In vivo investigations on anti-fibrotic potential of proteasome inhibition in lung and skin fibrosis
| Autor: | Jean-Michel Dayer, Carlo Chizzolini, Constance Barazzone Argiroffo, Sylvie Ferrari-Lacraz, Filippo Naso, Jean-Claude Pache, Souad Djaafar, Yves Donati, Laurence Goffin, Massimo Bongiovanni, Serena Fineschi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Male
Pathology Leupeptins Pulmonary Fibrosis Clinical Biochemistry Bortezomib chemistry.chemical_compound Mice Fibrosis Transforming Growth Factor beta Hydroxyproline/metabolism Medicine Lung Cells Cultured Skin Pulmonary Fibrosis/chemically induced/metabolism/pathology ddc:616 Boronic Acids/pharmacology Interstitial lung disease Protein-Serine-Threonine Kinases Boronic Acids Hydroxyproline medicine.anatomical_structure Lung/metabolism/pathology Pyrazines Pyrazines/pharmacology Proteasome Inhibitors Type I collagen Transforming Growth Factor beta/metabolism Proteasome Endopeptidase Complex/antagonists & inhibitors Signal Transduction Pulmonary and Respiratory Medicine medicine.medical_specialty Mice Transgenic Collagen Type I/metabolism Lung injury Protein Serine-Threonine Kinases Bleomycin Collagen Type I In vivo Animals Skin/metabolism/pathology Leupeptins/pharmacology Molecular Biology Scleroderma Systemic Scleroderma Systemic/genetics/metabolism/pathology business.industry Cell Biology medicine.disease Mice Inbred C57BL chemistry Cancer research business |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology, Vol. 39, No 4 (2008) pp. 458-465 |
| ISSN: | 1044-1549 |
| Popis: | 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. C57Bl/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. JNK 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 JNK 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. |
| Databáze: | OpenAIRE |
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