Abstract
Excessive mechanical ventilation exerts pathologic mechanical strain on lung vascular endothelium and promotes endothelial cell (EC) inflammatory activation; however, the specific mechanisms underlying EC inflammatory response caused by mechanical ventilation related cyclic stretch (CS) remain unclear. This study investigated the effects of chronic exposure to CS at physiologic (5%) and pathologic (18%) magnitude on pulmonary EC inflammatory status in control conditions and bacterial lipopolysacharide (LPS)-stimulated conditions. EC exposure to high or low CS magnitudes for 28–72 hrs had distinct effects on EC inflammatory activation. 18% CS increased surface expression of endothelial adhesion molecule ICAM1 and release of its soluble form (sICAM1) and inflammatory cytokine IL-8 by CS-stimulated pulmonary endothelial cells (EC). EC inflammatory activation was not observed in EC exposed to 5% CS. Chronic exposure to 18% CS, but not to 5% CS, augmented ICAM1 and IL-8 production and EC monolayer barrier disruption induced by LPS. 18% CS, but not 5% CS, stimulated expression of RhoA GTPase-specific guanine nucleotide exchange factor GEF-H1. GEF-H1 knockdown using gene-specific siRNA abolished 18% CS-induced ICAM1 expression and sICAM1 and IL-8 release by EC. GEF-H1 knockdown also prevented disruption of EC monolayer integrity and attenuated sICAM1 and IL-8 release in the two-hit model of EC barrier dysfunction caused by combined stimulation with 18% CS and LPS. These data demonstrate that exacerbation of inflammatory response by pulmonary endothelium exposed to excessive mechanical stretch is mediated by CS-induced induction of Rho activating protein GEF-H1.
Highlights
Ventilation support of critically ill patients with or without pre-existing lung pathology exerts excessive mechanical strain on certain regions in the lung
LPS-induced activation of ICAM1 expression was significantly enhanced in endothelial cell (EC) exposed to 72-hr 18% cyclic stretch (CS) compared to static control
The novel findings of this study are that: a) Guanine nucleotide exchange factor H1 (GEF-H1) expression is upregulated by pathologically relevant 18% CS in pulmonary EC; and b) GEF-H1 increased 18% CS-induced expression of inflammatory molecules ICAM1, VCAM1, IL-8, IL-6 and TNFα and augmented EC inflammatory response to LPS
Summary
Ventilation support of critically ill patients with or without pre-existing lung pathology exerts excessive mechanical strain on certain regions in the lung. This excessive mechanostimulation compromises the blood-gas barrier, and increase lung vascular permeability, which may lead to massive vascular barrier dysfunction, pulmonary edema and ventilator-induced lung injury (VILI) [1, 2]. Clinical data and experimental observations indicate that besides direct effects on epithelial and endothelial integrity and permeability [7, 8], mechanical ventilation at high tidal volumes causes release of inflammatory cytokines which further exacerbate ventilator-induced lung injury [9, 10]. Mechanical ventilation at high tidal volumes has been shown to enhance LPS-induced lung injury and vascular leak in animal models [11]
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