Resolvin D1 protects mice from LPS-induced acute lung injury

Abstract

Resolvin D1 (RvD1), an endogenous lipid molecule derived from docosahexaenoic acid (DHA), has been described to promote inflammatory resolution. The present study aimed to determine the protective effects and the underlying mechanisms of RvD1 on lipopolysaccharide (LPS)-induced acute lung injury (ALI). Pretreatment RvD1 to mice 30 min before inducing ALI by LPS decreased the mortality and improved lung pathological changes, inhibited LPS-induced increases in polymorphonulear and mononuclear leukocytes recruitment, total proteins content, tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) production in the bronchoalveolar lavage fluids (BALFs). In addition, RvD1 markedly reduced LPS-induced the expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and adhesion molecules, as well as myeloperoxidase (MPO) activity. Moreover, RvD1 markedly inhibited LPS-induced the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). Furthermore, pretreatment with Boc, a lipoxin A4 receptor (ALX) antagonist, significantly reversed these beneficial effects of RvD1 on LPS-induced acute lung injury in mice. Taken together, our study showed that RvD1 improved survival rate and attenuated ALI in mice induced by LPS, and the protective mechanisms might be related to selective reaction with ALX, which inhibits MAPKs and NF-κB pathway.

Introduction

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) is a critical pathological condition especially in some severe infectious respiratory diseases, it is characterized by alveolar-capillary membrane disruption, extensive leukocyte infiltration and release of pro-inflammatory mediators, pulmonary edema associated with proteinaceous alveolar exudates and deterioration of gas exchange, and finally respiratory failure [1], [2]. Despite advances in respiratory apparatus and careful nursing; it remains an extremely poor prognosis and high mortality to 30–40% in intensive care units [3], [4], [5].

Lipopolysaccharide (LPS), a glycolipid of the outermost membrane of gram-negative bacteria, is a common cause of leading to ALI [6]. In acute Gram-negative bacterial pneumonia, LPS is released from bacterial and induces host inflammatory response. The inflammatory response is advantageous for the eradication of bacteria, however, unrestrained and excessive inflammation is harmful to the host and, even fatal, owing to severe lung tissue damage, or acute respiratory distress (ARDS) [7], [8], [9]. Thereby, it is important to make effective preventions and therapies for controlling the imbalance of inflammatory response. In fact, the inflammatory response is normally regulated by negative feedback systems to prevent host from damage and to enable to return to homeostasis [10]. In recent some years, endogenous negative mediators and mechanisms of inflammatory resolution have become a new hotspot in governing inflammation.

Resolvin D1 (RvD1) is a novel lipid mediator identified in resolving inflammatory exudates that was enzymatically derived from docosahexaenoic acid (DHA) [11], [12]. Previous studies showed that RvD1 had potent anti-inflammatory effects in several disease models including peritonitis, inflammatory corneal hemangiogenesis, and ischemia-reperfusion-induced lung injury and kidney injury [11], [12], [13], [14], [15], [16], [17], [18]. Recent studies showed that DHA, which may be converted in vivo via lipoxygenase-initiated mechanisms to the 17 S hydroxy-containing RvD1, could modulate the balance between pro- and anti-inflammatory cytokines, alter the response of the host to pulmonary bacterial infection, and affect the early outcome of infection [19], [20].

Based on these effects of RvD1, in this study, we examined whether RvD1 could exert protective effects on LPS-induced acute lung injury and further revealed its underlying mechanism.