C-type natriuretic peptide attenuates bleomycin-induced pulmonary fibrosis in mice.
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-1beta 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.
Department of Internal Medicine, National Cardiovascular Center, Osaka 565-8565, Japan.
Shinsuke
S
Murakami
Noritoshi
N
Nagaya
Takefumi
T
Itoh
Takafumi
T
Fujii
Takashi
T
Iwase
Kaoru
K
Hamada
Hiroshi
H
Kimura
Kenji
K
Kangawa
D000818:Animals; D001761:Bleomycin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D005260:Female; D006909:Hydroxyproline / Q000378:metabolism; D007263:Infusions, Parenteral; D007375:Interleukin-1 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D020098:Natriuretic Peptide, C-Type / Q000008:administration & dosage / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D020098:Natriuretic Peptide, C-Type; D006909:Hydroxyproline