Regueira T, Andresen M, Djafarzadeh S
Departamento de Medicina Intensiva, Pontificia Universidad Católica de Chile, Santiago, Chile.
Med Intensiva. 2009 Nov;33(8):385-92. doi: 10.1016/j.medin.2008.10.002. Epub 2009 Sep 20.
There is a direct correlation between the development of the multiple organ dysfunction syndrome (MODS) and the elevated mortality associated with sepsis. The mechanisms responsible for MODS development are being studied, however, the main efforts regarding MODS evaluation have focused on oxygen delivery optimization and on the modulation of the characteristic inflammatory cascade of sepsis, all with negative results. Recent studies have shown that there is development of tissue acidosis, even when there are normal oxygen conditions and limited presence of tissue cellular necrosis or apoptosis, which would indicate that cellular energetic dysfunction may be a central element in MODS pathogenesis. Mitochondrias are the main source of cellular energy, central regulators of cell death and the main source for reactive oxygen species. Several mechanisms contribute to mitochondrial dysfunction during sepsis, that is blockage of pyruvate entry into the Krebs cycle, oxidative phosphorylation substrate use in other enzymatic complexes, enzymatic complex inhibition and membrane damage mediated by oxidative stress, and reduction in mitochondrial content. Hypoxia-inducible factor-1alpha (HIF-1alpha) is a nuclear transcription factor with a central role in the regulation of cellular oxygen homeostasis. Its induction under hypoxic conditions is associated to the expression of hundreds of genes that coordinate the optimization of cellular oxygen delivery and the cellular energy metabolism. HIF-1alpha can also be stabilized under normoxic condition during inflammation and this activation seems to be associated with a prominent pro-inflammatory profile, with lymphocytes dysfunction, and to a reduction in cellular oxygen consumption. Further studies should establish a role for HIF-1alpha as a therapeutic target.
多器官功能障碍综合征（MODS）的发展与脓毒症相关的死亡率升高之间存在直接关联。目前正在研究导致MODS发展的机制，然而，关于MODS评估的主要努力集中在优化氧输送以及调节脓毒症典型的炎症级联反应上，所有这些努力都产生了负面结果。最近的研究表明，即使在氧条件正常且组织细胞坏死或凋亡存在有限的情况下，仍会发生组织酸中毒，这表明细胞能量功能障碍可能是MODS发病机制中的核心要素。线粒体是细胞能量的主要来源、细胞死亡的核心调节因子以及活性氧的主要来源。脓毒症期间有多种机制导致线粒体功能障碍，即丙酮酸进入三羧酸循环受阻、其他酶复合物中氧化磷酸化底物的利用、酶复合物抑制以及氧化应激介导的膜损伤，以及线粒体含量减少。缺氧诱导因子-1α（HIF-1α）是一种核转录因子，在细胞氧稳态调节中起核心作用。其在缺氧条件下的诱导与数百个协调细胞氧输送优化和细胞能量代谢的基因的表达相关。在炎症期间的常氧条件下，HIF-1α也可被稳定，这种激活似乎与显著的促炎特征、淋巴细胞功能障碍以及细胞氧消耗减少有关。进一步的研究应确定HIF-1α作为治疗靶点的作用。
