Abstract
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, PaO2, 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.
Highlights
A distinguishing characteristic of the pulmonary circulation is its potential for exposure to environmental stressors originating from the air we breathe and/or from the circulation
Our study rationale was based on the current lack of knowledge regarding the natural evolution of ARDS4,9 induced by ESKAPE pathogens,[35] an emerging group of highly antibiotic-resistant microbes
In the present study we comprehensively describe the exudative and reparative/fibro-proliferative phases of acute respiratory distress syndrome (ARDS) using a rodent model of P. aeruginosa-induced pneumonia
Summary
A distinguishing characteristic of the pulmonary circulation is its potential for exposure to environmental stressors originating from the air we breathe and/or from the circulation. Fully driven by cardiac failure or fluid overload[7] but due to disruption of the epithelial and alveolar–capillary barriers, increased extravascular edema, and severe alterations in gas exchange and lung mechanics.[1,3,4,8,9] Extravascular edema is a compounding factor that physically disrupts lung function via inactivation of surfactant, causing alveolar collapse upon expiration and increasing tissue resistance to airflow.[10] In addition, perivascular edema further increases tissue resistance and decreases lung compliance,[11] typified by a loss of lung distensibility and increased work of breathing.[12,13] Compromise of the pulmonary capillaries increases physiological dead space, areas of the lung that are ventilated but not perfused, and increases pulmonary shunting, areas of the lung that are perfused but not ventilated.[1,3,9,14] This ventilation/perfusion (V/Q) mismatch impairs gas exchange, leading to decreased arterial oxygen tension (PaO2).[14,15,16] As the injury worsens or progresses towards resolution, cellular hyperplasia, microthrombi formation within the vasculature, and fibrinoid deposits within the matrix define the reparative/fibro-proliferative phase of ARDS.[3,4,9] Considering the vast array of underlying etiologies and the extremely complex nature of the host response to ARDS, therapeutic advances aimed at treating this clinical condition will rely on development of comprehensively characterized disease models
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