resolvin-d1 and Acute-Lung-Injury

Polymorphonuclear leukocyte (PMN)-mediated acute lung injury from ischemia/reperfusion (I/R) remains a major cause of morbidity and mortality in critical care medicine. Here, we report that inhaled low-dose carbon monoxide (CO) and intravenous resolvin D1 (RvD1) in mice each reduced PMN-mediated acute lung injury from I/R. Inhaled CO (125-250 ppm) and RvD1 (250-500 ng) each reduced PMN lung infiltration and gave additive lung protection. In mouse whole blood, CO and RvD1 attenuated PMN-platelet aggregates, reducing leukotrienes (LTs) and thromboxane B2 (TxB2) in I/R lungs. With human whole blood, CO (125-250 ppm) decreased PMN-platelet aggregates, expression of adhesion molecules, and cysteinyl LTs, as well as TxB2. RvD1 (1-100 nM) also dose dependently reduced platelet activating factor-stimulated PMN-platelet aggregates in human whole blood. In nonhuman primate (baboon) lung infection with Streptococcus pneumoniae, inhaled CO reduced urinary cysteinyl LTs. These results demonstrate lung protection by low-dose inhaled CO as well as RvD1 that each reduced PMN-mediated acute tissue injury, PMN-platelet interactions, and production of both cysteinyl LTs and TxB2. Together they suggest a potential therapeutic role of low-dose inhaled CO in organ protection, as demonstrated using mouse I/R-initiated lung injury, baboon infections, and human whole blood.

Topics: Acute Lung Injury; Animals; Antimetabolites; Carbon Monoxide; Cell Communication; Docosahexaenoic Acids; Female; Humans; Leukocytes, Mononuclear; Leukotrienes; Lung; Male; Mice; Papio; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Thromboxane B2

Topics: Acute Lung Injury; Animals; Docosahexaenoic Acids; Humans; Inflammation; Lipoxins; Lung; Mice; Permeability; Pneumonia, Pneumococcal; Receptors, Lipoxin; Respiratory Distress Syndrome

Acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) are life-threatening critical syndromes characterized by the infiltration of a large number of inflammatory cells that lead to an excessive inflammatory response. Resolvin D1 (RvD1), an endogenous lipid mediator, is believed to have anti-inflammatory and proresolving effects. In the present study, we examined the impact of RvD1 on the pulmonary inflammatory response, neutrophil influx, and lung damage in a murine model of lipopolysaccharide (LPS)-induced ALI. Treatment with RvD1 protected mice against LPS-induced ALI, and compared to untreated mice, RvD1-treated mice exhibited significantly ameliorated lung pathological changes, decreased tumor necrosis factor-α (TNF-α) concentrations and attenuated neutrophil infiltration. In addition, treatment with RvD1 attenuated LPS-induced neutrophil infiltration via the downregulation of CXCL2 expression on resident alveolar macrophages. Finally, BOC-2, which inhibits the RvD1 receptor lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2), reversed the protective effects of RvD1. These data demonstrate that RvD1 ameliorates LPS-induced ALI via the suppression of neutrophil infiltration by an ALX/FPR2-dependent reduction in CXCL2 expression on resident alveolar macrophages.

Topics: Acute Lung Injury; Animals; Chemokine CXCL2; Docosahexaenoic Acids; Lipopolysaccharides; Lung; Macrophages, Alveolar; Mice, Inbred C57BL; Neutrophil Infiltration

In the present study, we aimed to evaluate the role of aspirin-triggered resolvin D1 (AT-RvD1) in paraquat (PQ)-induced acute lung injury (ALI) in mice.. We used C57BL/6J mice as experimental subjects to establish mouse models of ALI via intraperitoneal (IP) injection of PQ (28 mg/kg). The mice were then administered AT-RvD1 (10 or 100 ng) via the tail vein 2 h after exposure to PQ and were sacrificed at 72 h post exposure to harvest bronchoalveolar lavage fluid (BALF), blood and lung tissue samples. The samples were used to evaluate the histopathological changes, inflammation reaction and oxidative stress in the lung tissues.. Compared with those of the PQ group, the administration of AT-RvD1 significantly (1) alleviated the histopathological changes in the lung tissues; (2) reduced the lung W/D weight ratio and the total protein content in the BALF; (3) activated nuclear factor erythroid-2 related factor 2 (Nrf2) and up-regulated the expression of its downstream genes (NADPH: quinone oxidoreductase-1, NQO1 and heme oxygenase-1, HO-1); (4) reduced the malondialdehyde(MDA) level in the lung tissues; (5) reduced the total cell, neutrophil, and macrophage counts in the BALF; (6) reduced the myeloperoxidase (MPO) activity in the lung tissues; (7) reduced the percent of Ly-6G. Administration of AT-RvD1 can effectively inhibit PQ-induced oxidative stress injury, inflammatory responses, and pulmonary edema, thereby alleviating PQ-induced ALI.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cytokines; Docosahexaenoic Acids; Herbicides; Inflammation; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Paraquat; Pulmonary Edema

