University of Illinois College of Medicine

1. Neuroanesthesia Research Laboratory. Directors: Dale Pelligrino. Ph.D and Zhoa Zhong Chong, Ph.D.

The UIC Neuroanesthesia Laboratory is focused on cerebral vascular dysfunction that manifests after subarachanoid hemorrhage (SAH) and ischemic stroke that leads to continuing neurological injury. This work utilizes animal models, biochemistry and molecular approaches, in vivo blood flow studies, confocal imaging and immunhistochemistry to discern the mechanism(s) that lead to impaired neurovascular coupling and subsequent neurological impairment. The two major lines of investigation include: 1) dysfunctional neurovascular coupling after stroke and, 2) enhanced S100B/RAGE activity that leads to increased neuroinflammation.

Project A. Investigate the mechanisms of dysfunctional neurovascular coupling after subarachanoid hemorrhage and ischemic stroke. Dysfunctional neurovascular coupling after subarachanoid hemorrhage and ischemic stroke results in impaired vasodilator activity of cerebral arterioles and likely contributes to vasospasm, a dreaded consequence of stroke that leads to significant secondary injury. The molecular mechanism(s) of impaired neurovascular coupling are being investigated with the goal of developing novel therapeutic compounds to restore normal vascular function.

Project B. Role of S100B/RAGE in SAH neuro-inflammation. A second major project is to unravel the role of S100B and it’s receptor (RAGE) in progressive neuroinflammation associated with stroke. S100B/RAGE activation and the induced neuroinflammation contribute to vasospasm and continuing neurological injury through as of yet unidentified mechanism(s). Demonstrating the contribution of S100B and RAGE in continuing post-stroke neuro-inflammation and neurological injury could identify new targets for immune-modulatory drugs designed to improve outcomes following SAH.

2. Acute Lung Injury/ARDS Projects: Richard D. Minshall, Ph.D. (Professor, Anesthesia, Pharmacology) and Guochang Hu, MD, PhD (Assoc. Professor of Anesthesiology, Pharmacology)

Project A. ALI/ARDS. Sepsis-induced acute lung injury is a common clinical disorder in critically ill patients that is associated with high mortality while ventilator-induced lung injury (VILI), a result of mechanical ventilation, accounts for as many as one-third of all deaths attributed to ALI/ARDS. The inflammatory responses mediated by infiltration of immune cells and release of pro-inflammatory cytokines play an essential role in the mechanisms of both sepsis-induced ALI and VILI. We are interested in elucidating the molecular mechanisms by which inflammatory response is triggered, exaggerated and resolved in the development of lung injury.

Project B. Vascular endothelial permeability: Adherens junctions predominate in endothelial cell-cell contacts and control endothelial barrier integrity. Stabilization of adherens junctions is dependent on the association of vascular endothelial (VE)-cadherin, β-catenin, p120-catenin, and α-catenin proteins and their linkage to the actin cytoskeleton. We are interested in determining the signaling mechanisms that regulate paracellular and transcellular endothelial permeability pathways in response to inflammatory insults.

Project C. Signaling mechanisms in innate immunity and inflammation: A central feature of inflammatory diseases is leukocytes adhesion to endothelial cell and the migration of leukocytes from the circulation into the infected tissue. Leukocyte extravasation is induced by chemokines produced by activated inflammatory cells at the inflammatory site. Pattern recognition receptors (PRR) on immune cells can sense pathogen-associated molecular patterns (PAMP) on bacteria and endogenous stress signals termed danger-associated molecular patterns (DAMP) from injured cells to initiate and perpetuate immune and inflammatory responses. We are interested in identifying novel molecules and signaling pathways responsible for leukocyte migration and cytokine productions.

3. Roth Laboratory: PI: Steven Roth, MD, FARVO, Michael Reese Professor of Anesthesiology; Professor of Ophthalmology, and Professor in the Honors College.

The Roth lab has a long-standing interest in the mechanisms of endogenous tolerance to ischemia. The lab uses in vivo retina experiments to examine ischemic tolerance. These studies have resulted in over 85 publications and > 200 presentations at meetings including ASA, Society for Neuroscience, and the Association for Research in Vision and Ophthalmology. In addition, Dr. Roth has an active clinical research program on the mechanisms of perioperative visual loss.

Project A: The Mechanisms of Ischemic Post-conditioning in the Retina. We investigate the mechanisms whereby the retina displays robust recovery following ischemia when challenged with a brief ischemic stimulus 24 h later. The studies are evaluating the mechanisms whereby the cells shift into a survival phenotype, the role of blood flow and the endothelium in this phenomena, and the cell signaling patterns that underlie the neuroprotection. The lab collaborates with Dr. Mahanz Shahidi, PhD, Professor and Director of Research, Department of Ophthalmology at UIC, and with Wei Zhang, PhD, Assistant Professor, (Bioinformatics) Northwestern.

Project B: Stem cell rescue of the Ischemic Retina: In this project, we are examining delayed rescue after ischemia using stem cells. The aims of this project are to study the mechanisms of stem cell rescue after ischemia, the mechanisms of augmentation by hypoxic-preconditioned cells, and novel means to deliver cells or their media to the retina. The lab collaborates with Maciej Lesniak, MD, Marchese Professor and Chair of Neurosurgery at Northwestern, Joon Kong, and Professor of Chemical Engineering, UIUC, and Orly Lazarov, Professor of Anatomy, UIC.

