Abstract
IntroductionEndothelial cell injury is an important component of acute lung injury. Platelet-endothelial cell adhesion molecule-1 (PECAM1) is a transmembrane protein that connects endothelial cells to one another and can be detected as a soluble, truncated protein (sPECAM1) in serum. We hypothesized that injurious mechanical ventilation (MV) leads to shedding of PECAM1 from lung endothelial cells resulting in increasing sPECAM1 levels in the systemic circulation.MethodsWe studied 36 Sprague–Dawley rats in two prospective, randomized, controlled studies (healthy and septic) using established animal models of ventilator-induced lung injury. Animals (n = 6 in each group) were randomized to spontaneous breathing or two MV strategies: low tidal volume (VT) (6 ml/kg) and high-VT (20 ml/kg) on 2 cmH2O of positive end-expiratory pressure (PEEP). In low-VT septic animals, 10 cmH2O of PEEP was applied. We performed pulmonary histological and physiological evaluation and measured lung PECAM1 protein content and serum sPECAM1 levels after four hours ventilation period.ResultsHigh-VT MV caused severe lung injury in healthy and septic animals, and decreased lung PECAM1 protein content (P < 0.001). Animals on high-VT had a four- to six-fold increase of mean sPECAM1 serum levels than the unventilated counterpart (35.4 ± 10.4 versus 5.6 ± 1.7 ng/ml in healthy rats; 156.8 ± 47.6 versus 35.6 ± 12.6 ng/ml in septic rats) (P < 0.0001). Low-VT MV prevented these changes. Levels of sPECAM1 in healthy animals on high-VT MV paralleled the sPECAM1 levels of non-ventilated septic animals.ConclusionsOur findings suggest that circulating sPECAM1 may represent a promising biomarker for the detection and monitoring of ventilator-induced lung injury.
Highlights
Endothelial cell injury is an important component of acute lung injury
Healthy animals ventilated with high-tidal volume (VT) and septic animals on spontaneous breathing or high-VT mechanical ventilation (MV) had histological and gas exchange evidence of lung injury (Figure 1A, B)
Mean ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) in the low-VT control group was over 400 mmHg; in contrast, mean PaO2/FiO2 in healthy high-VT animals (250 ± 20 mmHg), and in septic animals ventilated with low-VT plus positive end-expiratory pressure (PEEP) (265 ± 38 mmHg) or with high-VT (211 ± 28 mmHg) met oxygenation criteria for acute lung injury [5] (Figure 1B)
Summary
Endothelial cell injury is an important component of acute lung injury. Platelet-endothelial cell adhesion molecule-1 (PECAM1) is a transmembrane protein that connects endothelial cells to one another and can be detected as a soluble, truncated protein (sPECAM1) in serum. We hypothesized that injurious mechanical ventilation (MV) leads to shedding of PECAM1 from lung endothelial cells resulting in increasing sPECAM1 levels in the systemic circulation. Necessary to preserve life, MV can itself aggravate or cause lung damage through a variety of mechanisms collectively referred to as ventilator-induced lung injury (VILI) [1]. Since pulmonary inflammation is a central component of VILI, and PECAM1 has been shown to mediate endothelial cell permeability [12], we hypothesized that PECAM1 can be cleaved and shed from the surface of endothelial cells and detected in the systemic circulation after a short term of injurious MV in an experimental, clinically relevant animal model of VILI using healthy and septic animals
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