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Translational Respiratory Medicine

, 2:1

First Online: 03 January 2014Received: 17 October 2013Accepted: 27 November 2013DOI: 10.1186-2213-0802-2-1

Cite this article as: Ward, P.A. & Grailer, J.J. Transl Respir Med 2014 2: 1. doi:10.1186-2213-0802-2-1

Abstract

Acute respiratory distress syndrome ARDS in humans involves ≥ 200,000 individuals in the United States, and has a mortality rate 40% for which no specific drug has been approved for use in humans. We have studied experimental acute lung injury ALI in mice following airway deposition of bacterial lipopolysaccharide LPS or the recombinant mouse complement anaphylatoxin, C5a. As ALI developed over 6 hr, extracellular histones appeared in bronchoalveolar lavage fluids BALF. Extracellular histone appearance required both C5a receptors C5aR, C5L2 as well as neutrophils PMNs and lung macrophages, as genetic loss of either C5a receptor or depletion of PMNs or macrophages reduced histone levels found in BALF during ALI. It is possible that extracellular histones were derived from formation of neutrophil extracellular traps NETs in lung after PMN contact with C5a. When purified histones were delivered to lung via the airways, intense inflammatory injury ensued and type II cells developed large blebs indicating cellular damage and apoptosis. Detailed physiological measurements revealed severe disruption of blood-alveolar gas exchange. These data suggest a key role for histones in development of experimental ALI.

KeywordsC5a Histones ALI C5a receptors AbbreviationsALIAcute lung injury

ARDSAcute respiratory distress syndrome

APCActivated protein C

BALFBronchoalveolar lavage fluid

ELISAEnzyme-linked immunosorbent assay

H4Histone H4

LPSLipopolysaccharide

mAbMonoclonal antibody

NETsNeutrophil extracellular traps

PMNsNeutrophils

TLRToll-like receptor

WtWild type.

Electronic supplementary materialThe online version of this article doi:10.1186-2213-0802-2-1 contains supplementary material, which is available to authorized users.

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Autor: Peter A Ward - Jamison J Grailer

Fuente: https://link.springer.com/







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