Role of reactive O2 in phagocyte-induced hypermetabolism and pulmonary injury.
Activated phagocytes possess an enormous capacity for O2 consumption via NADPH oxidase. NADPH oxidase partially reduces O2, forming superoxide (O2-). Host enzymes rapidly complete O2- reduction to H2O, leaving little trace of its prior existence. Our objectives were to estimate the magnitude of whole body phagocyte respiration and determine the contribution of NADPH-derived O2- to the ensuing phagocyte-induced pulmonary injury. These objectives were accomplished using specific inhibitors of NADPH oxidase, diphenyl iodonium (DPI) and di-2-thienyl iodonium (DTI). Guinea pigs received intravenous injections of DPI (3.5 mg/kg), DTI (7.5 mg/kg), or vehicle followed by phorbol myristate acetate (PMA). Phagocyte activation by PMA immediately increased whole body respiration from 13.6 to 16.1 ml O2.kg-1.min-1 (P < 0.05). DPI and DTI completely blocked the increase in respiration induced by PMA injection (P < 0.05). Baseline respiration was unchanged by the NADPH oxidase inhibitor alone. Likewise, there was no effect on the respiration of isolated heart and kidney mitochondria from animals receiving the inhibitor with or without PMA. DPI attenuated the pulmonary injury induced by PMA. DPI attenuated the pulmonary injury induced by PMA. The ratio of lung water weight to dry weight was lower (6.4 +/- 0.3 vs. 8.3 +/- 0.6) and arterial PO2 was higher (86 +/- 9 vs. 56 +/- 6 Torr) in animals receiving DPI plus PMA than in those receiving PMA alone. In conclusion, phagocyte activation in vivo increased total body respiration by approximately 18%. The burst in respiration is attributed to the phagocyte respiratory burst in which NADPH oxidase partially O2 to O2-.(ABSTRACT TRUNCATED AT 250 WORDS)
Vlessis
A A
AA
Department of Surgery, Oregon Health Sciences University, Portland 97201.
Bartos
D
D
Muller
P
P
Trunkey
D D
DD
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001784:Blood Gas Analysis; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000378:metabolism; D007958:Leukocyte Count; D008171:Lung Diseases / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D009929:Organ Size / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D010586:Phagocytes / Q000201:enzymology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D013876:Thiophenes / Q000494:pharmacology
D000890:Anti-Infective Agents; D001713:Biphenyl Compounds; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D013876:Thiophenes; C031291:diphenyliodonium; C051503:iodonium thiophene; D006861:Hydrogen Peroxide; D009247:NADH, NADPH Oxidoreductases; D013755:Tetradecanoylphorbol Acetate