LIVER-LUNG INTERACTIONS DURING ESCHERICHIA-COLI ENDOTOXEMIA - TNF-ALPHA-LEUKOTRIENE AXIS
LIVER-LUNG INTERACTIONS DURING ESCHERICHIA-COLI ENDOTOXEMIA - TNF-ALPHA-LEUKOTRIENE AXIS
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DOI：
10.1164/ajrccm.149.1.8111596
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发表时间：
1994-01-01
影响因子：
24.7
通讯作者：
LECHNER, AJ
中科院分区：
文献类型：
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作者：
MATUSCHAK, GM;MATTINGLY, ME;LECHNER, AJ
肝脏通过产生和清除肿瘤坏死因子α（TNF α）和类花生酸脂氧合产物来调节宿主对内毒素血症的反应。在内毒素血症期间，肝血流量（QL）减少是常见的，但尚不清楚TNF-α和白三烯（LT）的动力学是否因此改变以放大肺部炎症。为了检验这一假设，在Sprague-Daw大鼠中通过端侧门腔静脉分流（PCS）对QL的降低进行建模。清醒动物静脉注射2.5mg/kg E.大肠杆菌脂多糖（LPS）血清型055：B5（PCS + LPS; n = 17）或生理盐水（n = 5）。将反应与假手术大鼠（假手术+ LPS; n = 13）和NSS攻击的对照大鼠（n = 5）中的反应进行比较。在t = 0、1.5、3.5和24 h时测定心脏功能变化、血清TNF-α和有形成分，同时用支气管肺泡灌洗液（BALF）中的TNF-α、LTB（4）和多形核中性粒细胞（PMN）测量器官湿/干比（W/D）。在PCS + LPS大鼠中，死亡率为59%，血清TNF-α在1.5 h达到峰值（2，784 +/- 658 U/ml，平均值+/- SEM），与低血压发作一致。尽管假手术+ LPS大鼠在1.5 h时内毒素血症和肝及肺相关TNF-α相当，但血清TNF-α峰值低38%，死亡率为15%（p < 0.05）。PCS + LPS大鼠心脏、肝脏和盲肠W/D与假手术+ LPS大鼠相比同样增加，BALF PMN也是如此（p < 0.05）。在平行研究中，输注rTNF-α的消失动力学在非内毒素血症PCS动物中没有改变，这表明PCS + LPS大鼠中LPS的肺摄取和TNF-α的全身输出增强。内毒素血症后用乙胺嗪（DEC）抑制脂氧合酶，或LPS激发前后给予MK-886，分别使血清TNF-α峰值降低72%（768 +/- 204 U/ml）和91%（247 +/- 74 U/ml）。此外，DEC可防止血压、盲肠W/D和死亡率的变化，同时减少BALF LTB（4）和PMNs（p < 0.005）。因此，内毒素血症早期QL的选择性降低通过交叉调节炎症的TNF-α：LT轴在功能上将肝脏和肺联系起来。
The liver modulates host responses to endotoxemia by production and clearance of tumor necrosis factor alpha (TNF alpha) and eicosanoid lipoxygenation products. Reductions in liver blood flow (QL) are common during endotoxemia, but it is unknown whether the kinetics of TNF-alpha and leukotrienes (LTs) are thereby altered to amplify lung inflammation. To test this hypothesis, reductions in QL were modeled by an end-to-side portacaval shunt (PCS) in Sprague-Daw(ey rats. Conscious animals received 2.5 mg/kg of intravenous E. coli lipopolysaccharide (LPS) serotype 055:B5 (PCS + LPS; n = 17) or saline (n = 5). Responses were compared with those in sham-operated rats(sham + LPS; n = 13) and NSS-challenged control rats (n = 5). Cardiopulmonary changes, serum TNF-alpha, and formed elements were determined at t = 0, 1.5, 3.5, and 24 h, when organ wet/dry ratios (W/D) were measured with TNF-alpha, LTB(4), and polymorphonuclear neutrophils (PMN) in bronchoalveolar lavage fluid (BALF). In PCS + LPS rats, mortality was 59% and serum TNF-alpha peaked at 1.5 h (2,784 +/- 658 U/ml, mean +/- SEM) coincident with the onset of hypotension. Despite equivalent endotoxemia and liver- and lung-associated TNF-alpha in sham + LPS rats at 1.5 h, peak serum TNF-alpha was 38% less and mortality was 15% (p < 0.05). Cardiac, hepatic, and cecal W/D were likewise increased in PCS + LPS versus sham + LPS rats, as were BALF PMNs (p < 0.05). In parallel studies, the disappearance kinetics of infused rTNF-alpha were not altered in nonendotoxemic PCS animals, implicating enhanced lung uptake of LPS and systemic export of TNF-alpha in PCS + LPS rats. Lipoxygenase inhibition with diethylcarbamazine (DEC) after endotoxemia or MK-886 given before and after LPS challenge lowered peak serum TNF-alpha by 72%(768 +/- 204 U/ml) and 91% (247 +/- 74 U/ml), respectively. Moreover, DEC prevented changes in blood pressure, cecal W/D, and mortality while reducing BALF LTB(4) and PMNs (p < 0.005). Thus, selective reductions in QL early during endotoxemia functionally link the liver and lungs via a cross-modulating TNF-c alpha:LT axis of inflammation.