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Activation of Liver X Receptor Attenuates Oleic Acid-Induced Acute Respiratory Distress Syndrome.

ABSTRACT: Liver X receptors (LXRs) were identified as receptors that sense oxidized cholesterol derivatives. LXRs are best known for their hepatic functions in regulating cholesterol metabolism and triglyceride synthesis, but whether and how LXRs play a role in the lung diseases is less understood. To study the function of LXRs in acute respiratory distress syndrome (ARDS), we applied the oleic acid (OA) model of ARDS to mice whose LXR was genetically or pharmacologically activated. The VP-LXRα knock-in (LXR-KI) mice, in which a constitutively activated LXRα (VP-LXRα) was inserted into the mouse LXRα locus, were used as the genetic gain-of-function model. We showed that the OA-induced lung damages, including the cytokine levels and total cell numbers and neutrophil numbers in the bronchoalveolar lavage fluid, the wet/dry weight ratio, and morphological abnormalities were reduced in the LXR-KI mice and wild-type mice treated with the LXR agonist GW3965. The pulmonoprotective effect of GW3965 was abolished in the LXR-null mice. Consistent with the pulmonoprotective effect of LXR and the induction of antioxidant enzymes by LXR, the OA-induced suppression of superoxide dismutase and catalase was attenuated in LXR-KI mice and GW3965-treated wild-type mice. Taken together, our results demonstrate that activation of LXRs can alleviate OA-induced ARDS by attenuating the inflammatory response and enhancing antioxidant capacity.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC5222979 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundA continuous gas flow provided by flow-controlled ventilation (FCV) facilitates accurate dynamic compliance measurement and allows the clinician to individually optimise positive end-expiratory and peak pressure settings accordingly.ObjectiveThe aim of this study was to compare the efficiency of gas exchange and impact on haemodynamics between individualised FCV and pressure-controlled ventilation (PCV) in a porcine model of oleic acid-induced acute respiratory distress syndrome (ARDS).DesignRandomised controlled interventional trial conducted on 16 pigs.SettingAnimal operating facility at the Medical University Innsbruck.InterventionsARDS was induced in lung healthy pigs by intravenous infusion of oleic acid until moderate-to-severe ARDS at a stable Horowitz quotient (PaO 2 FiO 2-1 ) of 80 to 120 over a period of 30 min was obtained. Ventilation was then either performed with individualised FCV ( n = 8) established by compliance-guided pressure titration or PCV ( n = 8) with compliance-guided titration of the positive end-expiratory pressure and peak pressure set to achieve a tidal volume of 6 ml kg -1 over a period of 2 h.Main outcome measuresGas exchange parameters were assessed by the PaO 2 FiO 2-1 quotient and CO 2 removal by the PaCO 2 value in relation to required respiratory minute volume. Required catecholamine support for haemodynamic stabilisation was measured.ResultsThe FCV group showed significantly improved oxygenation [149.2 vs. 110.4, median difference (MD) 38.7 (8.0 to 69.5) PaO 2 FiO 2-1 ; P = 0.027] and CO 2 removal [PaCO 2 7.25 vs. 9.05, MD -1.8 (-2.87 to -0.72) kPa; P = 0.006] at a significantly lower respiratory minute volume [8.4 vs. 11.9, MD -3.6 (-5.6 to -1.5) l min -1 ; P = 0.005] compared with PCV. In addition, in FCV-pigs, haemodynamic stabilisation occurred with a significant reduction of required catecholamine support [norepinephrine 0.26 vs. 0.86, MD -0.61 (-1.12 to -0.09) μg kg -1 min -1 ; P = 0.037] during 2 ventilation hours.ConclusionIn this oleic acid-induced porcine ARDS model, individualised FCV significantly improved gas exchange and haemodynamic stability compared with PCV.Trial registrationProtocol no.: BMBWF-66.011/0105-V/3b/2019).

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Activation of Liver X Receptor Attenuates Oleic Acid-Induced Acute Respiratory Distress Syndrome.

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