Improved effect of PPARγ activator on bleomycin-induced pulmonary fibrosis in mice
-
摘要:
目的 探讨过氧化物酶增殖激活受体γ(PPARγ)激活剂对博莱霉素诱导的小鼠肺纤维化的改善作用及相关机制。 方法 将36只BALB/c小鼠采用随机数字表法分成对照组、模型组和PPARγ激活组,每组12只。除对照组外,其余2组小鼠气管内注射博莱霉素5 mg/kg诱导肺纤维化模型。24 h后,PPARγ激活组小鼠口服灌胃100 mg/kg剂量的罗格列酮溶液。计算肺系数;ELISA法测定肺组织中丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GPx)、羟脯氨酸(HYP)和转化生长因子-β1(TGF-β1)的含量;HE和Masson染色观察小鼠肺组织病理变化;Western blotting法检测肺组织PPARγ、PPARγ共激活因子α(PGC-1α)、核因子类胡萝卜素2相关因子(Nrf2)蛋白含量。 结果 模型组小鼠肺系数、肺组织Ashcroft评分及HYP、TGF-β1、MDA水平均显著高于对照组和PPARγ激活组(均P < 0.05)。模型组肺组织中SOD、GPx水平显著低于对照组和PPARγ激活组(均P < 0.05)。与模型组相比,PPARγ激活组小鼠肺组织PPARγ、PGC-1α、Nrf2蛋白表达量显著升高(均P < 0.05)。 结论 PPARγ激活剂可抑制博莱霉素诱导的小鼠肺纤维化过程,可能与减轻炎症反应和氧化应激有关。 -
关键词:
- 过氧化物酶增殖激活受体-γ /
- 博莱霉素 /
- 肺纤维化 /
- 炎症反应 /
- 氧化应激
Abstract:Objective To explore the effect of peroxisome proliferator-activated receptor-γ (PPARγ) activator on bleomycin-induced pulmonary fibrosis in mice and its related mechanisms. Methods Thirty-six BALB/c mice were randomly divided into control group, model group and PPARγ-activated group, 12 mice in each group. Except for the control group, the other groups of mice were injected intratracheally with 5 mg/kg bleomycin to induce pulmonary fibrosis. After 24 h, the mice in the PPARγ-activated group were orally administered with 100 mg/kg rosiglitazone solution. The lung coefficient was calculated. The contents of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), hydroxyproline (HYP) and transforming growth factor-β1 (TGF-β1) in lung tissue were detected by ELISA. HE and masson staining were used to observe the pathological changes of lung tissue. The contents of PPARγ, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and nuclear factor erythroid-2-related factor (Nrf2) protein in lung tissue were detected by western blot. Results The lung coefficient, Ashcroft score of lung tissue, and the levels of HYP, TGF-β1 and MDA in the model group were significantly higher than those in the control group and PPARγ-activated group (all P < 0.05). The levels of SOD and GPx in the lung tissues of the model group were significantly lower than those of the control group and PPARγ-activated group (all P < 0.05). Compared with the model group, the expression of PPARγ, PGC-1α, and Nrf2 proteins in the lung tissue of rats in the PPARγ activation group increased significantly (all P < 0.05). Conclusion PPARγ activator can inhibit bleomycin-induced lung fibrosis in mice, which may be related to reducing inflammation and oxidative stress. -
表 1 3组小鼠肺组织HYP、TGF-β1水平比较(x±s, μg/mL)
组别 只数 HYP TGF-β1 对照组 12 1.86±0.32 1.07±0.29 模型组 12 5.57±0.59a 8.49±0.93a PPARγ激活组 12 3.83±0.46b 3.26±0.67b F值 156.114 311.916 P值 < 0.001 < 0.001 注:与对照组比较,aP < 0.05;与模型组比较,bP<0.05。 表 2 3组小鼠肺组织MDA、SOD、GPx水平比较(x±s)
组别 只数 MDA(nmol/mg) SOD(U/mg) GPx(U/mg) 对照组 12 8.45±0.79 12.86±1.08 84.59±11.37 模型组 12 26.71±1.53a 4.29±0.46a 22.16±6.49a PPARγ激活组 12 11.53±1.06b 9.37±0.75b 72.82±8.27b F值 701.152 287.120 137.672 P值 < 0.001 < 0.001 < 0.001 注:与对照组比较,aP < 0.05;与模型组比较,bP<0.05。 表 3 3组小鼠肺组织PPARγ、PGC-1α、Nrf2蛋白相对表达量比较(x±s)
组别 只数 PPARγ PGC-1α Nrf2 对照组 12 0.94±0.18 0.79±0.15 0.97±0.14 模型组 12 0.34±0.09a 0.18±0.08a 0.38±0.07a PPARγ激活组 12 0.89±0.11b 0.59±0.12b 0.89±0.09b F值 63.213 66.998 94.264 P值 < 0.001 < 0.001 < 0.001 注:与对照组比较,aP < 0.05;与模型组比较,bP<0.05。 -