Project C: Clinical Studies of Perioperative Visual Loss: We have recently demonstrated that the prevalence of perioperative visual loss in spine surgery is on the decline, and have shown a number of new associated risk factors for perioperative ischemic optic neuropathy. Current studies are examining the role of novel risk factors and also looking at risk factors in surgery other than spine. Collaborators include David Meltzer MD PhD, Pritzker Professor of Medicine, and Daniel Rubin MD, Assistant Professor of Anesthesia and Critical Care, University of Chicago; collaborators at UIC include Heather Moss MD PhD, Assistant Professor of Ophthalmology and Neurology, and Director of Neuro-ophthalmology, and Charlotte Joslin, Associate Professor of Ophthalmology and Epidemiology.

4. Lung Vascular Mechanotransduction & Glycocalyx Laboratory. Randal O. Dull, MD (Professor, Anesthesiology), Richard Minshall, Ph.D (Professor, Anesthesiology).

The endothelial glycocalyx is composed of proteoglycans, glycosaminoglycans and glycoproteins that form a polymer matrix on the cell surface and it extends over the cell-cell junction. The glycocalyx participates in regulation of permeability, hemostasis, as well as leukocyte and platelet binding to the cell surface. A key role of the glycocalyx it’s function as a sensor and transducer of blood pressure and blood flow. The ability of endothelial cells to sense and respond to changes in mechanical forces is called mechanotransduction and results in activation of a number of signaling pathways that influence permeability.

Project A. We are investigating the role of specific cell-surface heparan sulfate proteoglycans in mechanotransduction and how the downstream signals alter vascular permeability. We use animal models, isolated lung preparations and cell culture methods to study endothelial mechanotransduction. Numerous publications from our group have shown that heparan sulfate proteoglycans respond to changes in hydrostatic pressure by activating nitric oxide synthase and other oxidative pathways that lead to increased permeability. This change in permeability occurs by opening of intracellular junctions and increased transport of albumin via a caveolin-dependent mechanism. Uncovering the role of the glycocalyx in barrier regulation may lead to the development of novel therapies to treat change in vascular permeability.

Project 2. Hypertensive Pulmonary Edema. Hypertensive pulmonary edema (HPE) is common cause of “heart failure with preserved ejection fraction” (HFpEF), the most prevalent form of heart failure. We use an animal model of acute hypertension, induced by norepinephrine infusion, to study the effect of acutely elevated blood pressure on mechanotransduction and edema formation in lungs as well as the small bowel. Inhibition of endothelial mechanotransduction attenuates lung edema development, improves arterial oxygenations and reduces bowel edema demonstrating that mechanotransduction is a whole body, vascular phenomenon. Genetic deletion of glypican-1 heparan sulfate proteoglycan or caveolin-1 attenuates high-pressure induced lung edema. Caveolin-1 is a structural protein found in caveolea, specialized membrane vesicles, that participate in mechanotransduction and albumin transport. Using this clinically relevant model of hypertensive pulmonary edema we hope to demonstrate the importance of novel mechano-sensitive pathways in heart failure. Understanding the mechanisms of HPE could lead to important new therapies for treating congestive heart failure.

5. Use of Lipid Emulsion for Drug Overdose & Toxicity Treatment: Guy Weinberg, MD (Professor, Anesthesiology)/Douglas Feinstein, Ph.D. (Assoc. Professor, Anesthesiology).

Lipid emulsion, the formulation of base of the common anesthetic, propofol, was discovered to reverse the cardiotoxicity of local anesthetic following accidental intravenous injection during nerve blocks. This sentinel discovery for reversing local anesthetic toxicity was made by Dr. Guy Weinberg, MD at UIC. Dr. Weinberg’s laboratory continues to investigate the therapeutic mechanism(s) of lipid emulsion on local anesthetic toxicity using animal models, isolated heart models, biochemical and molecular techniques.

The concept of using lipid emulsion as an acute anti-toxin treatment was extend to investigate its potential against chemical weapons. Drs. Weinberg and Feinstein laboratories are currently funded by grants from an NIH U01 grant entitled “Intralipid: A novel countermeasure for brodifacoum (BDF) poisoning”. The goals of the grant are to understand how BDF, a 2nd generation rodenticide, causes death, to characterize the long term consequences of BDF poisoning on brain function and ultimately to develop treatment(s) to counteract BDF poisoning. The research has already found that in contrast to first generation rodenticides such as warfarin, BDF not only is a potent anti-coagulant but also directly interacts with cells to induce metabolic damage and cell death, and induces significant neuropathology in rats and rabbits. Studies are now optimizing treatment with intralipid to reduce toxicity and neuropathology. The second NIH grant is a pilot study whose main goals are to understand the association between alcohol consumption and induction of neuroinflammation. Studies focus on characterizing the genetic and epigenetic changes that occur in brain microglial cells following alcohol exposure and withdrawal, using primary microglia cultures as well as microglial cells acutely isolated from rats following chronic alcohol ingestion.