Pulmonary fibrosis (PF) is an irreversible and largely untreatable human disease with the causes often remaining unknown. Phosphodiesterase 4 (PDE4) is involved in the processes of inflammation, cell proliferation, differentiation and migration that are known to play an important role in tissue fibrosis. The aim of the study was, therefore, to determine the expression of PDE4 under conditions of PF and to investigate the effects of PDE4 inhibition on functional, histological and biochemical parameters in experimental PF.Pulmonary fibrosis was induced by cytostatic and profibrotic agent bleomycin in C57BL/6N mice. Expression profiles of the different PDE4 isoforms were analyzed at mRNA and protein levels in lungs with both experimental and human PF. Animals were treated with the selective PDE4 inhibitor cilomilast and/or vehicle and treatment effects were examined by means of bronchoalveolar lavage fluid (BALF) differential cell count, mRNA analysis for lung tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL6, pulmonary compliance measurement, quantified pathological examination of the lungs, collagen assay and survival analysis.Analysis of PDE4 expression showed significant upregulation of inflammation-related PDE4 isoform in lungs with both human and experimental PF. Treatment of mice with cilomilast resulted in significant reduction in total number of cells, number of macrophages and lymphocytes, but not neutrophils, in BALF at early inflammatory fibrosis stage (days 4 and 7). Lung TNFalpha, but not IL1beta, level was also significantly reduced by cilomilast while level of IL6 was significantly elevated. At later stage (days 14 and 21) cilomilast-treated mice demonstrated improved lung function and lesser fibrosis degree compared to non-treated group. Lung collagen content and overall survival were also partially restored by treatment with cilomilast.Our results suggest that selective PDE4 inhibition suppresses early inflammatory stage and has the potential to attenuate the late stage of pulmonary fibrosis in experimental fibrosis and thus may offer a new therapeutic option for patients with PF.
Verknüpfung zu Publikationen oder weiteren Datensätzen
