SC5b-9-Induced Pulmonary Microvascular Endothelial Hyperpermeability Participates in Ventilator-Induced Lung Injury

Abstract

Mechanical ventilation with large tidal volumes can increase lung alveolar permeability and initiate inflammatory responses, termed ventilator-induced lung injury (VILI). VILI is characterized by an influx of inflammatory cells, increased pulmonary permeability, and endothelial and epithelial cell death. But the underlying molecular mechanisms that regulate VILI remain unclear. The purpose of this study was to investigate the mechanisms that regulate pulmonary endothelial barrier in an animal model of VILI. These data suggest that SC5b-9, as the production of the complement activation, causes increase in rat pulmonary microvascular permeability by inducing activation of RhoA and subsequent phosphorylation of myosin light chain and contraction of endothelial cells, resulting in gap formation. In general, the complement-mediated increase in pulmonary microvascular permeability may participate in VILI.

Upregulation of sphingosine kinase�1 contributes to�ventilator-associated lung injury in a two-hit model

“…The increased production of ROS (1), and the disorganized structure of the actin and tubulin cytoskeleton (37), endothelial apoptosis (40) and disruptions in endothelial interactions (13) are the main causes of endothelial hyperpermeability in VALI. The present study and several previous reports revealed that RhoA/ROCK1-mediated phosphorylation of myosin light chain led to the contraction of endothelial cells and breakdown of the pulmonary endothelial barrier (14,27). In the present study, it was identified that SPHK inhibitor attenuated the activity of RhoA and ROCK1, and the phosphorylation of MYPT1 in vivo and in vitro ; consequently, the function of the pulmonary vascular endothelial barrier was found to be improved following SPHK inhibition.…”

“…The disruption of the endothelial barrier induces the transmigration of inflammatory cells, such as neutrophils, and the formation of edema. Our previous study showed that the activation of Ras homolog family member a (RhoA), and subsequent phosphorylation of myosin light chain and contraction of endothelial cells, may be involved in VALI (14). Furthermore, high tidal volume ventilation-induced lung inflammation was found to be associated with the upregulation of RhoA; treatment with RhoA inhibitor suppressed the expression of Rho-associated coiled-coil forming protein kinase (ROCK) and alleviated lung inflammation (15).…”

The proteomic response is linked to regional lung volumes in ventilator-induced lung injury

“…CCC are characteristic of acute lung injury [27,28] and other inflammatory conditions in the lung including pneumonia, and sepsis [27] and have been shown to be linked to ventilator induced lung injury (VILI) [29,30], and multi-organ failure [27]. In VILI, as a result of tidal stretch, both local and systemic complement systems are activated resulting in increased vascular permeability and pulmonary edema [29,31], which can subsequently limit lung expansion, and reduce lung compliance. As such, the CCC proteins are regarded as theoretical therapeutic targets to prevent VILI [28][29][30].…”

Molecular Mechanisms of Ventilator-Induced Lung Injury

“…Liu et al . [ 41 ] reported that the activity of serum complement was higher along with aggravated pulmonary edema in a rat model of VILI compared with the control group. At the same time, they found the permeability of pulmonary endothelial monolayer was increased after soluble C5b-9 stimulation.…”

“…Further research revealed that soluble C5b-9 caused a significant increase in rat pulmonary microvascular permeability by activating RhoA and led to higher expression of phosphorylated myosin light chain, finally resulted in stress fiber and gap formation. [ 41 ] Therefore, pulmonary endothelial barrier dysfunction mediated by complement activation may be involved in the pathogenesis of VILI.…”