Genetic partitioning of interleukin‐6 signalling in mice dissociates Stat3 from Smad3‐mediated lung fibrosis

O’Donoghue, Robert J.J.; Knight, Darryl A.; Richards, Carl D.; Prêle, Cecilia M.; Lau, Hui Ling; Jarnicki, Andrew G.; Jones, Juli E.; Bozinovski, Steven; Vlahos, Ross; Thiem, Stefan; McKenzie, Brent; Wang, Bo; Stumbles, Philip A.; Laurent, Geoffrey J.; McAnulty, Robin J.; Rose-John, Stefan; Zhu, Hong; Anderson, Gary P.; Ernst, Matthias; Mutsaers, Steven E.

doi:10.1002/emmm.201100604

Cited by 138 publications

(123 citation statements)

References 54 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…Activation of STAT3, AKT, and Wnt/ b-catenin pathways was also reported in mouse models of lung fibrosis (59,60). STAT3 activity is directly correlated to inflammatory infiltrates in the lungs and with the severity of fibrosis (61). In our model, thickening of lung connective tissue, collagen content, and alveolar luminal narrowing, all of which are histological features of lung fibrosis, are diminished by niclosamide in HOCl-mice.…”

Section: Discussionsupporting

confidence: 78%

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Morin

Kavian

Nicco

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vasculopathy, and immunological abnormalities. Recent insights on the implication of STAT3, AKT, and Wnt/β-catenin in fibrosis have prompted us to investigate, in a mouse model of ROS-induced SSc, the effects of niclosamide, an antihelmintic drug that inhibits both of these signaling pathways. SSc was induced in BALB/c mice by daily s.c. injections of hypochlorous acid (HOCl). Mice were treated or not every other day, 5 d a week, for 6 wk, by niclosamide. Skin and lung fibrosis as well as immunological features were studied. Mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase 1 autoantibodies. STAT3, AKT, and Wnt/β-catenin pathways were hyperactivated in the skin and the lungs of diseased mice. Niclosamide reversed fibrosis of the skin and the lungs. Beneficial immunological effects were also observed because niclosamide decreased the activation of CD4+ and CD8+ T cells, autoimmune B cell activation, as well as IL-4 and IL-13 production in the skin. The improvement permitted by niclosamide in the mouse model of HOCl-induced SSc as well as the well-documented safety profile of this drug provide a rationale for the evaluation of niclosamide in the management of patients affected by this disease.

show abstract

Section: Discussionsupporting

confidence: 78%

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Morin

Kavian

Nicco

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Alternatively, the fibrosis observed in Fgf2 2/2 mice may develop through a different mechanism than that observed in wild-type mice. For example, IL-6 is known to directly stimulate fibrosis independently of TGF-b1 (60,61), and Fgf2 2/2 mice have prolonged IL-6 expression at late time points after bleomycin.…”

Section: Our Results Show That Fgf2mentioning

confidence: 99%

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Guzy

Stoilov

Elton³

et al. 2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-b1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2 2/2) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2 2/2 mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2 2/2 mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2 2/2 mice similarly have deficient recovery of club cell secretory protein 1 bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo.Keywords: fibroblast growth factor 2; bleomycin; pulmonary fibrosis; lung injury; alveolar epithelial repair Clinical RelevanceFibroblast growth factors (FGFs) and, in particular, FGF2, are implicated in the pathogenesis of pulmonary fibrosis and recovery from airway epithelial cell (AEC) injury; however, the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. In this study, we have found that mice lacking FGF2 do not show altered levels of fibrosis in response to bleomycin, indicating that FGF2 is dispensable for the generation of bleomycin-induced pulmonary fibrosis. In addition, we show that FGF2 knockout mice have increased mortality and weight loss in response to bleomycin, accompanied by deficient recovery of mature alveolar epithelium and epithelial barrier function. These findings suggest that FGF2 is required for lung epithelial recovery, that pharmacological inhibition of FGF signaling could impair the response to lung injury, and that FGF2 administration or augmentation may have therapeutic benefit for lung injury.Lung alveolar epithelial cell (AEC) injury can be caused by a variety of insults, including infection, trauma, aspiration, and sepsis. Chronic AEC injury of unknown origin is central to ...

show abstract

“…Although IL-6 trans signaling is known to cause fibrosis, the underlying molecular mechanism is unknown. In a mouse model of fibrosis, it was shown that hyperactivation of STAT3 enhanced fibrosis (14), and excessive activation of STAT3 was found in the lung tissue of patients with idiopathic lung fibrosis. Consistent with a role of STAT3 in mediating fibrosis, keloid fibroblasts have excessive IL-6 secretion and respond to IL-6 stimulation with up-regulation of collagen transcription (15).…”

mentioning

confidence: 99%

Interleukin-6 (IL-6) Trans Signaling Drives a STAT3-dependent Pathway That Leads to Hyperactive Transforming Growth Factor-β (TGF-β) Signaling Promoting SMAD3 Activation and Fibrosis via Gremlin Protein

O’Reilly

Ciechomska

Cant

et al. 2014

Journal of Biological Chemistry

210

168

View full text Add to dashboard Cite

Genetic partitioning of interleukin‐6 signalling in mice dissociates Stat3 from Smad3‐mediated lung fibrosis

Cited by 138 publications

References 54 publications

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Interleukin-6 (IL-6) Trans Signaling Drives a STAT3-dependent Pathway That Leads to Hyperactive Transforming Growth Factor-β (TGF-β) Signaling Promoting SMAD3 Activation and Fibrosis via Gremlin Protein

Contact Info

Product

Resources

About