stase (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 Ͻ 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. emphysema; neurokinin-1 receptor; bronchopulmonary C-fibers; matrix metalloproteinase-12; chronic obstructive pulmonary disease METALLOELASTASE (MMP-12) is able to degrade many kinds of extracellular matrix proteins, including elastin (16). Loss of elastic recoil and damage of elastic fibers along with histological changes of emphysema implicate elastin degradation as an important factor in the pathogenesis of chronic obstructive pulmonary disease (COPD) (38). MMP-12 is increased in lung tissue (5) and macrophages (6) of cigarette smoke (CS)-exposed mice and in sputum from COPD patients (7, 40). Furthermore, an increase of the ratio of MMP-12 to the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) was also observed in COPD animal models (61). TIMP-1 can inhibit all matrix metalloproteinases (MMPs), including MMP-12, resulting in loss of proteolytic activity (27,54). Most importantly, MMP-12 gene-deficient mice do not develop emphysema after chronic CS exposure (19). Conversely, overexpression of MMP-12 in transgenic mice is associated with spontaneous development of pulmonary emphysema (41). Together, these results strongly suggest that MMP-12 plays a key role in the pathogenesis of COPD, at least in animal models. Substance P (SP) is a proinflammatory neuropeptide and neurogenic mediator with a high affinity for binding to the neurokinin-1 receptor (NK1R) (48). Previous studies have shown three lines of evidence implying the possible SP modulatory effects on pulmonary MMP-12. First, significantly correlated increases of pulmonary SP and MMP-12 have been observed in CS-exposed mice (61). Second, alveolar macrophages (AMs...