Abstract
BackgroundMetabolites of arachidonic acid such as prostacyclin (PGI2) 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 PGI2 analogue, could prevent bleomycin-induced pulmonary inflammation and fibrosis in a mouse model.MethodsMice 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.ResultsAdministration 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 IFNγ and CXCL10 in lung tissue measured by RT-PCR and their levels in BAL fluid as measured by ELISA. Levels of TNFα, IL-6 and TGFβ1 were lowered by iloprost.ConclusionsIloprost prevents bleomycin-induced pulmonary fibrosis, possibly by upregulating antifibrotic mediators (IFNγ and CXCL10) and downregulating pro-inflammatory and pro-fibrotic cytokines (TNFα, IL-6, and TGFβ1). Prostacyclin may represent a novel pharmacological agent for treating pulmonary fibrotic diseases.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressively fatal disorder characterized by inflammatory alveolitis and scarring in the pulmonary interstitium with loss of lung function; it is estimated that there is a 70% mortality within 5 years from initial diagnosis [1]
The mice treated with bleomycin lost more weight than the mice treated with bleomycin+iloprost (Figure 1B)
Animals were the mice treated with bleomycin than in the mice treated with iloprost+bleomycin (5.64 ± 0.18 vs 3.35 ± 0.54, P < 0.0001) (Figure 3B)
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressively fatal disorder characterized by inflammatory alveolitis and scarring in the pulmonary interstitium with loss of lung function; it is estimated that there is a 70% mortality within 5 years from initial diagnosis [1]. The mechanisms underlying the pathogenesis of IPF include the accumulation of inflammatory cells in the lungs, and the generation of pro-inflammatory and pro-fibrotic mediators, resulting in alveolar epithelial cell injury and fibroblast. Antagonizing LTB4 receptor attenuated the lung fibrosis induced by bleomycin in mice by suppressing the production of inflammatory and fibrotic cytokines and by promoting the antifibrotic cytokine, IFNg [6]. Metabolites of arachidonic acid such as prostacyclin (PGI2) 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 PGI2 analogue, could prevent bleomycin-induced pulmonary inflammation and fibrosis in a mouse model
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