Role of nitric oxide in chronic allergen-induced airway cell proliferation and inflammation.
Chronic cellular inflammation and airway wall remodeling with subepithelial fibrosis and airway smooth muscle thickening are features of chronic asthma. We determined the role of nitric oxide in the pathogenesis of allergen-induced airway cell proliferation and inflammation by studying the effects of a relatively selective prodrug inhibitor of nitric-oxide synthase type 2 (NOS2), L-N6-(1-iminoethyl)-lysine-5-tetrazole amide (SC-51). Brown-Norway rats were sensitized to ovalbumin and were exposed to ovalbumin aerosol every 3rd day on six occasions and were treated orally with either vehicle or SC-51 (10 mg. kg(-1); 12 doses). We measured inflammatory cell accumulation in the airways and proliferation of cells by incorporation of bromodeoxyuridine. There was an increase in the total number of airway smooth muscle cells expressing bromodeoxyuridine from 1.3% of airway smooth muscle cells in saline exposed to 5.4% after allergen-exposure (P < 0.001) and airway epithelial cells from 3.3 cells/mm basement membrane to 9.6 after allergen-exposure (P < 0.001). SC-51 had no effect on airway smooth muscle or epithelial cell proliferation. SC-51 attenuated the allergen-induced increase in major basic protein (MBP+) eosinophil (P < 0.05) and CD4+ T-cell (P < 0.05) accumulation. We conclude that nitric oxide derived during allergic inflammation is involved in the expression of eosinophilic inflammation and not in epithelial or airway smooth muscle cell DNA synthesis induced by chronic allergen exposure.
Eynott
Paul R
PR
National Heart and Lung Institute, Imperial College School of Science, Technology and Medicine, London, United Kingdom.
Paavolainen
Niko
N
Groneberg
David A
DA
Noble
Alistair
A
Salmon
Michael
M
Nath
Puneeta
P
Leung
Sum-Yee
SY
Chung
K Fan
KF
D000199:Actins / Q000096:biosynthesis; D000485:Allergens / Q000633:toxicity*; D000818:Animals; D001973:Bromodeoxyuridine; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D006709:Homoarginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007073:Immunoglobulin E / Q000096:biosynthesis; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D007527:Isoenzymes / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D010047:Ovalbumin / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D012137:Respiratory System / Q000166:cytology* / Q000187:drug effects / Q000473:pathology*
D000199:Actins; D000485:Allergens; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C446200:L-N(6)-(1-iminoethyl)lysine tetrazole-amide; D006709:Homoarginine; D009569:Nitric Oxide; D007073:Immunoglobulin E; D010047:Ovalbumin; D004247:DNA; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D001973:Bromodeoxyuridine