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Neutrophil-Derived IL-6 Limits Alveolar Barrier Disruption in Experimental Ventilator-Induced Lung Injury¹

Paul J. Wolters^*, Charlie Wray, Rachel E. Sutherland^*, Sophia S. Kim^*, Jon Koff^*, Ying Mao and James A. Frank^2,*,,

^* Department of Medicine, Division of Pulmonary and Critical Care Medicine and Cardiovascular Research Institute, University of California, San Francisco, CA 94143; Northern California Institute for Research and Education/Veterans Health Research Institute, San Francisco, CA 94121; and San Francisco Veterans Administration Medical Center, San Francisco, CA 94121

IL-6 is a biological marker of ventilator-associated lung injury that may contribute to alveolar barrier dysfunction in acute respiratory distress syndrome. To determine whether IL-6 affects alveolar barrier disruption in a model of ventilator-induced lung injury, we examined alveolar barrier albumin flux in wild-type (WT) mice given an IL-6-blocking Ab (IL6AB) and mice deficient in IL-6 (IL6KO). Albumin flux was significantly higher in mice given IL6AB compared with mice given a control Ab. Unexpectedly, albumin flux was similar in WT and IL6KO mice. To examine the mechanisms for these findings, lung neutrophil accumulation (myeloperoxidase activity) was compared, revealing a correlation between lung neutrophil accumulation and albumin flux. IL6AB mice had significantly more lung neutrophils than WT and IL6KO mice, which were similar. Therefore, to determine whether the cellular source of IL-6 influences neutrophil accumulation and alveolar barrier function, chimeric mice were compared. WT/KO chimeras (WT mice with IL6KO hematopoietic cells) showed significantly greater albumin flux and neutrophil accumulation with mechanical ventilation than WT/WT mice. Neutrophil depletion decreased albumin flux in WT and WT/KO mice. IL6KO neutrophils were more adherent in an in vitro assay compared with WT neutrophils. IL-6 from a hematopoietic cell source limits alveolar barrier disruption potentially by reducing neutrophil contact with the endothelium. Modulation of IL-6 signaling in a cell type-specific fashion may be a therapeutic target for patients with 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 work was supported by funding from the National Institutes of Health and National Heart, Lung and Blood Institute Grants HL088440 (to J.A.F.) and HL075026 (to P.J.W.).

² Address correspondence and reprint requests to Dr. James A. Frank, Cardiovascular Research Institute, San Francisco Veterans Affairs Medical Center, and Veterans Health Research Institute, University of California, San Francisco, 4150 Clement Street, Box 111D, San Francisco, CA 94121. E-mail address: james.frank{at}ucsf.edu

³ Abbreviations used in this paper: ARDS, acute respiratory distress syndrome; rmIL-6, recombinant mouse IL-6; WT, wild type; EVP%, extravascular plasma equivalent; VILI, ventilator-induced lung injury; BAL, bronchoalveolar lavage; MPO, myeloperoxidase.