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Am J Physiol Lung Cell Mol Physiol (July 30, 2004). doi:10.1152/ajplung.00087.2004
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Submitted on March 12, 2004
Accepted on July 21, 2004

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

Shinsuke Murakami1, Noritoshi Nagaya1*, Takefumi Itoh1, Takafumi Fujii1, Takashi Iwase1, Kaoru Hamada1, Hiroshi Kimura1, and Kenji Kangawa1

1 Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan

* To whom correspondence should be addressed. E-mail: nnagaya{at}ri.ncvc.go.jp.

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 (BALF). Interestingly, CNP markedly reduced BALF IL-1{beta} level. 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 anti-proliferative 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.




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