Mice lacking the VIP gene show airway hyperresponsiveness and airway inflammation, partially reversible by VIP.
The mechanisms leading to asthma, and those guarding against it, are yet to be fully defined. The neuropeptide VIP is a cotransmitter, together with nitric oxide (NO), of airway relaxation, and a modulator of immune and inflammatory responses. NO-storing molecules in the lung were recently shown to modulate airway reactivity and were proposed to have a protective role against the disease. We report here that mice with targeted deletion of the VIP gene spontaneously exhibit airway hyperresponsiveness to the cholinergic agonist methacholine as well as peribronchiolar and perivascular cellular infiltrates and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid. Immunologic sensitization and challenge with ovalbumin generally enhanced the airway hyperresponsiveness and airway inflammation in all mice. Intraperitoneal administration of VIP over a 2-wk period in knockout mice virtually eliminated the airway hyperresponsiveness and reduced the airway inflammation in previously sensitized and challenged mice. The findings suggest that 1) VIP may be an important component of endogenous anti-asthma mechanisms, 2) deficiency of the VIP gene may predispose to asthma pathogenesis, and 3) treatment with VIP or a suitable agonist may offer potentially effective replacement therapy for this disease.
Szema
Anthony M
AM
Department of Medicine, State University of New York at Stony Brook, NY 11794-8172, USA.
Hamidi
Sayyed A
SA
Lyubsky
Sergey
S
Dickman
Kathleen G
KG
Mathew
Suni
S
Abdel-Razek
Tarek
T
Chen
John J
JJ
Waschek
James A
JA
Said
Sami I
SI
D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010447:Peptide Hydrolases / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D012720:Severity of Illness Index; D014660:Vasoactive Intestinal Peptide / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology*
D018925:Chemokines; D016207:Cytokines; D014660:Vasoactive Intestinal Peptide; D010447:Peptide Hydrolases