Novel anti-inflammatory effects of the inhaled corticosteroid fluticasone propionate during lung myofibroblastic differentiation

Asthma is characterized by an irreversible subepithelial fibrosis with the appearance of myofibroblasts, which can be now considered important early p articipants in inflammatory responses as well as potential targets for anti -inflammatory drugs. In this study, we show that fluticasone propionate (FP ), a powerful inhaled corticosteroid (ICS), displays novel anti-inflammator y effects on human lung fibroblasts during their myofibroblastic differenti ation. Indeed, FP inhibits in lung myofibroblasts, at a very early stage of differentiation, the activation of Janus kinase/STAT pathways induced by I L-13 (tyrosine kinase 2, STAT1, STAT3, STAT6, mitogen-activated protein kin ase). Contrarily, in mildly or fully differentiated myofibroblastic culture s, FP still displays a potential anti-inflammatory activity even if it only inhibits tyrosine kinase 2 phosphorylation. Moreover, FP inhibits constitu tive and TGF-beta -induced expression of alpha -smooth muscle actin, the ma in marker of myofibroblastic differentiation, both in very early and in mil d differentiated myofibroblasts. Finally, FP displays an additional powerfu l anti-inflammatory effect, decreasing nuclear translocation of NF-kappaB i ndependent of the degree of myofibroblastic differentiation. These data 1) suggest that myofibroblasts are priority targets for ICS, which is able to revert them to a normal phenotype even if they appear to be already engaged in their differentiation, and 2) may help to explain why asthma is improve d by an early ICS treatment, whereas advanced asthma is more resistant to t hese drugs.