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
Liver disease, inflammation, wound-healing response, hepatic fibrosis, hepatic stellate cell biology, congenital hepatic fibrosis/ARPKD, alcohol
Our group is interested in liver fibrosis. While focused on alcohol-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 hepatic anti-oxidant genes. We have recently identified one gene, NAD(P)H dehydrogenase, quinone 1 (Nqo1) as a direct target of Egr-1; preliminary data suggest that Nqo1-mediated homeostatic control of NAD+/NADH ratios is important for Egr-1-mediated hepatoprotection after carbon tetrachloride exposure in mice. 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 pharmacologic approaches, we are testing the hypothesis that ethanol feeding to mice exacerbates carbon tetrachloride-induced hepatic fibrogenesis through reduced, Egr-1-dependent, Nqo1 expression and regulation of normal hepatic NAD+/NADH ratios.
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 different 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 wild-type mice and in mice deficient in enzymes responsible for HA biosynthesis. Our preliminary data suggest that deficiency of certain hyaluronan synthase (HAS) isoforms enhances acute carbon tetrachloride-induced inflammation and profibrogenic changes in the liver, but not frank fibrosis after chronic carbon tetrachloride. We have recently identified matrix metalloprotienase 13 as a critical mediator of enhanced resolution of hepatic fibrosis in HAS enzyme deficient mice.
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 the perinatal period 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 CHF/ARPKD are extremely limited and rely on combined kidney and liver transplant for patient survival. We use the polycystic kidney (PCK) rat model which harbors a mutation in a gene orthologous to the human PKHD1 gene for our studies. Mutation in the pck gene in the PCK rat recapitulates the human disease, making this a valuable tool for our research.
We are currently interrogating a 'pathogenic triumvirate' consisting of inflammation, cyst wall epithelial cell proliferation and fibrogenesis as interconnected phenomena contributing to CHF. We are testing 2 novel hypotheses which involve elucidation of the roles of hepatic mast cells and connective tissue growth factor (CTGF) in disease pathogenesis. In a third study, in close collaboration with Udayan Apte, Ph.D., DABT, we are testing the hypothesis that the Yap1-TEAD transcription regulatory complex is critical for cyst wall cell epithelial cell proliferation. The observation that CTGF, a Yap1 target gene, is robustly overexpressed in PCK rats suggests potential areas of overlap in two of our studies while studies by others demonstrating that mast cell granule contents promote proliferation of biliary cells cholestatic liver disease suggest intriguing overlap in another two studies. Finally, while we are focused on liver disease, we collect kidneys in each of our studies in the hopes that new pathogenic mechanisms or therapeutic interventions which improve liver pathology are also relevant to kidney disease in ARPKD.
(* 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.