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

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

doi:10.1152/ajplung.90590.2008

Cited by 74 publications

(82 citation statements)

References 47 publications

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“…Cell Culture-WT and Rac1 null macrophages were obtained from WT and Rac1 null mice as described previously (23). Cells were maintained in RPMI 1640 medium containing 10% newborn calf serum, 0.5 mM ␤-mercaptoethanol, and penicillin/streptomycin.…”

Section: Methodsmentioning

confidence: 99%

“…We recently demonstrated that Rac1 activity in alveolar macrophages, via H 2 O 2 production, is required for asbestosinduced pulmonary fibrosis (23). We now investigated the mechanisms for Rac1-mediated ROS signaling focusing on the transcriptional regulation of MMP-9.…”

Section: Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

“…Null Cells-Our previous observations demonstrated that deletion of Rac1 from macrophages protects mice from asbestos-induced pulmonary fibrosis (23). To determine whether increased matrix degradation in Rac1 null mice accounted, in part, for this effect, we evaluated MMP-9 expression in WT and Rac1 null macrophages.…”

Section: Mmp-9 Expression Is Increased In Rac1mentioning

confidence: 99%

“…H 2 O 2 Inhibits MMP-9 Expression-We have previously demonstrated that asbestos-induced pulmonary fibrosis in WT mice is accompanied by increased ROS generation in alveolar macrophages and that intratracheal administration of catalase significantly attenuates pulmonary fibrosis in these mice (23). Because Rac1 has been shown to increase H 2 O 2 generation (21, 37), we evaluated the effect of H 2 O 2 on MMP-9 expression.…”

Section: Mmp-9 Expression Is Increased In Rac1mentioning

confidence: 99%

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Rac1-mediated Mitochondrial H2O2 Generation Regulates MMP-9 Gene Expression in Macrophages via Inhibition of SP-1 and AP-1

Murthy

Ryan

et al. 2010

Journal of Biological Chemistry

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Aberrant matrix deposition is a hallmark of pulmonary fibrosis and is characterized by an imbalance between matrix deposition and degradation. We have previously shown that mice harboring a conditional deletion of the GTP-binding protein, Rac1, in macrophages are protected from asbestos-induced pulmonary fibrosis. To investigate the contribution of aberrant matrix degradation, we addressed the role of Rac1 in regulating expression of macrophage-specific MMP-9 (matrix metalloproteinase-9). We found that MMP-9 gene transcription was significantly greater in Rac1 null macrophages. Deletion and mutational analysis of the MMP-9 promoter revealed that both SP-1 and AP-1 are essential for MMP-9 transcription. Overexpression of constitutive active Rac1 (V12) revealed that H 2 O 2 was derived from the mitochondria. Rac1-induced H 2 O 2 generation down-regulated MMP-9 gene transcription, whereas catalase overexpression in WT cells enhanced MMP-9 expression. SP-1 interacted directly with both c-Jun and c-Fos, and H 2 O 2 decreased this binding, suggesting that SP-1 and AP-1 function cooperatively to regulate MMP-9 transcription. Rac1-mediated H 2 O 2 inhibited the ERK MAPK, which was essential for activation of SP-1 and AP-1. ERK activation and MMP-9 expression were recovered by overexpressing catalase or transfecting siRNA for the mitochondrial iron-sulfur protein, Rieske. These observations were recapitulated in vivo. MMP-9 mRNA was higher in alveolar macrophages isolated from Rac1 null mice and wild type mice given catalase. Rac1 regulates MMP-9 transcription via mitochondrial H 2 O 2 generation, providing a potential mechanism by which Rac1 null mice fail to develop pulmonary fibrosis.

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Section: Methodsmentioning

confidence: 99%

Section: Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

Section: Mmp-9 Expression Is Increased In Rac1mentioning

confidence: 99%

Section: Mmp-9 Expression Is Increased In Rac1mentioning

confidence: 99%

See 2 more Smart Citations

Rac1-mediated Mitochondrial H2O2 Generation Regulates MMP-9 Gene Expression in Macrophages via Inhibition of SP-1 and AP-1

Murthy

Ryan

et al. 2010

Journal of Biological Chemistry

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show abstract

“…[57][58][59][60] Conversely, catalase or other antioxidants can also be administered therapeutically, in various pre-clincal models, which then prevents the onset of fibrosis. [61][62][63][64][65][66] In this context, it is interesting to note that activated myofibroblasts are known to produce and secrete hydrogen peroxide, which can have deleterious paracrine effects on adjacent normal epithelial cells. 67 Furthermore, breast cancer patients show systemic evidence of increased oxidative stress and a decreased anti-oxidant defense, which increases with aging and tumor progression.…”

confidence: 99%