Anticancer agent 2-methoxyestradiol improves survival in septic mice by reducing the production of cytokines and nitric oxide

Ching Hua Yeh, Willy Chou, Chin Chen Chu, Edmund Cheung So, Huai-Chia Chang, Jhi Joung Wang, Chung-Hsi Hsing

研究成果: 雜誌貢獻文章同行評審

29 引文 斯高帕斯(Scopus)

摘要

Cytokine production is critical in sepsis. 2-Methoxyestradiol (2ME2), an endogenous metabolite of estradiol, inhibits hypoxia-inducible factor 1α (HIF-1α) and is an antiangiogenic and antitumor agent. We investigated the effect of 2ME2 on cytokine production and survival in septic mice. Using i.p. LPS or cecal ligation and puncture (CLP), sepsis was induced in BALB/c mice that were simultaneously or later treated with 2ME2 or vehicle. Twelve hours after the LPS injection, serum and peritoneal fluid cytokine and nitric oxide (NO) levels were analyzed using enzyme-linked immunosorbent assay and the Griess reaction. Lung injuries were histologically analyzed, and liver and kidney injuries were biochemically analyzed. Survival was determined 7 days after LPS injection or CLP procedure. In vivo and in vitro effects of 2ME2 on LPS-induced macrophage inflammation were determined. The effect of 2ME2 on HIF-1α expression, nuclear factor κB (NF-κB), and inducible NO synthase (iNOS) in LPS-treated RAW264.7 cells, a murine macrophage cell line, was determined using Western blotting. 2-Methoxyestradiol treatment reduced LPS-induced lung, liver, and kidney injury. Both early and late 2ME2 treatment prolonged survival in LPS-and CLP-induced sepsis. 2-Methoxyestradiol significantly reduced IL-1β, IL-6, TNF-α, and NO levels in septic mice as well as in LPS-stimulated peritoneal macrophages. 2-Methoxyestradiol treatment also reduced the LPS-induced expression of HIF-1α, iNOS, and pNF-κB in RAW264.7 cells, as well as iNOS and pNF-κB expression in siHIF-1α-RAW264.7 cells. 2-Methoxyestradiol prolongs survival and reduces lung, liver, and kidney injury in septic mice by inhibiting iNOS/NO and cytokines through HIF-1α and NF-κB signaling.

原文英語
頁(從 - 到)510-516
頁數7
期刊Shock
36
發行號5
DOIs
出版狀態已發佈 - 11月 2011

ASJC Scopus subject areas

  • 重症監護和重症監護醫學
  • 急診醫學

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