The severity of sepsis is significantly affected by advanced age; however, age-dependent molecular mechanisms of this susceptibility are unknown. Nuclear liver X receptor-α (LXRα) is a regulator of li Show more
The severity of sepsis is significantly affected by advanced age; however, age-dependent molecular mechanisms of this susceptibility are unknown. Nuclear liver X receptor-α (LXRα) is a regulator of lipid metabolism with associated anti-inflammatory properties. Here, we investigated the role of LXRα in age-dependent lung injury and outcome of sepsis. Male C57BL/6, LXRα-deficient (LXRα(-/-)) and wild type (WT) (LXRα(+/+)) mice of different ages were subjected to sepsis by cecal ligation and puncture (CLP). In pharmacological studies, treatment with the LXRα ligand T0901317 reduced lung neutrophil infiltration in C57BL/6 mice aged from 1 to 8 mo when compared with vehicle-treated animals subjected to CLP. The LXRα ligand improved survival in young mice (2-3 mo old) but did not affect survival or neutrophil infiltration in mature adult mice (11-13 mo old). Immunoblotting revealed an age-dependent decrease of lung LXRα levels. Young LXRα(-/-) mice (2-3 mo old) exhibited earlier mortality than age-matched WT mice after CLP. Lung damage and neutrophil infiltration, lung activation of the pro-inflammatory NF-κB and plasma IL-6 levels were higher in LXRα(-/-) mice 18 h after CLP compared with LXRα(+/+) mice. This study suggests that the anti-inflammatory properties of LXRα in sepsis are age-dependent and severely compromised in mature adult animals. Show less
Liver X receptor α (LXRα) is a nuclear transcription factor that regulates lipid metabolism. Recently, it has been shown that activation of LXRα with synthetic ligands has anti-inflammatory effects in Show more
Liver X receptor α (LXRα) is a nuclear transcription factor that regulates lipid metabolism. Recently, it has been shown that activation of LXRα with synthetic ligands has anti-inflammatory effects in atherosclerosis and chemical-induced dermatitis. We investigated the effect of the LXRα agonist, T0901317, on lung inflammation in a rodent model of hemorrhagic shock. Hemorrhagic shock was induced in male rats by withdrawing blood to a goal mean arterial blood pressure of 50 mmHg. Blood pressure was maintained at this level for 3 h, at which point rats were rapidly resuscitated with shed blood. Animals were then treated with T0901317 (50 mg · kg) or vehicle i.p. and sacrificed at 1, 2, and 3 h after resuscitation. Treatment with T0901317 significantly improved the cardiac and stroke volume indices as well as the heart rate of rats during the resuscitation period as compared with vehicle-treated rats. The T0901317-treated animals showed significant improvement in the plasma level of lactate, whereas base deficit and bicarbonate levels both trended toward improvement. The T0901317-treated animals also showed lower levels of plasma cytokines and chemokines monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, TNF-α, KC, and IL-6. Lung injury and neutrophil infiltration were reduced by treatment with T0901317, as evaluated by histology and myeloperoxidase assay. At molecular analysis, treatment with T0901317 increased nuclear LXRα expression and DNA binding while also inhibiting activation of nuclear factor κB, a proinflammatory transcription factor, in the lung. Thus, our data suggest that LXRα is an important modulator of the inflammatory response and lung injury after severe hemorrhagic shock, likely through the inhibition of the nuclear factor κB pathway. Show less