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Charles Frevert, D.V.M, Sc.D.
Iowa State University School of Veterinary Medicine
Tufts University School of Veterinary Medicine, Large Animal Internal Medicine Residency
Harvard School of Public Health, Doctor of Science Degree (Sc.D.) in Physiology and Cell Biology
1997 - Research Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine/Department of Medicine
2002 - Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine/Department of Medicine
2008 - Associate Professor Department of Comparative Medicine
With the evolution of multidrug-resistant pathogens, an increase in zoonotic lung infections, the threat of bioterrorism, an aging population, and an increasingly urban, yet globally mobile society, we are more vulnerable to lung infection today than at any time in our history. Research in my laboratory focuses on the early response of the immune system to viral and bacterial infections, which is mediated by the innate immune system. The goal is to better understand the cellular and molecular mechanisms that regulate the innate immune system and the mechanisms that are responsible for the successful clearance of bacteria and viruses from the lungs. This has included work on CD14/Toll-like receptor signaling pathways. An important and recent focus of my laboratory is to determine the role that proteoglycans and their associated glycosaminoglycans play in the innate immune response to lung infection.A growing literature, including work from my laboratory, shows that proteoglycans and glycosaminoglycans are able to modulate the innate immune response to lung infection through a number of different mechanisms (Figure 1).
Figure 7: Activation of the innate immune response by bacteria in an infected alveolus.The recognition of bacteria and viruses in the lungs results in the activation of Toll-like receptor (TLR) signalling pathways, which leads to pulmonary inflammation and under ideal conditions the clearance of the pathogen. Proteoglycans and/or their glycosaminoglycans modify the inflammatory response in lungs through at least six different mechanisms.
- The release of soluble proteoglycans such as biglycan or degradation of glycosaminoglycan such as hyaluronan and heparan sulfate can activate TLRs.
- Cytokines, chemokines, and growth factors bind to glycosaminoglycans, which can either increase or decrease their biological activity.
- Adhesion molecules including the selectins, integrins, and CD44 bind to proteoglycans and glycosaminoglycan, which suggests that these proteins play a critical role in leukocyte adhesion and migration.
- Chemokine-glycosaminoglycan interactions provide fine-tune control of chemokine-gradient formation and leukocyte migration in tissue.
- Activation of stromal and immune cells results in the release of matrix metalloproteinases (MMPs). Growing evidence shows that interactions between proteoglycans and MMPs play important roles in the regulation of the innate immune response.
- Degradation of proteoglycans by MMPs and other proteases controls the amount and localization of proteoglycans in lungs. In addition, proteolytic cleavage of proteoglycans leads to the unmasking of cryptic fragments.
The drawing by Mark Baskin was published in, Gill, S., Wight, T.N., and Frevert, C.W., Proteoglycans: Key Regulators of Pulmonary Inflammation and the Innate Immune Response to Lung Infection. Anat. Rec. 2010 (In Press).
Frevert CW, Huang SL, Danaee H, Paulauskis JD, Kobzik L. Functional characterization of the rat chemokine KC and its importance in neutrophil recruitment in a rat model of pulmonary inflammation. J Immunol 1995;154:335-344.
Frevert CW, Matute-Bello G, Skerrett SJ, Goodman RB, Kajikawa O, Sittipunt T, Martin TR. Effect of CD14 Blockade in rabbits with Escherichia coli pneumonia and sepsis. J of Immunol 2000;164:5439-5445.
Frevert CW, Goodman RB, Kinsella MG, Kajikawa O, Ballman K, Clark-Lewis I, Proudfoot AEI, Wells TNC, Martin TR. Tissue-specific mechanisms control the retention of interleukin-8 in lungs and skin. J Immunol 2002; 168(7):3550-3556.
Frevert CW, Kinsella MG, Vathanaprida C, Goodman RB, Baskin DG, Proudfoot A, Wells T, Wight TN, Martin TR. Binding of IL-8 to Heparan Sulfate and Chondroitin Sulfate in Lung Tissue. Am J Respir Cell Mol Biol 2003;28:464-472.
Frevert CW, Boggy G, Keenan TM, and Folch A. Measurement of cell migration in response to an evolving radial chemokine gradient triggered by a microvalve, Lab on a Chip 2006;6:849-856.
Smith LS, Kajikawa O, Elson G, Wick M, Mongovin S, Kosco-Vilbois M, Martin TR, Frevert CW. Effect of TLR4 Blockade on Pulmonary Inflammation Caused by Mechanical Ventilation and Bacterial Endotoxin, Exp Lung Res, 2008; 34(5): 225-43.
Webb-Robertson BM, Mccue LA, Beagly N, Mcdermott JE, Wunschel DS, Varnum S, Hu JZ, Isern NG, Buchko GW, Mcateer K, Skerrett SJ, Liggitt D, Pounds JG, Frevert, CW. A Bayesian Integration Model of High-Throughput Proteomics and Metabolomics Data for Improved Early Detection of Microbial Infections. Pac Symp Biocomput. In Press
Hukkanen, R.R., H. Denny Liggitt H.D, Murnane R.D., Frevert C.W. Systemic Inflammatory Response Syndrome in Non-human Primates Culminating in Multiple Organ Failure, Acute Lung Injury, and Disseminated Intravascular Coagulation, Toxicol. Pathol. 2009: 37:799-804
Tanino Y, DR Coombe, SE Gill, WC Kett, O Kajikawa, AE Proudfoot, TN Wells, WC Parks, TN Wight, TR Martin, CW Frevert. Kinetics of chemokine-glycosaminoglycan interactions control neutrophil migration into the airspaces of the lungs. J Immunol. 2010 (In Press).