Gene therapy for gastrointestinal ulcer healing. Cellular and molecular mechanisms of gastroduodenal mucosal injury (alcohol, NSAIDs), protection and repair.
319 peer-reviewed publications, (including papers in Nature Medicine, Lancet, J. Clin Invest, FASEB J, Am J Med, Gastroenterology, Gut, Am J Pathol, Am J Physiol, Hepatology), 19 book chapters, 467 abstracts, 436 presentations at national (US) or international meetings and
14 peer reviewed (NIH RO-1, VA Merit Review grants), including two active peer–review grants.
1988 - Glaxo Scientific Award for Outstanding Research - International Gastroenterology Congress, Rome, Italy
2001 - Athalie-Clarke Award for Outstanding Research, UCI.
2001 - Finalist, F. Berry Award, featured in US Medicine.
2002 – Geza Hetenyi Award, Semmelweiss University, Hungary 2002.
1998, 2003 & 2007 - Special Contribution Award for Research, Department of Veterans Affairs.
2007 – Gold Medal Award, Pioneers in Physiology and Gastroenterology, University Medical School Krakow, Poland.
Dr. Tarnawski’s research focuses on gastric mucosal injury, protection and gastrointestinal tissue injury and ulcer healing. He and his research team has made important scientific contributions to the concept of cytoprotection demonstrating for the first time: (1) the protective action of prostaglandin against liver injury induced by necrotizing agents, (2) the cellular mechanisms of protection by prostaglandins of human gastric mucosa in vivo against ethanol injury and (3) that prostaglandin are able to protect isolated human gastric glands against injury by indomethacin and alcohol, in a condition excluding systemic neural and vascular factors. Furthermore, he demonstrated that gastric mucosa acquires tolerance to chronic alcohol administration and that this tolerance (adaptation) is associated with the overexpression of EGF-R, EGF, TGF? and that prostaglandin E2 exerts a trophic and growth-promoting action on normal gastrointestinal mucosa and promotes growth of colon cancers by transactivating EGF receptor (Nature Medicine 2002).
Dr. Tarnawski has characterized sequential cellular events of gastric ulcer healing and demonstrated for the first time that gastric ulceration: (a) triggers activation of genes encoding for EGF and its receptor, EGF-R, in epithelial cells of the ulcer margin (Gastroenterology 1992); (b) induces EGF-R phosphorylation which results in activation of MAPK (Erk-1, -2) signal transduction pathway (Gastroenterology 1998); (c) the activated Erk-1 and -2 translocate to the nuclei of epithelial cells of the ulcer margin and trigger activation of c-fos gene (J. Physiol & Pharmacol 1998); (d) MAPK activation during ulcer healing occurs via adapter proteins (Grb-2, Shc and Sos), Ras and Raf-1 kinase, but not PKC (Am. J. Pathol 1999), and (e) specific inhibitor of MAPK pathway dramatically delays ulcer healing (Gastroenterology 1998). He also demonstrated that VacA cytotoxin of Helicobacter pylori inhibits EGF-triggered MAPK signal transduction pathway in the human gastric epithelial cells, thus providing the molecular basis for H. pylori interference with the ulcer healing processes (Am. J. Pathol 1998). Moreover, Dr. Tarnawski pioneered gene therapy for healing of experimental gastric ulcer (Gastroenterology 2001), demonstrated for the first time molecular mechanisms of esophageal ulcer healing (Gastroenterology 2002; Am. J. Pathol 2002), demonstrated critical role of serum response factor in ulcer healing and angiogenesis (Gastroenterology 2004; FASEB J. 2004), and essential role of insulin like growth factor-1 (IGF-1) in ulcer healing (Am. J. Pathol 2007). His lab also showed that anti-apoptosis protein survivin and IGF-1 are expressed in progenitor cells of normal gastric mucosa in humans and rats and are a major target for gastric mucosal injury by NSAIDs (Gastroenterology 2005;2007 and Am. J. Pathol 2007). In several studies, Dr Tarnawski has examined the role of angiogenesis - formation of new capillary vessels - in gastric ulcer healing and studied the mechanisms of this process in vitro and in vivo in injured gastric mucosa. He demonstrated that: (1) both selective and non-selective NSAIDs inhibit angiogenesis; (2) this anti-angiogenic effect of NSAIDs is mediated through inhibition of MAP kinase (Erk2), and is independent of PKC; (3) inhibition of angiogenesis by NSAIDs involves both prostaglandin-dependent and prostaglandin-independent components, and (4) both COX-1 and COX-2 are important for the regulation of angiogenesis (Nature Medicine 1999).
