Persistence of inflammatory cytokines cause a spectrum of chronic progressive diseases: Implications for therapy
Persistence of inflammatory cytokines cause a spectrum of chronic progressive diseases: Implications for therapy
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DOI：
10.1016/j.mehy.2005.03.010
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发表时间：
2005-01-01
影响因子：
4.7
通讯作者：
Bick-Forrester, J
中科院分区：
文献类型：
--
作者：
Forrester, JS;Bick-Forrester, J
慢性进行性疾病(CPD)是西方世界死亡的主要原因[1](国家卫生统计中心。第52卷。《全国重要的176项统计报告》。死亡人数：2001年最终数据；2003年，第3页)。大多数慢性病都会出现功能失调的器官特有的症状和体征。尽管如此，在组织和细胞水平上还是可以识别出实质性的共性。这些包括组织和血清中炎性细胞因子的显著增加，伴随着组织破坏、细胞凋亡和组织纤维化。单个炎性细胞因子在体外和体内都具有诱导这些组织效应的能力。此外，全身细胞因子和C反应蛋白水平的升高预示着这些疾病所有阶段的风险都会增加。抑制刺激物、介体或对持续性炎症反应的疗法似乎对特定疾病的进展有抑制作用。我们假设，基于这些观察，可以构建CPD的统一范式。不稳定刺激激活组织中正常的保护性稳态炎症反应。随着刺激的消除和组织的愈合，炎症反应减弱，重新建立动态平衡。然而，如果炎性细胞因子持续存在，则可以诱导细胞凋亡和组织纤维化。进化的两个方面为这一假说提供了潜在的机制基础。我们可能会推测，达尔文式的选择有利于早期开发一种通过通用反应系统引导广泛的外部和内部挑战的系统。因此，对有害刺激作出反应的媒介在整个生物体和物种中都是普遍存在的。由于这些遗传反应在分化前是所有细胞DNA编程的一部分，因此组织对炎症的反应在性质上也是一致的，而且范围也很窄。随后的细胞分化导致组织功能的巨大差异，以至于器官功能障碍伴随着我们所认为的个体疾病的无数症状和体征而出现。干扰炎性细胞因子，例如HMG CoA还原酶抑制剂，可抑制一系列慢性进展性疾病，而不受任何降低低密度脂蛋白的影响。(C)2005爱思唯尔有限公司。保留所有权利。
Chronic progressive disease (CPD) are the Western world's major cause of mortality [1] (National Center for Health Statistics. Vol. 52. National vital 176 statistics reports. Deaths: final data for 2001; 2003, p. 3). Most chronic diseases present with symptoms and signs specific for the dysfunctional organ. Nonetheless, substantial commonalities are identifiable at the tissue and cellular level. These include a striking increase in inflammatory cytokines in both the tissue and the serum, accompanied by tissue destruction, apoptosis and tissue fibrosis. Individual inflammatory cytokines possess the capacity to induce these tissue effects in vitro and in vivo. Further, an elevation in systemic levels of cytokines and CRP predict an increase risk at all stages of these diseases. Therapies that inhibit the stimuli, the mediators or the responses to persistent inflammation appear to have an inhibitory effect on progression of specific diseases. We hypothesize that a unifying paradigm for CPD can be constructed based on these observations. Destabilizing stimuli activate the normal protective homeostatic inflammatory response in tissue. As the stimulus is eliminated and tissue heals, the inflammatory response recedes, re-establishing homeostasis. If inflammatory cytokines persist, however, both cell apoptosis and tissue fibrosis can be induced.Two aspects of evolution provide a potential mechanistic basis for this hypothesis. We may speculate that Darwinian selection favored early development of a system that channeled a broad spectrum of external and internal challenges through a generic response system. Thus, the mediators that respond to noxious stimuli became universal throughout organisms and species. Because these genetic responses were part of the DNA programming of all cells prior to differentiation, the tissue response to inflammation is also both uniform in nature, and narrow in scope. Subsequent cell differentiation resulted in vast differences in tissue function, so that organ dysfunction appears with the myriad symptoms and signs we recognize as individual diseases. Interference with inflammatory cytokines, e.g., with HMG Coa reductase inhibitors, inhibits a spectrum of chronic progressive diseases, independent of any LDL lowering effect. (c) 2005 Elsevier Ltd. All rights reserved.