Dr. Bruce D. Uhal

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Michigan State University
College of Human Medicine
Physiology Department
Associate ProfessorAppointed: 2000
Professional Headshot of Bruce D. Uhal

Mailing Address

310 Giltner Hall
Michigan State University
Department of Physiology
East Lansing, Michigan 48824
United States

Contact Information

Phone: (517) 355-6475
Fax: (517) 366-5125
uhal@msu.edu

Qualifications

Ph.D., Saint Louis University School of Medicine, Biochemistry, 1987.
M.Sc., Ohio State University, Nutrition, 1982.

Expertise and Research Interests

We are funded by NHLBI to define the cell cycle and its regulation in pulmonary alveolar epithelial stem cells. These cells are critical in the response of the lung to toxic injury and are key determinants in the pathways to fibrogenesis and/or carcinogenesis of the lung. In 1995 we identified a protein fraction, synthesized by human or rat lung fibroblasts, which induces apoptosis of the epithelial stem cells and thus limits their proliferative capacity and accelerates fibrogenesis. We now know that thisprotein fraction consists of angiotensin peptides, which we recently showed are potent inducers of apoptosis in the alveolar epithelium. These findings are exciting because they provide an explanation for the previously observed ability of ACE inhibitorsand other antagonists of the renin/angiotensin system to attenuate experimental lung fibrogenesis, an observation which is well-supported but poorly understood.

Our current renewal of HL-45136 proposes to further define the roles of the local renin/angiotensin system (RAS) in the control of apoptosis by these cells and in the pathogenesis of interstitial pulmonary fibrosis. To this aim we use flow cytometry, imaging and molecular techniques to study both cultured cells and whole lung specimens derived from animal models of fibrosis (primarily rat) and from human lung biopsies obtained from normal and fibrotic patients. In general, our overall hypothesis is that abnormal expression of RAS components induces inappropriate apoptosis of key stem cell populations which otherwise repair damage and prevent collagen deposition.

In recent work, we found that ACE inhibitors or angiotensin receptor antagonists are potent inhibitors of apoptosis in response to Fas or TNF-alpha. This action is due to blockage ofangiotensin II generation that is required for apoptosis in response to Fas or TNF receptor activation in alveolar epithelial cells. We now know that the action of angiotensin II is mediated by the receptor AT1.

Other Expertise

We have begun related investigations of apoptosis in the heart, particularly as it relates to fibrosis and heart failure. We have found expression of FAS (APO1, CD95) in biopsies of failing human heart, and we hypothesize that FAS-induced apoptosis mediates the expansion of fibrotic foci that accompanies decompensation of myocardial function. In recent work, we found that the ACE inhibitor captopril is a potent inhibitor of apoptosis in response to Fas. We now know that this action is due to blockage of angiotensin II generation that is required for apoptosis. Inhibition of apoptosis in the myocardium may explain the known influence of AEC inhibitors on cardiac remodeling.


Future Research

Future studies will involve the use of antisense oligonucleotides against angiotensinogen mRNA, administered to the lung in vivo, as a potential means of blocking epithelial apoptosis in response to lung injury. It is hypothesized that this treatment alsowill prevent or inhibit the fibrotic response subsequent to injury. The same tactic also will be attempted with antisense oligonucleotides against the mRNA for the AT1 receptor.


Industrial Relevance

Our work suggests previously unknown therapeutic potential for ACE inhibitors and angiotensin receptor antagonists, i.e., the prevention of lung injury and/or lung fibrogenic reactions. We have shown that the popular antiarrythmic amiodarone also inducesapoptosis in alveolar epithelial cells, and we believe that this mechanism is part of Amiodarone-Induced Pulmonary Toxicity (AIPT). The possibility that ACE inhibitors reduce AIPT during concurrent administration with amiodarone is currently being investigated through reanalyses of clinical trial data.


Keywords

COS Keywords:

Apoptosis, Cell Cycle, Flow Cytometry, Lung Cancer.

Additional Terms:

Alveolar Epithelium, Angiotensin, Apoptosis, Epithelial Stem Cell, Pulmonary Fibrosis.