Acute lung injury (ALI), which presents as acute respiratory failure, is a major clinical problem that requires aggressive care, and patients who require prolonged oxygen exposure are at risk of developing this disease. Although molecular determinants of ALI have been reported, the molecules involved in disease catabasis associated with oxygen toxicity have not been well studied. It has been reported that lung mucosa is rich in omega-3 fatty acid dicosahexanoic acid (DHA), which has antiinflammatory properties. Aspirin-triggered resolvin D1 (AT-RvD1) is a potent proresolution metabolite of DHA that can curb the inflammatory effects in various acute injuries, yet the effect of AT-RvD1 on hyperoxic acute lung injury (HALI) or in the oxygen toxicity setting in general has not been investigated. The effects of AT-RvD1 on HALI were determined for the first time in 8- to 10-week-old C57BL/6 mice that were exposed to hyperoxia (≥95% O2) for 48 hours. Mice were given AT-RvD1 (100 ng) in saline or a saline vehicle for 24 hours in normoxic (≈21% O2) conditions after hyperoxia. Lung tissue and bronchoalveolar lavage (BAL) fluid were collected for analysis associated with proinflammatory signaling and lung inflammation. AT-RvD1 treatment resulted in reduced oxidative stress, increased glutathione production, and significantly decreased tissue inflammation. AT-RvD1 treatment also significantly reduced the lung wet/dry ratio, protein in BAL fluid, and decreased apoptotic and NF-κB signaling. These results show that AT-RvD1 curbs oxygen-induced lung edema, permeability, inflammation, and apoptosis and is thus an effective therapy for prolonged hyperoxia exposure in this murine model.

Topics: Acute Lung Injury; Airway Resistance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Aspirin; Docosahexaenoic Acids; Drug Evaluation, Preclinical; Hyperoxia; Lung; Mice, Inbred C57BL; Neutrophil Infiltration; Oxidative Stress

Inflammation is a key hallmark of ALI and is mediated through ungoverned cytokine signaling. One such cytokine, interleukin-1beta (IL-1β) has been demonstrated to be the most bioactive cytokine in ALI patients. Macrophages are the key players responsible for IL-1β secretion into the alveolar space. Following the binding of IL-1β to its receptor, "activated" alveolar epithelial cells show enhanced barrier dysfunction, adhesion molecule expression, cytokine secretion, and leukocyte attachment. More importantly, it is an important communication molecule between the macrophage and alveolar epithelium. While the molecular determinants of this inflammatory event have been well documented, endogenous resolution processes that decrease IL-1β secretion and resolve alveolar epithelial cell activation and tissue inflammation have not been well characterized. Lipid mediator Aspirin-Triggered Resolvin D1 (AT-RvD1) has demonstrated potent pro-resolutionary effects in vivo models of lung injury; however, the contribution of the alveoli to the protective benefits of this molecule has not been well documented. In this study, we demonstrate that AT-RvD1 treatment lead to a significant decrease in oxidant induced macrophage IL-1β secretion and production, IL-1β-mediated cytokine secretion, adhesion molecule expression, leukocyte adhesion and inflammatory signaling.. THP-1 macrophages were treated with hydrogen peroxide and extracellular ATP in the presence or absence of AT-RvD1 (1000-0.1 nM). A549 alveolar-like epithelial cells were treated with IL-1β (10 ng/mL) in the presence or absence of AT-RvD1 (0.1 μM). Following treatment, cell lysate and cell culture supernatants were collected for Western blot, qPCR and ELISA analysis of pro-inflammatory molecules. Functional consequences of IL-1β induced alveolar epithelial cell and macrophage activation were also measured following treatment with IL-1β ± AT-RvD1.. Results demonstrate that macrophages exposed to H2O2 and ATP in the presence of resolvins show decreased IL-1β production and activity. A549 cells treated with IL-1β in the presence of AT-RvD1 show a reduced level of proinflammatory cytokines IL-6 and IL-8. Further, IL-1β-mediated adhesion molecule expression was also reduced with AT-RvD1 treatment, which was correlated with decreased leukocyte adhesion. AT-RvD1 treatment demonstrated reduced MAP-Kinase signaling. Taken together, our results demonstrate AT-RvD1 treatment reduced IL-1β-mediated alveolar epithelial cell activation. This is a key step in unraveling the protective effects of resolvins, especially AT-RvD1, during injury.

