Dhaliwal et al (2012) Monocytes Control Second-phase Neutrophil Emigration in Established LPS-induced Murine Lung Injury. Am J Respir Crit Care Med. 186(6):514-24.

Monocytes Control Second-phase Neutrophil Emigration in Established LPS-induced Murine Lung Injury.

Dhaliwal, K., Scholefield, E., Ferenbach, D., Gibbons, M., Duffin, R., Dorward, D., Conway Morris, A., Humphries, D., Mackinnon, A., Wilkinson, T., Wallace, W. A., Rooijen, N. V., Mack, M., Rossi, A. G., Davidson, D. J., Hirani, N., Hughes, J., Haslett, C., Simpson, A. J.
Am J Respir Crit Care Med (2012)  186(6):514-24.    PubMed

Davidson lab supported by funding from: MRC

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 utilized; 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. Both Gr1hi and Gr1lo PBM sub-populations contribute to this process. PBM depletion resulted in up to 60% reduction in alveolar neutrophilia, 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 either systemic or local pulmonary infusion of mature macrophages or lymphocytes.
CONCLUSIONS:These results suggest that PBMs themselves, or the mechanisms by which they influence pulmonary neutrophil emigration, could represent therapeutic targets in established ALI.


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