resolvin-d1 and Pulmonary-Edema

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

Unresolved inflammation is a major contributor to the development of heart failure following myocardial infarction (MI). Pro-resolving lipid mediators, such as resolvins (e.g. RvD1), are biosynthesized endogenously. The role of RvD1 in resolving post-MI inflammation has not been elucidated due to its unstable nature. Here, we have tested the role for two forms of RvD1, after incorporation into liposomes (Lipo-RvD1) and its free acid form (RvD1) in the left ventricle (LV) and splenic remodeling post-MI. 8 to 12-week old male, C57BL/6J-mice were subjected to coronary artery ligation and Lipo-RvD1 or RvD1 (3 μg/kg/day) was injected 3h post-MI for day (d)1 or until d5. No-MI mice and saline-injected MI mice served as controls. RvD1 injected groups showed improved fractional shortening post-MI; preserving transient changes in the splenic reservoir compared to MI-saline. RvD1-groups showed an early exit of neutrophils from LV and spleen at d5 post-MI with an increased expression of lipoxin A4 receptor (ALX; synonym formyl peptide receptor; FPR2) compared to the MI-saline group. The levels of pro-resolving mediators RvD1, RvD2, Maresin 1 (MaR1) and Lipoxin A4 (LXA4) were increased in spleens from RvD1 injected mice at d5 post-MI. RvD1 administration reduced macrophage density, ccr5 and cxcl5 levels at d5 post-MI compared to saline injected mice (both, p < 0.05). Increased transcripts of mrc-1, arg-1 and Ym-1 (all, p < 0.05) suggest macrophage-mediated clearance of necrotic cells in RvD1-groups. RvD1 reduced the pro-fibrotic genes (colla1, coll2a1 and tnc (all; p < 0.05)) and decreased collagen deposition, thereby reducing post-MI fibrosis and thus stabilizing the extracellular matrix. In summary, RvD1 and Lipo-RvD1 promote the resolution of acute inflammation initiated by MI, thereby delaying the onset of heart failure.

Topics: Animals; Arachidonate 5-Lipoxygenase; Cardiomegaly; Cell Count; Cell Polarity; Collagen; Docosahexaenoic Acids; Extracellular Matrix; Heart Ventricles; Inflammation; Macrophages; Male; Mice, Inbred C57BL; Myocardial Infarction; Neutrophil Infiltration; Prostaglandin-Endoperoxide Synthases; Pulmonary Edema; Receptors, Formyl Peptide; Spleen; Ultrasonography; Ventricular Function; Ventricular Remodeling

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