Extracellular histones are essential effectors of C5aR‐ and C5L2‐mediated tissue damage and inflammation in acute lung injury

• DOI: 10.1096/fj.13-236380
• Publication Date: 2013-08-28T00:22:55Z
• Authors: Markus Bosmann; Jamison J. Grailer; Robert Ruemmler; Norman F. Russkamp; Firas S. Zetoune; J. Vidya Sarma; Theodore J. Stand...; Peter A. Ward
• Keywords: C5a receptor

We investigated how complement activation promotes tissue injury and organ dysfunction during acute inflammation. Three models of lung (ALI) induced by LPS, IgG immune complexes, or C5a were used in C57BL/6 mice, all requiring availability both receptors (C5aR C5L2) for full development ALI. Ligation C5aR C5L2 with triggered the appearance histones (H3 H4) bronchoalveolar lavage fluid (BALF). BALF from humans ALI contained H4 histone. Histones absent control healthy volunteers. In mice ALI, vivo neutralization antibody reduced intensity Neutrophil depletion markedly presence was highly protective. The direct damaging effects extracellular demonstrated airway administration into rats (Sprague-Dawley), which resulted that receptor-independent, associated intense inflammation, PMN accumulation, damage/destruction alveolar epithelial cells, together release cytokines/chemokines. High-resolution magnetic resonance imaging damage, edema consolidation histone-injured lungs. These studies confirm destructive C5a-dependent linked to histones.