TACHYKININS INDUCE GELATINASE PRODUCTION BY GUINEA-PIG ALVEOLAR MACROPHAGES - INVOLVEMENT OF NK2 RECEPTORS

To determine whether tachykinins induce gelatinase production by guinea pig alveolar macrophages (AM), and to characterize the mechanism involved, we incubated AM with substance P (SP), neurokinin A (NKA), or the NH2-terminal fragment of SP, SP(1-7). The effects of increasing concentrations of selective NK1 and NK2 agonists on tachykinin-induced gelatinase production were also evaluated, as were the effects of a selective NK2 antagonist. Gelatinase activity in conditioned culture media (CCM) was assessed by zymography and quantified by image analysis. SP increased 92-kDa gelatinase activity in CCM of AM in a concentration-dependent manner, with a maximum increase at 10(-4) M. NKA, the NH2-terminal fragment of SP, and an NK1-selective agonist had no effect. In contrast, a selective NK2 agonist induced a concentration-dependent increase in gelatinase activity. The increase in this activity induced by SP and the selective NK2 agonist was inhibited by a selective NK2 antagonist. We conclude that SP induces gelatinase production by AM through NK2 receptor activation. The release of gelatinase may constitute one mechanism through which SP contributes to the epithelial lesions observed in bronchial hyperreactivity and asthma.