A cytokine-driven acute increase in vascular permeability is an essential feature of the inflammatory response leading to tissue repair and pathogen clearing. However, prolonged or exacerbated permeability increases -known as vascular leakage- can result in tissue damage and organ dysfunction. This in turn can lead to death or irreversible organ damage, as in the case of septic shock. Preventing or reversing vascular leakage is crucial to minimize tissue injury. However, the mechanisms leading to sustained vascular leakage are poorly understood and we lack a viable therapeutic strategy to restore endothelial barrier function. As a consequence, there are no available treatments to block vascular leakage during excessive inflammation. To design these new treatments, we need to understand the signaling pathways in endothelial cells that culminate in this prolonged increase in vascular permeability. Despite the well-accepted role of IL-6 in inflammatory diseases, including vascular barrier breakdown, little is known about the signaling pathways required for IL-6-induced barrier loss, beyond the IL-6-induced activation of JAK kinase activity. In vivo, IL-6 and JAK signaling are critical factors in the development of edema following LPS or VEGF treatment as well as in models of heart ischemia/reperfusion, hemorrhagic shock, and focal cerebral ischemia. In vitro, IL-6-induced increases in permeability in the endothelium require JAK as demonstrated using inhibitors of JAK activity. We recently showed that IL-6 promotes an increase in endothelial monolayer permeability that lasts over 24 h and demonstrate that activation of Src and MEK/Erk pathways are required only for short-term increases in permeability, being dispensable after 2 h. Instead, JAK-mediated STAT3 phosphorylation at Y705 and de novo synthesis of RNA and proteins mediate the sustained increase in permeability.

Our current work is focused on determining how STAT3 can promote the sustained response and which downstream genes mediate the loss of endothelial barrier function. We identified several potential candidates in vitro and we are now testing whether these proteins mediate the drastic inflammatory response in two murine models of sepsis: systemic endotoxin and cecal ligation and puncture.