HEPATIC FIBROSIS IN A LONG-TERM MURINE MODEL OF SEPSIS
HEPATIC FIBROSIS IN A LONG-TERM MURINE MODEL OF SEPSIS
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DOI：
10.1097/shk.0b013e31824a670b
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发表时间：
2012-04-01
期刊：
影响因子：
3.1
通讯作者：
Kinne, Raimund W.
中科院分区：
文献类型：
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作者：
Gonnert, Falk A.;Kunisch, Elke;Kinne, Raimund W.
脓毒症的慢性后遗症是一个重大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，炎症使纤维化持续存在，但尚未研究全身性炎症急性期后纤维化的发展。因此，基于抗生素保护下的多种微生物腹膜炎，建立了脓毒症急性后遗症小鼠模型。 7 天内生存率下降至约 40%，并保持稳定直至第 28 天（急性期后）。幸存者在 1 周内观察到临床恢复，而白细胞和血小板计数以及肝损伤标志物直到第 28 天仍保持升高。宏观上，在腹膜间隙和肝脏上/内检测到炎症和脓肿形成。显微镜下观察到急性慢性炎症伴导管增生、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潜在致病性巨噬细胞和α-平滑肌肌动蛋白阳性细胞（可能是活化的肝星状细胞）数量增加。纤维化与弹性蛋白的存在以及 I 型和 III 型胶原蛋白的产生/沉积增加有关。微阵列分析揭示了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的特点是脓肿形成、持续性炎症以及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的增加以及I型和III型胶原蛋白的沉积有关。这表明星状细胞持续激活，并伴有连续纤维化（慢性肝病的标志），这是急性危及生命的感染的结果。
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 alpha-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/alpha-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.