[1] LEDERER D J, MARTINEZ F J. Idiopathic pulmonary fibrosis[J]. N Engl J Med, 2018, 378(19): 1811-1823. doi: 10.1056/NEJMra1705751 [2] SGALLA G, IOVENE B, CALVELLO M, et al. Idiopathic pulmonary fibrosis: Pathogenesis and management[J]. Respir Res, 2018, 19(1): 32. doi: 10.1186/s12931-018-0730-2 [3] WAKWAYA Y, BROWN K K. Idiopathic pulmonary fibrosis: Epidemiology, diagnosis and outcomes[J]. Am J Med Sci, 2019, 357(5): 359-369. doi: 10.1016/j.amjms.2019.02.013 [4] 笪苗, 吴巍, 毛新峰, 等. PPARγ基因在结直肠癌伴高脂血症患者中的临床意义[J]. 中华全科医学, 2019, 17(8): 1312-1316. https://www.cnki.com.cn/Article/CJFDTOTAL-SYQY201908019.htm [5] PIAO L M, YU C L, XU W H, et al. Adiponectin/AdiopR1 signal inactivation contributes to impaired angiogenesis in mice of advanced age[J]. Int J Cardiol, 2018, 267(1): 150-155. http://www.onacademic.com/detail/journal_1000040418017810_a91c.html [6] HUANG S, GOPLEN N P, ZHU B B, et al. Macrophage PPAR-γ suppresses long-term lung fibrotic sequelae following acute influenza infection[J]. PLoS One, 2019, 14(10): e0223430. doi: 10.1371/journal.pone.0223430 [7] ASHCROFT T, SIMPSON J M, TIMBRELL V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale[J]. J Clin Pathol, 1988, 41(4): 467-470. doi: 10.1136/jcp.41.4.467 [8] CAMINATI A, LONATI C, CASSANDRO R, et al. Comorbidities in idiopathic pulmonary fibrosis: An underestimated issue[J]. Eur Respir Rev, 2019, 28(153): 190044. doi: 10.1183/16000617.0044-2019 [9] GULATI S, THANNICKAL V J. The aging lung and idiopathic pulmonary fibrosis[J]. Am J Med Sci, 2019, 357(5): 384-389. doi: 10.1016/j.amjms.2019.02.008 [10] ASAI T T, OIKAWA F, YOSHIKAWA K, et al. Food-derived collagen peptides, Prolyl-Hydroxyproline (Pro-Hyp), and Hydroxyprolyl-Glycine (Hyp-Gly) enhance growth of primary cultured mouseskin fibroblast using fetal bovine serum free from hydroxyprolyl peptide[J]. Int J Mol Sci, 2019, 21(1): 229. doi: 10.3390/ijms21010229 [11] KIM K K, SHEPPARD D, CHAPMAN H A. TGF-β1 signaling and tissue fibrosis[J]. Cold Spring Harb Perspect Biol, 2018, 10(4): a022293. doi: 10.1101/cshperspect.a022293 [12] LEE E H, PARK K I, KIM K Y, et al. Liquiritigenin inhibits hepatic fibrogenesis and TGF-β1/Smad with Hippo/YAP signal[J]. Phytomedicine, 2019, 62(1): 152780. http://www.onacademic.com/detail/journal_1000041593006899_f10b.html [13] ZHANG H L, YOU L, ZHAO M. Rosiglitazone attenuates paraquat-induced lung fibrosis in rats in a PPAR gamma-dependent manner[J]. Eur J Pharmacol, 2019, 851(1): 133-143. http://www.ncbi.nlm.nih.gov/pubmed/30797787 [14] CAI W, YANG T, LIU H, et al. Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair[J]. Prog Neurobiol, 2018, 163-164(1): 27-58. http://www.onacademic.com/detail/journal_1000040095552610_0141.html [15] YU W C, MI L Y, LONG T. Efficacies of rosiglitazone and retinoin on bleomycin-induced pulmonary fibrosis in rats[J]. Exp Ther Med, 2017, 14(1): 609-615. doi: 10.3892/etm.2017.4555 [16] WANG G Q, WANG L, SUN X G, et al. Haematoma scavenging in intracerebral haemorrhage: From mechanisms to the clinic[J]. J Cell Mol Med, 2018, 22(2): 768-777. http://www.onacademic.com/detail/journal_1000040149855510_03e3.html [17] WU Q Q, XIAO Y, LIU C, et al. The protective effect of high mobility group protein HMGA2 in pressure overload-induced cardiac remodeling[J]. J Mol Cell Cardiol, 2019, 128(1): 160-178. http://www.ncbi.nlm.nih.gov/pubmed/30711544 [18] ZHANG X X, JI R P, SUN H J, et al. Scutellarin ameliorates nonalcoholic fatty liver disease through the PPARγ/PGC-1α-Nrf2 pathway[J]. Free Radic Res, 2018, 52(2): 198-211. doi: 10.1080/10715762.2017.1422602