Department of Medicine, Thuringia Clinic Georgius Agricola Saalfeld, Teaching Hospital University Jena, Germany.
J Physiol Pharmacol. 2010 Aug;61(4):429-36.
Diabetes mellitus increases susceptibility to acute gastric injury and impairs ulcer healing. Pioglitazone as an agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) is used as anti-diabetic drug and has additionally gastroprotective activities. However, the effect of pioglitazone on the protection and healing of gastric mucosa under diabetic conditions is poorly understood. The aim of the present study was: 1) to compare the effects of treatment with PPARg ligand (pioglitazone) on healing of acetic acid-induced gastric ulcers and prevention of acute water immersion and restraint stress (WRS)-induced gastric lesions in normal rats and those with streptozotocin (STZ)-induced diabetes mellitus; 2) to assess the effects of pioglitazone on the mRNA expression of cyclooxygenase-2 (COX-2), c-NOS, interleukin-1beta and hypoxia inducible factor-1 alpha (HIF-1alpha) in the gastric mucosa of rats with or without STZ-induced diabetes mellitus; 3) to investigate the involvement of endogenous NO and proinflammatory cytokines (IL-1beta, TNF-alpha) in healing of chronic gastric ulcers and in prevention of acute stress lesions by pioglitazone in rats with or without STZ-induced diabetes mellitus. Diabetes was induced in rats by single injection of STZ (70 mg/kg i.p.) four weeks prior to production of gastric ulcers by acetic acid method or induction of stress lesions by 3.5 hours of WRS. Non-diabetic rats were used as controls. Two major animal groups (A and B) were tested; A) diabetic and non-diabetic rats with chronic gastric ulcers treated with 1) pioglitazone (40 mg/kg-d i.g.), 2) pioglitazone in combination of blocker of NO synthase (L-NNA 20 mg/kg-d i.p.), and 3) saline (vehicle-control); and B) diabetic and non-diabetic rats exposed to 3.5 hours of WRS and pretreated with 1) pioglitazone (40 mg/kg i.g.), 2) pioglitazone in combination of blocker of NO synthase (L-NNA 20 mg/kg i.p.), and 3) saline (vehicle-control). The gastric mucosal blood flow was assessed by H(2)-gas clearance method. The area of chronic acetic acid ulcers and number of acute WRS-induced gastric lesions were assessed by planimetry or by counting of number of lesions, respectively. In rats with chronic ulcers, the mRNA expression of HIF-1alpha, IL-1beta and COX-2 was assessed by RT-PCR and protein expression of platelet endothelial cell adhesion molecule-1 (PECAM-1), COX-2 and cNOS was examined by Western blot. In rats with stress lesions, the protein expression of COX-2, cNOS, catalase, PPAR and heat shock protein 70 (HSP70) was examined by Western blot. In diabetic rats, a marked delay in ulcer healing and increased susceptibility to WRS lesions were observed and these effects were accompanied by a significant decrease in GBF. Pioglitazone significantly increased healing of chronic gastric ulcers and exerted a strong protective effect against WRS-induced lesions, but these effects were attenuated by NO-inhibition with L-NNA. Interestingly, the ulcer healing and gastroprotective effects of pioglitazone were weak under diabetic conditions, and this effect on ulcer healing was accompanied by impaired angiogenesis due to decreased PECAM-1 expression, attenuated expression of COX-2 and the increased expression of proinflammatory cytokines compared to those in diabetic rats treated with vehicle. We conclude that: 1) experimental diabetes in rats impairs healing of chronic ulcers and enhances acute stress lesions due to an increase in the expression and release of proinflammatory cytokines such as TNF-alpha and IL-1beta; 2) the ulcer healing effect of pioglitazone, which is, at least in part, mediated by endogenous NO, is significantly attenuated by L-NNA in diabetic rats despite increased COX-2 expression at the ulcer edge; 3) the formation of acute gastric lesions induced by WRS is also attenuated by pretreatment with pioglitazone due to increased GBF probably mediated by NO, as the administration of L-NNA reversed, in part, the preventive action induced by this PPARgamma ligand, and 4) pioglitazone is effective both in healing of chronic ulcers and protection against WRS lesions though its action under diabetic conditions seems to be attenuated, possibly due to reduction in NOS-NO system, angiogenesis and increased expression and release of proinflammatory cytokines.
