Acute Lung Injury and Fibrosis in a Baboon Model of Escherichia coli Sepsis
Acute Lung Injury and Fibrosis in a Baboon Model of Escherichia coli Sepsis
复制标题
DOI：
10.1165/rcmb.2013-0219oc
复制
发表时间：
2014-02-01
影响因子：
6.4
通讯作者：
Lupu, Florea
中科院分区：
文献类型：
--
作者：
Keshari, Ravi S.;Silasi-Mansat, Robert;Lupu, Florea
脓毒症引起的肺部炎症导致急性呼吸窘迫综合征（ARDS），这可能引发持续性纤维化。ARDS的病理机制复杂，目前对其认识不多，治疗方法也有限。我们用狒狒大肠杆菌败血症模型模拟人类疾病的复杂性来研究ARDS的病理生理学。我们进行了广泛的生化，组织学和功能分析，以表征疾病进展和脓毒症对肺结构和功能的长期影响。与人类相似，狒狒脓毒症诱导的ARDS显示早期炎症渗出期，伴有广泛坏死。随后是再生阶段，主要是2型上皮细胞的增殖、上皮-间充质转化标志物的表达、肌成纤维细胞迁移和增殖以及胶原蛋白合成。在败血症急性发作后6-27个月，存活下来的狒狒表现出持续的炎症和胶原蛋白沉积。与年龄匹配的对照组动物相比，长期存活的动物肺中胶原蛋白的含量几乎是对照组动物的两倍。前胶原的免疫染色显示成纤维细胞灶和肺泡间隔内持续活跃的胶原合成。成纤维细胞表达转化生长因子-β和血小板衍生生长因子信号传导的标志物，表明其作为肌成纤维细胞迁移和增殖以及胶原沉积的介质的潜在作用。同时，细胞外蛋白酶抑制剂的上调支持可能促成纤维化的失调的基质重塑。败血症诱导的ARDS的灵长类动物模型模拟了人类的疾病进展，包括慢性炎症和持久的纤维化。该模型有助于我们理解纤维化的病理生理学和新疗法的测试。
Sepsis-induced inflammation of the lung leads to acute respiratory distress syndrome (ARDS), which may trigger persistent fibrosis. The pathology of ARDS is complex and poorly understood, and the therapeutic approaches are limited. We used a baboon model of Escherichia coli sepsis that mimics the complexity of human disease to study the pathophysiology of ARDS. We performed extensive biochemical, histological, and functional analyses to characterize the disease progression and the long-term effects of sepsis on the lung structure and function. Similar to humans, sepsis-induced ARDS in baboons displays an early inflammatory exudative phase, with extensive necrosis. This is followed by a regenerative phase dominated by proliferation of type 2 epithelial cells, expression of epithelial-to-mesenchymal transition markers, myofibroblast migration and proliferation, and collagen synthesis. Baboons that survived sepsis showed persistent inflammation and collagen deposition 6-27 months after the acute episodes. Long-term survivors had almost double the amount of collagen in the lung as compared with age-matched control animals. Immunostaining for procollagens showed persistent active collagen synthesis within the fibroblastic foci and interalveolar septa. Fibroblasts expressed markers of transforming growth factor-beta and platelet-derived growth factor signaling, suggesting their potential role as mediators of myofibroblast migration and proliferation, and collagen deposition. In parallel, up-regulation of the inhibitors of extracellular proteases supports a deregulated matrix remodeling that may contribute to fibrosis. The primate model of sepsis-induced ARDS mimics the disease progression in humans, including chronic inflammation and long-lasting fibrosis. This model helps our understanding of the pathophysiology of fibrosis and the testing of new therapies.