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* Department of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom; and
Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands
The specialized role of mouse Gr-1high monocytes in local inflammatory reactions has been well documented, but the trafficking and responsiveness of this subset during systemic inflammation and their contribution to sepsis-related organ injury has not been investigated. Using flow cytometry, we studied monocyte subset margination to the pulmonary microcirculation during subclinical endotoxemia in mice and investigated whether marginated monocytes contribute to lung injury in response to further septic stimuli. Subclinical low-dose i.v. LPS induced a rapid (within 2 h), large-scale mobilization of bone marrow Gr-1high monocytes and their prolonged margination to the lungs. With secondary LPS challenge, membrane TNF expression on these premarginated monocytes substantially increased, indicating their functional priming in vivo. Zymosan challenge produced small increases in pulmonary vascular permeability, which were markedly enhanced by the preadministration of low-dose LPS. The LPS-zymosan-induced permeability increases were effectively abrogated by pretreatment (30 min before zymosan challenge) with the platelet-activating factor antagonist WEB 2086 in combination with the phosphatidylcholine-phospholipase C inhibitor D609, suggesting the involvement of platelet-activating factor/ceramide-mediated pathways in this model. Depletion of monocytes (at 18 h after clodronate-liposome treatment) significantly attenuated the LPS-zymosan-induced permeability increase. However, restoration of normal LPS-induced Gr-1high monocyte margination to the lungs (at 48 h after clodronate-liposome treatment) resulted in the loss of this protective effect. These results demonstrate that mobilization and margination of Gr-1high monocytes during subclinical endotoxemia primes the lungs toward further septic stimuli and suggest a central role for this monocyte subset in the development of sepsis-related acute lung injury.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by grants from Biotechnology and Biological Sciences Research Council U.K. (Grant D01820X) and Wellcome Trust (Grant 081208).
2 Address correspondence and reprint requests to Dr. Masao Takata, Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, U.K. Email address: m.takata{at}imperial.ac.uk
3 Abbreviations used in this paper: ALI, acute lung injury; PIM, pulmonary intravascular macrophage; memTNF, membrane-bound TNF; PAF, platelet-activating factor; PC-PLC, phosphatidylcholine-phospholipase.
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  M. R. Wilson, K. P. O'Dea, D. Zhang, A. D. Shearman, N. van Rooijen, and M. Takata Role of Lung-marginated Monocytes in an In Vivo Mouse Model of Ventilator-induced Lung Injury Am. J. Respir. Crit. Care Med., May 15, 2009; 179(10): 914 - 922. [Abstract] [Full Text] [PDF]
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