Dr. Tarnawski in collaboration with Dr. I.J. Sarfeh has identified gastric abnormalities in patients with portal hypertension due to liver cirrhosis and established a new concept – “portal hypertensive gastropathy” (Gastroenterology 1983, & 1987, 1988; Hepatelogy 1986). They demonstrated that the hallmark of portal hypertensive gastropathy in patients with this entity and in animal models are capillary endothelial abnormalities which result in 3.5-fold reduction in mucosal capillary lumen causing diminished capillary blood flow and reduced mucosal oxygenation. Furthermore, they demonstrated a dramatic, 10-fold reduction of gastric angiogenesis in response to alcohol injury in portal hypertensive gastric mucosa (Gastroenterology 1994). Subsequently, they demonstrated in portal hypertensive gastric mucosa activation of TNFa ?gene and overexpression of eNOS with resulting increased formation of peroxynitrate (Gastroenterology 1996, 1997, Hepatology 1998, 2001 & 2002, FASEBJ 2001 & 2003). The above studies provided new insight into the mechanisms of portal hypertensive gastropathy and its increased predisposition to injury.
Most recently, Dr. Tarnawski lab demonstrated novel molecular abnormalities and mechanisms operating in aging gastric mucosa. They showed that aging gastric mucosa has a 60% reduction in mucosal blood flow, prominent hypoxia, increased egr-1 and PTEN mRNAs and proteins compared to young gastric mucosa. It also has increased expression of pro-apoptotic proteins caspase-3 and caspase-9; reduced survivin and a 6-fold increased apoptosis vs. young mucosa. Ethanol-induced gastric mucosal injury in aging mucosa was significantly increased. The downregulation of PTEN in gastric mucosa of aging rats completely reversed its increased susceptibility to ethanol injury. In aging human gastric mucosa PTEN expression was significantly increased, while survivin is significantly reduced. These changes increase susceptibility of aging gastric mucosa to injury. Based on these abnormalities, Dr. Tarnawski coined new term – aging gastropathy (Gastroenterology 2007).
Selected Publications out of 319 peer-review papers (for full list please see Pub Med under Tarnawski A).
A. Tarnawski, D. Hollander, J. Stachura, W.J. Krause, H. Gergely: Prostaglandin protection of the gastric mucosa against alcohol injury a dynamic time related process. Gastroenterology 88:334 359, 1985.
A. Tarnawski, T. Brzozowski, I.J. Sarfeh, W.J. Krause, T.R. Ulich, H. Gergely, D. Hollander. Prostaglandin protection of human isolated gastric glands against indomethacin and alcohol injury. Evidence for direct cellular action of prostaglandin. J. Clin. Invest. 81:1081-89, 1988.
A. Tarnawski, J. Stachura, T. Durbin, I.J. Sarfeh, H. Gergely. Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats. Gastroenterology 102:695-698, 1992.
Y. Ichikawa, A. Tarnawski, I.J. Sarfeh, T. Ishikawa, H. Shimada. Distorted angioarchitecture and impaired angiogenesis in gastric mucosa of portal hypertensive rat. Gastroenterology 106:702-708, 1994.