Languages

(Reading, Writing, Speaking)

English: (Fluent, Fluent, Fluent)
Spanish: (Basic, Basic, Functional)

Memberships

American Heart Association
American Physiological Society
International Society for Analytical Cytology

Honors and Awards

1999-2000, House Staff Appreciation Award, Michael Reese Hospital, Michael Reese Hospital, Chicago, research mentoring
1996-2000, RO1 HL-45136, NIH, Michael Reese Hospital, Chicago, lung epithelial stem cell function in fibrosis
1996-1999, Career Investigator Award, American Lung Association of Metropolitan Chicago:, Rush Medical College, Chicago
1990-1996, PHS First Independent Research and Transition Award HL45136, NIH, Pennsylvania State University, lung epithelial stem cell function
1989-1991, Grant-In-Aid, American Heart Association, Pennsylvania State University, Type II Cells In Compensatory Lung Growth
1987-1990, National Research Service Award recipient, T32 HL07223, NIH, Pennsylvania State University, lung epithelial stem cell physiology
1984-1987, National Research Service Award recipient, T32 HL07050, NIH, Saint Louis University, lung phospholipid biochemistry
1979-1980, Departmental Scholarship, Department of Food Science and Nutrition, Ohio State University, undergraduate studies

Previous Positions

1997-2000, Director, Michael Reese Hospital, Chicago, IL, Cardiovascular Institute, Medicine, Research
1997-2000, Research Associate Professor, University of Illinois at Chicago, Medicine, Pulmonary and Critical Care Medicine
1993-1996, Assistant Professor of Pharmacology, Rush University Medical Center, Medicine, Pharmacology
1993-1993, Technical Advisor, Pennsylvania State University, Medicine, Hershey, Medicine, Flow Cytometry Laboratory
1990-1993, Assistant Professor, Pennsylvania State University, Medicine, Hershey, Cellular and Molecular Physiology
1987-1990, Postdoctoral Fellow, Pennsylvania State University, Medicine, Hershey, Cellular and Molecular Physiology

Patents

Methods for Treating Pulmonary Fibrosis, Patent Number: 60/164052, , Joint Agreement, Self and, United States.

Funding Received

  • National Institutes of Health (NIH): Control of Type II Pneumocyte Proliferation- PHS (NHLBI) 2RO1-HL45136-12, $777,000, Sep 1, 2000 to Aug 31, 2004.

