A prostacyclin analogue, iloprost, protects from bleomycin-induced pulmonary fibrosis in mice

Background: Metabolites of arachidonic acid such as prostacyclin (PGI(2)) have been shown to participate in the pathogenesis of pulmonary fibrosis by inhibiting the expression of pro-inflammatory and pro-fibrotic mediators. In this investigation, we examined whether iloprost, a stable PGI(2) analogue, could prevent bleomycin-induced pulmonary inflammation and fibrosis in a mouse model. Methods: Mice received a single intratracheal injection of bleomycin with or without intraperitoneal iloprost. Pulmonary inflammation and fibrosis were analysed by histological evaluation, cellular composition of bronchoalveolar lavage (BAL) fluid, and hydroxyproline content. Lung mechanics were measured. We also analysed the expression of inflammatory mediators in BAL fluid and lung tissue. Results: Administration of iloprost significantly improved survival rate and reduced weight loss in the mice induced by bleomycin. The severe inflammatory response and fibrotic changes were significantly attenuated in the mice treated with iloprost as shown by reduction in infiltration of inflammatory cells into the airways and pulmonary parenchyma, diminution in interstitial collagen deposition, and lung hydroxyproline content. Iloprost significantly improved lung static compliance and tissue elastance. It increased the expression of IFN gamma and CXCL10 in lung tissue measured by RT-PCR and their levels in BAL fluid as measured by ELISA. Levels of TNF alpha, IL-6 and TGF beta 1 were lowered by iloprost. Conclusions: Iloprost prevents bleomycin-induced pulmonary fibrosis, possibly by upregulating antifibrotic mediators (IFN gamma and CXCL10) and downregulating pro-inflammatory and pro-fibrotic cytokines (TNF alpha, IL-6, and TGF beta 1). Prostacyclin may represent a novel pharmacological agent for treating pulmonary fibrotic diseases.