Billiar T R, Maddaus M A, West M A, Curran R D, Wells C A, Simmons R L
Department of Surgery, University of Pittsburgh, Pennsylvania 15261.
Ann Surg. 1988 Oct;208(4):532-40. doi: 10.1097/00000658-198810000-00015.
A number of disease states and therapeutic maneuvers common to surgical patients can result in changes in the intestinal flora, permitting bacterial overgrowth and translocation of bacteria to gut lymphoid tissue. It is possible that these changes in gut flora increase portal levels of several factors that are capable of altering macrophage activation state, including endotoxin, lymphokines, and eicosanoids. Since Kupffer cells are directly exposed to gut factors via the portal circulation, changes in intestinal flora may influence Kupffer cell responses. Using germfree rats, it has previously been shown that the presence of gut bacterial flora is important in inducing Kupffer cells to respond to endotoxin, and that an overgrowth of gram-negative bacteria can further augment Kupffer cell responses, supporting the above-mentioned hypothesis. The current set of experiments examines how intestinal gram-negative bacterial overgrowth in normal adult rats effects the response of Kupffer cells to septic stimuli. Kupffer cells were obtained from conventional rats with induced intestinal overgrowth with Escherichia coli C25 for 2 or 7 days. After 2 days of overgrowth, Kupffer cells were only slightly less responsive to lipopolysaccharide (LPS) than control Kupffer cells. However, after 7 days of overgrowth, when placed in coculture with normal hepatocytes, Kupffer cells were significantly more responsive to LPS (p less than 0.001), inducing a greater degree of suppression in hepatocyte protein synthesis at lower LPS concentrations. When cultured alone, Kupffer cells from these animals also produced more interleukin-1 (p less than 0.002) and prostaglandin E2 (PGE2) (p less than 0.009) in response to LPS. These results show that intestinal gram-negative bacterial overgrowth in conventional rats can have direct influences on the response of hepatic macrophages to septic stimuli, and provides further support to the hypothesis that imbalances in the intestinal flora can effect the responses of immune cells in other sites of the body.
外科患者常见的一些疾病状态和治疗手段可导致肠道菌群发生变化，使细菌过度生长并向肠道淋巴组织移位。肠道菌群的这些变化可能会增加几种能够改变巨噬细胞激活状态的因子的门静脉水平，这些因子包括内毒素、淋巴因子和类花生酸。由于库普弗细胞通过门静脉循环直接接触肠道因子，肠道菌群的变化可能会影响库普弗细胞的反应。此前使用无菌大鼠的研究表明，肠道细菌菌群的存在对于诱导库普弗细胞对内毒素作出反应很重要，革兰氏阴性菌的过度生长可进一步增强库普弗细胞的反应，这支持了上述假说。当前这组实验研究了正常成年大鼠肠道革兰氏阴性菌过度生长如何影响库普弗细胞对脓毒症刺激的反应。从用大肠杆菌C25诱导肠道过度生长2天或7天的普通大鼠中获取库普弗细胞。过度生长2天后，库普弗细胞对脂多糖（LPS）的反应仅略低于对照库普弗细胞。然而，过度生长7天后，当与正常肝细胞共培养时，库普弗细胞对LPS的反应明显更强（p小于0.001），在较低LPS浓度下对肝细胞蛋白质合成的抑制程度更大。当单独培养时，来自这些动物的库普弗细胞对LPS的反应也产生了更多的白细胞介素-1（p小于0.002）和前列腺素E2（PGE2）（p小于0.009）。这些结果表明，普通大鼠肠道革兰氏阴性菌过度生长可直接影响肝巨噬细胞对脓毒症刺激的反应，并为肠道菌群失衡可影响身体其他部位免疫细胞反应的假说提供了进一步支持。
