Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis.
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.
Murthy
Shubha
S
Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Adamcakova-Dodd
Andrea
A
Perry
Sarah S
SS
Tephly
Linda A
LA
Keller
Richard M
RM
Metwali
Nervana
N
Meyerholz
David K
DK
Wang
Yongqiang
Y
Glogauer
Michael
M
Thorne
Peter S
PS
Carter
A Brent
AB
D000818:Animals; D001194:Asbestos; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002374:Catalase / Q000494:pharmacology*; D002452:Cell Count; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000172:deficiency / Q000378:metabolism*
D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D001194:Asbestos; D002374:Catalase; D020830:rac1 GTP-Binding Protein
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