VIP INHIBITS BASAL AND HISTAMINE-STIMULATED PROLIFERATION OF HUMAN AIRWAY SMOOTH-MUSCLE CELLS

Airway smooth muscle (ASM) cell proliferation contributes to increased airway resistance in bronchial asthma. We have examined the modulatio n of ASM proliferation by vasoactive intestinal peptide (VIP), a cotra nsmitter of airway relaxation. Human ASM cells were grown in culture a s a monolayer. VIP (1.0 nM-1.0 mu M) inhibited proliferation in a dose -dependent manner by up to 82% on clay 2, but the related peptide gluc agon had no effect. Histamine (100 nM-100 mu M) increased cell counts by 66%, but in the presence of VIP, cell counts and [H-3]thymidine inc orporation were reduced by up to 55%. Adenosine 3',5'-cyclic monophosp hate (cAMP)-promoting agents, including 3-isobutyl-1-methylxanthine, f orskolin, and 8-bromo-adenosine 3',5'-cyclic monophosphate, alone and especially combined with VIP, reduced cell counts and [H-3]thymidine i ncorporation, in correlation with cAMP levels. KT-5720 (1.0 nM-1.0 mu M), a selective inhibitor of cAMP-dependent protein kinase A (PKA), ab olished the inhibitory effect of VIP. The results show that VIP select ively and potently inhibits human ASM cell growth and multiplication, and nullifies the mitogenic effect of histamine, by a PKA-mediated mec hanism. A deficiency of VIP may lead to ASM hyperplasia due to unoppos ed stimulation by endogenous mitogens.