Lindsey Ashley S, Sullivan Lydia M, Housley Nicole A, Koloteva Anna, King Judy A, Audia Jonathon P, Alvarez Diego F
1 Department of Physiology and Cell Biology, University of South Alabama, Alabama, USA.
2 Department of Microbiology and Immunology, University of South Alabama, Alabama, USA.
Pulm Circ. 2019 Jan-Mar;9(1):2045894019826941. doi: 10.1177/2045894019826941.
Herein we describe lung vascular injury and repair using a rodent model of Pseudomonas aeruginosa pneumonia-induced acute respiratory distress syndrome (ARDS) during: 1) the exudative phase (48-hour survivors) and 2) the reparative/fibro-proliferative phase (1-week survivors). Pneumonia was induced by intratracheal instillation of P. aeruginosa strain PA103, and lung morphology and pulmonary vascular function were determined subsequently. Pulmonary vascular function was assessed in mechanically ventilated animals in vivo (air dead space, PO, and lung mechanics) and lung permeability was determined in isolated perfused lungs ex vivo (vascular filtration coefficient and extravascular lung water). At 48 hours post infection, histological analyses demonstrated capillary endothelial disruption, diffuse alveolar damage, perivascular cuffs, and neutrophil influx into lung parenchyma. Infected animals displayed clinical hallmarks of ARDS, including increased vascular permeability, increased dead space, impaired gas exchange, and decreased lung compliance. Overall, the animal infection model recapitulated the morphological and functional changes typically observed in lungs from patients during the exudative phase of ARDS. At 1 week post infection, there was lung histological and pulmonary vascular functional evidence of repair when compared with 48 hours post infection; however, some parameters were still impaired when compared with uninfected controls. Importantly, lungs displayed increased fibrosis and cellular hyperplasia reminiscent of lungs from patients during the fibro-proliferative phase of ARDS. Control, sham inoculated animals showed normal lung histology and function. These data represent the first comprehensive assessment of lung pathophysiology during the exudative and reparative/fibro-proliferative phases of P. aeruginosa pneumonia-induced ARDS, and position this pre-clinical model for use in interventional studies aimed at advancing clinical care.
在此，我们描述了使用铜绿假单胞菌肺炎诱导的急性呼吸窘迫综合征（ARDS）啮齿动物模型，在以下两个阶段对肺血管损伤和修复情况进行的研究：1）渗出期（48小时存活者）和2）修复/纤维增殖期（1周存活者）。通过气管内滴注铜绿假单胞菌PA103菌株诱导肺炎，随后测定肺形态和肺血管功能。在机械通气的动物体内评估肺血管功能（气道无效腔、氧分压和肺力学），并在离体灌注肺中测定肺通透性（血管滤过系数和血管外肺水）。感染后48小时，组织学分析显示毛细血管内皮破坏、弥漫性肺泡损伤、血管周围套袖样浸润以及中性粒细胞流入肺实质。感染动物表现出ARDS的临床特征，包括血管通透性增加、无效腔增加、气体交换受损和肺顺应性降低。总体而言，该动物感染模型概括了ARDS渗出期患者肺部通常观察到的形态和功能变化。感染后第1周，与感染后48小时相比，有肺组织学和肺血管功能修复的证据；然而，与未感染对照相比，一些参数仍受损。重要的是，肺显示出纤维化增加和细胞增生，这让人联想到ARDS纤维增殖期患者的肺。对照、假接种动物显示肺组织学和功能正常。这些数据代表了对铜绿假单胞菌肺炎诱导的ARDS渗出期和修复/纤维增殖期肺病理生理学的首次全面评估，并将此临床前模型定位用于旨在推进临床护理的干预研究。
