Bhatty Minny, Tan Wei, Basco Maria, Pruett Stephen, Nanduri Bindu
Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, MS, USA.
Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, MS, USA.
Alcohol. 2017 Sep;63:9-17. doi: 10.1016/j.alcohol.2016.11.007. Epub 2016 Nov 27.
Alcohol abuse increases vulnerability to infections and infection-related mortality. In previous studies, we found that acute alcohol abuse in a binge-drinking model in mice decreased resistance to bacterial sepsis when alcohol was administered near the time of bacterial challenge. In the present study, we investigated the effects of alcohol administered later in the course of sepsis (18 h after injection of Escherichia coli). Our working hypothesis was that decreased production of cytokines caused by alcohol at this time would actually improve survival, because overproduction of pro-inflammatory mediators is thought to be the proximate cause of mortality in sepsis. Unexpectedly, administration of alcohol late in the course of sepsis led to a rapid increase in the number of viable bacteria in the peritoneal cavity. Significant increases in the concentrations of several cytokines and chemokines coincided with the increased number of bacteria in alcohol-treated mice and decreased survival time. These results demonstrated our working hypothesis to be incorrect, and reiterated the complexity of sepsis. Hypothermia is a consistent feature in this model of sepsis. In control mice (E. coli only), body temperature was near normal by 18 h or 21 h after administration of E. coli, but in mice treated with alcohol 18 h after E. coli, hypothermia was significant 3 h later and ultimately mortality was significantly increased. However, counteracting the hypothermic effect of alcohol by external warming of mice led to earlier mortality, demonstrating that hypothermia was not the major cause of mortality. These results, along with previous results from studies in which alcohol was given before initiation of sepsis, suggest that decreased cytokine and chemokine production may not be the key effect of alcohol that decreases resistance to sepsis. It seems more likely that suppression of mechanisms by which macrophages and neutrophils kill bacteria is critical, and this can occur even in the presence of high levels of cytokines and chemokines.
酒精滥用会增加感染易感性以及与感染相关的死亡率。在之前的研究中，我们发现，在小鼠暴饮模型中，若在细菌攻击前后给予酒精，急性酒精滥用会降低对细菌性败血症的抵抗力。在本研究中，我们调查了在败血症病程后期（注射大肠杆菌后18小时）给予酒精的影响。我们的工作假设是，此时酒精导致的细胞因子产生减少实际上会提高存活率，因为促炎介质的过度产生被认为是败血症死亡的直接原因。出乎意料的是，在败血症病程后期给予酒精会导致腹腔内活菌数量迅速增加。几种细胞因子和趋化因子浓度的显著增加与酒精处理小鼠体内细菌数量的增加以及存活时间的缩短相一致。这些结果表明我们的工作假设是错误的，并重申了败血症的复杂性。体温过低是该败血症模型的一个持续特征。在对照小鼠（仅注射大肠杆菌）中，给予大肠杆菌后18小时或21小时体温接近正常，但在大肠杆菌注射后18小时给予酒精的小鼠中，3小时后体温过低显著，最终死亡率显著增加。然而，通过对小鼠进行外部加热来抵消酒精的体温过低效应会导致更早死亡，这表明体温过低不是死亡的主要原因。这些结果，连同之前在败血症开始前给予酒精的研究结果，表明细胞因子和趋化因子产生减少可能不是酒精降低对败血症抵抗力的关键作用。更有可能的是，巨噬细胞和中性粒细胞杀灭细菌的机制受到抑制才是关键，即使在细胞因子和趋化因子水平较高的情况下也会发生这种情况。
