title: VIP inhibits basal and histamine-stimulated proliferation of human airway smooth muscle cells.
abstract: Airway smooth muscle (ASM) cell proliferation contributes to increased airway resistance in bronchial asthma. We have examined the modulation of ASM proliferation by vasoactive intestinal peptide (VIP), a cotransmitter of airway relaxation. Human ASM cells were grown in culture as a monolayer. VIP (1.0 nM-1.0 microM) inhibited proliferation in a dose-dependent manner by up to 82% on day 2, but the related peptide glucagon had no effect. Histamine (100 nM-100 microM) increased cell counts by 66%, but in the presence of VIP, cell counts and [3H]thymidine incorporation were reduced by up to 55%. Adenosine 3',5'-cyclic monophosphate (cAMP)-promoting agents, including 3-isobutyl-1-methylxanthine, forskolin, and 8-bromo-adenosine 3',5'-cyclic monophosphate, alone and especially combined with VIP, reduced cell counts and [3H]thymidine incorporation, in correlation with cAMP levels. KT-5720 (1.0 nM-1.0 microM), a selective inhibitor of cAMP-dependent protein kinase A (PKA), abolished the inhibitory effect of VIP. The results show that VIP selectively and potently inhibits human ASM cell growth and multiplication, and nullifies the mitogenic effect of histamine, by a PKA-mediated mechanism. A deficiency of VIP may lead to ASM hyperplasia due to unopposed stimulation by endogenous mitogens.
authors.affiliation: Department of Veterans Affairs Medical Center, Northport, New York 11768, USA.
authors.forename: K
authors.initials: K
authors.lastname: Maruno
authors.forename: A
authors.initials: A
authors.lastname: Absood
authors.forename: S I
authors.initials: SI
authors.lastname: Said
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D002227:Carbazoles; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014132:Trachea; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
chemical_list: D002227:Carbazoles; D006633:Histamine Antagonists; D007211:Indoles; D011758:Pyrroles; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D014660:Vasoactive Intestinal Peptide; C057416:KT 5720; D006632:Histamine; D004247:DNA; D005934:Glucagon; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015056:1-Methyl-3-isobutylxanthine; D013936:Thymidine