Tachykinin regulation of airway smooth muscle cell
proliferation.
Noveral, James P., and Michael M. Grunstein.
Division of Pulmonary Medicine, Joseph Stokes, Jr. Research
Institute, The Children's Hospital of Philadelphia, University of
Pennsylvania School of Medicine, Philadelphia, PA 19104
APStracts 2:0070L, 1995.
The tachykinins, substance P (SP), neurokinins A (NKA) and B (NKB),
have been identified in the respiratory tract and implicated in
mediating neurogenic inflammation of the airways. To the extent that
these neuropeptides may be involved in the pathogenesis of asthma, a
condition associated with hyperplasia of airway smooth muscle (ASM),
we examined the mitogenic effects and mechanisms of action of
tachykinins in cultured rabbit ASM cells. SP was found to elicit
dose-dependent (10-14-10-4 M) stimulation of ASM cell proliferation,
with a mean (+/- SE) maximal increase in cell number of 169 (+/-
6.1)% of control. In contrast, NKA and NKB had little and no effect
on ASM cell growth, respectively. Since SP is non-selective in its
binding to the tachykinin receptors, to identify the specific
neurokinin (NK) receptor subtype(s) mediating the promitogenic action
of SP, in separate studies we found that: 1) the NK1-receptor
-specific agonist, [[beta]-Ala4, Sar9, Met(O2)11]-SP(4-11) induced
stimulation of ASM cell growth similar in magnitude to that elicited
by SP; 2) in contrast, neither the NK1- nor NK2 -receptor-specific
agonists, [[beta]-Ala8]-NKA(4-10) and [MePhe7]-NKB, respectively, had
any effect on ASM cell growth; and 3) the promitogenic action of SP
was inhibited by the NK1- receptor antagonist, GR 82,334. Moreover,
in extended experiments, we found that the phospholipase C and
phospholipase A2 inhibitors, neomycin and quinacrine, respectively,
each inhibited SP-induced ASM cell proliferation by 45%.
Collectively, 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-receptor.
Received 8 March 1995; accepted in final form 25 April 1995.
APS Manuscript Number L74-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 2 May 1995.