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Mechanisms underlying STAT3-induced lung fibrosis

Prêle, C., Green, A., Handoko, A., Lau, H., O'Donoghue, R., McAnulty, R., Laurent, G., Anderson, G., Knight, D., Ernst, M. and Mutsaers, S. (2014) Mechanisms underlying STAT3-induced lung fibrosis. Respirology, 19 . pp. 54-56.

Link to Published Version: https://doi.org/10.1111/resp.12262_21
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Abstract

Introduction: We previously examined bleomycin-induced lung fibrosis in mice with different capacities to activate gp130-mediated Erk1/2 and Stat1/3 pathways. We observed increased collagen deposition/fibrosis with exaggerated gp130-STAT signalling in gp130757F mice compared to wild-type (wt) and gp130757F; Stat3+/− mice, demonstrating that STAT3 signalling is fundamental to the development of lung fibrosis.

Hypothesis and Aims: STAT3-mediated lung fibrosis is driven by interleukin (IL)-6 family cytokines through mechanisms including epithelial to mesenchymal transition (EMT). This study examined the roles of IL-6 and IL-11 in bleomycin-induced lung fibrosis and determined whether the lungs of bleomycin-treated gp130757F mice demonstrated increased EMT.

Method: Bleomycin or saline was administered intranasally to wt, gp130757F and IL-6 (IL-6-/-) and IL-11 α-receptor knockout (IL-11αR-/-) mice separately or crossed onto a gp130757F background (gp130757F;IL-6-/- and gp130757F;IL-11αR-/- respectively). Collagen and fibrosis were examined by HPLC and histology of lung tissue from all genotypes 30 days post bleomycin treatment. IL-6 family cytokines, EMT markers and inflammatory mediator mRNA and protein were measured in lung tissue and serum at 3 and 30 days following bleomycin.

Results: IL-6, OSM, IL-1 β and TNFα mRNA were significantly increased in gp130757F lung tissue but not in serum 3 days post-bleomycin compared to saline. Furthermore, a two-fold increase in MMP2 and 9 activity was demonstrated in gp130757F mice. We observed evidence of increased epithelial cell hyperplasia and fibroblast number, possibly due to increased EMT, since snail and slug expression were significantly increased in gp130757F lung tissue at 3 and 30 days post-bleomycin. Genetic ablation of IL-6 but not IL-11αR significantly reduced collagen production/fibrosis in bleomycin-treated mice but eliminating either IL-6 or IL-11R in gp130757F mice reduced bleomycin-induced fibrosis in both genotypes.

Conclusion: These data indicate that IL-6 cytokines play a significant role in bleomycin-induced lung fibrosis and that fibroblast accumulation and activity may be driven by STAT3-mediated EMT.

Item Type: Journal Article
Publisher: Wiley-Blackwell
Copyright: © 2014 The Authors/Asian Pacific Society of Respirology
Other Information: Abstracts of the Thoracic Society of Australia & New Zealand and the Australian & New Zealand Society of Respiratory Science 2014 Annual Scientific Meetings, 4‐9 April 2014, Adelaide Convention Centre, Adelaide, SA
URI: http://researchrepository.murdoch.edu.au/id/eprint/64353
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