Publications

  • Wang R, Ibarra-Sunga O, Verlinski L, Pick R, Uhal BD, Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor, American Journal of Physiology. Lung Cellular and Molecular Physiology, 279(1), L143-51, July 2000 Abstract
  • Bargout R, Jankov A, Dincer E, Wang R, Komodromos T, Ibarra-Sunga O, Filippatos G, Uhal BD, Amiodarone induces apoptosis of human and rat alveolar epithelial cells in vitro, American Journal of Physiology. Lung Cellular and Molecular Physiology, 278(5), L1039-44, May 2000 Abstract
  • Segura-Valdez L, Pardo A, Gaxiola M, Uhal BD, Becerril C, Selman M, Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD, Chest, 117(3), 684-94, March 2000 Abstract
  • Wang R, Zagariya A, Ang E, Ibarra-Sunga O, Uhal BD, Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction, American Journal of Physiology, 277(6 Pt 1), L1245-50, December 1999 Abstract
  • Wang R, Ramos C, Joshi I, Zagariya A, Pardo A, Selman M, Uhal BD, Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides, American Journal of Physiology, 277(6 Pt 1), L1158-64, December 1999 Abstract
  • Filippatos G, Leche C, Sunga R, Tsoukas A, Anthopoulos P, Joshi I, Bifero A, Pick R, Uhal BD, Expression of FAS adjacent to fibrotic foci in the failing human heart is not associated with increased apoptosis, American Journal of Physiology, 277(2 Pt 2), H445-51, August 1999 Abstract
  • Wang R, Zagariya A, Ibarra-Sunga O, Gidea C, Ang E, Deshmukh S, Chaudhary G, Baraboutis J, Filippatos G, Uhal BD, Angiotensin II induces apoptosis in human and rat alveolar epithelial cells, American Journal of Physiology, 276(5 Pt 1), L885-9, May 1999 Abstract
  • Uhal BD, Joshi I, Hughes WF, Ramos C, Pardo A, Selman M, Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung, American Journal of Physiology, 275(6 Pt 1), L1192-9, December 1998 Abstract
  • Uhal BD, Gidea C, Bargout R, Bifero A, Ibarra-Sunga O, Papp M, Flynn K, Filippatos G, Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism, American Journal of Physiology, 275(5 Pt 1), L1013-7, November 1998 Abstract
  • Uhal BD, Ramos C, Joshi I, Bifero A, Pardo A, Selman M, Cell size, cell cycle, and alpha-smooth muscle actin expression by primary human lung fibroblasts, American Journal of Physiology, 275(5 Pt 1), L998-L1005, November 1998 Abstract
  • Uhal BD, Papp M, Flynn K, Steck ME, Cholera toxin stimulates type II pneumocyte proliferation by a cyclic AMP-independent mechanism, Biochimica Et Biophysica Acta, 1405(1-3), 99-109, October 1998 Abstract
  • Uhal BD, Cell cycle kinetics in the alveolar epithelium, American Journal of Physiology, 272(6 Pt 1), L1031-45, June 1997 Abstract
  • Filippatos GS, Hughes WF, Qiao R, Sznajder JI, Uhal BD, Mechanisms of liquid flux across pulmonary alveolar epithelial cell monolayers, In Vitro Cellular and Developmental Biology. Animal, 33(3), 195-200, March 1997 Abstract
  • Uhal BD, Joshi I, True AL, Mundle S, Raza A, Pardo A, Selman M, Fibroblasts isolated after fibrotic lung injury induce apoptosis of alveolar epithelial cells in vitro, American Journal of Physiology, 269(6 Pt 1), L819-28, December 1995 Abstract
  • Uhal BD, Flow cytometric study of the type II pneumocyte cell cycle in vivo and in vitro, Cytometry, 15(1), 46-52, January 1994 Abstract
  • Uhal BD, Etter MD, Type II pneumocyte hypertrophy without activation of surfactant biosynthesis after partial pneumonectomy, American Journal of Physiology, 264(2 Pt 1), L153-9, February 1993 Abstract
  • Uhal BD, Rannels DE, DNA distribution analysis of type II pneumocytes by laser flow cytometry: technical considerations, American Journal of Physiology, 261(4 Pt 1), L296-306, October 1991 Abstract
  • Uhal BD, Flowers KM, Rannels DE, Type II pneumocyte proliferation in vitro: problems and future directions, American Journal of Physiology, 261(4 Suppl), 110-7, October 1991 Abstract
  • Rybin VO, Uhal BD, Russo LA, Rannels DE, ADP ribosylation of type II pulmonary epithelial cell G proteins, American Journal of Physiology, 260(6 Pt 1), L539-47, June 1991 Abstract
  • Uhal BD, Rannels SR, Rannels DE, Flow cytometric identification and isolation of hypertrophic type II pneumocytes after partial pneumonectomy, American Journal of Physiology, 257(3 Pt 1), C528-36, September 1989 Abstract
  • Uhal BD, Hess GD, Rannels DE, Density-independent isolation of type II pneumocytes after partial pneumonectomy, American Journal of Physiology, 256(3 Pt 1), C515-21, March 1989 Abstract
  • Uhal BD, Longmore WJ, Glycerol as a substrate for phospholipid biosynthesis in type II pneumocytes isolated from streptozotocin-diabetic rats, Biochimica Et Biophysica Acta, 961(1), 122-8, July 1988 Abstract
  • Uhal BD, Longmore WJ, Glycerol metabolism in type II pneumocytes isolated from streptozotocin-diabetic rats, Biochimica Et Biophysica Acta, 958(2), 279-88, February 1988 Abstract
  • Uhal BD, Longmore WJ, Altered phospholipid biosynthesis in type II pneumocytes isolated from streptozotocin-diabetic rats, Biochimica Et Biophysica Acta, 878(2), 266-72, September 1986 Abstract

Profile Details

Last Updated: 9/5/2000

COS Expertise ID #894419
Reference this profile directly: http://myprofile.cos.com/uhal