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Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis
Journal article   Open access   Peer reviewed

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

Shubha Murthy, Andrea Adamcakova-Dodd, Sarah S Perry, Linda A Tephly, Richard M Keller, Nervana Metwali, David K Meyerholz, Yongqiang Wang, Michael Glogauer, Peter S Thorne, …
American journal of physiology. Lung cellular and molecular physiology, Vol.297(5), pp.L846-L855
11/2009
DOI: 10.1152/ajplung.90590.2008
PMCID: PMC2777495
PMID: 19684199
url
https://doi.org/10.1152/ajplung.90590.2008View
Published (Version of record) Open Access

Abstract

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-alpha and ROS in a Rac1-dependent manner. TNF-alpha 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.
 Asbestos Catalase - pharmacology Tumor Necrosis Factor-alpha - metabolism Cell Line Lung - pathology Reactive Oxygen Species - metabolism Cell Count Humans Transforming Growth Factor beta1 - metabolism rac1 GTP-Binding Protein - deficiency Pulmonary Fibrosis - pathology Enzyme Activation - drug effects Lung - enzymology Cell Movement - drug effects Animals Interleukin-1beta - metabolism Lung - drug effects Pulmonary Fibrosis - enzymology Pulmonary Fibrosis - prevention & control Pulmonary Fibrosis - chemically induced Bronchoalveolar Lavage Fluid - cytology Mice rac1 GTP-Binding Protein - metabolism

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