Session Information
Date: Monday, November 9, 2015
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics I
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose:
Activation of sphingosine-1-phosphate (S1P) signaling has been extensively documented in various fibrotic conditions including pulmonary fibrosis. The aim of this study was to provide a molecular basis for therapeutic intervention in lung fibrosis associated with scleroderma by inhibition of S1P using a novel S1P receptor 2 antagonist, AB22. AB22 has improved pharmacokinetics over other S1P receptor antagonists such as AB1 and JTE013.
Methods: AB22 and AB1 comparative efficacy was investigated in lung fibroblasts isolated from patients with scleroderma pulmonary fibrosis and in mice with bleomycin-induced pulmonary fibrosis. Lung injury was induced in 6-8 week old female C57BL/6 mice by a single intratracheal instillation of bleomycin. AB22 (Arroyo BioSciences, LLC, USA) was administrated once daily by gavage beginning on day 1 (early treatment, anti-inflammatory effect) or on day 8 (late treatment, anti-fibrotic effect) following bleomycin instillation. Two and three weeks after bleomycin instillation mice were euthanized, and broncho-alveolar lavage fluid (BALF) and lung tissue were investigated. Multiple sections from each lung were stained with hematoxylin and eosin (H&E) or with trichrome staining for collagen and other extracellular matrix proteins. For the area analysis of fibrotic changes, a quantitative fibrotic scale (Ashcroft scale) was used. Collagen, TGFβ, connective tissue growth factor (CTGF, CCN2), and α-smooth muscle actin (SMA) were studied by immunoblotting and immunofluorescent staining.
Results:
AB22 reduced collagen and CTGF in lung fibroblasts isolated from patients with scleroderma pulmonary fibrosis and in TGFβ-stimulated control fibroblasts to a higher extent as compared with AB1 and was selected for further testing in animal model of pulmonary fibrosis. Both early and late treatment with AB22 attenuated the development of bleomycin-induced pulmonary fibrosis, increased mouse survival, and decreased histological lung inflammation and fibrosis. AB22 significantly reduced inflammatory cells and protein concentrations in BALF and diminished collagen, TGFβ, CTGF, and α-SMA expression in mice with bleomycin-induced lung fibrosis, whereas it had no effect on basal levels of these proteins.
Conclusion:
We conclude that inhibition of S1P receptor 2 using the oral antagonist AB22 restrains profibrotic events in lung fibroblasts and has marked anti-inflammatory and anti-fibrotic effects in a bleomycin model of lung injury. Inhibition of S1P signaling by AB22 may serve as a potential novel therapeutic avenue for the treatment of pulmonary fibrosis associated with scleroderma and other fibrosing diseases.
To cite this abstract in AMA style:
Atanelishvili I, Shirai Y, Akter T, Stolarzewicz E, Swenson RE, Silver R, Bogatkevich GS. Inhibition of Sphingosine-1-Phosphate Signaling By AB22 As a Novel Strategy in the Treatment of Pulmonary Fibrosis Associated with Scleroderma [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/inhibition-of-sphingosine-1-phosphate-signaling-by-ab22-as-a-novel-strategy-in-the-treatment-of-pulmonary-fibrosis-associated-with-scleroderma/. Accessed .« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-sphingosine-1-phosphate-signaling-by-ab22-as-a-novel-strategy-in-the-treatment-of-pulmonary-fibrosis-associated-with-scleroderma/