Ph.D. State University of New York at Buffalo, Roswell Park Graduate Division, 2003
Postdoctoral Fellow, Case Western Reserve University, 2006
Postdoctoral Fellow, Cleveland Clinic, 2008
Research Associate, Cleveland Clinic, 2009
Project Scientist, Cleveland Clinic, 2011
Assistant Professor, Case Western Reserve University, 2012
Alcoholic liver disease, inflammation, wound-healing response, hepatic fibrosis, hepatic stellate cell biology, congenital hepatic fibrosis/ARPKD
Our group is interested in liver fibrosis. While focused on ethanol-induced liver disease, we hypothesize that identification of new pathways which contribute to liver fibrosis in alcoholics may also contribute to liver fibrosis of different etiologies. Knowledge of these common pathways will provide opportunities for development of novel therapeutic interventions to treat a large spectrum of patients with hepatic fibrosis. We have three projects aimed to elucidate those potential pathways.
1. Liver fibrosis and ethanol: Role of the transcription factor, Egr-1
Early growth response (Egr)-1 is a redox-sensitive transcription factor that regulates a broad array of genes involved in inflammatory, anti-oxidant and wound-healing responses. Our previous data demonstrated that Egr-1 is a positive regulator of ethanol-induced fatty liver injury and acute hepatic inflammation in mice. Paradoxically, in a mouse model of carbon tetrachloride-induced liver injury and fibrosis, Egr-1 is protective. Collectively, these data illustrate the importance of differential gene regulation in the hepatic injury vs wound healing responses.
The reactive byproducts of ethanol metabolism cause oxidative injury to the liver. Moderate ethanol feeding to mice exacerbates carbon tetrachloride-induced profibrotic changes in the liver in wild-type mice in the absence of increased liver injury. Interestingly, this effect is worsened if the mice are deficient in Egr-1 and is associated with reduced expression of anti-oxidant genes in liver. Hepatic stellate cells (HSC) are mainly responsible for fibrotic changes in the liver. Consistent with our in vivo data, HSC isolated from Egr-1-deficient mice exhibit an increased fibrotic phenotype after activation on tissue culture plastic when compared to HSC isolated from wild-type mice.
Using a combination of genetic and therapeutic approaches, we are testing the hypothesis that ethanol feeding to mice exacerbates carbon tetrachloride-induced hepatic fibrogenesis through reduced, Egr-1-dependent, antioxidant defenses.
2. Hyaluronan and hepatic fibrosis
Hyaluronan (HA), an extracellular matrix glycosaminoglycan, is increased in the plasma of patients with liver disease; HA plasma concentration directly correlates with liver disease severity. HA has differential biological functions based on molecular mass; low molecular mass HA promotes inflammation and angiogenesis while high molecular mass HA promotes tissue homeostasis. While much research is devoted to understanding the roles of HA in inflammation and fibrosis in the skin and lung, little is known about the role of HA in liver fibrosis.
In our current studies, we are investigating the roles of HA in hepatic inflammation and fibrosis. We hypothesize that HA modulates the hepatic microenvironment during liver injury and repair processes. To test this hypothesis, we are characterizing carbon tetrachloride-induced fibrosis in mice deficient in enzymes responsible for HA biosynthesis. Our preliminary data suggest that deficiency of certain hyaluronan synthase (Has) isoforms enhances carbon tetrachloride-induced profibrotic changes in the liver. Consistently, the fibrotic phenotype of primary hepatic stellate cells activated on tissue culture plastic is also greater in cells isolated from certain Has-deficient mice compared to controls.
3. Congenital hepatic fibrosis in autosomal recessive polycystic kidney disease
Congenital hepatic fibrosis (CHF), the most common extra-renal manifestation of autosomal recessive polycystic kidney disease (ARPKD), is associated with excessive extracellular matrix deposition which encapsulates ductal plate cell-derived cysts. CHF is generally detected in perinatal period and is often fatal. Infants who survive perinatal lethality develop severe portal hypertension associated with the CHF around the progressively developing hepatic cysts. The precise mechanisms of hepatic cystogenesis and associated CHF are unknown. In addition, therapeutic options for ARPKD/CHF are extremely limited and rely on combined kidney and liver transplant for patient survival. Very recently, in collaboration with Udayan Apte, PhD, DABT also in the Department of Pharmacology, we have begun to elucidate the molecular mechanisms responsible for CHF in ARPKD. In these studies, we are using the polycystic kidney (PCK) rat model which harbors a mutation in the PKHD1 gene, the same gene affected in human ARPKD. Mutation in PKHD1 in the PCK rat recapitulates the human disease, making this a valuable model for our research. We are comparing our animal model data to human patient samples to validate the relevance our findings to the human disease.
