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C-type natriuretic peptide attenuates bleomycin-induced pulmonary fibrosis in mice

¹Department of Internal Medicine, National Cardiovascular Center, Osaka 565-8565; ²Second Department of Internal Medicine, Nara Medical University, Nara 634-8522; ³Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Osaka 565-8565; and ⁴Department of Cardiac Physiology and ⁵Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan

Submitted 12 March 2004 ; accepted in final form 21 July 2004

C-type natriuretic peptide (CNP) has been shown to play an important role in the regulation of vascular tone and remodeling. However, the physiological role of CNP in the lung remains unknown. Accordingly, we investigated whether CNP infusion attenuates bleomycin (BLM)-induced pulmonary fibrosis in mice. After intratracheal injection of BLM or saline, mice were randomized to receive continuous infusion of CNP or vehicle for 14 days. CNP infusion significantly reduced the total number of cells and the numbers of macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid. Interestingly, CNP markedly reduced bronchoalveolar lavage fluid IL-1 levels. Immunohistochemical analysis demonstrated that CNP significantly inhibited infiltration of macrophages into the alveolar and interstitial regions. CNP infusion significantly attenuated BLM-induced pulmonary fibrosis, as indicated by significant decreases in Ashcroft score and lung hydroxyproline content. CNP markedly decreased the number of Ki-67-positive cells in fibrotic lesions of the lung, suggesting antiproliferative effects of CNP on pulmonary fibrosis. Kaplan-Meier survival curves demonstrated that BLM mice treated with CNP had a significantly higher survival rate than those given vehicle. These results suggest that continuous infusion of CNP attenuates BLM-induced pulmonary fibrosis and improves survival in BLM mice, at least in part by inhibition of pulmonary inflammation and cell proliferation.

inflammation; fibroblast; survival

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