Abstract：
Glomerulonephritis remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). We have reported that expression of HER2/ErbB2, a member of the EGFR family, is increased in kidneys of patients and mice with lupus nephritis. We therefore asked if EGFR-family inhibition could ameliorate murine lupus nephritis. We used lapatinib, an EGFR-ErbB2 dual kinase inhibitor in female lupus-prone NZBxW/F1 mice, in which lupus onset was accelerated by injecting an IFN-α-expressing adenovirus. Mice received lapatinib (75 mg/Kg) or vehicle from the beginning of the acceleration or after the mice developed severe proteinuria (>300 mg/dL). Autoantibodies, kidney disease and markers of fibrosis and wound healing were analyzed. Exposure to IFNα induced ErbB2 expression in the kidney of lupus prone mice. Lapatinib, administered before but not after renal disease onset, lowered autoantibody titers and lessened immune complex deposition in the kidney. However, lapatinib increased proteinuria, kidney fibrosis and mouse mortality. Lapatinib also inhibited an in vitro wound healing assay testing renal cells. Our results suggest that EGFR-ErbB2 dual kinase inhibitor lapatinib decreases autoimmunity but worsens renal disease in IFNα-accelerated lupus, by increasing fibrosis and inhibiting wound healing. Type I Interferons are highlighted as important regulators of HER2/ErbB2 expression in the kidney. Further studies are required to parse the beneficial aspects of EGFR inhibition on autoimmunity from its negative effects on wound healing in lupus nephritis.
摘要：
肾小球肾炎仍然是系统性红斑狼疮（SLE）发病和死亡的主要原因。我们报道了EGFR家族成员HER2/ErbB2的表达,在患有狼疮性肾炎的患者和小鼠的肾脏中增加。因此，我们询问EGFR家族抑制是否可以改善小鼠狼疮性肾炎。我们用了拉帕替尼,一种EGFR-ErbB2双激酶抑制剂在雌性狼疮易感NZBxW/F1小鼠中，其中通过注射表达IFN-α的腺病毒加速了狼疮的发作。小鼠从加速开始或在小鼠出现严重蛋白尿(>300mg/dL)之后接受拉帕替尼(75mg/Kg)或媒介物。自身抗体,肾脏疾病和纤维化和伤口愈合的标志物进行了分析。暴露于IFNα诱导狼疮易感小鼠肾脏中的ErbB2表达。拉帕替尼,在肾病发作之前但不在肾病发作之后给药，降低自身抗体滴度，减少免疫复合物在肾脏中的沉积。然而,拉帕替尼增加蛋白尿，肾脏纤维化和小鼠死亡率。拉帕替尼还抑制体外伤口愈合测定测试肾细胞。我们的结果表明，EGFR-ErbB2双重激酶抑制剂拉帕替尼降低自身免疫，但在IFNα加速狼疮中恶化肾脏疾病，通过增加纤维化和抑制伤口愈合。I型干扰素被强调为肾脏中HER2/ErbB2表达的重要调节因子。需要进一步的研究来解析EGFR抑制对自身免疫的有益方面,从其对狼疮性肾炎中伤口愈合的负面影响。
