17(R)-resolvin D1 ameliorates bleomycin-induced pulmonary fibrosis in mice

Abstract

Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. Inflammation plays an integral role in the development of pulmonary fibrosis. Unresolved inflammatory responses can lead to substantial tissue injury, chronic inflammation, and fibrosis. The resolvins are a family of endogenous ω‐3 fatty acid derived‐lipid mediators of inflammation resolution. Resolvin D1 (RvD1) displays potent anti‐inflammatory, pro‐resolving activity, without causing immunosuppression. Its epimer, 17(R)‐resolvin D1 (17(R)‐RvD1), exhibits equivalent functionality to RvD1. In addition, 17(R)‐RvD1 is resistant to rapid inactivation by eicosanoid oxidoreductases. In the present study, we tested the hypothesis that 17(R)‐RvD1 can provide a therapeutic benefit in IPF by reducing inflammation and pulmonary fibrosis, while leaving the normal immune response intact. Mice were exposed to bleomycin (BLM) via micro‐osmotic pump to induce pulmonary fibrosis, and were then treated with 17(R)‐RvD1 or vehicle by intraperitoneal injection. Administration of 17(R)‐RvD1 from the start of BLM treatment attenuated neutrophil alveolar infiltration, lung collagen content, and Interleukin‐1β (IL‐1β), transforming growth factor‐β1 (TGF‐β1), connective tissue growth factor (CTGF), and type I collagen mRNA expression, along with subsequent reduction in histologically detectable fibrosis. The 17(R)‐RvD1‐induced infiltration of inflammatory cells was inhibited by an antagonist of lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2). The administration of 17(R)‐RvD1 at the later fibrotic stage also improved the lung failure. These results suggest that 17(R)‐RvD1 attenuates pulmonary fibrosis by promoting the resolution of neutrophilic inflammation and also provides pulmonary restoration. These data highlight the therapeutic potential of 17(R)‐RvD1 in the management of this intractable disease.

Effect of preventive or therapeutic treatment with angiotensin 1–7 in a model of bleomycin-induced lung fibrosis in mice

“…Indeed, treatment with resolving D1 decreased inflammatory cell recruitment, production of TGF-, and collagen content in a murine model of BLMinduced lung fibrosis. 29 In the latter experiments, resolving D1 was effective even when given many days after BLM instillation. In contrast, therapeutic administration of Ang- (1-7), which also has clear proresolving activities, 28 failed to decrease BLM-induced lung fibrosis at a dose that worked in a preventive manner.…”

“…At least one other study has shown the effect of another proresolving molecule, resolving D1, in a model of fibrosis in mice. Indeed, treatment with resolving D1 decreased inflammatory cell recruitment, production of TGF‐β, and collagen content in a murine model of BLM‐induced lung fibrosis . In the latter experiments, resolving D1 was effective even when given many days after BLM instillation.…”

An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques

“…In support of these findings, RvE1 increased collagen in the context of periodontal ligament repair 49 and 17 R -RvD1 was shown to increase matrix synthesis in a model of arthritis 50 . On the other hand, RvD1 was found to decrease cardiac collagen in the setting of myocardial infarction 51 , and there are several reports that suggest SPMs exert anti-fibrotic actions 52 53 . Thus, the role of SPMs in fibrosis appears to be context-specific, and factors that control its actions in collagen synthesis versus degradation in advanced atherosclerosis represents an important area for future investigation.…”

Specialized pro-resolving mediators in cardiovascular diseases

“…Furthermore, RvE1 increases collagen in the periodontal ligament post injury 41 , and 17 R -RvD1 stimulates matrix synthesis in a model of arthritis 42 . Conversely, RvD1 decreases cardiac collagen in the setting of myocardial infarction 43 , and there other reports suggesting that SPMs exert anti-fibrotic actions 44, 45 . Thus, the role of SPMs in collagen synthesis and fibrosis is context-specific, and an understanding of the mechanisms whereby SPMs increase collagen synthesis in advanced atherosclerotic plaques is likely to be a fruitful area of future investigation.…”