Matheson Paul J, Mays Michael P, Hurt Ryan T, Harris Patrick D, Garrison R Neal
Department of Surgery, University of Louisville, 800 Zorn Avenue, Research Bldg. 19, Louisville, KY 40206, USA.
Am J Surg. 2003 Nov;186(5):519-25. doi: 10.1016/j.amjsurg.2003.07.009.
A clinical hallmark of sepsis is an early, hyperdynamic cardiac phase (increased cardiac output) that degrades to a hypodynamic phase, which results in poor gut perfusion and subsequent gastrointestinal (GI) hypoxemia, tissue ischemia, necrosis and loss of gut barrier function. Studies in rat cecal-ligation and puncture suggest that the potent vasodilator adrenomedullin (AM) might initiate or maintain the hypodynamic phase. We hypothesize that AM expression is increased in acute Escherichia coli bacteremia and chronic E coli-Bacteroides fragilis sepsis.
Acute bacteremia: male Sprague-Dawley rats were anesthetized (urethane/alpha-chloralose), tracheotomized, and cannulated for monitoring blood pressure (MABP) and heart rate (HR) and for infusion of E coli (10(9) colony-forming units [CFU] E coli per 1 mL normal saline) and blood sampling. Arterial blood was withdrawn for arterial blood gas (ABG) measurements every 60 minutes. After 6 hours, we harvested lung, liver, kidney, spleen, and small intestine tissue samples and drew arterial and portal blood for AM enzyme-linked immunosorbent assay (ELISA). Chronic sepsis: a sterile gauze pad was implanted and animals recovered for 5 days. Twenty-four hours (10(9) CFU E coli and 10(9) CFU B fragilis per 1 mL normal saline; 1 injection) or 72 hours (2 injections) after the inoculation of the back sponge, rats were anesthetized, intubated, and cannulated as above. MABP, HR, and ABG were measured for 1 hour before tissue and serum harvest for AM ELISA.
Sepsis increased HR and MABP in all groups. Acute sepsis caused a respiratory alkalosis and pH was also elevated in chronic sepsis. Serum AM levels were increased in all groups compared with baseline and remained elevated at every time point, but were not different between saline controls and septic animals at any time point, except for the portal serum from the 72-hour chronic sepsis, which was elevated.
These data suggest that surgical manipulation alone is sufficient to stimulate AM secretion, most probably from endothelial cells. While the AM levels were decreasing at 72 hours compared with 6 hours or 24 hours in the arterial blood and the saline control portal blood, it remained elevated in the septic portal samples, suggesting that the sepsis-induced increase of AM was derived from the gut by a different mechanism than that which elevated arterial serum levels.
脓毒症的一个临床特征是早期的高动力心脏期（心输出量增加），随后会恶化为低动力期，这会导致肠道灌注不良以及随后的胃肠道低氧血症、组织缺血、坏死和肠道屏障功能丧失。对大鼠盲肠结扎穿孔的研究表明，强效血管舒张剂肾上腺髓质素（AM）可能引发或维持低动力期。我们假设在急性大肠杆菌菌血症和慢性大肠杆菌 - 脆弱拟杆菌脓毒症中AM表达会增加。
急性菌血症：雄性Sprague - Dawley大鼠经乌拉坦/α - 氯醛糖麻醉、气管切开，并插管用于监测血压（平均动脉压，MABP）和心率（HR），以及输注大肠杆菌（每1 mL生理盐水含10⁹菌落形成单位[CFU]大肠杆菌）和采血。每隔60分钟抽取动脉血进行动脉血气（ABG）测量。6小时后，采集肺、肝、肾、脾和小肠组织样本，并抽取动脉血和门静脉血进行AM酶联免疫吸附测定（ELISA）。慢性脓毒症：植入无菌纱布垫，动物恢复5天。在背部海绵接种后24小时（每1 mL生理盐水含10⁹CFU大肠杆菌和10⁹CFU脆弱拟杆菌；1次注射）或72小时（2次注射），大鼠按上述方法麻醉、插管并插管。在采集组织和血清用于AM ELISA之前，测量MABP、HR和ABG 1小时。
脓毒症使所有组的HR和MABP升高。急性脓毒症导致呼吸性碱中毒，慢性脓毒症中pH也升高。与基线相比，所有组血清AM水平均升高，且在每个时间点均保持升高，但在任何时间点，生理盐水对照组和脓毒症动物之间无差异，除了72小时慢性脓毒症的门静脉血清升高。
这些数据表明，单独的手术操作就足以刺激AM分泌，很可能来自内皮细胞。虽然与6小时或24小时相比，72小时时动脉血和生理盐水对照门静脉血中的AM水平在下降，但在脓毒症门静脉样本中仍保持升高，这表明脓毒症诱导的AM升高是通过与升高动脉血清水平不同的机制从肠道产生的。
