【摘要】 目的研究特异性Caspaso-1抑制剂对狼疮性肾炎(LN)的治疗作用及其作用机制。方法应用特异性Caspase-1抑制剂AC-YVAD-CMK处理LN模型．BXSB小鼠4周,然后观察此潜在药物对该模型尿蛋白浓度、肾功能和血清自身抗体水平以及肾脏病理形态学的影响,继之检测它对。肾脏局部及全身系统Caspase-1活性以及其下游细胞因子IL-18和IFN-γ表达的影响。结果未治疗LN模型血清肌酐(Scr)、血清抗ds-DNA抗体水平以及尿蛋白浓度显著升高(P均<0．05);肾小球IgG沉积及肾小球病理损伤程度显著较对照小鼠严重(P均<0．005);肾脏及脾脏Caspase-1活性显著升高(P< 0．01),成熟形式IL-18蛋白表达升高(P<0．001),IFN-γmRNA表达显著上调(JP<0．05);血清IFT-γ水平也显著升高(P<0．01)。IcE抑制剂处理后Scr、抗ds-DNA抗体水平及尿蛋白浓度显著回降(P< 0．05);肾小球病理损伤较未处理组显著减轻(P<0．05),但肾小球IgG沉积差异无统计学意义(P> 0．05);肾脏及脾脏Caspase-1活性、成熟IL-18蛋白表达和IFN-γ mRNA表达均有不同程度回降(P均< 0．05),血清IFN-γ水平也显著回降(P<0．05)。结论选择性Caspase-1抑制剂对LN肾损伤具有良好的保护作用,抑制Caspase-1活性,进而抑制IL-18等细胞因子的活化和下游因子IFN-γ等的表达是其主要作用机制。更多还原

【Abstract】 To study the effects of selective Caspase-1 (interleukin-1β converting enzyme, ICE) inhibitor on lupus nephritis(LN) , and explore its mechanisms. Methods LN model BXSB mice were treated with specific Caspase-1 inhibitor, AC-YVAD-CMK for 4 weeks. Protecting effects of ICE inhibitor was estimated by renal function assay and morphological studies. Furthermore, renal Caspase-1 activity, mature IL-18 protein expression and IFN-γ mRNA expression in kidneys and spleens were detected by fluorescent enzyme link immunosor-bent assay, FLISA and semi-quantity RT-PCR respectively. Results The levels of serum creatinine (Scr )and anti-ds-DNA antibody as well as urinary protein concentration increased significantly in untreated LN mice ( P < 0.01). Glomerular IgG deposition and glomerular morphologic lesion were much more seveive in untreated LN mice than in normal control mice. Caspase-1 activity, mature IL-18 protein expression and IFN-γ mRNA expression in kidneys and spleens were also significantly increased in untreated LN mice compared to normal controls. Levels of Scr, anti-ds-DNA antibody as well as urinary protein concentration in AC-YVAD-CMK therapy LN mice were significantly decreased. Glomerular pathological lesion was also allevated significantly compared with untreated group. Furthermore, AC-YVAD-CMK therapy also decreased Caspase-1 activity, mature IL-18 protein expression and IFN-γ mRNA expression siginificantly in kidneys and spleens( P < 0.05 respectively ) . Conclusion Selective ICE inhibitor protects LN mice from renal lesion and the renoprotecting effects are depended on decreased renal Caspase-1 activity, suppressed IL-18 maturating and IFN-γ transcription in local renal tissue as well as systemic immune system.更多还原