Böhmer Ana Elisa, Mendes Ribeiro Corrêa André, de Souza Débora Guerini, Knorr Luisa, Hansel Gisele, Corbellini Luís Gustavo, Driemeier David, Portela Luis Valmor, Souza Diogo Onofre
Department of Biochemistry, ICBS, Federal University of Rio Grande do Sul, Avenida Ramiro Barcelos, 2600-Anexo, 90035-003 Porto Alegre, RS, Brazil.
Exp Toxicol Pathol. 2011 Jan;63(1-2):119-23. doi: 10.1016/j.etp.2009.10.005. Epub 2009 Nov 24.
The immunosuppressant agent cyclosporine (CsA) is currently used in transplanted patients and in the therapy of autoimmune disorders. CsA treatment has significant acute and chronic side effects on the liver and kidney. However, in the clinical setting, it is difficult to distinguish a direct effect of CsA treatment from other confounding variables, such as allograft rejection and effects due to other drug therapies. In the present study, we assessed for direct associations between CsA immunosuppressive therapy and cytokines levels, kidney and liver functionality, as well as lung histopathological status in rats submitted to chronic CsA treatment without undergoing any transplantation. Male Wistar rats were divided into three groups. The control group received vehicle (corn oil), and treated groups received CsA 5 or 15 mg/kg, by daily gastric gavage during 8 weeks. The results demonstrated that CsA treatment decreases blood levels of interleukins 1α (IL-1α), 1β (IL-1β) and interleukin 2 (IL-2), but does not alter interleukin 6 (IL-6) and IFN-γ levels. Serum biochemical markers of renal (creatinine) and hepatic (SGPT and SGOT) injury/dysfunction did not vary with CsA treatment, despite the presence of small histological alterations, suggesting that the function of these metabolic organs were preserved. Pulmonary histopathological lesions were observed in the CsA groups, and they were attributed to the activation of the local immunoresponse mechanisms by the normal microbiota in immunosuppressive CsA cases. These results suggest that the CsA concentrations administered in our experimental protocol were able to induce immunosuppression in rats without causing nephro and hepatotoxicity.
免疫抑制剂环孢素（CsA）目前用于移植患者和自身免疫性疾病的治疗。CsA治疗对肝脏和肾脏有显著的急性和慢性副作用。然而，在临床环境中，很难将CsA治疗的直接作用与其他混杂变量区分开来，如移植排斥反应和其他药物治疗的影响。在本研究中，我们评估了在未进行任何移植的情况下接受慢性CsA治疗的大鼠中，CsA免疫抑制治疗与细胞因子水平、肾脏和肝脏功能以及肺组织病理学状态之间的直接关联。雄性Wistar大鼠分为三组。对照组接受赋形剂（玉米油），治疗组在8周内每天通过胃管给予5或15mg/kg的CsA。结果表明，CsA治疗可降低白细胞介素1α（IL-1α）、1β（IL-1β）和白细胞介素2（IL-2）的血液水平，但不改变白细胞介素6（IL-6）和IFN-γ水平。尽管存在轻微的组织学改变，但肾脏（肌酐）和肝脏（SGPT和SGOT）损伤/功能障碍的血清生化标志物并未随CsA治疗而变化，这表明这些代谢器官的功能得以保留。在CsA组中观察到肺部组织病理学病变，这些病变归因于免疫抑制CsA病例中正常微生物群对局部免疫反应机制的激活。这些结果表明，我们实验方案中给予的CsA浓度能够在大鼠中诱导免疫抑制，而不会引起肾毒性和肝毒性。
