| Background:γ-glutamylcysteine synthetase(γ-GCS) which consist of catalytic heavy chain(γ-GCS-HS) and regulating light chain(γ-GCS-LS),as the first line of defence of scavenging antioxidants,is a vital antioxidase in asthma. NF-E2 related factor 2 (Nrf2) can up-regulate the expression of antioxidase such asγ-GCS through binding the anti-oxidative response elements(ARE),which plays a central role in oxidatie stress. Studys in vitro showed Peroxisome proliferator activated receptors-gammar(PPARγ) is a kind of intranuclear receptor activated by ligand, Peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α) which can up-regulate the expression of PPARγthrough binding PPARγ,is a kind of transcriptional coactivator. PPARγ/PGC-1αcan up-regulated the expression of Nrf2/γ-GCS-h.Objective: To investigate the mechanisms that PPARγ/PGC-1αregulates the expression of Nrf2/γ-GCS-h in whole level and the effect of that in pathogenesis of bronchial asthma.Methods: The whole experiment was divided into two parts,animal research and clinic reseach.40 healthy adult male guinea pigs were randomly divided into control group (group A),asthmatic group (group B),dexamethasone group(group C), rogridone group(group D).Asthmatic model was established through ovalbumin challenge method. The malonaldehyde and active oxygen concentration of the lung tissue homogena and inflammatory cells in bronchoalveolar lavage fluid was detected in four groups.The mRNA and protein expression of PPAR-γ,PGC-1α,Nrf2,γ-GCS in lung tissue and the mRNA and protein expression of PPAR-γ,Nrf2,γ-GCS in cells of bronchoalveolar lavage fluid(BALF) were measured.Clinic research was included three groups,healthy control group,asthma group,post-treatment group.The malonaldehyde and active oxygen concentration in inflammatory cells of Sputum Pulmonary function test was carried out in each group.The protein and mRNA expression of PPAR-γ,Nrf2,γ-GCS in cells in sputum from each group were measured.Results: (1) The malonaldehyde(nmol/mg prot) and active oxygen(U/mg prot) concentration of the lung tissue homogena and inflammatory cells in bronchoalveolar lavage fluid from guinea pigs in group B was significantly higher than that in group A,group C and group D(all P <0.05).The concentration of malonaldehyde(nmol/mg prot) and active oxygen(U/mg prot) in inflammatory cells from asthmatic patient was signifcantly higher than that in healthy control group and treatment group(all P <0.05).(2) The mRNA and protein expression of PPAR-γ,PGC-1α,Nrf2,γ-GCS in group B was lower than that in group A,group C and group D from the lung tissue (all P <0.05).(3) The mRNA and protein expression of PPAR-γ,Nrf2,γ-GCS in group B was lower than that in group A,group C and group D in inflammatory cells of BALF(all P <0.05).(4) The mRNA and protein expression of PPAR-γ,Nrf2,γ-GCS in cells in sputum from asthmatic patient after treatment significantly higher than that before treament(all P <0.05).(5) There were positive correlation between the cellular expression of Nrf2/γ-GCS-h and PPAR-γ/PGC-1αin lung tissue , cells of BALF from guinea pigs and cells in sputum from asthmatic patients,but negtive correlation between PPAR-γ,PGC-1α,Nrf2,γ-GCS and the malonaldehyde and active oxygen concentration in lung tissue , cells of BALF from guinea pigs and cells in sputum from asthmatic patients(all P <0.05). Conclutions: The disequilibrium of oxidation/antioxygen plays a key role in the pathogenesis of bronchial asthma. Nrf2/γ-GCS can reduce oxidative damage of parasitifer. PPAR-γ/PGC-1αmay up-regulate the expression of Nrf2/γ-GCS,which can protect the tissue or cells through increasing the capability of anti-oxidation decreasing that of oxidation. of guinea pigs and asthmatic patient. and the capability of anti-oxidation being increased by treatment may be due to up-regulate the expression PPAR-γ/PGC-1αand which increase expression of Nrf2/γ-GCS.
|
PDF Full Text Request