A possible involvement of oxidative lung injury in endotoxin-induced bronchial hyperresponsiveness to substance P in guinea pigs.
Reactive oxygen-derived free radical species have been implicated in the pathogenesis and pathophysiology of inflammatory lung diseases. In a guinea pig model of aerosolized endotoxin-induced bronchial hyperresponsiveness to substance P, a possible involvement of oxidative lung injury was assessed by measuring the changes in membrane-bound neutral endopeptidase activity in the airway tissues and the level of lipid peroxides in the plasma. Vehicle-treated animals developed a neutrophilic airway inflammation, bronchial hyperresponsiveness to substance P associated with neutral endopeptidase hypoactivity, and elevation of lipid peroxides at 18 to 24 h after an exposure to endotoxin (75 microgram/ml, 40 min). A nonselective phosphodiesterase inhibitor, aminophylline, and selective phosphodiesterase isoenzyme inhibitors, SDZ-ISQ-844 (type III/IV) and SDZ-MKS-492 (type III), attenuated the neutrophilic airway inflammation induced by endotoxin. Aminophylline, SDZ-MKS-492, and a superoxide anion-generating NADPH-oxidase inhibitor apocynin inhibited bronchial hyperresponsiveness to substance P with attenuation of neutral endopeptidase inactivation induced by endotoxin. SDZ-ISQ-844, SDZ-MKS-492, and apocynin attenuated the elevation of lipid peroxides. The generation of hypochlorite (OCl-) from whole blood leukocytes was attenuated by aminophylline, SDZ-ISQ-844, SDZ-MKS-492, and apocynin at 1 to 2 h after exposure. These results suggest that reactive oxygen-derived free radical species-mediated oxidative lung injury may play an important role in endotoxin-induced bronchial hyperresponsiveness to substance P, and that phosphodiesterase isoenzyme inhibitors may be potentially useful as anti-inflammatory drugs.
First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma, Japan.
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Iwamae
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Tsukagoshi
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T
Hisada
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D
Uno
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Mori
D000098:Acetophenones / Q000494:pharmacology; D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism*; D004342:Drug Hypersensitivity / Q000209:etiology; D004731:Endotoxins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006997:Hypochlorous Acid / Q000097:blood; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008054:Lipid Peroxides / Q000097:blood; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D010208:Papaverine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011688:Purinones / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species; D013373:Substance P / Q000633:toxicity*
D000098:Acetophenones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004731:Endotoxins; D004791:Enzyme Inhibitors; D008054:Lipid Peroxides; D011688:Purinones; D017382:Reactive Oxygen Species; C073029:SDZ MKS 492; C088309:SDZ ISQ 844; D000628:Aminophylline; D013373:Substance P; D006997:Hypochlorous Acid; C056165:acetovanillone; D010208:Papaverine; D010727:Phosphoric Diester Hydrolases; D015260:Neprilysin