Soares Miguel P, Bach Fritz H
Instituto Gulbenkian de Ciencia, Oeiras, Portugal, Oeiras, Portugal.
Front Biosci. 2007 Sep 1;12:4932-45. doi: 10.2741/2439.
Cells have a plethora of defense mechanisms that are activated upon exposure to oxidative stress. These aim at limiting the deleterious effects of oxidative stress and re-establishing homeostasis. In the particular context of organ transplantation, these defense mechanisms contribute to sustain graft survival via at least two interrelated mechanisms. First, cytoprotection per se should support survival and function of cells within a transplanted organ. Second, cytoprotection could reduce immunogenicity of the graft and modulate the activation of the recipient's immune system to promote regulatory (suppressive) responses that sustain graft survival. Others and we have gathered evidence, to suggest that the stress-responsive enzyme Heme Oxygenase-1 (HO-1 encoded by the gene Hmox1) acts in such a manner. Upon organ transplantation, HO-1 is ubiquitously expressed in a transplanted organ, becoming the rate-limiting enzyme in the catabolism of heme into carbon monoxide (CO), iron (Fe) and biliverdin (1). There is accumulating evidence to support the notion that HO-1 expression in a graft and in the recipient can prevent rejection and promote immune tolerance. We will argue that these effects are mediated to a large extent by limiting the deleterious effects of free heme as well as by the inherent cytoprotective and/or anti-inflammatory effects of the end-products generated via heme catabolism.
细胞具有大量的防御机制，在暴露于氧化应激时会被激活。这些机制旨在限制氧化应激的有害影响并重新建立体内平衡。在器官移植的特定背景下，这些防御机制通过至少两种相互关联的机制有助于维持移植物存活。首先，细胞保护本身应支持移植器官内细胞的存活和功能。其次，细胞保护可以降低移植物的免疫原性并调节受体免疫系统的激活，以促进维持移植物存活的调节（抑制）反应。我们和其他人已经收集了证据，表明应激反应酶血红素加氧酶-1（由基因Hmox1编码的HO-1）以这种方式发挥作用。在器官移植时，HO-1在移植器官中普遍表达，成为血红素分解代谢为一氧化碳（CO）、铁（Fe）和胆绿素过程中的限速酶（1）。越来越多的证据支持这样的观点，即移植物和受体中HO-1的表达可以预防排斥反应并促进免疫耐受。我们将论证，这些作用在很大程度上是通过限制游离血红素的有害影响以及血红素分解代谢产生的终产物固有的细胞保护和/或抗炎作用来介导的。
