Yuan Fang, Tabor Dana E, Nelson Richard K, Yuan Hongjiang, Zhang Yijia, Nuxoll Jenny, Bynoté Kimberly K, Lele Subodh M, Wang Dong, Gould Karen A
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
PLoS One. 2013 Nov 28;8(11):e81483. doi: 10.1371/journal.pone.0081483. eCollection 2013.
We evaluated the ability of a macromolecular prodrug of dexamethasone (P-Dex) to treat lupus nephritis in (NZB × NZW)F1 mice. We also explored the mechanism underlying the anti-inflammatory effects of this prodrug. P-Dex eliminated albuminuria in most (NZB × NZW)F1 mice. Furthermore, P-Dex reduced the incidence of severe nephritis and extended lifespan in these mice. P-Dex treatment also prevented the development of lupus-associated hypertension and vasculitis. Although P-Dex did not reduce serum levels of anti-dsDNA antibodies or glomerular immune complexes, P-Dex reduced macrophage recruitment to the kidney and attenuated tubulointerstitial injury. In contrast to what was observed with free dexamethasone, P-Dex did not induce any deterioration of bone quality. However, P-Dex did lead to reduced peripheral white blood cell counts and adrenal gland atrophy. These results suggest that P-Dex is more effective and less toxic than free dexamethasone for the treatment of lupus nephritis in (NZB × NZW)F1 mice. Furthermore, the data suggest that P-Dex may treat nephritis by attenuating the renal inflammatory response to immune complexes, leading to decreased immune cell infiltration and diminished renal inflammation and injury.
我们评估了地塞米松大分子前药（P-Dex）治疗（NZB×NZW）F1小鼠狼疮性肾炎的能力。我们还探究了这种前药抗炎作用的潜在机制。P-Dex使大多数（NZB×NZW）F1小鼠的蛋白尿消失。此外，P-Dex降低了这些小鼠严重肾炎的发生率并延长了其寿命。P-Dex治疗还预防了狼疮相关高血压和血管炎的发生。尽管P-Dex没有降低血清抗双链DNA抗体水平或肾小球免疫复合物水平，但P-Dex减少了巨噬细胞向肾脏的募集并减轻了肾小管间质损伤。与游离地塞米松的情况相反，P-Dex没有导致任何骨质恶化。然而，P-Dex确实导致外周白细胞计数减少和肾上腺萎缩。这些结果表明，在治疗（NZB×NZW）F1小鼠狼疮性肾炎方面，P-Dex比游离地塞米松更有效且毒性更小。此外，数据表明P-Dex可能通过减弱对免疫复合物的肾脏炎症反应来治疗肾炎，从而导致免疫细胞浸润减少以及肾脏炎症和损伤减轻。