糖尿病使机体对急性胃损伤的易感性增加，并损害溃疡愈合。吡格列酮作为过氧化物酶体增殖物激活受体γ（PPARγ）的激动剂，被用作抗糖尿病药物，并且具有额外的胃保护活性。然而，在糖尿病条件下，吡格列酮对胃黏膜的保护和愈合作用知之甚少。本研究的目的是：1）比较 PPAR 配体（吡格列酮）治疗对正常大鼠和链脲佐菌素（STZ）诱导的糖尿病大鼠乙酸诱导的胃溃疡愈合和水浸和束缚应激（WRS）诱导的胃损伤预防的影响；2）评估吡格列酮对 STZ 诱导的糖尿病大鼠胃黏膜中环氧化酶-2（COX-2）、cNOS、白细胞介素-1β和缺氧诱导因子-1α（HIF-1α）的 mRNA 表达的影响；3）研究内源性 NO 和促炎细胞因子（IL-1β、TNF-α）在吡格列酮治疗慢性胃溃疡愈合和预防 STZ 诱导的糖尿病大鼠急性应激损伤中的作用。通过单次腹腔注射 STZ（70mg/kg）在乙酸法产生胃溃疡或 WRS 诱导应激损伤前 4 周诱导大鼠糖尿病。正常大鼠作为对照。测试了两个主要的动物组（A 和 B）：A）糖尿病和非糖尿病大鼠慢性胃溃疡，用 1）吡格列酮（40mg/kg-d ig），2）吡格列酮联合一氧化氮合酶抑制剂（L-NNA 20mg/kg-d ip），和 3）生理盐水（载体对照）治疗；B）糖尿病和非糖尿病大鼠暴露于 3.5 小时的 WRS，并在预处理时用 1）吡格列酮（40mg/kg ig），2）吡格列酮联合一氧化氮合酶抑制剂（L-NNA 20mg/kg ip），和 3）生理盐水（载体对照）。胃黏膜血流通过 H（2）-气体清除法评估。慢性乙酸溃疡面积和 WRS 诱导的急性胃损伤数量通过定积分或损伤数量计数分别评估。在慢性溃疡大鼠中，通过 RT-PCR 评估 HIF-1α、IL-1β 和 COX-2 的 mRNA 表达，通过 Western blot 检查血小板内皮细胞黏附分子-1（PECAM-1）、COX-2 和 cNOS 的蛋白表达。在应激损伤大鼠中，通过 Western blot 检查 COX-2、cNOS、过氧化氢酶、PPAR 和热休克蛋白 70（HSP70）的蛋白表达。在糖尿病大鼠中，观察到溃疡愈合明显延迟，对 WRS 损伤的易感性增加，这些影响伴随着胃黏膜血流的显著减少。吡格列酮显著增加慢性胃溃疡的愈合，并对 WRS 诱导的损伤产生强烈的保护作用，但这些作用被 L-NNA 抑制 NO 所减弱。有趣的是，在糖尿病条件下，吡格列酮的溃疡愈合和胃保护作用较弱，与糖尿病大鼠相比，与血管生成受损相关的 PECAM-1 表达减少，COX-2 表达减弱，促炎细胞因子表达增加，与溃疡愈合相关。我们得出结论：1）大鼠实验性糖尿病导致慢性溃疡愈合受损，并增加促炎细胞因子如 TNF-α和 IL-1β的表达和释放，从而增强急性应激损伤；2）吡格列酮的溃疡愈合作用，至少部分是由内源性 NO 介导的，在糖尿病大鼠中被 L-NNA 显著减弱，尽管溃疡边缘的 COX-2 表达增加；3）WRS 诱导的急性胃损伤的形成也被吡格列酮的预处理所减弱，可能是通过 NO 介导的，因为 L-NNA 的给药部分逆转了这种 PPARγ配体的预防作用，4）吡格列酮在慢性溃疡愈合和 WRS 损伤保护方面均有效，但在糖尿病条件下的作用似乎减弱，可能是由于 NOS-NO 系统、血管生成和促炎细胞因子表达和释放增加所致。
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