Vascular leakage due to prolonged or exacerbated inflammation leads to organ damage, long-term sequelae and increased mortality. The mechanisms that mediate long-term responses are poorly understood. We propose that transcriptional changes in the endothelium may explain long-term changes in vascular permeability. Preventing or reversing vascular leakage is crucial to minimize tissue damage, but we lack a viable therapeutic strategy to restore endothelial barrier function. While loss of endothelial STAT3 increases vascular leakage, inhibition of its phosphorylation is anti-inflammatory and reduces endothelial permeability. We recently demonstrated that prolonged STAT3 Y705 phosphorylation promotes an inflammatory transcriptional response that is a requisite for IL-6-mediated vascular leakage. New data generated in our lab shows that this transcriptional response includes the dramatic increase in several enzymes that can degrade the endothelial glycocalyx components, including the hyaluronidases TMEM2 and CEMIP, and the aggrecanase ADAMTS-4. These increases were observed not only in HUVEC treated with IL-6 but also in lungs of septic mice, using two models of sepsis: systemic endotoxin and cecal ligation and puncture. Our hypothesis is that an IL-6/STAT3-induced endothelial transcriptional response that includes several glycocalyx catabolic enzymes mediates the loss of glycocalyx and the prolonged permeability increase. We will test this hypothesis in the following aims: 1) determine the causal roles of IL6/STAT3-dependent glycocalyx catabolism in the regulation of barrier function in vitro. 2) establish if adult endothelial STAT3 expression is required in the endothelial response to proinflammatory challenges in vivo, including enzyme expression. 3) determine if the loss of endothelial glycocalyx and barrier function in vitro and in vivo is dependent on a JAK/STAT3 negative feedback loop mediated by SOCS3.Our novel proposal challenges the current thinking of how STAT3 regulates endothelial barrier function. Although the loss of endothelial glycocalyx is a well-known fact in patients with severe inflammation, the mechanism of glycocalyx degradation is not well understood. We propose to study a new mechanism that may explain this clinical finding. This project is expected to have a positive impact on the management of edema by identifying novel therapeutic targets to prevent and/or revert the systemic vascular leakage.
|Program type||Transformational Project Award|
|Effective start/end date||07/01/2018 → 09/19/2018|