, there was no evidence for epithelial- and endothelial-to-mesenchymal transition (EMT and EndoMT, respectively) based on staining for the mesenchymal markers vimentin and α-SMA, respectively. These results indicate the potential of this new airway epithelial–endothelial model for lung research. In addition, since the PTMC membrane is flexible, the model can be expanded by introducing cyclic stretch for enabling mechanical stimulation of the cells. Furthermore, the model can form the basis for biomimetic airway epithelial–endothelial and alveolar–endothelial models with primary lung epithelial cells.
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Keely, Simon, Louise E. Glover, Thomas Weissmueller, Christopher F. MacManus, Sophie Fillon, Blair Fennimore, and Sean P. Colgan. "Hypoxia-inducible Factor-dependent Regulation of Platelet-activating Factor Receptor as a Route for Gram-Positive Bacterial Translocation across Epithelia." Molecular Biology of the Cell 21, no. 4 (February 15, 2010): 538–46. http://dx.doi.org/10.1091/mbc.e09-07-0573.
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Mucosal surfaces, such as the lung and intestine, are lined by a monolayer of epithelia that provides tissue barrier and transport function. It is recently appreciated that a common feature of inflammatory processes within the mucosa is hypoxia (so-called inflammatory hypoxia). Given the strong association between bacterial translocation and mucosal inflammatory disease, we hypothesized that intestinal epithelial hypoxia influences bacterial translocation. Initial studies revealed that exposure of cultured intestinal epithelia to hypoxia (pO2, 20 torr; 24–48 h) resulted in a increase of up to 40-fold in the translocation of some strains of Gram-positive bacteria, independently of epithelial barrier function. A screen of relevant pathway inhibitors identified a prominent role for the platelet-activating factor receptor (PAFr) in hypoxia-associated bacterial translocation, wherein pharmacologic antagonists of PAFr blocked bacterial translocation by as much as 80 ± 6%. Extensions of these studies revealed that hypoxia prominently induces PAFr through a hypoxia-inducible factor (HIF)-dependent mechanism. Indeed, HIF and PAFr loss of function studies (short hairpin RNA) revealed that apically expressed PAFr is central to the induction of translocation for the Gram-positive bacteria Enterococcus faecalis . Together, these findings reveal that some strains of Gram-positive bacteria exploit HIF-regulated PAFr as a means for translocation through intestinal epithelial cells.
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Ahdieh, Minoo, Tim Vandenbos, and Adel Youakim. "Lung epithelial barrier function and wound healing are decreased by IL-4 and IL-13 and enhanced by IFN-γ." American Journal of Physiology-Cell Physiology 281, no. 6 (December 1, 2001): C2029—C2038. http://dx.doi.org/10.1152/ajpcell.2001.281.6.c2029.
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To understand the effects of cytokines on epithelial cells in asthma, we have investigated the effects of interleukin (IL)-4, IL-13, and interferon (IFN)-γ on barrier function and wound healing in Calu-3 human lung epithelial cells. IL-4 and IL-13 treatment of Calu-3 cells grown on Transwell filters resulted in a 70–75% decrease in barrier function as assessed by electrophysiological and [14C]mannitol flux measurements. In contrast, IFN-γ enhanced barrier function threefold using these same parameters. Cells treated concurrently with IFN-γ and IL-4 or IL-13 showed an initial decline in barrier function that was reversed within 2 days, resulting in barrier levels comparable to control cells. Analysis of the tight junction-associated proteins ZO-1 and occludin showed that IL-4 and IL-13 significantly reduced ZO-1 expression and modestly decreased occludin expression compared with controls. IFN-γ, quite unexpectedly given its enhancing effect on barrier function, reduced expression of ZO-1 and occludin to almost undetectable levels compared with controls. In wound-healing assays of cells grown on collagen I, IL-4 and IL-13 decreased migration, whereas IFN-γ treatment enhanced migration, compared with control cells. Addition of IFN-γ, in combination with IL-4 or IL-13, restored migration of cells to control levels. Migration differences observed between the various cytokine treatments was correlated with expression of the collagen I-binding α2β1-integrin at the leading edge of cells at the wound front; α2β1-integrin expression was decreased in IFN-γ-treated cells compared with controls, whereas it was highest in IL-4- and IL-13-treated cells. These results demonstrate that IL-4 and IL-13 diminish the capacity of Calu-3 cells to maintain barrier function and repair wounds, whereas IFN-γ promotes epithelial restitution by enhancing barrier function and wound healing.