R. Pai, F.A.Wyle, T.L. Cover, ...., A. Tarnawski. H. pylori culture supernatant interferes with EGF-activated signal transduction in human gastric Kato III cells. Am. J. Pathol. 152;1617-1624, 1998.
M.K. Jones, E. Sasaki, F. Halter, R. Pai, T. Nakamura, T. Arakawa, T. Kuroki, A.S. Tarnawski. HGF triggers activation of Cox-2 gene in rat gastric epithelial cells: action mediated through the ERK2 signaling pathway. FASEB J. 155:1759-166, 1999.
M.K. Jones, H. Wang, E. Levin, R.M. Itani, I.J. Sarfeh, A.S. Tarnawski. Inhibition of angiogenesis by NSAIDs. Insight into the mechanisms and implications for cancer growth and ulcer healing. Nature Medicine 13:2186-2195, 1999.
H. Kawanaka, M. Tomikawa, M.K. Jones, R. Pai, I.L. Szabo, K. Sugimachi, I.J. Sarfeh, A. Tarnawski. Portal hypertensive gastric mucosa has reduced activation of MAP kinase (ERK2) in response to alcohol injury: A key to impaired healing? FASEB J. 15:574-576, 2001.
A. Tarnawski, I. Szabo. Apoptosis – programmed cell death and its reference to GI epithelium. Survival signals from the matrix. Gastroenterology 120:294-298, 2001.
M.K. Jones, H. Kawanaka, D. Baatar, I.L. Szabo, R. Pai, G.Y. Koh, I. Kim, I.J. Sarfeh, A.S. Tarnawski. Gene therapy for gastric ulcers. Single local injection of VEGF and angiopoietin-1 DNAs dramatically accelerates gastric ulcers healing and improves quality of scar. Gastroenterology 121:1040-47, 2001.
D. Baatar, H. Kawanaka, I.L. Szabo, R. Pai, M.K. Jones, S. Kitano, A.S. Tarnawski. Esophageal ulceration activates genes encoding keratinocyte growth factor and its receptor in rats: A key to esophageal ulcer healing? Gastroenterology 122;458-468, 2002.
M.K. Jones, I.L. Szabo, H. Kawanaka, S.S. Husain, A.S. Tarnawski. Von Hippel Lindau tumor suppressor and HIF-1a - new targets of NSAIDs inhibition of hypoxia-induced angiogenesis. FASEB J 16:264-266,2002.
D. Baatar, M.K. Jones, R. Pai, H, Kawanaka, I.L. Szabo, W.S. Moon, S. Kitano, A.S. Tarnawski. Selective Cox-2 blocker delays healing of experimental esophageal ulcers and inhibits ulceration – triggered c-Met/HGF receptor induction and ERK2 activation. Am. J. Pathol, 160:963-972, 2002.
M.K. Jones, I.L. Szabo, H. Kawanaka, S.S. Husain, A.S. Tarnawski. Von Hippel Lindau tumor suppressor and HIF-1a - new targets of NSAIDs inhibition of hypoxia-induced angiogenesis. FASEB J 16(2):264-266, 2002.
D. Baatar, M.K. Jones, K. Tsugawa, R. Pai, W.S. Moon, G.Y. Koh, I. Kim, S. Kitano, A. S. Tarnawski. Esophageal ulceration triggers expression of hypoxia-inducible factor-1alpha and activates vascular endothelial growth factor gene: implications for angiogenesis and ulcer healing. Am. J. Pathol 161:1449-57, 2002
R. Pai, B.A. Soreghan, I.L. Szabo, M. Pavelka, D. Baatar, A.S. Tarnawski. Prostaglandin E2 transactivates EGF receptor: A novel mechanisms for promoting colon cancer growth and gastrointestinal hypertrophy. Nature Medicine 8:289-293, 2002.
