title: Neither neutrophils nor reactive oxygen species contribute to tissue damage during Pneumocystis pneumonia in mice.
abstract: Neutrophils are implicated in the damage of lung tissue in many disease states, including infectious diseases and environmental insults. These effects may be due to oxidative or nonoxidative functions of the neutrophil or both. We examined the role of neutrophils in pulmonary damage during infection with the opportunistic fungal pathogen Pneumocystis sp. in four mouse models of neutrophil dysfunction. These were (i) a knockout of the gp91(phox) component of NADPH oxidase, in which reactive oxygen species (ROS) production is greatly reduced; (ii) a double knockout of gp91(phox) and inducible nitric oxide synthase, in which ROS and nitric oxide production is greatly decreased; (iii) a knockout of the chemokine receptor CXCR2, in which accumulation of intra-alveolar neutrophils is severely diminished; and (iv) antibody depletion of circulating neutrophils in wild-type mice with the monoclonal antibody RB6. Surprisingly, in each case, indicators of pulmonary damage (respiratory rates, arterial oxygen partial pressures, and intra-alveolar albumin concentrations) were the same in knockout mice and comparable wild-type mice. Therefore, whereas neutrophils are a valid correlative marker of lung damage during Pneumocystis infection, neither neutrophils nor ROS appear to be the causative agent of tissue damage. We also show that there is no difference in Pneumocystis burdens between wild-type and knockout mice, which supports the idea that neutrophils do not have a major role in the clearance of this organism.
authors.affiliation: Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717, USA. uvsss@montana.edu
authors.forename: Steve D
authors.initials: SD
authors.lastname: Swain
authors.forename: Terry W
authors.initials: TW
authors.lastname: Wright
authors.forename: Peter M
authors.initials: PM
authors.lastname: Degel
authors.forename: Francis
authors.initials: F
authors.lastname: Gigliotti
authors.forename: Allen G
authors.initials: AG
authors.lastname: Harmsen
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D017353:Gene Deletion; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011020:Pneumonia, Pneumocystis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000172:deficiency / Q000235:genetics; D012119:Respiration
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D023063:Receptors, Interleukin-8B; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases