TACHYKININ REGULATION OF AIRWAY SMOOTH-MUSCLE CELL-PROLIFERATION

The tachykinins, substance P (SP) and neurokinins A (NKA) and B (NKB), have been identified in the respiratory tract and implicated in media ting neurogenic inflammation of the airways. To the extent that these neuropeptides may be involved in the pathogenesis of asthma, a conditi on associated with hyperplasia of airway smooth muscle (ASM), we exami ned the mitogenic effects and mechanisms of action of tachykinins in c ultured rabbit ASM cells. SP was found to elicit dose-dependent (10(-1 4) to 10(-4) M) stimulation of ASM cell proliferation, with a mean (+/ -SE) maximal increase in cell number of 169 +/- 6.1% of control. In co ntrast, NKA and NKB had little and no effect on ASM cell growth, respe ctively. Because SP is nonselective in its binding to the tachykinin r eceptors, to identify the specific NK receptor subtype(s) mediating th e promitogenic action of SP, in separate studies we found that 1) the NK1-receptor-specific agonist, [beta-Ala(4), Sar(9), Met(O-2)(11)]SP-( 4-11) induced stimulation of ASM cell growth similar in magnitude to t hat elicited by SP; 2) in contrast, neither the NK1- nor NK2-receptor- specific agonists, [beta-Ala(8)]NKA-(4-10) and [MePhe(7)]NKB, respecti vely, had any effect on ASM cell growth; and 3) the promitogenic actio n of SP was inhibited by the NK1-receptor antagonist, GR-82,334. Moreo ver, in extended experiments, we found that the phospholipase C and ph ospholipase A(2) inhibitors, neomycin and quinacrine, respectively, ea ch inhibited SP-induced ASM cell proliferation by similar to 45%. Coll ectively, these observations provide new evidence that the tachykinin SP induces ASM cell proliferation, and that this action is mediated by transmembrane signaling coupled to selective activation of the NK1 re ceptor.