S.K. Chiou, W.S. Moon, M.K. Jones, A.S. Tarnawski. Survivin expression in the stomach: implications for mucosal integrity and protection. Biochem Biophys Res Commun 305:374-9, 2003.
A.S. Tarnawski, M.K. Jones. Inhibition of angiogenesis by NSAIDs: Molecular mechanisms and clinical implications. J. Mol. Med. 81:627-36, 2003.
R. Pai, T. Nakamura, W.S. Moon, A.S. Tarnawski. Prostaglandins promote colon cancer cell invasion. Signaling by cross-talk between two distinct growth factor receptors. FASEB J. 17:1640-47, 2003.
K, Tsugawa, M.K. Jones, T. Akahoshi, W.S. Moon, Y. Maehara, M. Hashizume, I.J. Sarfeh, A.S. Tarnawski. Abnormal PTEN expression in portal hypertensive gastric mucosa: A key to impaired PI 3-kinase/Akt activation and delayed injury healing? FASEB J. 17:2316-18, 2003.
W.S. Moon, K.H. Rhyu, M.K. Kang, D.G. Lee, H.C. Uy, J.H. Yeum, G.Y. Koh, A.S. Tarnawski. Overexpression of VEGF and angiopoietin 2: A key to high vascularity of hepatocellular carcinoma. Modern Pathol 16:552-57, 2003.
W.S. Moon, S.K. Chiou, A.S. Tarnawski. Nuclear translocation of survivin in hepatocellular carcinoma: a key to cancer cell growth? Human Pathology 34:1119-26, 2003.
J.Chai, D. Baatar, A.S. Tarnawski. Serum response factor is a critical requirement for VEGF signaling in endothelial cells and VEGF-induced angiogenesis: Insight into the mechanisms. FASEB J. 18:1264-6, 2004.
J. Chai, D. Baatar and A.S. Tarnawski. Serum response factor promotes re-epithelialization and muscular structure restoration during gastric ulcer healing. Gastroenterology 126:1809-1818, 2004.
W.S. Moon, K. Chang, A. S. Tarnawski. Overexpression of metastatic tumor antigen 1 (MTA1) in hepatocellular carcinoma: Relationship to vascular invasion and estrogen receptor-?. Human Pathology 34:424-249, 2004.
W.S. Moon, K.J. Chang, AP Majumdar, A.S. Tarnawski. Reduced expression of epidermal growth factor receptor-related protein in hepatocellular carcinoma: Implications for cancer growth. Digestion 69:219-224, 2004.
R. Pai, T. Tran, A. Tarnawski. Deoxycholic acid activates ?-catenin signaling pathway and increases colon cell cancer growth and invasiveness. Mol. Biol Cell 15:2156-63, 2004.
A.S. Tarnawski, T.C. Caves. Aspirin in the XXI century: its major clinical impact, novel mechanisms of action, and new safer formulations. Gastroenterology 127:341-3, 2004.
E.C. Chu, J. Chai, A.S. Tarnawski. NSAIDs activate PTEN and other phosphatases in human colon cancer cells novel mechanisms for chemopreventive action of NSAIDs. Biochem Biophys Res Commun 320:875-9, 2004.
WS Moon, J Chai, J.T. Yang, A.S. Tarnawski, A.P.N. Majumdar. Reduced expression of epidermal growth factor receptor related protein in gastric cancer. Gut 54:201-206, 2004.
S-K Chiou, T Tanigawa, T Akahoshi, B Abdelkarim, MK Jones, AS Tarnawski. Survivin – a novel target for indomethacin-induced gastric injury. Gastroenterology 128:63-73, 2005.
T Tanigawa, R Pai, T Arakawa, K Higuchi, AS Tarnawski. TGF-beta signaling pathway: its role in gastrointestinal pathophysiology and modulation of ulcer healing. J Physiol & Pharmacol 56:3-13, 2005.
