Metalloelastase in lungs and alveolar macrophages is modulated by extracellular substance P in mice.
Metalloelastase (MMP-12), mainly produced by macrophages, has been shown to play a key role in the pathogenesis of emphysema in animal models. Chronic cigarette smoke increases pulmonary MMP-12, which is closely correlated with an elevation of pulmonary substance P (SP). Because alveolar macrophages (AMs) contain the neurokinin-1 receptor (NK1R), we tested whether SP was able to trigger the upregulation of MMP-12 synthesis in AMs by acting on the NK1R. AMs isolated from bronchoalveolar lavage cells in C3H/HeN mice were cultured with control medium or SP that was coupled without or with NK1R antagonists (CP-99,994 or aprepitant) for 24 h. We found that SP significantly increased the mRNA of MMP-12 and NK1R by 11-fold and 82%, respectively, in AMs (P<0.05), and these responses were abolished by NK1R antagonists with little change in the cells' viability. Because pulmonary SP is primarily released by bronchopulmonary C-fibers (PCFs), we further asked whether destruction of PCFs would reduce SP and MMP-12. Two groups of mice were pretreated with vehicle and neonatal capsaicin (NCAP) to degenerate PCFs, respectively. Our results show that NCAP treatment significantly decreased mRNA and protein levels of SP associated with a reduction NK1R and MMP-12 in the lungs and AMs. These findings suggest that SP has a modulatory effect on pulmonary MMP-12 by acting on NK1R to trigger MMP-12 syntheses in the AMs.
Xu
J
J
Pathophysiology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.
Xu
F
F
Barrett
E
E
D000818:Animals; D018893:Bronchoalveolar Lavage; D002211:Capsaicin / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008168:Lung / Q000201:enzymology*; D016676:Macrophages, Alveolar / Q000201:enzymology*; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis*; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D011656:Pulmonary Emphysema / Q000201:enzymology; D012333:RNA, Messenger / Q000096:biosynthesis; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism; D013373:Substance P / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D010880:Piperidines; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D053508:Matrix Metalloproteinase 12; D002211:Capsaicin