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.
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ABSTRACT: Acute lung injury is a severe illness with a high rate of mortality. Maresin1 (MaR1) was recently reported to regulate inflammatory responses. We used a lipopolysaccharide (LPS)-induced acute lung injury model to determine whether MaR1 could mitigate the lung injury. Male BALB/c mice were exposed to intratracheal administration of either LPS (3 mg/kg) or normal saline (1.5 ml/kg). After this, normal saline, a low dose of MaR1 (0.1 ng/mouse) or a high dose of MaR1 (1 ng/mouse) was given intravenously. Lung injury was evaluated by detecting arterial blood gas, pathohistological examination, pulmonary edema, inflammatory cells infiltration, inflammatory cytokines in the bronchoalveolar lavage fluid, and neutrophil-platelet interactions. The high dose of MaR1 was significantly protective in treating LPS-induced acute lung injury through restoring oxygenation, attenuating pulmonary edema and mitigating pathohistological changes. A combination of enzyme-linked immunosorbent assay and immunohistochemistry showed that high dose MaR1 attenuated LPS-induced increases in pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6), chemokines (keratinocyte chemokine (KC), monocyte chemoattractant protein (MCP)-5, macrophage inflammatory protein (MIP)-1α, and MIP-1γ), pulmonary myeloperoxidase activity, and neutrophil infiltration in the lung tissues. Consistent with these observations, flow cytometry and western blotting indicated that MaR1 down-regulated LPS-induced neutrophil adhesions and suppressed the expression of intercellular adhesion molecule (ICAM)-1, P-selection and CD24. High dose MaR1 mitigated LPS-induced lung injury in mice by inhibiting neutrophil adhesions and decreasing levels of pro-inflammatory cytokines.British Journal of Pharmacology 04/2014; · 5.07 Impact Factor
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ABSTRACT: BACKGROUND: Docosahexaenoic acid (DHA) and DHA-derived lipid mediators have recently been shown to possess anti-inflammatory and pro-resolving properties. In fact, DHA can down-regulate lipolysaccharide (LPS)-induced activation of NF-kappaB via a PPARgamma-dependent pathway. We sought to investigate the effects of the novel DHA-derived mediator resolvin D1 (RvD1) on LPS-induced acute lung injury and to determine whether these effects occur via a PPARgamma-dependent pathway. METHODS: BALB/c mice aged 6--8 weeks were randomly divided into seven groups: two control groups receiving saline or RvD1 (600 ng) without LPS; a control group receiving LPS only; an experimental group receiving RvD1 (300 ng) or RvD1 (600 ng), followed by LPS; a group receiving the PPARgamma antagonist GW9662; and a group receiving GW9662, then RvD1 (600 ng) and finally LPS. LPS (50 muM) and saline were administered intratracheally. RvD1 was injected intravenously 24 h and 30 min before LPS, while GW9662 was injected intravenously 30 min before RvD1. Mice were killed at 6, 12, and 24 h. Samples of bronchoalveolar lavage fluid (BALF) were analyzed for cell counts and cytokine analysis. Lung tissues were collected for histology, Western blotting and electrophoretic mobility shift assays (EMSAs). RESULTS: At all three time points, groups receiving either dose of RvD1 followed by LPS had significantly lower total leukocyte counts and levels of TNF-alpha and IL-6 levels in BALF than did the group given only LPS. RvD1 markedly attenuated LPS-induced lung inflammation at 24 h, based on hematoxylin-eosin staining of histology sections. RvD1 activated PPARgamma and suppressed IkappaBalpha degradation and NF-kappaB p65 nuclear translocation, based on Western blots and EMSAs. The PPARgamma inhibitor GW9662 partially reversed RvD1-induced suppression of IkappaBalpha degradation and p65 nuclear translocation. CONCLUSIONS: These results suggest that RvD1 may attenuate lung inflammation of LPS-induced acute lung injury by suppressing NF-kappaB activation through a mechanism partly dependent on PPARgamma activation.Respiratory research 12/2012; 13(1):110. · 3.64 Impact Factor
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ABSTRACT: Pulmonary inflammation and tissue remodelling are common elements of chronic respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and pulmonary hypertension (PH). In disease, pulmonary mesenchymal cells not only contribute to tissue remodelling, but also have an important role in pulmonary inflammation. This review will describe the immunomodulatory functions of pulmonary mesenchymal cells, such as airway smooth muscle (ASM) cells and lung fibroblasts, in chronic respiratory disease. An important theme of the review is that pulmonary mesenchymal cells not only respond to inflammatory mediators, but produce their own mediators, whether pro-inflammatory or pro-resolving, which influence the quantity and quality of the lung immune response. The notion that defective pro-inflammatory or pro-resolving signalling in these cells potentially contributes to disease progression is also discussed. Finally, the concept of specifically targeting pulmonary mesenchymal cell immunomodulatory function to improve therapeutic control of chronic respiratory disease is considered.Pulmonary Pharmacology & Therapeutics 01/2014; · 2.54 Impact Factor