Mechanical ventilation creates excessive mechanical stress that directly augments lung injury in critically ill patients with respiratory failure due to ARDS, a syndrome known as ventilator-induced lung injury (VILI). There have been little insights into the specific mechanisms involved in VILI-induced pulmonary capillary endothelial cell (EC) leakage, a key therapeutic target in ARDS/VILI. Project #1 will examine how excessive mechanical stress suppresses SOX18 expression, a transcription factor (TF) intimately involved in preservation of EC barrier integrity via transcriptional regulation of the tight junction protein, claudin 5 (CLDN5). We have shown that fluid shear stress increases Sox18 expression, however, EC exposed to 18% cyclic stretch (CS) or LPS exhibit decreased Sox18 expression. In addition, enhanced mouse lung Sox18 expression attenuates EC barrier disruption induced by exposure to high tidal volume mechanical ventilation or LPS. Project #1 will investigate mechanisms by which LPS and excessive mechanical stress reduce Sox18 expression in both human lung EC and the mouse lung. We will explore how the initial inflammatory phase of VILI, via inflammatory signaling evoked by nuclear factor (NF)-?B, suppresses SOX18 expression. Further, Project #1 will extend our published data and examine how excessive mechanical stress regulates NF-?B signaling proteins via increased ROS- mediated post-translational NF-?B modifications (PTMs) including nitration and phosphorylation. These events, in concert with recruitment of histone deacetylases, appear to be critical to suppressing SOX18 promoter activity.
Specific Aim #1 (SA #1) will define the role of NF-?B signaling in mechanical stress-mediated downregulation of SOX18 and CLDN5 expression and loss of EC junctional integrity. SA #1 will also investigate the influence of ARDS/VILI related SOX18 and CLDN5 promoter SNPs on Sox18 and CLDN5 expression in response to mechanical stress. SA #2 will define the role of nitration-mediated PTMs in the mechanical stress- mediated activation of NF-?B signaling and investigate the involvement of the mechanosensitive receptor, TRPV4. SA #3 will translate SAs #1 & 2 data into actionable information and define the therapeutic efficacy of directly increasing Sox18 expression, preventing the epigenetic down-regulation of SOX18 (HDAC inhibitors), preventing nitration-mediated NF-?B activation (shielding peptides) and reducing mitochondrial-derived ROS (mitochondrial targeted peptides). Together with each PPG Project and the expertise residing in each PPG Core, these explorations will advance our understanding of the interplay between genetics, epigenetics and PTMs in regulating the SOX18-CLDN5 axis and EC barrier integrity. Further, our studies will promote a more thorough understanding of VILI pathobiology while highlighting the application of individualized therapies for the critically ill.
/RELEVANCE: Acute respiratory distress syndrome (ARDS) is a devastating inflammatory lung disease with an estimated 200,000 cases/yr in the United States and an unacceptable high mortality rate of 30-40%. Mechanical ventilation directly contributes to de novo lung injury and exaggerates established acute lung injury, a condition known as ventilator-induced lung injury (VILI). Despite recent advances in care of the critically ill, there remains a need for improved understanding of VILI/ARDS pathophysiology and a need for improved therapeutic options for these patients that are currently severely limited. The goal of this Project is to develop a better understanding of the mechanisms by which loss of Sox18 expression in the lung leads to endothelial barrier disruption. Emphasis is placed on understanding both novel mechanisms and on developing novel reagents to restore EC barrier function during VILI/ARDS.
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