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

Abstract

Murakami, Shinsuke, Noritoshi Nagaya, Takefumi Itoh, Takafumi Fujii, Takashi Iwase, Kaoru Hamada, Hiroshi Kimura, and Kenji Kangawa. C-type natriuretic peptide attenuates bleomycininduced pulmonary fibrosis in mice. Am J Physiol Lung Cell Mol Physiol 287: L1172-L1177, 2004. First published July 30, 2004 doi:10.1152/ajplung.00087.2004.-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.

Parenchymal trafficking of pleural mesothelial cells in idiopathic pulmonary fibrosis

“…Whether the number of calretinin-positive cells was measured as a raw number or as percentage of the total nucleated cells seen in a photomicrograph, the correlation with the degree of fibrosis was highly significant. The Ashcroft score was originally described in 1988, but over more than 20 yrs, it has remained the best and most enduring score for histopathological grading of pulmonary fibrosis [27][28][29][30][31][32]. The scale starts at 0, which indicates a normal lung; a score of 1 represents minimal fibrosis, 3 represents minimal fibrosis with preserved architecture, 5 indicates definite distortion with fibrous bands, 7 denotes severe distortion with honeycomb change and 8 connotes total fibrous obliteration.…”

Mechanism of C-type natriuretic peptide-induced endothelial cell hyperpolarization

“…Like ANP and BNP, CNP has been demonstrated to relax blood vessels in a number of vascular beds (8,14,20,39,40). Furthermore, CNP appears to have both anti-inflammatory (18,26,33) and anti-mitogenic (12,18,26) properties. Thus CNP may serve a potentially useful therapeutic agent, especially in the pulmonary circulation, where it has been found to attenuate both bleomycin-induced lung fibrosis and monocrotaline-induced pulmonary hypertension (18,26).…”

“…Furthermore, CNP appears to have both anti-inflammatory (18,26,33) and anti-mitogenic (12,18,26) properties. Thus CNP may serve a potentially useful therapeutic agent, especially in the pulmonary circulation, where it has been found to attenuate both bleomycin-induced lung fibrosis and monocrotaline-induced pulmonary hypertension (18,26). However, although the physiological effects of CNP are intriguing, the signaling mechanisms that underlie many of its vascular activities remain incompletely described.…”

Atorvastatin inhibits collar-induced intimal thickening of rat carotid artery: Effect on C-type natriuretic peptide expression

“…In contrast, CNP is secreted by vascular endothelial cells and acts locally as a regulator of vascular tone and growth through intracellular accumulation of cyclic guanosine monophosphate (cGMP) (14,15). Furthermore, CNP appears to have both anti-inflammatory and anti-mitogenic properties, suggesting that it may also be protective against the development of atherosclerotic lesions (16,17). In support of this, CNP has been reported to inhibit the intimal thickening in a number of experimental models of atherosclerosis, and expression of CNP and its receptors NP receptor (NPR)-B and -C in human coronary arteries are inversely correlated with severity of atherosclerotic lesions (18)(19)(20)(21).…”