Reactive oxygen species regulate neutrophil recruitment and survival in pneumococcal pneumonia.
BACKGROUND
The role of NADPH oxidase activation in pneumonia is complex because reactive oxygen species contribute to both microbial killing and regulation of the acute pulmonary infiltrate. The relative importance of each role remains poorly defined in community-acquired pneumonia.


OBJECTIVE
We evaluated the contribution of NADPH oxidase-derived reactive oxygen species to the pathogenesis of pneumococcal pneumonia, addressing both the contribution to microbial killing and regulation of the inflammatory response.


METHODS
Mice deficient in the gp91(phox) component of the phagocyte NADPH oxidase were studied after pneumococcal challenge.


RESULTS
gp91(phox)(-/-) mice demonstrated no defect in microbial clearance as compared with wild-type C57BL/6 mice. A significant increase in bacterial clearance from the lungs of gp91(phox)(-/-) mice was associated with increased numbers of neutrophils in the lung, lower rates of neutrophil apoptosis, and enhanced activation. Marked alterations in pulmonary cytokine/chemokine expression were also noted in the lungs of gp91(phox)(-/-) mice, characterized by elevated levels of tumor necrosis factor-alpha, KC, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and IL-6. The greater numbers of neutrophils in gp91(phox)(-/-) mice were not associated with increased lung injury. Levels of neutrophil elastase in bronchoalveolar lavage were not decreased in gp91(phox)(-/-) mice.


CONCLUSIONS
During pneumococcal pneumonia, NADPH oxidase-derived reactive oxygen species are redundant for host defense but limit neutrophil recruitment and survival. Decreased NADPH oxidase-dependent reactive oxygen species production is well tolerated and improves disease outcome during pneumococcal pneumonia by removing neutrophils from the tight constraints of reactive oxygen species-mediated regulation.
Marriott
Helen M
HM
Section of Infection and Inflammation, School of Medicine and Biomedical Sciences, University of Sheffield, LU107, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK.
Jackson
Laura E
LE
Wilkinson
Thomas S
TS
Simpson
A John
AJ
Mitchell
Tim J
TJ
Buttle
David J
DJ
Cross
Simon S
SS
Ince
Paul G
PG
Hellewell
Paul G
PG
Whyte
Moira K B
MK
Dockrell
David H
DH
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000276:immunology*; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000276:immunology
D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases