Tobacco smoke induces epithelial barrier dysfunction via receptor EphA2 signaling.
Erythropoietin-producing human hepatocellular carcinoma (Eph) receptors are the largest family of receptor tyrosine kinases (RTKs) that mediate various cellular and developmental processes. The degrees of expression of these key molecules control the cell-cell interactions. Although the role of Eph receptors and their ligand Ephrins is well studied in developmental processes, their function in tobacco smoke (TS)-induced epithelial barrier dysfunction is unknown. We hypothesized that TS may induce permeability in bronchial airway epithelial cell (BAEpC) monolayer by modulating receptor EphA2 expression, actin cytoskeleton, adherens junction, and focal adhesion proteins. Here we report that in BAEpCs, acute TS exposure significantly upregulated EphA2 and EphrinA1 expression, disrupted the actin filaments, decreased E-cadherin expression, and increased protein permeability, whereas the focal adhesion protein paxillin was unaffected. Silencing the receptor EphA2 expression with silencing interference RNA (siRNA) significantly attenuated TS-induced hyperpermeability in BAEpCs. In addition, when BAEpC monolayer was transfected with EphA2-expressing plasmid and treated with recombinant EphrinA1, the transepithelial electrical resistance decreased significantly. Furthermore, TS downregulated E-cadherin expression and induced hyperpermeability across BAEpC monolayer in a Erk1/Erk2, p38, and JNK MAPK-dependent manner. TS induced hyperpermeability in BAEpC monolayer by targeting cell-cell adhesions, and interestingly cell-matrix adhesions were unaffected. The present data suggest that TS causes significant damage to the BAEpCs via induction of EphA2 and downregulation of E-cadherin. Induction of EphA2 in the BAEpCs exposed to TS may be an important signaling event in the pathogenesis of TS-induced epithelial injury.
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida; and North Florida/South Georgia Veterans Health Care System, Malcom Randall Veterans Affairs Medical Center, University of Florida, Gainesville, Florida.
Najmunnisa
N
Nasreen
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida; and North Florida/South Georgia Veterans Health Care System, Malcom Randall Veterans Affairs Medical Center, University of Florida, Gainesville, Florida.
Nazli
N
Khodayari
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida; and North Florida/South Georgia Veterans Health Care System, Malcom Randall Veterans Affairs Medical Center, University of Florida, Gainesville, Florida.
Peruvemba S
PS
Sriram
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida; and North Florida/South Georgia Veterans Health Care System, Malcom Randall Veterans Affairs Medical Center, University of Florida, Gainesville, Florida.
Jawaharlal
J
Patel
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida; and North Florida/South Georgia Veterans Health Care System, Malcom Randall Veterans Affairs Medical Center, University of Florida, Gainesville, Florida mkamal@medicine.ufl.edu.
Kamal A
KA
Mohammed
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D015820:Cadherins; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D036382:Ephrin-A1 / Q000096:biosynthesis* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D036104:Receptor, EphA2 / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
D015820:Cadherins; D036382:Ephrin-A1; D014028:Tobacco Smoke Pollution; D036104:Receptor, EphA2
E-cadherin; EphA2 receptor; paxillin; permeability; tobacco smoke