R Pai, C Lin, T Tran, AS Tarnawski. Leptin activates STAT and ERK2 pathways and induces gastric cancer cell proliferation. Biochem Biophys Res Commun 331:984-92, 2005.
A. Tarnawski, R. Pai, SK Chiou, J Chai, EC Chu. Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B. Biochem Biophys Res Commun 334:207-212, 2005.
T. Arakawa, K. Higuchi, Y. Fujiwara, T. Watanabe, K. Tominaga, E. Saski, N. Oshitani, T. Yoshikawa, A.S. Tarnawski. 15th anniversary of rebamipide: looking ahead to the new mechanisms and new applications. Dig Dis Sci 15 (Suppl 1):S3-S11, 2005.
A, Tarnawski. Cellular and molecular mechanisms of gastrointestinal ulcer healing. Dig Dis Sci (Suppl 1):S24-33, 2005.
RH Huang, J Chai, AS Tarnawski. Identification of specific genes and pathways involved in NSAIDs induced apoptosis of human colon cancer cells. World J. Gastroenterology 12:644-52, 2006.
Zs Sandor, X.M.Deng, T. Khomenko, A.S.Tarnawski, S. Szabo. Altered angiogenic balance in ulcerative colitis: A key to impaired healing? Biochem Biophys Res Com 350;147-150, 2006.
J. Chai, M. Norng, A.S. Tarnawski, J. Chow. A critical role of serum response factor in myofibroblast differentiation during experimental esophageal ulcer healing in rat. Gut 56:621-30, 2007.
S. Mandayam, R. Huang, A.S. Tarnawski, S-K. Chiou. Roles of survivin isoforms in the chemopreventive actions of NSAIDs on colon cancer cells. Apoptosis 12:1109-116, 2007.
T. Tanigawa, R. Pai, T. Arakawa, A.S. Tarnawski. Rebamipide inhibits gastric cancer cell growth. Dig Dis Sci 52;240-7, 2007.
A. Li, G. Cheng, G.H. Zhu, A.S. Tarnawski. Ghrelin stimulates angiogenesis in human microvascular endothelial cells: Implications beyond GH release. Biochem Biophys Res Commun 352:238-43, 2007.
E. Phan, A. Ahluwalia, A.S. Tarnawski. Role of SPARC - matricellular protein in pathophysiology and tissue injury healing. Implications for gastritis and gastric ulcers. Med Sci Monit. 13(2):RA, 2007.
T. Nguyen, J. Chai, T. Tanigawa, A. Li, A. Tarnawski. Novel roles of local IGF-1 activation in rat gastric ulcer healing: promotes actin polymerization, cell proliferation, re-epithelialization and induces COX-2 in a PI3K-dependent manner. Am. J. Pathol 170:1219-28, 2007.
E. Chu, A.S. Tarnawski. Rapid colonoscopic detection and quantification of colonic ischemia using Laser-Doppler Flowmeter. Gastrointestinal Endoscopy May 21, 2007 [Epub ahead of print].
E. C Chu., J.Chai, A.S. Tarnawski. Mesalazine downregulates c-Myc and genes promoting survival and proliferation of colon cancer cells. A key to its chemoprevention action? Aliment Pharmacol Therap 25:1443-49, 2007.
A. Tarnawski, R. Pai, X. Deng, A. Ahluwalia, T. Khomenko, T. Tanigawa, T. Akahoshi, Zs. Sandor, S. Szabo. Aging gastropathy - novel mechanisms: hypoxia, upregulation of multifunctional phosphatase PTEN and proapoptotic factors. Gastroenterology 2007 (in press).
American Gastroenterological Association
British Society of Gastroenterology (Oversees Member)
Bockus International Society of Gastroenterology
American College of Gastroenterology (Fellow)
Japanese Society of Gastroenterology, (Honorary Member)
Hungarian Society of Gastroenterology, (Honorary Member)
Am Soc Investigative Pathology (elected)
Association of American Physicians (elected)