Robert S. McCuskey
Professor and Head of Cell Biology and Anatomy
Professor of Physiology, and Professor of Pediatrics
Ph. D., Case Western Reserve University
Microcirculation; in vivo microscopy; Liver Pathobiology
E-mail: mccuskey@email.arizona.edu
Our laboratory is studying dynamic biological processes in intact living organs such as the liver, spleen, pancreas, kidney, etc., using a combination of high resolution, light microscopic and electronic imaging techniques. During the past 40 years, such high resolution in vivo microscopic studies have expanded knowledge of dynamic structure-function relationships during health and disease since the methods permit the rate, duration, magnitude and direction of dynamic events to be directly visualized, evaluated, quantified and recorded continuously in life at the light microscopic level. Much of this work has been, and continues to be, focused on the mechanisms that regulate blood flow through small blood vessels in vital organs, such as liver, and how these are affected by drugs and various diseases. Advances in molecular and cellular biology have stimulated our laboratory also to use some of the fluorescence and spectrophotometric methods developed for studying molecular events in cultured individual cells isolated from organs; these techniques are being applied to studies of cells in their native environment within intact organs using the laboratory's unique microscopic techniques. Such studies are imperative in order to understand: (a) how individual cells function and communicate with each other in the intact, living organism; (b) how these functions are modified by disease, toxic substances, or drugs, and (c) how therapy can be developed to combat cellular dysfunction resulting from disease. For example, the results from such studies have tremendous potential for improving knowledge of biological molecular transport processes, cellular responses to drugs and disease, the interaction of tumor cells with host cells of the immune systems interact with foreign and host cells, as well as determining the distribution, interaction and effectiveness of therapeutic substances and novel drug delivery systems, such as liposomes, that are targeted to specific sites in the body, etc.
Current research using the above methodologies is focused on studying Kupffer cells and sinusoidal endothelial cells which are cellular components of the exchange vessels (sinusoids) in the liver. Kupffer cells produce a variety of mediators which are thought to play a key role in regulating blood flow through hepatic sinusoids, participate in host defense mechanisms, and influence liver cellular function. The endothelial cells are an early cellular target for injury by toxic substances altering sinusoidal blood flow and oxygen delivery. We are particularly interested in, not only the mechanisms in health and aging, but also how they are modified by alcohol consumption alone or in combination with other toxicants as well as with viral or bacterial infection. In addition, we are studying the effects of biologically active substances in breast milk on the development of the liver and intestine in suckling rats as well as in necrotizing enterocolitis.
Selected Publications:
McCuskey, R.S., N.W. Machen, X. Wang, M.K. McCuskey, E. Abril, D.L. Earnest, and L.D. DeLeve. A single ethanol binge exacerbates early acetaminophen- induced centrilobular injury to the sinusoidal endothelium and alters sinusoidal blood flow. In: Cells of the Hepatic Sinusoid VIII. (eds.) E. Wisse, D.L. Knook, M. Arthur. Kupffer Cell Foundation, Leiden, pp 68-70, 2001.
Lukita-Atmadja, Y. Ito, G.L. Baker, and R.S. McCuskey. Effect of curcuminoids as anti-inflammatory agents on the hepatic microvascular response to endotoxin. Shock 17: 399-403, 2002.
Dvorak, B., M.D. Halpern, H. Holubec, C.S. Williams, D.L. McWilliam, J.A. Dominguez, R. Stepankova, C.M. Payne, and R.S. McCuskey. Epidermal growth factor reduces the development of necrotizing enterocolitis in a neonatal rat model. Amer. J. Physiol. 282: G156-164, 2002.
Slehria, S., P. Rajvanshi, Y. Ito, R.P. Sokhi, K.K. Bhargava, C.J. Palestro, R.S. McCuskey, and S. Gupta. Hepatic sinusoidal dilatation prior to hepatocyte transplantation improves cell engraftment with amelioration of hepatic microcirculatory pertabations. Hepatology 35: 1320-1328, 2002.
