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Abstract Number: 744

Integrin Inhibitor Modulates Pulmonary Fibrosis in the Reactive Oxygen Species Murine Model of Systemic Sclerosis

Gianluca Bagnato1, Alessandra Bitto2, Natasha Irrera2, Gabriele Pizzino2, Neal Roberts3, Domenica Altavilla2, Francesco Squadrito2, Antonino Saitta4 and Gianfilippo Bagnato5, 1Rheumatology, University of Messina, Messina, Italy, 2Pharmacology, University of Messina, Messina, Italy, 3University of Louisville, Louisville, KY, 4Internal Medicine, University of Messina, Messina, Italy, 5Via C. Colombo, 41, Universita Messina, Villafranca Tirrena, Italy

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Animal models, Integrins, interstitial lung disease and systemic sclerosis

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Session Information

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic sclerosis (SSc) is an acquired connective tissue disorder in which inflammation, immune dysregulation and vascular damage lead to fibroblast activation that results in fibrosis of the skin and internal organs. Development of therapies is hampered by lack of understanding of the underlying mechanism of disease. It has been recently shown that alterations in cell–matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes [1]. Both SSc fibroblasts [2] and pulmonary T cells of patients affected by SSc with interstitial lung disease highly express αVβ3 and αVβ5 integrins and they are required for lymphocytic infiltration and collagen accumulation [3]. The aim of the study is therefore to evaluate the effect of the αVβ3 and αVβ5 inhibitor (cilengitide) on the development of pulmonary fibrosis in the HOCl-induced murine model of systemic sclerosis.

Methods: Chronic oxidant stress SSc was induced in BALB/c mice by daily s.c. injections of HOCl for 6 weeks. 25 Mice were randomized in three arms: HOCl alone (n=10), HOCl + Cilengitide (n=10) or vehicle alone (n=5). Treatment with cilengitide 20 (mg/kg/i.p./day) was started four weeks after the administration of HOCl and maintained throughout the remaining experimental period (2 weeks). Lung fibrosis was evaluated by histological methods. The severity of fibrosis was assessed using ordinal or nominal scales and the results compared nonparametrically. Lung concentrations of focal adhesion kinase (FAK) were evaluated by western blot analysis.

Results: The administration of HOCl induced lung fibrosis as demonstrated by routine histological analysis. Cilengitide significantly reduced the histopathological change of HOCl-induced pulmonary fibrosis (Figure 1A-D). Additionally, pulmonary FAK expression was increased in mice treated with HOCl and significantly modulated by cilengitide administration (Figure 1E).

Conclusion: The inhibition of integrin signaling could prove useful as future therapeutic targets for treatment of SSc. Further confirmatory results in a second animal model are needed to better assess the specific effect of cilengitide on the development of fibrosis and myofibroblasts differentiation.

References:

1. Gerber EE, Gallo EM, Fontana SC et al. Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature 2013 Nov 7;503 (7474):126-30

2. AsanoY, Ihn H, Yamane K et al. Increased expression of integrin alphavbeta3 contributes to the establishment of autocrine TGF-beta signaling in scleroderma fibroblasts. J. Immunol. 2005 Dec 1;175(11):7708-18

3. Luzina IG, Todd NW, Nacu N et al. Regulation of pulmonary inflammation and fibrosis through the expression of integrins alphavbeta3 and alphavbeta5 on pulmonary T lymphocytes. Arthritis and Rheum. 2009 May;60(5):15309

 

Figure 1


Disclosure:

G. Bagnato,
None;

A. Bitto,
None;

N. Irrera,
None;

G. Pizzino,
None;

N. Roberts,
None;

D. Altavilla,
None;

F. Squadrito,
None;

A. Saitta,
None;

G. Bagnato,
None.

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