Modulation of TGFβ1-induced Fibroblast-to-Myofibroblast Transition in response to Prostaglandin E2 Production by Human Rhinovirus-Infected Airway Epithelial Cells
One of the cardinal features of asthma is the presence of airway remodeling, the structural changes that contribute to exaggerated narrowing of the airway. Fibroblast-to-myofibroblast transition (FMT) is an airway remodeling phenomenon whereby fibroblasts develop phenotypic characteristics of myofibroblasts. This increase in myofibroblasts leads to the excessive deposition of extracellular matrix proteins, leading to the thickening of the airway walls. Transforming growth factor beta-1 (TGFβ1) is highly expressed in asthmatics and is known to upregulate fibroblast alpha-smooth muscle actin (α-SMA) expression, a characteristic marker of myofibroblasts. Given that human rhinovirus (HRV) infections are postulated to be involved in the pathogenesis of airway remodeling in asthma, we originally hypothesized that human airway epithelial cells promoted TGFβ1-induced FMT based on α-SMA expression by secreting mediator(s) upon HRV infection. Interestingly, our data consistently demonstrated that supernatants from HRV-infected epithelial cells inhibited TGFβ1-induced α-SMA in fibroblasts compared to supernatants from non-infected epithelial cells. This led us to hypothesize that HRV-infected airway epithelial cells released PGE2 which acts via EP1-4 receptors on fibroblasts to suppress TGFβ1-induced α-SMA expression. Using an in vitro cell culture model, we confirmed HRV-infection of epithelial cells result in the upregulation of PGE2 and validated that PGE2 inhibits TGFβ1-induced α-SMA protein in fibroblasts. Furthermore, supernatants from epithelial cells treated with diclofenac, a non-selective cyclooxygenase inhibitor, prior to HRV infection had reduced ability to inhibit TGFβ1-induced α-SMA expression in fibroblasts. Finally, we demonstrated that PGE2 acts on the fibroblast EP2 receptor to downregulate TGFβ1-induced FMT. In conclusion, our research findings may account for why healthy, non-asthmatic individuals are prevented from developing TGFβ1-induced FMT following repeated rhinovirus infections. This thesis instigates future investigation on whether well-characterized asthmatic cells behave differently to render it vulnerable to TGFβ1-induced FMT following rhinovirus infections.
Prostaglandin E2, Fibrosis, Fibroblast, Myofibroblast, Airway Remodeling
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