Journal Article

Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia

Mitchell, Tim J, Marriott, Helen M, Cross, Simon S, Simpson, A. John, Hellewell, Paul G, Jackson, Laura E, Buttle, David J, Wilkinson, Thomas S, Ince, Paul G, Dockrell, David H, Whyte, Moira K. B

2008

Overview

Abstract Rationale 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. Objectives 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 gp91phox component of the phagocyte NADPH oxidase were studied after pneumococcal challenge. Measurements and Main Results gp91phox−/− 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 gp91phox−/− 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 gp91phox−/− mice, characterized by elevated levels of tumor necrosis factor-α, KC, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and IL-6. The greater numbers of neutrophils in gp91phox−/− mice were not associated with increased lung injury. Levels of neutrophil elastase in bronchoalveolar lavage were not decreased in gp91phox−/− 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.

• Publisher: Am Thoracic Soc,Oxford University Press,American Lung Association,American Thoracic Society
• Subject: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Animals / Apoptosis / Biological and medical sciences / Cytokines / Disease Models, Animal / Diseases of the respiratory system / E. Pulmonary Infections / Female / Inflammation / Intensive care medicine / Laboratories / Lavage / Lungs / Medical sciences / Membrane Glycoproteins - deficiency / Membrane Glycoproteins - immunology / Mice / Mice, Knockout / NADPH Oxidase 2 / NADPH Oxidases - deficiency / NADPH Oxidases - immunology / Neutrophil Infiltration / Neutrophils / Neutrophils - immunology / Neutrophils - microbiology / Pathogenesis / Pneumonia / Pneumonia, Pneumococcal - immunology / Pneumonia, Pneumococcal - physiopathology / Proteins / Protons / Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects) / Reactive Oxygen Species - immunology / Streptococcus infections / Streptococcus pneumoniae / Tumor necrosis factor-TNF