Amelioration of Systemic Fibrosis in Mice by Angiotensin II Receptor Blockade

Abstract

Objective. Systemic sclerosis (SSc) is characterized by microvascular damage, fibrosis of skin and visceral organs, and autoimmunity. Previous studies have shown that angiotensin II is involved in the synthesis of type I collagen. We investigated whether the blockade of angiotensin II receptor type I (AT 1 ) by irbesartan reduces skin and lung fibrosis in 2 murine models of SSc. Methods. SSc was induced by daily intradermal injection of HOCl into the backs of BALB/c mice (HOCl-induced SSc). Mice were treated daily with irbesartan by oral gavage.Results. Irbesartan reduced dermal thickness, collagen concentration, Smad2/3, and ␣-smooth muscle actin expression, as well as fibroblast proliferation and H-Ras expression in the skin of mice with HOClinduced SSc. Mice treated with irbesartan also displayed less lung fibrosis, less inflammation, and a lower concentration of collagen in the lungs than untreated mice. Exhaled nitric oxide, inducible nitric oxide synthase, and 3-nitrotyrosine expression in the lungs were decreased following irbesartan treatment. Moreover, irbesartan reduced the number and the proliferation of splenic B and T cells and the serum levels of anti-DNA topoisomerase I autoantibodies.Conclusion. Irbesartan, an AT 1 antagonist, prevents fibrosis and inflammation and inhibits nitric oxide production in HOCl-induced models of systemic fibrosis. Our findings extend the indication of an AT 1 antagonist to SSc patients with diffuse fibrosis, especially those with lung involvement.

The cytokines of pulmonary fibrosis: Much learned, much more to learn

“…Cytokine-like molecules, such as endothelin, a systemic and renal vasoconstrictor and a natriuretic hormone known for its involvement in the regulation of inflammation and fibrosis [83,84]; the ''satiety hormone'' leptin, known for its contribution to fibrosis [85]; and a reproductive hormone relaxin, known for its antifibrotic properties [86,87], are therefore not included in this discussion. Non-cytokine soluble factors with both systemic effects and engagement in fibrosis, such as angiotensin [88,89], lysophosphatidic acid [90], eicosanoids [91,92], serotonin [93], adenosine [94], and numerous other molecules, are also not discussed, because their contributions would require a separate review article.…”

A novel model for treatment of hypertrophic pachymeningitis

“…LATY136F mutant mice aged 3 weeks ( N = 6 LATY136 mutant mice and N = 5 WT mice) were orally administered PBS as a placebo or 50 mg/kg per day of irbesartan (Wako Pure Chemical Industries Ltd., Osaka, Japan) for three consecutive weeks, based on a previous report . These mice were sacrificed at 6 weeks of age.…”

Cellular and molecular mechanisms in the pathophysiology of systemic sclerosis

“…Attenuated fibrosis in SCID mice argued for a significant synergistic role of the immune systems via generation of advanced oxidation protein products (AOPP), responsible for profibrotic effects on fibroblasts in this model [91]. Many signaling pathways have been implicated in the pathophysiology of this experimental disease, comprising the cannabinoids [92], the Notch proteins activated by metalloprotease ADAM-17 [93], PDGF [94], and angiotensin II [95]. Interestingly, treatment of HOCl-intoxicated mice by pro-oxidants such as arsenic trioxide (As 2 O 3 ) or the organotellurique catalyst ([PHTE] 2 NQ) permitted to ''kill'' activated fibroblasts and therefore reduce skin and lung fibrosis in this murine model of SSc [96].…”