Joseph, B., H. Malhi, K.K. Bhargava, C.J. Palestro, R.S. McCuskey, and S.Gupta. Kupffer cells participate in early clearance of syngeneic hepatocytes transplanted in the rat liver. Gastroenterology 123:1677-1685, 2002.
Halpern MD. Holubec H. Dominguez JA. Williams CS. Meza YG. McWilliam DL. Payne CM. McCuskey RS. Besselsen DG. Dvorak B. Up-regulation of IL-18 and IL-12 in the ileum of neonatal rats with necrotizing enterocolitis. Ped.Res. 51:733-739, 2002.
Wiest, R., G. Cadelina, G. Garcia-Tsao, S. Milstien, R.S. McCuskey, R.J.Groszmann. Upregulation of GTP-cylcohydrolase I by bacterial translocation and endotoxemia in mesenteric vasculature of cirrhotic rats. Hepatology: In press.
Ito, Y., N.W. Machen, G.L. Baker, M.K. McCuskey, R. Urbaschek, and R.S.McCuskey. Hepatic microcirculatory dysfunction during cholestatic liver injury in rats. Microcirculation 10: 421-432, 2003.
Ito, Y., N.W. Machen, E.R. Abril, and R.S. McCuskey. Early hepatic microvascular injury in response to acetaminophen toxicity. Microcirculation 10: 391-400, 2003.
Halpern, M.D., H. Holubec, J.A. Domingues, Y.G. Meza, C.S. Williams, M.C.Ruth, R.S. McCuskey, and B. Dvorak. Hepatic inflammatory mediators contribute to intestinal damage in necrotizing enterocolitis. Amer. J. Physiol. 284: G695-702, 2003.
Dvorak, B., M.D. Halpern, H. Holubec, K. Dvorakova, J.A. Dominguez, C.S.Williams, Y.G. Meza, H. Kozakova, and R.S. McCuskey. Maternal milk reduces severity of necrotizing enterocolitis and increases intestinal IL-10 in a neonatal rat model. Ped. Res. 53: 426-433, 2003.
DeLeve, L.D., Y. Ito, N.W. Machen, M.K. McCuskey, X. Wang, and R.S.McCuskey. Embolization by sinusoidal lining cells obstructs the microcirculation in rat sinusoidal obstruction syndrome (hepatic venoocclusive disease). Amer. J. Physiol. 284: G1045-1052, 2003.
DeLeve, L.D., X. Wang, G.C. Kanel, Y. Ito, N.W. Bethea, M.K. McCuskey, Z.A.Tokes, J. Tsai, and R.S. McCuskey. Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndrome. Hepatology 38: 900-908, 2003.
Sturm, J.W., M.A. Keese, B. Petruch. R.G. Bönninghoff, H. Zhang, N. Gretz, M. Hafner, S. Post, and R.S. McCuskey. Enhanced green fluorescent protein-transfection of murine colon carcinoma cells: key for early tumor detection and quantification. Clin. Exper. Metastasis 20: 395-405, 2003.
McCuskey, R.S., W. Ekataksin, A.V. LeBouton, J. Nishida, M.K. McCuskey, D. McDonnell, C.S. Williams, N.W. Bethea, B. Dvorak, and O. Koldovsky. Hepatic microvascular development in relation to the morphogenesis of hepatocellular plates in neonatal rats. Anat. Rec. 275A: 1019-1030, 2003.
Ito, Y., E.R. Abril, N.W. Bethea, and R.S. McCuskey. Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice. Amer. J. Physiol.: 286: G60-67, 2003.
McCuskey, R.S., Y. Ito, G.R. Robertson, M.K. McCuskey, M. Perry, and G.C. Farrell. Hepatic microvascular dysfunction during evolution of dietary steatohepatitis in mice. Hepatology 40: 386-393, 2004.
McCuskey, R.S. Anatomy of efferent hepatic nerves. Anat. Rec. 280A:821-826, 2004.
DeLeve, L.D., X. Wang, L. Hu, M.K. McCuskey, and R.S. McCuskey. Rat sinusoidal endothelial cell phenotype is maintained by paracrine and autocrine regulation. Amer. J. Physiol. 287: G757-763, 2004.
