Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 39, Issue 4, Pages 458-465Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2007-0320OC
Keywords
proteasome inhibitors; bleomycin-induced pulmonary fibrosis; TSK-1/+mice; TGF-beta
Funding
- Swiss National Science Foundation [310000-112180/1]
- Association des Sclerodermiques de France
- AMPLI
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In systemic sclerosis (SSc), a disease characterized by fibrosis of the skin and internal organs, the occurrence of interstitial lung disease is responsible for high morbidity and mortality. We previously demonstrated that proteasome inhibitors (PI) show anti-fibrotic properties in vitro by reducing Collagen production and favoring Collagen degradation in a c-jun N-terminal kinase (JNK)-dependent manner in human fibroblasts. Therefore, we tested whether PI could control fibrosis development in bleomycin-induced lung injury, which is preceded by massive inflammation. We extended the study to test PI in TSK-1/+mice, where skin fibrosis develops in the absence of overt inflammation. C57BI/6 mice received bleomycin intratracheally and were treated or not with PI. Lung inflammation and fibrosis were assessed by histology and quantification of hydroxyproline content, type I collagen mRNA, and TGF-beta at Days 7,15, and 21, respectively. Histology was used to detect skin fibrosis in TSK-1/+mice. The chymotryptic activity of 20S proteasome was assessed in mice blood. INK and Smad2 phosphorylation were evaluated by Western blot on lung protein extracts. PI reduced Collagen mRNA levels in murine lung fibroblasts, without affecting their viability in vitro. In addition PI inhibited the chymotryptic activity of proteasome and enhanced INK and TGF-beta signaling in vivo. PI failed to prevent bleomycin-induced lung inflammation and fibrosis and to attenuate skin fibrosis in TSK-1/+mice. In conclusion, our results provide direct evidence that, despite promising in vitro results, proteasome blockade may not be a strategy easily applicable to control fibrosis development in diseases such as lung fibrosis and scleroderma.
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