Topics: Acute Lung Injury; Cell Line, Tumor; Docosahexaenoic Acids; Epithelial Cells; Humans; Interleukin-1beta; Macrophages; Models, Biological; Oxidative Stress; Pulmonary Alveoli; Signal Transduction

The recruitment of neutrophils plays an important role in the progress of acute lung injury (ALI). Excessive neutrophils released from bone marrow accumulate in lung, release proinflammatory factors, and cause tissue damage. CXCL-12/CXCR4 is an important signaling pathway, which regulates the migration of bone marrow hematopoietic cells out of bone marrow and involves in neutrophil accumulation and retention in the inflammatory site. Resolvin D1 (RvD1) is a kind of lipid mediators, which can alleviate many inflammatory diseases. We hypothesized that RvD1 can alleviate lipopolysaccharide (LPS)-induced ALI through regulating CXCL-12/CXCR4 pathway.. We randomized mice into five groups: control group, RvD1 group, LPS group, LPS plus RvD1 group, and LPS plus AMD3100 group. ALI was established by intratracheal instillation of LPS. After 24 and 72 h, mice were sacrificed, and lung tissues were harvested for histologic analysis, wet-to-dry ratio, myeloperoxidase activity, and CXCL-12 expression. Bronchoalveolar fluid was collected for protein analysis, cytokines assay, and flow cytometry analysis.. Histologic findings as well as wet-to-dry ratio, protein concentration, cytokines assay, neutrophil number, and myeloperoxidase activity confirmed that RvD1 and AMD3100 alleviated LPS-induced ALI. RvD1 decreased CXCL-12 messenger RNA expression in lung. However, RvD1 promoted CXCR4 expression in neutrophils in the initial stage of inflammation and reduced its level in the later stage.. RvD1 protects LPS-induced ALI partially through regulating CXCL-12/CXCR4 pathway.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Chemokine CXCL12; Docosahexaenoic Acids; Drug Evaluation, Preclinical; Interleukin-1beta; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase; Random Allocation; Receptors, CXCR4; Signal Transduction; Tumor Necrosis Factor-alpha

