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Attenuation of IgG immune complex-induced acute lung injury by silencing C5aR in lung epithelial cells

Lei Sun^*,1, Ren-Feng Guo^*,,1, Hongwei Gao^*, J. Vidya Sarma^*, Firas S. Zetoune^* and Peter A. Ward^*,2

^* Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; and

Department of Trauma Surgery, Hannover Medical School, Hannover, Germany

² Correspondence: Department of Pathology, University of Michigan Medical School, 1301 Catherine Rd., Ann Arbor, MI 48109-5602, USA. E-mail: pward{at}umich.edu

Acute lung injury (ALI) in mouse lung occurs after distal airway deposition of IgG immune complexes (IgGICs), resulting in a breakdown of the vascular-airway barrier, causing intrapulmonary edema, hemorrhage, and accumulation of neutrophils [polymorphonuclear leukocytes (PMNs)] in the alveolar compartment, these changes being complement (C5a) and C5a receptor (C5aR) dependent. In this ALI model, C5aR expression (protein) was found to occur on upper (bronchial) and lower (alveolar) airway epithelial cells. An adenovirus construct (siRNA) was used to silence mRNA for C5aR in the lung. Under such conditions, C5aR protein was markedly reduced on lung epithelial cells, resulting in much reduced leakage of albumin into the lung, diminished buildup of PMNs, and lower levels of proinflammatory mediators in bronchoalveolar lavage fluids. These studies indicate that bronchial and alveolar epithelial cell C5aR is up-regulated and greatly contributes to inflammation and injury in the lung. The use of siRNA administered into the airways avoids systemic suppression of C5aR, which might compromise innate immunity. It is possible that such an intervention might be employed in humans with ALI or acute respiratory distress syndrome as well as in upper-airway inflammatory diseases, such as chronic obstructive pulmonary disease and asthma, where there is evidence for complement activation and buildup of PMNs.—Sun, L., Guo, R.-F., Gao, H., Sarma, J. V., Zetoune, F. S., Ward, P. A. Attenuation of IgG immune complex-induced acute lung injury by silencing C5aR in lung epithelial cells.

Key Words: complement • siRNA • PMNs • inflammation