C. Wayne Smith, M.D.
Professor, Pediatrics, Immunology
Head, Section of Leukocyte Biology
Baylor College of Medicine
Mechanisms of Leukocyte Accumulation at Sites of Inflammation and Tissue Injury
My research focuses on inflammation and wound healing, the mechanisms of leukocyte accumulation at sites of inflammation and tissue injury, and the influence of dietary factors on these processes. We (including students and postdoctoral fellows) are using several models for these investigations. Specific molecular mechanisms are analyzed in vitro with isolated leukocytes and endothelial monolayers in flow chambers that simulate some aspects of blood flow in post-capillary venules. Here we assess adhesion, transendothelial migration, and the phenotypic changes leukocytes undergo during and after the process of transendothelial migration. Application of these insights to physiology in vivo involves mouse models of inflammation. Here we use a model of ocular surface injury (simple corneal abrasion) to induce an inflammatory response to injury. We also use intravital microscopy to directly visualize in real time the inflammatory events in the cornea and in other vascular beds that are directly accessible to observation. The use of knockout and transgenic mice, blocking monoclonal antibodies, and targeted inhibition allow analysis of molecular mechanisms.
Our studies of the influence of dietary factors on the inflammatory process are currently limited to the effects of high fat diets in murine models. Using insights from the basic research on inflammation, we analyze cytokines, chemokines, leukocyte changes, adhesion molecules, toll-like receptors and injury in tissues of mice fed ad lib. diets high in either milk fat (“Western diet”) or corn oil and high sucrose. These studies currently focus on the inflammatory and anti-inflammatory changes in adipose tissues, liver, blood, and corneal wound responses. We are analyzing the increases in number and subtypes of macrophages, lymphocytes, neutrophils and platelets, their phenotypic changes as obesity progresses, and the changes in inflammatory mediators (e.g, chemokines and cytokines) and inhibitors (e.g., anti-inflammatory cytokines). Transgenic and knockout strains of mice are used to evaluate specific molecular contributions to the progression of inflammation.
Collaborations have been developed with some clinical investigators to assess when possible the relevance of observations in obese mice in human obesity.
D.K Brake and C.W. Smith. 2007. Flow Cytometry on the Stromal-Vascular Fraction of White Adipose Tissue in Adipose Tissue Protocols. (Ailhaud, G. ed), Humana Press. (in press).
Z. Li, A.R. Burns, R.E. Rumbaut, and C.W. Smith. 2007. γδT cells are necessary for platelet and neutrophil accumulation in limbal vessels and efficient epithelial repair following corneal abrasion. Am.J.Pathol. 171:838-845.
A. Chakraborty, H. Brooks, P. Zhang, C.W. Smith, M.R. McReynolds, J.B. Hoying, R. Bick, L. Truong, B. Poindexter, H. Lan, W. El-Bjeirami, and D. Sheikh-Hamad. 2007. Stanniocalcin-1 regulates endothelial gene expression and modulates trans-endothelial migration of leukocytes. Am.J.Physiol.Renal Physiol. 292:F895-904.
H. Wu, S. Ghosh, X.D. Perrard, G. Thakker, J. F. Sweeney, L. C. B. Chan, C.W. Smith, C. M. Ballantyne. 2007. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation (RANTES) in adipose tissue in obesity. Circulation 115:1029-38.
A.L. Gonzalez, W. El-Bjeirami, J.L. West, L.V. McIntire, and C.W. Smith. 2007. Transendothelial migration enhances integrin dependent human neutrophil chemokinesis. J.Leuk.Biol. 81:686-95
Quiros-Tejeira RE, Rivera CA, Ziba TT, Mehta N, Smith CW, Butte NF. Risk for nonalcoholic fatty liver disease in Hispanic youth with BMI > or =95th percentile. J Pediatr Gastroenterol Nutr. 44:228-36, 2007.
D.K. Brake, E.O. Smith, H. Mersmann, C.W. Smith, and R. Robker. 2006. ICAM-1 expression in adipose tissue: Effects of diet-induced obesity in mice. Am.J.Physiol.Cell Physiol. 291:C1232-9.
Z. Li, R.E. Rumbaut, A.R. Burns, and C.W. Smith. 2006. Platelet response to corneal abrasion is necessary for acute inflammation and efficient re-epithelialization. Invest.,Opthalmol.Vis.Sci. 47:4794-4802.
C.A. Rivera, S.H. Abrams, M.H. Tcharmtchi, M. Allman, T.T. Ziba, M.J. Finegold, and C.W. Smith. 2006. Feeding a corn oil/sucrose-enriched diet enhances steatohepatitis in sedentary rats. Am.J.Physiol.GI Liver Physiol. 290:G386-G393.
Z. Li, A.R. Burns, and C.W. Smith. 2006. LFA-1-dependent inhibition of corneal wound healing. Am.J.Pathol. 169:1590-1600.
R.L. Robker, R.G. Collins, A.L. Beaudet, H.J. Mersmann, and C.W. Smith. 2004. Leukocyte migration in adipose tissue of mice null for ICAM-1 and Mac-1 adhesion receptors. Obesity Res. 12:936-940.