Investigation of therapeutic potential of Chinese herbal medicinal components on lupus nephritis targeting pathophysiological mechanisms

• Main Authors: Pei-Yi Tsai, 蔡佩宜
• Other Authors: Ann Chen
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/71269850055781274606

博士 === 國防醫學院 === 醫學科學研究所 === 99 === Systemic lupus erythematosus (SLE) is an autoimmune disorder involving multiple organs injury due to autoantibody production and abnormal cell immunity. Lupus nephritis, one of the most severe complications of SLE, is associated with significant morbidity and mortality. The cumulative risks of end stage renal failure were particularly high in patients with severe lupus nephritis, the histopathology of which comprises distinct patterns of injury that were initially defined by the World Health Organization Classification of 1982 as category III, category IV, and categories Vc and Vd. Although the exact mechanisms for the development or the progression of lupus nephritis remain unclear, abnormal cellular and humoral autoimmunity, inflammation, and oxidative stress have been implicated. Current therapies for lupus nephritis are various combinations of corticosteroids with other cytotoxic agents or immunomodulators, but many of these have various side effects. Importantly, Chinese herbal medicines have long been considered as typically a mild remedy with little or no side effects, and endeavors on developing them to be used as complementary components or adjuvants to Western medicines have been increasingly made over the past years in pharmaceutical research and industry. This thesis study tested the hypothesis that DCB-SLE1, an extract of a mixture of Chinese medicinal herbs, and antroquinonol, a purified compound with a major effective component of Antrodia camphorata, might ameliorate accelerated severe lupus nephritis by modulating pathophysiological pathways of abnormal immunity, inflammation, and oxidative stress. Moreover, we also tested the hypothesis that epigallocatechin-3-gallate (EGCG), the major bioactive polyphenol presents in green tea with antioxidant and free radical scavenging activities, can prevent development of lupus nephritis by long-term administering it to New Zealand black/white (NZB/W) F1 lupus-prone mice. The results showed that: (1) DCB-SLE1 protected the kidney from autoimmune response-mediated acute and severe damage through systemic immune modulation and anti-inflammation pathways; (2) Antroquinonol administration significantly ameliorated the development of severe renal lesions via differentially regulating T cell function and lowering interleukin-18 production, but promoting nuclear factor erythroid-2-related factor-2 (Nrf2) activation; (3) EGCG had prophylactic effects on lupus nephritis in NZB/W F1 mice that are highly associated with its effects of enhancing the Nrf2 antioxidant signaling pathway, decreasing renal NLRP3 inflammasome activation, and increasing systemic regulatory T cell activity. Therefore, DCB-SLE1, antroquinonol, and EGCG have the potential to develop as therapeutic agents or adjuvants for the prevention and treatment of lupus nephritis in the future.