A variety of inflammatory mediators and effector cells participate together in acute lung injury, and lead to secondary injury that is due to an inflammatory cascade and secondary diffuse lung parenchyma injury. Inflammation is associated with an oxidative stress reaction, which is produced in the development of airway inflammation, and which has positive feedback on inflammation itself. Resolvin D1 can reduce the infiltration of neutrophils, regulate cytokine levels and reduce the inflammation reaction, and thereby promote the resolution of inflammation. The purpose of this study is to investigate the effects of resolvin D1 on an inflammatory response and oxidative stress during lipopolysaccharide (LPS)-induced acute lung injury.. LPS (3 mg/kg) was used to induce the acute lung injury model. Pretreatment resolvin D1 (100 ng/mouse) was given to mice 30 minutes before inducing acute lung injury. Mice were observed at 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days and 7 days after LPS was administrated, then they were humanely sacrificed. We collected bronchoalveolar lavage fluid (BALF) and the lung tissues for further analysis. Paraffin section and HE staining of the lung tissues were made for histopathology observations. Parts of the lung tissues were evaluated for wet-to-dry (W/D) weight ratio. tumor necrosis factor (TNF)-α, inter leukin (IL)-1β, IL-10 and myeloperoxidase (MPO) were detected by enzyme-linked immunosorbent assay (ELISA). A lipid peroxidation malondialdehyde (MDA) assay kit was used to detect MDA. A total superoxide dismutase assay kit with WST-1 was used to analyze superoxide dismutase (SOD). We determined the apoptosis of neutrophils by Flow Cytometry. A real-time quantitative PCR Detecting System detected the expression of mRNA for heme oxygenase (HO)-1.. Pretreatment with resolvin D1 reduced the pathological damage in the lung, decreased the recruitment of neutrophils and stimulated their apoptosis. It markedly decreased the expressions of TNF-α, IL-1β and increased the expressions of IL-10, and decreased the production of MDA and increased the expressions of SOD. The mRNA expression of HO-1 was also significantly increased.. Resolvin D1 displays potent anti-inflammatory actions by regulating cytokines, inhibiting aberrant neutrophil recruitment and stimulating apoptosis of neutrophils. Resolvin D1 can also relieve the injury due to oxidative stress. The mechanisms might be related to increase HO-1 expression.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Docosahexaenoic Acids; Interleukin-10; Interleukin-1beta; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Oxidative Stress; Peroxidase; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Resolvin D1 (7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) (RvD1), generated from ω-3 fatty docosahexaenoic acids, is believed to exert anti-inflammatory properties including inhibition of neutrophil activation and regulating inflammatory cytokines. In this study, we sought to investigate the effect of RvD1 in modulating alveolar fluid clearance (AFC) on LPS-induced acute lung injury. In vivo, RvD1 was injected i.v. (5 μg/kg) 8 h after LPS (20 mg/kg) administration, which markedly stimulated AFC in LPS-induced lung injury, with the outcome of decreased pulmonary edema. In addition, rat lung tissue protein was isolated after intervention and we found RvD1 improved epithelial sodium channel (ENaC) α, γ, Na,K-adenosine triphosphatase (ATPase) α1, β1 subunit protein expression and Na,K-ATPase activity. In primary rat alveolar type II epithelial cells stimulated with LPS, RvD1 not only upregulated ENaC α, γ and Na,K-ATPase α1 subunits protein expression, but also increased Na+ currents and Na,K-ATPase activity. Finally, protein kinase A and cGMP were not responsible for RvD1's function because a protein kinase A inhibitor (H89) and cGMP inhibitor (Rp-cGMP) did not reduce RvD1's effects. However, the RvD1 receptor (formyl-peptide receptor type 2 [FPR2], also called ALX [the lipoxin A4 receptor]) inhibitor (BOC-2), cAMP inhibitor (Rp-cAMP), and PI3K inhibitor (LY294002) not only blocked RvD1's effects on the expression of ENaC α in vitro, but also inhibited the AFC in vivo. In summary, RvD1 stimulates AFC through a mechanism partly dependent on alveolar epithelial ENaC and Na,K-ATPase activation via the ALX/cAMP/PI3K signaling pathway.

Topics: Acute Lung Injury; Alveolar Epithelial Cells; Animals; Cyclic AMP; Docosahexaenoic Acids; Enzyme Activation; Epithelial Sodium Channels; Gene Expression Regulation; Lipopolysaccharides; Lung; Male; Phosphatidylinositol 3-Kinases; Rats; Receptors, Lipoxin; Signal Transduction; Sodium-Potassium-Exchanging ATPase

Increasing evidence suggests that the novel anti-inflammatory and proresolving mediators such as the resolvins play an important role during inflammation. However, the functions of these lipid mediators in immune complex-induced lung injury remain unknown. In this study, we determined the role of aspirin-triggered resolvin D1 (AT-RvD1) and its metabolically stable analog, 17R-hydroxy-19-para-fluorophenoxy-resolvin D1 methyl ester (p-RvD1), in IgG immune complex-induced inflammatory responses in myeloid cells and injury in the lung. We show that lung vascular permeability in the AT-RvD1- or p-RvD1-treated mice was significantly reduced when compared with values in mice receiving control vesicle during the injury. Furthermore, i.v. administration of either AT-RvD1 or p-RvD1 caused significant decreases in the bronchoalveolar lavage fluid contents of neutrophils, inflammatory cytokines, and chemokines. Of interest, AT-RvD1 or p-RvD1 significantly reduced bronchoalveolar lavage fluid complement C5a level. By EMSA, we demonstrate that IgG immune complex-induced activation of NF-κB and C/EBPβ transcription factors in the lung was significantly inhibited by AT-RvD1 and p-RvD1. Moreover, AT-RvD1 dramatically mitigates IgG immune complex-induced NF-κB and C/EBP activity in alveolar macrophages. Also, secretion of TNF-α, IL-6, keratinocyte cell-derived chemokine, and MIP-1α from IgG immune complex-stimulated alveolar macrophages or neutrophils was significantly decreased by AT-RvD1. These results suggest a new approach to the blocking of immune complex-induced inflammation.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigen-Antibody Complex; Aspirin; Bronchoalveolar Lavage Fluid; CCAAT-Enhancer-Binding Proteins; Cell Line; Chemokine CCL3; Complement C5a; Cytokines; Docosahexaenoic Acids; Immunoglobulin G; Macrophages, Alveolar; Mice; Neutrophils; NF-kappa B; Pneumonia