(* indicates manuscripts for which I am corresponding author.)
D.A. DeSantis, P. Lee, S.K. Doerner, C.W. Ko, J.H. Kawasoe, A.E. Hill-Baskin, S.R. Ernest, P. Bhargava, K.Y. Hur, G. Cresci, M.T. Pritchard, C.H. Lee, L.E. Nagy, J.H. Nadeau and C.M. Croniger. Genetic resistance to liver fibrosis on A/J mouse chromosome 17. Alcohol. Clin. Exp. Res. Accepted manuscript, June 2013
D.J. Chiang, S. Roychowdhury, K. Bush, M.R. McMullen, S. Pisano, M.T. Pritchard and L.E. Nagy. Adenosine 2A receptor antagonist prevented and reversed liver fibrosis in a mouse model of ethanol-exacerbated liver fibrosis. PLoS ONE, 8(7):e69114, 2013.
L.J. Dixon, M.A. Barnes, H. Tang, M.T. Pritchard and L.E. Nagy. Kupffer cells in the liver. Compr Physiol, 3:785-797, 2013.
* M.T. Pritchard, R.N. Malinak and L.E. Nagy: Early growth response (Egr)-1 is required for timely cell cycle entry and progression in hepatocytes after acute carbon tetrachloride exposure in mice. Am. J. Physiol.- Gastr. Liver Physiol., 300(6):G1124-31, 2011.
*M.T. Pritchard, J.I Cohen, S. Roychowdhury, B.T. Pratt and L.E. Nagy. Egr-1promotes hepatoprotection and attenuates carbon tetrachloride-induced liver injury in mice. J Hepatol. 53(4):655-662, 2010.
*M.T. Pritchard and L.E. Nagy. Hepatic fibrosis is enhanced and accompanied by robust oval cell activation in Egr-1-deficient mice after chronic carbon tetrachloride administration. Am J Pathol, 176(6): 2743 - 2752, 2010.
S. Roychowdhury, M.R. McMullen, M.T. Pritchard, W. Lei, R.G. Solomon and L.E. Nagy. Formation of -ketoaldehyde-protein adducts during ethanol-induced liver injury in mice. Free Rad. Biol. Med. 47:1526-1538, 2009. PMCID: PMC2783279
S. Roychowdhury, M.R. McMullen, M.T. Pritchard, M.E. Medof, A.B. Stavitsky and L.E. Nagy. An early complement dependent and TLR4 independent phase in the pathogenesis of ethanol-induced liver injury. Hepatology, 49:1326-1334, 2009. PMCID: PMC2666108
M.T. Pritchard, M.R. McMullen, M.E. Medof, A.B. Stavitsky and L.E. Nagy. Role of complement in ethanol-induced liver injury. Invited book chapter in Current Topics on Complement, Volume II, John D. Lambris, Ph.D. Editor. Adv in Exp Med Biol., 632:175-186, 2008.
* M.T. Pritchard, S. Roychowdhury, M.R. McMullen, L. Guo, G.E. Arteel and L.E. Nagy. Early growth response-1 contributes to galactosamine/lipopolysaccharide-induced acute liver injury in mice. Am. J. Physiol.- Gastr. Liver Biol., 293:G1124-G1133, 2007.
M.T. Pritchard, M.R. McMullen, A.B. Stavitsky, J.I. Cohen, F. Lin, M.E. Medof, L.E. Nagy. Differential contributions of C3, C5 and decay accelerating factor to ethanol-induced fatty liver in mice. Gastroenterology, 132(3):1117-1126, 2007. PMCID: PMC1838572
M.T. Pritchard and L. E. Nagy. Ethanol-induced liver injury: potential roles for Egr-1. Invited review. Alcohol. Clin. Exp. Res., 29:146S-150S, 2005.
M.R. McMullen, M.T. Pritchard, Q. Wang and L.E. Nagy. Early growth response-1 transcription factor is essential in the development of ethanol-induced fatty liver injury in mice. Gastroenterology, 128:2066-2076, 2005.