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Acute Lung Injury Induced by Lipopolysaccharide Is Independent of Complement Activation¹

Daniel Rittirsch^*, Michael A. Flierl^*, Danielle E. Day^*, Brian A. Nadeau^*, Stephanie R. McGuire^*, Laszlo M. Hoesel^*,, Kyros Ipaktchi, Firas S. Zetoune^*, J. Vidya Sarma^*, Lin Leng^¶, Markus S. Huber-Lang, Thomas A. Neff, Richard Bucala^¶ and Peter A. Ward^2,*

^* Department of Pathology and Department of Traumatology, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Anesthesiology, University Hospital Zurich, Zurich, Switzerland; Department of Traumatology, Hand, Plastic, and Reconstructive Surgery, University Hospital Ulm, Ulm, Germany; and ^¶ Department of Medicine and Pathology, Yale University School of Medicine, The Anlyan Center, New Haven, CT 06520

Although acute lung injury (ALI) is an important problem in humans, its pathogenesis is poorly understood. Airway instillation of bacterial LPS, a known complement activator, represents a frequently used model of ALI. In the present study, pathways in the immunopathogenesis of ALI were evaluated. ALI was induced in wild-type, C3^–/–, and C5^–/– mice by airway deposition of LPS. To assess the relevant inflammatory mediators, bronchoalveolar lavage fluids were evaluated by ELISA analyses and various neutralizing Abs and receptor antagonists were administered in vivo. LPS-induced ALI was neutrophil-dependent, but it was not associated with generation of C5a in the lung and was independent of C3, C5, or C5a. Instead, LPS injury was associated with robust generation of macrophage migration inhibitory factor (MIF), leukotriene B₄ (LTB4), and high mobility group box 1 protein (HMGB1) and required engagement of receptors for both MIF and LTB4. Neutralization of MIF or blockade of the MIF receptor and/or LTB4 receptor resulted in protection from LPS-induced ALI. These findings indicate that the MIF and LTB4 mediator pathways are involved in the immunopathogenesis of LPS-induced experimental ALI. Most strikingly, complement activation does not contribute to the development of ALI in the LPS model.

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 work was supported by National Institutes of Health Grants GM-29507 and HL-31963 (to P.A.W.), AI43210 (to R.B.), and Deutsche Forschungsgemeinschaft Grant HU 823/2-2 (to M.S.H.-L.).

² Address correspondence and reprint requests to Dr. Peter A. Ward, Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109. E-mail address: pward{at}umich.edu

³ Abbreviations used in this paper: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; BAL, bronchoalveolar lavage; HMGB1, high mobility group box 1 protein; KC, CXCL1; LIX, LPS-induced CXC chemokine; LTB4, leukotriene B₄; MIF, migration inhibitory factor; MPO, myeloperoxidase; WT, wild type.