Brealey David, Singer Mervyn
Bloomsbury Institute of Intensive Care Medicine, Wolfson Institute of Biomedical Research, University College London, Gower Street, London, WC1E 6BT, UK.
Curr Infect Dis Rep. 2003 Oct;5(5):365-371. doi: 10.1007/s11908-003-0015-9.
Sepsis is an increasingly common problem, particularly among critically ill patients. Mechanisms by which sepsis induces organ dysfunction have not been elucidated. The coexisting findings (unique to sepsis) of metabolic acidosis yet increased tissue oxygen tensions suggest cellular availability but decreased use of oxygen (tissue dysoxia). Because mitochondria use more than 90% of total body oxygen consumption for adenosine triphosphate (ATP) generation, a bioenergetic abnormality is implied. Cell and animal data have shown that nitric oxide (and its metabolites), produced in considerable excess in patients with sepsis, can affect oxidative phosphorylation by inhibiting several of its component respiratory enzymes. Human data are scarce. However, in skeletal muscle biopsies taken from patients with sepsis, we have recently demonstrated a relationship between increased nitric oxide production, antioxidant depletion, reduced respiratory chain complex I activity, and low ATP levels. These findings correlated with severity of disease and outcome and support the notion that mitochondrial dysfunction resulting in bioenergetic failure may be an important factor in the pathophysiology of sepsis-associated multiorgan failure. However, a reasonable argument can be made that the reduction in energy supply could represent a last-ditch adaptive response to ongoing inflammation, resulting in a cellular shutdown analogous to hibernation that allows eventual restoration of organ function and long-term survival in patients fit enough to survive the acute phase.
脓毒症是一个日益常见的问题，在重症患者中尤为突出。脓毒症诱发器官功能障碍的机制尚未阐明。脓毒症特有的代谢性酸中毒与组织氧张力增加并存的现象提示细胞可获取氧，但氧的利用减少（组织性低氧血症）。由于线粒体利用全身超过90%的氧消耗来生成三磷酸腺苷（ATP），这意味着存在生物能量异常。细胞和动物实验数据表明，脓毒症患者体内大量过量产生的一氧化氮（及其代谢产物）可通过抑制其几种呼吸酶成分来影响氧化磷酸化。人体数据较少。然而，最近我们在对脓毒症患者进行的骨骼肌活检中发现，一氧化氮生成增加、抗氧化剂耗竭、呼吸链复合体I活性降低与ATP水平降低之间存在关联。这些发现与疾病严重程度及预后相关，支持了这样一种观点，即线粒体功能障碍导致生物能量衰竭可能是脓毒症相关多器官功能衰竭病理生理学中的一个重要因素。然而，也有合理的观点认为，能量供应减少可能是对持续炎症的一种最后一搏的适应性反应，导致细胞类似冬眠的关闭状态，从而使足够健康以度过急性期的患者最终恢复器官功能并长期存活。
