resolvin-d1 and Hyperoxia

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

The critical fatty acids Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) decline in preterm infants within the first postnatal week and are associated with neonatal morbidities, including bronchopulmonary dysplasia (BPD). DHA and AA are precursors to downstream metabolites that terminate the inflammatory response. We hypothesized that treatment with Resolvin D1 and/or Lipoxin A4 would prevent lung injury in a murine model of BPD.. To determine the effect of Resolvin D1 and/or Lipoxin A4 on hyperoxia-induced lung injury.. C57/BL6 pups were randomized at birth to Room Air, Hyperoxia (>90% oxygen), Hyperoxia + Resolvin D1, Hyperoxia + Lipoxin A4, or Hyperoxia + Resolvin D1/Lipoxin A4. Resolvin D1 and/or Lipoxin A4 (2 ng/g) were given IP on days 0, 3, 6, and 9. On day 10, mice were sacrificed and lungs collected for morphometric analyses including Mean Linear Intercept (MLI), Radial Alveolar Count (RAC), and Septal Thickness (ST); RT-PCR analyses of biomarkers of lung development and inflammation; and ELISA for TGFβ1 and TGFβ2.. The increased ST observed with hyperoxia exposure was normalized by both Resolvin D1 and Lipoxin A4; while, hyperoxia-induced alveolar simplification was attenuated by Lipoxin A4. Relative to hyperoxia, Resolvin D1 reduced the gene expression of CXCL2 (2.9 fold), TIMP1 (6.7 fold), and PPARγ (4.8 fold). Treatment with Lipoxin A4 also led to a reduction of CXCL2 (2.4 fold) while selectively increasing TGFβ2 (2.1 fold) and Smad3 (1.58 fold).. The histologic and biochemical changes seen in hyperoxia-induced lung injury in this murine model can be reversed by the addition of DHA and AA fatty acid downstream metabolites that terminate the inflammatory pathways and modulate growth factors. These fatty acids or their metabolites may be novel therapies to prevent or treat lung injury in preterm infants.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Docosahexaenoic Acids; Female; Hyperoxia; Lipoxins; Lung Injury; Male; Mice; Mice, Inbred C57BL; Pulmonary Alveoli