Quaglio Ana E V, Castilho Anthony C S, Di Stasi Luiz C
Laboratory of Phytomedicines, Pharmacology and Biotechnology (PhytoPharmaTech), Department of Pharmacology, Institute of Biosciences, São Paulo State University - UNESP, Botucatu, São Paulo CEP 18618-000, Brazil.
Laboratory of Phytomedicines, Pharmacology and Biotechnology (PhytoPharmaTech), Department of Pharmacology, Institute of Biosciences, São Paulo State University - UNESP, Botucatu, São Paulo CEP 18618-000, Brazil.
Life Sci. 2015 Nov 15;141:179-87. doi: 10.1016/j.lfs.2015.09.023. Epub 2015 Oct 3.
Etiopathogenesis of inflammatory bowel disease is unclear and results from a complex interplay of genetic, microbial, environmental and immune factors. Elucidating the mechanisms that drive IBD depends on the detailed characterization of human inflammatory mediators in animal models. Therefore, we studied how intestinal inflammation affects heparanase, NF-κB and Hsp70 gene expression in rats, and if current intestinal anti-inflammatory drugs (sulphasalazine, prednisolone and azathioprine) act on these expressions. Moreover, we investigated the relationships among these genes with colonic cytokines levels (IL-1β, TNF-α, IL-6, INF-γ and IL-10) and oxidative stress that have fundamental role in IBD.
Macroscopic parameters (diarrhea, extension of lesion, colonic weight/length ratio and damage score), biochemical markers (myeloperoxidase and alkaline phosphatase activities, and glutathione, IL-1β, TNF-α, IL-6, INF-γ and IL-10 levels), gene expressions (heparanase, NF-κB and Hsp70), and microscopic evaluations (optic, electronic scanning and transmission microscopic) were performed in rats.
Expression of heparanase, Hsp70 and NF-κB and oxidative stress were increased by inflammatory process and differentially modulated by sulphasalazine, prednisolone and azathioprine treatments. Protective effects of drugs were also related to differential modulation of cytokine changes induced by inflammatory process, showing different mechanisms to control inflammation.
Heparanase, NF-κB and Hsp70 gene expression participate in the inflammatory response induced by TNBS and represent pharmacological targets of the intestinal anti-inflammatory drugs. In addition, current drugs used to treat IBD (sulphasalazine, prednisolone and azathioprine) differentially modulate heparanase, NF-κB and Hsp70 gene expression, cytokine production and oxidative stress.
炎症性肠病的病因尚不清楚，是遗传、微生物、环境和免疫因素复杂相互作用的结果。阐明驱动炎症性肠病的机制取决于在动物模型中对人类炎症介质的详细表征。因此，我们研究了肠道炎症如何影响大鼠体内乙酰肝素酶、核因子κB（NF-κB）和热休克蛋白70（Hsp70）基因的表达，以及目前的肠道抗炎药物（柳氮磺胺吡啶、泼尼松龙和硫唑嘌呤）是否对这些表达有作用。此外，我们研究了这些基因与在炎症性肠病中起重要作用的结肠细胞因子水平（白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、干扰素-γ（INF-γ）和白细胞介素-10（IL-10））以及氧化应激之间的关系。
对大鼠进行宏观参数（腹泻、病变范围、结肠重量/长度比和损伤评分）、生化标志物（髓过氧化物酶和碱性磷酸酶活性，以及谷胱甘肽、IL-1β、TNF-α、IL-6、INF-γ和IL-10水平）、基因表达（乙酰肝素酶、NF-κB和Hsp70）以及微观评估（光学、电子扫描和透射显微镜检查）。
炎症过程增加了乙酰肝素酶、Hsp70和NF-κB的表达以及氧化应激，柳氮磺胺吡啶、泼尼松龙和硫唑嘌呤治疗对其有不同程度的调节作用。药物的保护作用还与炎症过程诱导的细胞因子变化的不同调节有关，显示出控制炎症的不同机制。
乙酰肝素酶、NF-κB和Hsp70基因表达参与了三硝基苯磺酸（TNBS）诱导的炎症反应，是肠道抗炎药物的药理学靶点。此外，目前用于治疗炎症性肠病的药物（柳氮磺胺吡啶、泼尼松龙和硫唑嘌呤）对乙酰肝素酶、NF-κB和Hsp70基因表达、细胞因子产生和氧化应激有不同程度的调节作用。
