Resolvin D1 Reduces Emphysema and Chronic Inflammation

Abstract

Chronic obstructive pulmonary disease is characterized, in part, by chronic inflammation that persists even after smoking cessation, suggesting that a failure to resolve inflammation plays an important role in the pathogenesis of the disease. It is widely recognized that the resolution of inflammation is an active process, governed by specialized proresolving lipid mediators, including lipoxins, resolvins, maresins, and protectins. Here, we report that proresolving signaling and metabolic pathways are disrupted in lung tissue from patients with chronic obstructive pulmonary disease, suggesting that supplementation with proresolving lipid mediators might reduce the development of emphysema by controlling chronic inflammation. Groups of mice were exposed long-term to cigarette smoke and treated with the proresolving mediator resolvin D1. Resolvin D1 was associated with a reduced development of cigarette smokeeinduced emphysema and airspace enlargement, with concurrent reductions in inflammation, oxidative stress, and cell death. Interestingly, resolvin D1 did not promote the differentiation of M2 macrophages and did not promote tissue fibrosis. Taken together, our results suggest that cigarette smoking disrupts endogenous proresolving pathways and that supplementation with specialized proresolving lipid mediators is an important therapeutic strategy in chronic lung disease, especially if endogenous specialized proresolving lipid mediator signaling is impaired. (Am J Pathol 2015, 185: 3189e3201; http:// dx.doi.org/10.1016/j.ajpath.2015 Chronic obstructive pulmonary disease (COPD) is a major global health problem and a leading cause of death and disability. Tobacco smoking remains the major causative factor in the development of COPD; however, new evidence suggests that household air pollution from fuel used for indoor cooking and heating is also a significant cause.

Anti-inflammatory effects of an oxylipin-containing lyophilised biomass from a microalga in a murine recurrent colitis model

“…It has been recently suggested that these pro-resolution-inducing agents could suppress reactive oxygen species (ROS) production, enhance wound healing and have cytoprotective properties in IBD without causing immunosuppression (40) . Although their mechanisms of action are poorly understood, supplementation with specialised pro-resolving lipid mediators may be an important therapeutic strategy in chronic inflammatory diseases (37,41,42) . Inflammatory cells infiltrate the wounded colonic mucosa and create oxidative stress, producing ROS and nitrogen reactive species, respectively, which contribute to chronic inflammation-associated neoplastic transformation (43) .…”

Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes

“…Other studies have shown that SPM receptors (specifically GPR32 and ALX/FPR2) are dysregulated in chronic disease (39,40). These data point to increased expression of SPMs receptors as a compensatory mechanism or feedback loop in response to inflammation.…”

Resolvin D1 Dampens Pulmonary Inflammation and Promotes Clearance of Nontypeable Haemophilus influenzae

“…While SPMs do not have direct antibacterial properties, they can enhance internalization of bacteria, TNFα expression, and ROS production to mediate killing (25, 33). Although we have not yet demonstrated that AT-RvD1 or other SPMs can improve phagocytosis and bacterial killing in the context of chronic lung inflammatory disease, we recently reported that AT-RvD1 attenuates cigarette smoke-induced emphysema in a mouse model, with reductions in inflammatory signaling and oxidative stress (49). Future studies that evaluate SPMs in a setting of infection following chronic lung disease will be important to understand the translation potential of these compounds.…”