Activation of PPARγ attenuates LPS-induced acute lung injury by inhibition of HMGB1-RAGE levels

et al. 2015

Acta Pharmacol Sin

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Aim: Rosiglitazone is one of the specific PPARγ agonists showing potential therapeutic effects in asthma. Though PPARγ activation was considered protective in inhibiting airway inflammation and remodeling in asthma, the specific mechanisms are still unclear. This study was aimed to investigate whether heme oxygenase-1 (HO-1) related pathways were involved in rosiglitazone-activated PPARγ signaling in asthma treatment. Methods: Asthma was induced in mice by multiple exposures to ovalbumin (OVA) in 8 weeks. Prior to every OVA challenge, the mice received rosiglitazone (5 mg/kg, po). After the mice were sacrificed, the bronchoalveolar lavage fluid (BALF), blood samples and lungs were collected for analyses. The activities of HO-1, MMP-2 and MMP-9 in airway tissue were assessed, and the expression of PPARγ, HO-1 and p21 proteins was also examined. Results: Rosiglitazone administration significantly attenuated airway inflammation and remodeling in mice with OVA-induced asthma, which were evidenced by decreased counts of total cells, eosinophils and neutrophils, and decreased levels of IL-5 and IL-13 in BALF, and by decreased airway smooth muscle layer thickness and reduced airway collagen deposition. Furthermore, rosiglitazone administration significantly increased PPARγ, HO-1 and p21 expression and HO-1 activity, decreased MMP-2 and MMP-9 activities in airway tissue. All the therapeutic effects of rosiglitazone were significantly impaired by co-administration of the HO-1 inhibitor ZnPP. Conclusion: Rosiglitazone effectively attenuates airway inflammation and remodeling in OVA-induced asthma of mice by activating PPARγ/HO-1 signaling pathway.

Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma

Zhu

et al. 2015

Acta Pharmacol Sin

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“…Control mice received intratracheal instillation of sterile phosphate-buffered saline (PBS) alone. Models of ALI were induced by the intratracheal instillation of 50 µl LPS (100 µg) for 24 h as previously described (12). Mice of the third group were pre-treated with metformin (250 mg/kg) by intraperitoneal injection at 0.5 h prior to stimulation with LPS.…”

Section: Methodsmentioning

confidence: 99%

“…The cell pellets were resuspended in PBS. Total cells were counted under light microscopy using a hemocytometer and neutrophils were determined as described previously (12).…”

Section: Harvesting Of Bronchoalveolar Lavage Fluid (Balf)mentioning

confidence: 99%

Activation of AMPK attenuates LPS-induced acute lung injury by upregulation of PGC1α and SOD1

Experimental and Therapeutic Medicine

Song

Feng

et al. 2016

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Abstract. Evidence suggests that an imbalance between oxidation and antioxidation is involved in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Activation of AMP-activated protein kinase (AMPK) has been shown to inhibit the occurrence of ALI/ARDS. However, it is unknown whether activation of AMPK benefits ALI/ARDS by restoration of the oxidant and antioxidant balance, and which mechanisms are responsible for this process. The present study aimed to address these issues. Lipopolysaccharide (LPS) induced pronounced pathological changes of ALI in mice; these were accompanied by elevated production of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) compared with control mice. Prior treatment of mice with the AMPK agonist metformin significantly suppressed the LPS-induced development of ALI, reduced the elevation of MDA and increased the activity of SOD. Further analysis indicated that activation of AMPK also stimulated the protein expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and superoxide dismutase 1 (SOD1). This study suggests that activation of AMPK by metformin inhibits oxidative stress by upregulation of PGC1α and SOD1, thereby suppressing the development of ALI/ARDS, and has potential value in the clinical treatment of such conditions.

Activation of PPARγ by baicalin attenuates pulmonary hypertension in an infant rat model by suppressing HMGB1/RAGE signaling

Chen

2017

FEBS Open Bio

Pulmonary hypertension (PH) is a vascular disease, and proinflammatory factors are strongly implicated in its pathogenesis, causing right ventricular (RV) hypertrophy and heart failure. Baicalin exhibits potent anti‐inflammation activity. This study aimed to investigate the curative effects of baicalin in an infant rodent model of PH and to further explore the underlying mechanisms. A PH model in infant rats was induced by hypoxia and the resulting rats were administered baicalin in incremental dosages. Invasive hemodynamic methods were used to measure mean pulmonary arterial pressure (mPAP) and RV end‐diastolic pressure (RVEDP). RV hypertrophy was assessed by mass pathology and histology. ELISAs were used to determine concentrations of high‐mobility group box 1 (HMGB1), secretory receptor for advanced glycation end products (sRAGE), interleukin 6 (IL6) and transforming growth factor β (TGFβ1) in bronchoalveolar lavage fluid (BALF). Electrophoretic mobility shift and phosphorylation in nuclear extracts were used to evaluate the activation of peroxisome proliferator‐activated receptor γ (PPARγ). Western blotting was used to detect the expression levels of heme oxygenase 1 (HO1), HMGB1, RAGE, IL6 and TGFβ1 in lung tissue. Baicalin administration significantly attenuated mPAP, RVEDP and RV hypertrophy in infant rats with PH. HMGB1, sRAGE, IL6 and TGFβ1 levels in BALF were also reduced by baicalin treatment. Baicalin activated PPARγ, which promoted expression of HO1. Furthermore, expression levels of HMGB1, RAGE, IL6 and TGFβ1 in lung tissue were dramatically decreased by baicalin in a dosage‐dependent manner. Baicalin showed curative effects in infant rats with PH. Activation of PPARγ that inhibited HMGB1/RAGE inflammatory signaling was involved.