Preservation of complement-induced lung injury in mice with deficiency of NADPH oxidase.
Mice with chronic granulomatous disease (X-CGD mice) generated by mutating the X-linked gene for a subunit of NADPH oxidase have been analyzed for their ability to respond to intravenous injection of purified cobra venom factor (CVF). This agent in wild-type mice produces a neutrophil-dependent and catalase-sensitive form of lung injury. Lung injury was evaluated by measuring the accumulation of extravascular albumin. Quite unexpectedly, the lungs of X-CGD mice showed no difference in the increased accumulation of extravascular albumin after injection of CVF when compared to wild-type mice. In both X-CGD and wild-type mice, full development of injury required neutrophils. While catalase was highly protective in wild-type mice, its protective effects were completely lost in the X-CGD mice. Furthermore, a competitive antagonist of L-arginine, N(G)-methyl-L-arginine, was protective in X-CGD mice but not in wild-type mice. Allopurinol was protective in both types of mice. Both the basal and the CVF-inducible lung mRNA for inducible nitric oxide synthase and IL-1beta was similar in X-CGD and wild-type mice. These data indicate that oxygen radical production and lung injury in response to injection of CVF occurs through alternative pathways in mice with genetic deletion of NADPH oxidase.
Kubo
H
H
Herman B. Wells Center for Pediatric Research, Indiana University Medical Center, Indianapolis 46202, USA.
Morgenstern
D
D
Quinian
W M
WM
Ward
P A
PA
Dinauer
M C
MC
Doerschuk
C M
CM
D000704:Analysis of Variance; D000818:Animals; D002374:Catalase / Q000494:pharmacology; D003165:Complement System Proteins / Q000502:physiology*; D003520:Cyclophosphamide / Q000633:toxicity; D004546:Elapid Venoms / Q000633:toxicity*; D004790:Enzyme Induction; D006105:Granulomatous Disease, Chronic / Q000276:immunology / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D007527:Isoenzymes / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000503:physiopathology*; D055370:Lung Injury; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency* / Q000235:genetics; D019255:NADPH Oxidases; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D012016:Reference Values; D012709:Serum Albumin / Q000032:analysis; D014158:Transcription, Genetic; D014960:X Chromosome
D004546:Elapid Venoms; D007375:Interleukin-1; D007527:Isoenzymes; D012333:RNA, Messenger; D012709:Serum Albumin; C016310:cobra venom factor; D018799:Intercellular Adhesion Molecule-1; D003520:Cyclophosphamide; D003165:Complement System Proteins; D002374:Catalase; D019001:Nitric Oxide Synthase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases