A possible involvement of oxidative lung injury in endotoxin-induced bronchial hyperresponsiveness to substance P in guinea pigs.

Abstract

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.

• Authors: S Iwamae, H Tsukagoshi, T Hisada, D Uno, M Mori
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 151 Issue 2 Pg. 245-53 (Aug 1998) ISSN: 0041-008X [Print] United States
• PMID: 9707501 (Publication Type: Journal Article)
• Copyright: Copyright 1998 Academic Press.

Chemical References

• Acetophenones
• Anti-Inflammatory Agents, Non-Steroidal
• Endotoxins
• Enzyme Inhibitors
• Lipid Peroxides
• Purinones
• Reactive Oxygen Species
• SDZ MKS 492
• SDZ ISQ 844
• Aminophylline
• Substance P
• Hypochlorous Acid
• acetovanillone
• Papaverine
• Phosphoric Diester Hydrolases
• Neprilysin

Topics

• Acetophenones (pharmacology)
• Aminophylline (pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Bronchi (drug effects, enzymology, metabolism)
• Bronchial Hyperreactivity (chemically induced, metabolism)
• Drug Hypersensitivity (etiology)
• Endotoxins (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Guinea Pigs
• Hypochlorous Acid (blood)
• Leukocytes (drug effects, metabolism)
• Lipid Peroxides (blood)
• Lung (drug effects, pathology)
• Male
• Neprilysin (antagonists & inhibitors, metabolism)
• Oxidative Stress
• Papaverine (analogs & derivatives, pharmacology, therapeutic use)
• Phosphoric Diester Hydrolases (metabolism)
• Purinones (pharmacology, therapeutic use)
• Reactive Oxygen Species
• Substance P (toxicity)