Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production.
Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production.
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DOI：
10.4049/jimmunol.0903816
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发表时间：
2010-06-01
期刊：
影响因子：
--
通讯作者：
Moore AR
中科院分区：
文献类型：
--
作者：
Chan MM;Moore AR
急性炎症遵循确定的诱导、炎症和消退阶段，消退是通过需要环氧合酶-2 (COX-2) 活性的主动过程来实现的。本研究旨在解决这种范式是否扩展到公认的慢性炎症模型。我们证明，小鼠胶原诱导的关节炎遵循类似的顺序过程。有趣的是，COX-2 及其代谢物（可能是促炎性 PGE2）在消退过程中存在于关节中，在此期间阻断 COX-2 活性和 PGE2 的产生会使炎症持续存在，而不是减弱。补充 PGE2 类似物可以恢复体内平衡，这种功能是由促分解脂氧合酶代谢物脂氧素 A4 介导的，脂氧素 A4 是一种有效的停止信号。因此，该研究为环氧合酶-脂氧合酶途径之间的天然内源性联系提供了体内证据，并表明 PGE2 作为反馈抑制剂对于限制自身免疫性关节炎的慢性炎症至关重要。这些发现可能解释了为什么 COX-2 抑制剂对人类只能起到姑息作用而不是治愈作用的谜团，因为阻断消退可能会削弱预防诱导的益处。
Acute inflammation follows defined phases of induction, inflammation and resolution, and resolution occurs by an active process that requires cyclooxygenase-2 (COX-2) activity. This study aims to address whether this paradigm extends to recognized model of chronic inflammation. We demonstrated that murine collagen-induced arthritis follows a similar sequential course. Interestingly, COX-2 and its metabolite, the presumably proinflammatory PGE2, are present in the joints during resolution, and blocking COX-2 activity and PGE2 production within this period perpetuated, instead of attenuated, inflammation. Repletion with PGE2 analogs restored homeostasis, and this function is mediated by the proresolving lipoxygenase metabolite, lipoxin A4, a potent stop signal. Thus, the study provided in vivo evidence for a natural, endogenous link between the cyclooxygenase–lipoxygenase pathways and showed that PGE2 serves as a feedback inhibitor essential for limiting chronic inflammation in autoimmune arthritis. These findings may explain the enigma regarding why COX-2 inhibitors are palliative rather than curative in humans, because blocking resolution may mitigate the benefit of preventing induction.
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影响因子：
82.9
作者：
Gilroy, DW;Colville-Nash, PR;Willoughby, DA
通讯作者：
Willoughby, DA
影响因子：
6.2
作者：
Ogawa, Masahito;Suzuki, Jun-Ichi;Isobe, Mitsuaki
通讯作者：
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DOI：
10.1084/jem.162.4.1336
发表时间：
1985-10-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
Cathcart ES
影响因子：
4.4
作者：
Fukunaga, K;Kohli, P;Levy, BD
通讯作者：
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影响因子：
4.4
作者：
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通讯作者：
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