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Dr. Dull MD, Ph.D., the Director of Anesthesia Research, studies glycobiology and mechanobiology of the lung and vascular system; his work has identified novel mechanism(s) regulating vascular permeability and the susceptibility of the lung to mechanical forces. Specifically, Dr. Dull and his collaborators have demonstrated that heparan sulfate proteoglycans are flow and pressure sensors that activate oxidative pathway(s) leading to increased vascular permeability. Increases in capillary pressure activate a heparan sulfate-nitric oxide dependent pathway that leads to increased edema formation.
Project 1. Using isolated perfused lung preparation, the role of endothelial glycoproteins and associated downstream signaling pathways are being characterized for their role in mechanotransduction and edema development. Knock-out animals, pharmacological inhibitors and gene transfection studies are being employed to identify novel targets for therapeutic intervention. In parallel, cell culture models of the lung vascular barrier are being used to validate key signaling processes.
Project 2. We made the novel observation that key regulatory enzymes involved in heparan sulfate biosynthesis are altered in animal models of neonatal respiratory distress. In parallel, other investigators have shown that knock-out of these key enzymes also cause neonatal respiratory failure. Collectively, these observations provide a foundation to understand developmental susceptibility to mechanically-induced lung injury in neonatal patients. Characterization of heparan sulfate glycomics and the functional significance on pulmonary function and cellular responses to mechanical ventilation are underway.
Project 3. Trauma is the leading cause of death for people under 45 years of age. Motor vehicle accidents are the leading cause of injury leading to traumatic brain injury and thoracic contusions. Platelets are the immediate cellular participant in response to vascular insult and they are a rich source of heparanase that degrades vascular heparan sulfates, recruit neutrophils and initiate coagulation. We are assessing the role of platelet heparanase in traumatic lung injury and hypothesize that by inhibiting platelet heparanase early in the insult, we can attenuate acute lung injury.
There are important reciprocating brain-lung interaction during trauma; brain injury results in lung inflammation via neurokinins and primary lung injury results in brain inflammation. The role of subarachanoid hemorrhage (SAH) on lung injury is being studied with the goal of identifying key immunomodulatory proteins that establish the brain-lung axis.