Macrophage migration inhibitory factor within the alveolar spaces induces changes in the heart during late experimental sepsis
Macrophage migration inhibitory factor within the alveolar spaces induces changes in the heart during late experimental sepsis
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DOI：
10.1097/01.shk.0000183238.70374.a8
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发表时间：
2005-12-01
期刊：
影响因子：
3.1
通讯作者：
Miller, EJ
中科院分区：
文献类型：
--
作者：
Lin, XC;Sakuragi, T;Miller, EJ
败血症期间呼吸功能障碍很常见。然而，尽管肺功能通常可以得到充分的支持，但心血管衰竭经常导致死亡。尽管有大量的研究，脓毒症的心肌功能障碍的机制仍然不清楚。巨噬细胞移动抑制因子（MIF）是脓毒症和急性呼吸窘迫综合征中释放的一种重要细胞因子，是已知的心脏炎症因子。我们推测脓毒症时肺释放的MIF导致心肌功能障碍。在多微生物脓毒症的小鼠模型中，我们证明了在脓毒症诱导后20和30小时之间，肺中总的和可冲洗的MIF显著增加。在脓毒症后30小时，肺部释放MIF进入肺循环，使血浆浓度在单次通过中增加高达51%。外源性MIF，滴入肺，增加肺泡角质形成细胞衍生的趋化因子（KC），巨噬细胞炎性蛋白2（MIP 2），和肿瘤坏死因子α（TNF α）在3小时，和血浆KC和MIP 2在滴注后6小时。这与p38丝裂原活化蛋白激酶和c-Jun N-末端激酶磷酸化的增加有关。由于丝裂原活化蛋白激酶活化的变化可导致心肌抑制，这些数据表明，从肺释放的MIF可能是负责的，至少部分，在脓毒症的晚期阶段看到的心功能障碍。
Respiratory dysfunction during sepsis is common. However, although lung function can often be adequately supported, death frequently results from cardiovascular collapse. Despite intense investigation, the mechanism underlying the myocardial dysfunction of sepsis remains unclear. Macrophage migration inhibitory factor (MIF), an important cytokine released in sepsis and the acute respiratory distress syndrome, is a known cardiac depressant. We hypothesized that MIF released from the lung results in myocardial dysfunction during sepsis. In murine models of polymicrobial sepsis, we demonstrate a significant increase in the lungs of total and lavagable MIF between 20 and 30 h post induction of sepsis. At 30 h post sepsis, the lungs released MIF into the pulmonary circulation, increasing the plasma concentration by up to 51% in a single pass. Exogenous MIF, instilled into the lungs, increased alveolar keratinocyte-derived chemokine (KC), Macrophage inflammatory protein-2 (MIP2), and tumor necrosis factor alpha (TNF alpha) at 3 h, and plasma KC and MIP2 at 6 h postinstillation. This was associated with an increase in p38 mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation. Because changes in mitogen-activated protein kinase activation can lead to myocardial depression, these data suggest that MIF released from the lungs may be responsible, at least in part, for the cardiac dysfunction seen in the late stages of sepsis.