Integrated Research and Treatment Center-Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
Shock. 2012 Apr;37(4):399-407. doi: 10.1097/SHK.0b013e31824a670b.
Chronic sequelae of sepsis represent a major, yet underappreciated clinical problem, contributing to long-term mortality and quality-of-life impairment. In chronic liver disease, inflammation perpetuates fibrogenesis, but development of fibrosis in the post-acute phase of systemic inflammation has not been studied. Therefore, a mouse model of post-acute sequelae of sepsis was established based on polymicrobial peritonitis under antibiotic protection. Survival decreased to approximately 40% within 7 days and remained constant until day 28 (post-acute phase). In survivors, clinical recovery was observed within 1 week, whereas white blood cell and platelet count, as well as markers of liver injury, remained elevated until day 28. Macroscopically, inflammation and abscess formation were detected in the peritoneal space and on/in the liver. Microscopically, acute-chronic inflammation with ductular proliferation, focal granuloma formation in the parenchyma, and substantial hepatic fibrosis were observed. Increased numbers of potentially pathogenetic macrophages and α-smooth muscle actin-positive cells, presumably activated hepatic stellate cells, were detected in the vicinity of fibrotic areas. Fibrosis was associated with the presence of elastin and an augmented production/deposition of collagen types I and III. Microarray analyses revealed early activation of canonical and noncanonical pathways of hepatic stellate cell transdifferentiation. Thus, chronic sequelae of experimental sepsis were characterized by abscess formation, persistent inflammation, and substantial liver injury and fibrosis, the latter associated with increased numbers of macrophages/α-smooth muscle actin-positive cells and deposition of collagen types I and III. This suggests persistent activation of stellate cells, with consecutive fibrosis-a hallmark of chronic liver disease-as a result of acute life-threatening infection.
脓毒症的慢性后遗症是一个主要但未被充分认识的临床问题，导致长期死亡率和生活质量受损。在慢性肝病中，炎症会持续促进纤维化，但全身炎症的急性后期发生纤维化的情况尚未得到研究。因此，基于抗生素保护下的多微生物性腹膜炎，建立了脓毒症急性后期后遗症的小鼠模型。在 7 天内，存活率下降到约 40%，并一直持续到第 28 天（急性后期）。在幸存者中，观察到临床恢复在 1 周内，而白细胞和血小板计数以及肝损伤标志物仍持续升高至第 28 天。大体上，在腹膜腔和肝脏上检测到炎症和脓肿形成。显微镜下，观察到急性-慢性炎症伴胆管增生、实质内局灶性肉芽肿形成和大量肝纤维化。在纤维化区域附近检测到大量潜在致病性巨噬细胞和α-平滑肌肌动蛋白阳性细胞，推测为激活的肝星状细胞。纤维化与弹性蛋白的存在以及胶原 I 和 III 型的产生/沉积增加有关。微阵列分析显示肝星状细胞转分化的经典和非经典途径的早期激活。因此，实验性脓毒症的慢性后遗症表现为脓肿形成、持续炎症和严重的肝损伤和纤维化，后者与巨噬细胞/α-平滑肌肌动蛋白阳性细胞数量增加和胶原 I 和 III 型沉积有关。这表明由于急性危及生命的感染，星状细胞持续激活，随后发生纤维化——这是慢性肝病的标志。
