Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis

• Published in: American journal of physiology. Lung cellular and molecular physiology 2009-11, Vol.297 (5), p.L846-L855
• Main Authors: Murthy, Shubha, Adamcakova-Dodd, Andrea, Perry, Sarah S, Tephly, Linda A, Keller, Richard M, Metwali, Nervana, Meyerholz, David K, Wang, Yongqiang, Glogauer, Michael, Thorne, Peter S, Carter, A. Brent
• Format: Article
• Language: English
• Subjects: Animals; Asbestos; Bronchoalveolar Lavage Fluid - cytology; Catalase - pharmacology; Cell Count; Cell Line; Cell Movement - drug effects; Cystic fibrosis; Cytokines; Enzyme Activation - drug effects; Humans; Interleukin-1beta - metabolism; Lung - drug effects; Lung - enzymology; Lung - pathology; Mice; Oxygen; Pathogens; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - enzymology; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - prevention & control; rac1 GTP-Binding Protein - deficiency; rac1 GTP-Binding Protein - metabolism; Reactive Oxygen Species - metabolism; Respiratory diseases; Studies; Transforming Growth Factor beta1 - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.90590.2008

Departments of 1 Internal Medicine, ; 3 Pathology, and ; 6 Free Radical and Radiation Biology, Carver College of Medicine, ; Departments of 2 Occupational and Environmental Health and ; 5 Human Toxicology, College of Public Health, University of Iowa, Iowa City, Iowa; and ; 4 Canadian Institutes of Health Research Group in Matrix Dynamics, University of Toronto, Toronto, Ontario, Canada Submitted 26 November 2008 ; accepted in final form 10 August 2009 The release of reactive oxygen species (ROS) and cytokines by alveolar macrophages has been demonstrated in asbestos-induced pulmonary fibrosis, but the mechanism linking alveolar macrophages to the pathogenesis is not known. The GTPase Rac1 is a second messenger that plays an important role in host defense. In this study, we demonstrate that Rac1 null mice are protected from asbestos-induced pulmonary fibrosis, as determined by histological and biochemical analysis. We hypothesized that Rac1 induced pulmonary fibrosis via generation of ROS. Asbestos increased TNF- and ROS in a Rac1-dependent manner. TNF- was elevated only 1 day after exposure, whereas ROS generation progressively increased in bronchoalveolar lavage cells obtained from wild-type (WT) mice. To determine whether ROS generation contributed to pulmonary fibrosis, we overexpressed catalase in WT monocytes and observed a decrease in ROS generation in vitro . More importantly, administration of catalase to WT mice attenuated the development of fibrosis in vivo. For the first time, these results demonstrate that Rac1 plays a crucial role in asbestos-induced pulmonary fibrosis. Moreover, it suggests that a simple intervention may be useful to prevent progression of the disease. macrophages Address for reprint requests and other correspondence: A. B. Carter, C33 GH, Univ. of Iowa Carver College of Medicine, Iowa City, IA 52242 (e-mail: brent-carter{at}uiowa.edu ).