Novel Anti-inflammatory Effects of the Inhaled Corticosteroid Fluticasone Propionate During Lung Myofibroblastic Differentiation

Abstract

Asthma is characterized by an irreversible subepithelial fibrosis with the appearance of myofibroblasts, which can be now considered important early participants 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-inflammatory effects on human lung fibroblasts during their myofibroblastic differentiation. Indeed, FP inhibits in lung myofibroblasts, at a very early stage of differentiation, the activation of Janus kinase/STAT pathways induced by IL-13 (tyrosine kinase 2, STAT1, STAT3, STAT6, mitogen-activated protein kinase). Contrarily, in mildly or fully differentiated myofibroblastic cultures, FP still displays a potential anti-inflammatory activity even if it only inhibits tyrosine kinase 2 phosphorylation. Moreover, FP inhibits constitutive and TGF-β-induced expression of α-smooth muscle actin, the main marker of myofibroblastic differentiation, both in very early and in mild differentiated myofibroblasts. Finally, FP displays an additional powerful anti-inflammatory effect, decreasing nuclear translocation of NF-κB independent 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 improved by an early ICS treatment, whereas advanced asthma is more resistant to these drugs.

Fluticasone propionate and Salmeterol combination induces SOCS-3 expression in airway epithelial cells

“…In addition, glucocorticoids have been shown to inhibit il-13 induced myofibroblast differentiation via blocking JAK/STAT pathway [50]. In animal models of lung injury glucocorticoids reduce leakage of surfactant proteins from the lungs to systemic compartment indicating attenuation of inflammation associated with injury [37].…”

Asthma therapy and airway remodeling

“…At early stages of differentiation, FP inhibits the activation of Janus kinase/signal transducer and activator of transcription pathways induced by IL-13 in lung myofibroblasts. 73 FP also inhibits constitutive and TGFb-induced expression of a-smooth muscle actin in fibroblasts, the main marker of myofibroblastic differentiation, both in very early and in mild differentiated myofibroblasts. 73 These in vitro results have been extended by in vivo studies.…”

Asthma Therapy and Its Effect on Airway Remodelling

“…The inhibitory effect of GCs on ASM proliferation was shown to be defective in asthma and that is mediated by an abnormal interaction between C/EBPa and the GC receptor [139]. In culture, fluticasone propionate, through its effect on NF-jB signalling, has been found to prevent myofibroblast differentiation, a possible precursor of ASM cells [140]. In a murine asthma model, Leung et al [141] showed that intratracheal administration of ciclesonide or fluticasone, both powerful GCs, resulted in the inhibition of features of inflammation and remodelling, including ASM hyperplasia.…”