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is characterized by increased pulmonary permeability with high mortality. Resolvin D1 (RvD1), which has potent anti-inflammatory and pro-resolving activity, can attenuate pulmonary edema in the animal model of ALI. However, the mechanism underlying the protection of RvD1 on pulmonary edema is still unknown. Here we explore the effects and mechanism of RvD1 on the disruption of tight junction protein that results in the permeability edema in a model of lipopolysaccharide (LPS)-induced ALI. The severity of pulmonary edema was assessed by wet-to-dry rate and Evans blue infiltration; expressions of tight junction (TJ) proteins occludin and zona occludin-1 (ZO-1) were examined by immunofluorescence staining and western blot; mRNA in lung tissue was studied by real time-PCR; the TUNEL kit was performed for the detection of apoptosis of pulmonary barrier. Twenty-four hours after LPS inhalation by mice, wet-to-dry rate and Evans blue infiltration indicated that pretreatment with RvD1 relieved the pulmonary edema and pulmonary capillary permeability. Moreover, RvD1 attenuated the LPS-induced deterioration of TJ protein ZO-1 and occludin significantly. And we found that RvD1 increased heme oxygenase-1 (HO-1) expression contributed to the protection on the deterioration of TJs. In addition, we found that RvD1 could reduce pulmonary cellular apoptosis in LPS-induced mice. In conclusion, RvD1 possesses the ability that relieves the pulmonary edema and restores pulmonary capillary permeability and reduces disruption of TJs in LPS-induced ALI of mice, at least in part, by upregulating HO-1 expression.

Topics: Acute Lung Injury; Analysis of Variance; Animals; Apoptosis; Capillary Permeability; Docosahexaenoic Acids; Heme Oxygenase-1; In Situ Nick-End Labeling; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Pneumonia; Protective Agents; Real-Time Polymerase Chain Reaction; Tight Junction Proteins; Up-Regulation

Acute lung injury (ALI) is a severe illness with excess mortality and no specific therapy. Protective actions were recently uncovered for docosahexaenoic acid-derived mediators, including D-series resolvins. Here, we used a murine self-limited model of hydrochloric acid-induced ALI to determine the effects of aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) on mucosal injury. RvD1 and its receptor ALX/FPR2 were identified in murine lung after ALI. AT-RvD1 (~0.5-5 μg kg(-1)) decreased peak inflammation, including bronchoalveolar lavage fluid (BALF) neutrophils by ~75%. Animals treated with AT-RvD1 had improved epithelial and endothelial barrier integrity and decreased airway resistance concomitant with increased BALF epinephrine levels. AT-RvD1 inhibited neutrophil-platelet heterotypic interactions by downregulating both P-selectin and its ligand CD24. AT-RvD1 also significantly decreased levels of BALF pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, Kupffer cells, and tumor necrosis factor-α, and decreased nuclear factor-κB-phosphorylated p65 nuclear translocation. Taken together, these findings indicate that AT-RvD1 displays potent mucosal protection and promotes catabasis after ALI.

Topics: Acute Lung Injury; Adaptor Proteins, Signal Transducing; Airway Resistance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Platelets; Blood-Air Barrier; Disease Models, Animal; Docosahexaenoic Acids; Epinephrine; Inflammation; Inflammation Mediators; Leukocytes; Macrophages, Alveolar; Male; Mice; Neutrophils; Pulmonary Edema; Receptors, Formyl Peptide; Respiratory Mucosa; Transcription Factor RelA

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-κB via a PPARγ-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 PPARγ-dependent pathway.. 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 PPARγ antagonist GW9662; and a group receiving GW9662, then RvD1 (600 ng) and finally LPS. LPS (50 μM) 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).. At all three time points, groups receiving either dose of RvD1 followed by LPS had significantly lower total leukocyte counts and levels of TNF-α 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 PPARγ and suppressed IκBα degradation and NF-κB p65 nuclear translocation, based on Western blots and EMSAs. The PPARγ inhibitor GW9662 partially reversed RvD1-induced suppression of IκBα degradation and p65 nuclear translocation.. These results suggest that RvD1 may attenuate lung inflammation of LPS-induced acute lung injury by suppressing NF-κB activation through a mechanism partly dependent on PPARγ activation.

Topics: Acute Lung Injury; Animals; Docosahexaenoic Acids; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Pneumonia; PPAR gamma; Signal Transduction; Treatment Outcome

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.

Topics: Acute Lung Injury; Animals; Cell Adhesion Molecules; Dinoprostone; Docosahexaenoic Acids; Leukocyte Count; Lipopolysaccharides; Lung; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase