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Modulation of reactive oxygen species and MMP9 by Rac1 prevents asbestos‐induced pulmonary fibrosis
Author(s) -
Murthy Shubha,
Tephly Linda,
Perry Sarah,
AdamcakovaDodd Andrea,
Keller Richard,
Metwali Nervana,
Wang Yongqiang,
Glogauer Michael,
Thorne Peter,
Carter A. Brent
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.572.4
Subject(s) - mmp9 , reactive oxygen species , pulmonary fibrosis , rac1 , fibrosis , biology , chemistry , microbiology and biotechnology , cancer research , pathology , downregulation and upregulation , medicine , biochemistry , signal transduction , gene
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. We hypothesized that Rac1 induced pulmonary fibrosis via generation of ROS. Asbestos increased ROS in a Rac1‐dependent manner with ROS being significantly greater in wild type (WT) mice compared to Rac1 null mice. Extracellular matrix degradation was dependent on Rac1 activity and ROS. Expression of the macrophage specific metalloproteinase, MMP9, was significantly less in WT cells compared to Rac1 null cells. In addition, Rac1 null cells exhibited enhanced gene expression driven by AP1, an important transcription factor in MMP9 expression. Over expression of catalase decreased ROS generation and increased MMP9 expression in vitro. 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. This work was supported by NIH grant ES‐015981.