Dexamethasone Restores TNFα-induced Epithelial Barrier Dysfunction in Primary Rat Alveolar Epithelial Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2023 Dec 27

PMID 38150443

Authors

Naokata Kutsuzawa

Yoko Ito

Shizuko Kagawa

Chinatsu Kohno

Hiroto Takiguchi

Koichiro Asano

Affiliations

Soon will be listed here.

Abstract

Alveolar barrier dysfunction is one of the major pathophysiological changes in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). In ALI/ARDS, tumor necrosis factor-alpha (TNFα) disrupts the barriers of alveolar epithelium and endothelium. Glucocorticoids (GCs) exert anti-inflammatory effects and ameliorate pulmonary edema in ALI/ARDS. However, the involvement of GCs in the restoration of alveolar epithelial barrier dysfunction has not been extensively studied. Here, we elucidated that dexamethasone (Dex) restored TNFα-induced alveolar epithelial barrier dysfunction in vitro using primary rat alveolar epithelial cells isolated from Sprague-Dawley rats. Moreover, Dex promoted the alveolar epithelial cell barrier integrity by initiating GC receptor-mediated signaling via the downregulation of myosin light chain kinase (MLCK) expression and the dephosphorylation of myosin light chain (MLC) 2. Further investigation revealed that Dex enhanced the expression of zonula occludens-1 (ZO-1), a tight junction-related protein, at intercellular junction sites. These findings suggest that GCs strengthen the integrity of the alveolar epithelial barrier in ALI/ARDS via the GR-MLCK-pMLC2 axis.

References

Schlingmann B, Molina S, Koval M . Claudins: Gatekeepers of lung epithelial function. Semin Cell Dev Biol. 2015; 42:47-57. PMC: 4562902. DOI: 10.1016/j.semcdb.2015.04.009. View

Baumgart D, Carding S . Inflammatory bowel disease: cause and immunobiology. Lancet. 2007; 369(9573):1627-40. DOI: 10.1016/S0140-6736(07)60750-8. View

Fanning A, Jameson B, Jesaitis L, Anderson J . The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem. 1998; 273(45):29745-53. DOI: 10.1074/jbc.273.45.29745. View

Collard H, Ryerson C, Corte T, Jenkins G, Kondoh Y, Lederer D . Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report. Am J Respir Crit Care Med. 2016; 194(3):265-75. DOI: 10.1164/rccm.201604-0801CI. View

Ridley A . Rho family proteins: coordinating cell responses. Trends Cell Biol. 2001; 11(12):471-7. DOI: 10.1016/s0962-8924(01)02153-5. View

Dobbs L, Geppert E, Williams M, Greenleaf R, Mason R . Metabolic properties and ultrastructure of alveolar type II cells isolated with elastase. Biochim Biophys Acta. 1980; 618(3):510-23. DOI: 10.1016/0005-2760(80)90270-2. View

Meng G, Zhao J, Wang H, Ding R, Zhang X, Huang C . Injury of cell tight junctions and changes of actin level in acute lung injury caused by the perfluoroisobutylene exposure and the role of Myosin light chain kinase. J Occup Health. 2011; 53(4):250-7. DOI: 10.1539/joh.10-0055-oa. View

He W, Wang Y, Wang P, Wang F . Intestinal barrier dysfunction in severe burn injury. Burns Trauma. 2019; 7:24. PMC: 6659221. DOI: 10.1186/s41038-019-0162-3. View

Coyne C, Vanhook M, Gambling T, Carson J, Boucher R, Johnson L . Regulation of airway tight junctions by proinflammatory cytokines. Mol Biol Cell. 2002; 13(9):3218-34. PMC: 124154. DOI: 10.1091/mbc.e02-03-0134. View

10.

Soler A, Marano C, Bryans M, Miller R, Garulacan L, Mauldin S . Activation of NF-kappaB is necessary for the restoration of the barrier function of an epithelium undergoing TNF-alpha-induced apoptosis. Eur J Cell Biol. 1999; 78(1):56-66. DOI: 10.1016/s0171-9335(99)80007-7. View

11.

Ito Y, Oshinden K, Kutsuzawa N, Kohno C, Isaki S, Yokoyama K . Heat-Not-Burn cigarette induces oxidative stress response in primary rat alveolar epithelial cells. PLoS One. 2020; 15(11):e0242789. PMC: 7688177. DOI: 10.1371/journal.pone.0242789. View

12.

Hartsock A, Nelson W . Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta. 2007; 1778(3):660-9. PMC: 2682436. DOI: 10.1016/j.bbamem.2007.07.012. View

13.

Song H, Zhang J, He W, Wang P, Wang F . Activation of Cofilin Increases Intestinal Permeability Depolymerization of F-Actin During Hypoxia . Front Physiol. 2019; 10:1455. PMC: 6901426. DOI: 10.3389/fphys.2019.01455. View

14.

Ma T, Tran D, Hoa N, Nguyen D, Merryfield M, Tarnawski A . Mechanism of extracellular calcium regulation of intestinal epithelial tight junction permeability: role of cytoskeletal involvement. Microsc Res Tech. 2000; 51(2):156-68. DOI: 10.1002/1097-0029(20001015)51:2<156::AID-JEMT7>3.0.CO;2-J. View

15.

Fischer A, Gluth M, Weege F, Pape U, Wiedenmann B, Baumgart D . Glucocorticoids regulate barrier function and claudin expression in intestinal epithelial cells via MKP-1. Am J Physiol Gastrointest Liver Physiol. 2013; 306(3):G218-28. DOI: 10.1152/ajpgi.00095.2013. View

16.

Dagenais A, Frechette R, Clermont M, Masse C, Prive A, Brochiero E . Dexamethasone inhibits the action of TNF on ENaC expression and activity. Am J Physiol Lung Cell Mol Physiol. 2006; 291(6):L1220-31. DOI: 10.1152/ajplung.00511.2005. View

17.

Boivin M, Ye D, Kennedy J, Al-Sadi R, Shepela C, Ma T . Mechanism of glucocorticoid regulation of the intestinal tight junction barrier. Am J Physiol Gastrointest Liver Physiol. 2006; 292(2):G590-8. PMC: 3724219. DOI: 10.1152/ajpgi.00252.2006. View

18.

Jiang L, Wang J, Su C, Qian W, Chen J, Zhu B . α-ENaC, a therapeutic target of dexamethasone on hydrogen sulfide induced acute pulmonary edema. Environ Toxicol Pharmacol. 2014; 38(2):616-24. DOI: 10.1016/j.etap.2014.08.012. View

19.

Xu P, Elizalde M, Masclee A, Pierik M, Jonkers D . Corticosteroid enhances epithelial barrier function in intestinal organoids derived from patients with Crohn's disease. J Mol Med (Berl). 2021; 99(6):805-815. PMC: 8164603. DOI: 10.1007/s00109-021-02045-7. View

20.

Schneider J, Wrede C, Hegermann J, Weibel E, Muhlfeld C, Ochs M . On the Topological Complexity of Human Alveolar Epithelial Type 1 Cells. Am J Respir Crit Care Med. 2019; 199(9):1153-1156. DOI: 10.1164/rccm.201810-1866LE. View