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Monocytes control second-phase neutrophil emigration in established lipopolysaccharide-induced murine lung injury

Lookup NU author(s): Professor John SimpsonORCiD

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Abstract

Rationale: Acute lung injury (ALI) is an important cause of morbidity and mortality, with no currently effective pharmacological therapies. Neutrophils have been specifically implicated in the pathogenesis of ALI, and there has been significant research into the mechanisms of early neutrophil recruitment, but those controlling the later phases of neutrophil emigration that characterize disease are poorly understood. Objectives: To determine the influence of peripheral blood monocytes (PBMs) in established ALI. Methods: In a murine model of LPS-induced ALI, three separate models of conditional monocyte ablation were used: systemic liposomal clodronate (sLC), inducible depletion using CD11b diphtheria toxin receptor (CD11b DTR) transgenic mice, and antibody-dependent ablation of CCR2hi monocytes. Measurements and Main Results: PBMs play a critical role in regulating neutrophil emigration in established murine LPS-induced lung injury. Gr1hi and Gr1lo PBM subpopulations contribute to this process. PBM depletion is associated with a significant reduction in measures of lung injury. The specificity of PBM depletion was demonstrated by replenishment studies in which the effects were reversed by systemic PBM infusion but not by systemic or local pulmonary infusion of mature macrophages or lymphocytes. Conclusions: These results suggest that PBMs, or the mechanisms by which they influence pulmonary neutrophil emigration, could represent therapeutic targets in established ALI.

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Author(s): Dhaliwal K, Scholefield E, Ferenbach D, Gibbons M, Duffin R, Dorward DA, Morris AC, Humphries D, Mackinnon A, Wilkinson TS, Wallace WA, vanRooijen N, Mack N, Rossi AG, Davidson DJ, Hirani N, Hughes J, Haslett C, Simpson AJ

Publication type: Article

Publication status: Published

Journal: American Journal of Respiratory and Critical Care Medicine

Year: 2012

Volume: 186

Issue: 6

Pages: 514-524

Print publication date: 15/09/2012

ISSN (print): 1073-449X

ISSN (electronic): 1535-4970

Publisher: American Thoracic Society

URL: http://dx.doi.org/10.1164/rccm.201112-2132OC

DOI: 10.1164/rccm.201112-2132OC

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