PHA/ATS/Pfizer Research Fellowship in Pulmonary Arterial Hypertension Grant Winner 2010

Tim Lahm, MDTim Lahm, MD

Indiana University
“Estrogen Metabolism and Autophagy in Hypoxic Pulmonary Hypertension”
Term: September 2010 – August 2012

Summary of Research Project:

Estrogen Metabolism and Autophagy in Hypoxic Pulmonary Hypertension

Hypoxic pulmonary hypertension (HPH) is a frequent clinical problem leading to right heart failure and death. No pharmacologic treatments for HPH exist. We have previously demonstrated that females exhibit less severe HPH than males; protection that is, at least in part, attributed to beneficial effects of 17beta-estradiol (E2). However, the exact mechanisms by which E2 exerts protection for HPH remain unknown. A better understanding may lead to targeted, nonhormonal therapies for HPH patients of either sex. We have also demonstrated that inhibition of the conversion of E2 to certain metabolites further enhances the E2-mediated protection in HPH. One of the mechanisms by which E2 exerts protective effects is by inducing autophagy, a mechanism that enables cells to adapt to environmental stresses (e.g. hypoxia). While intuitively, the induction of autophagy is protective, its role in the pathogenesis of HPH has not yet been investigated. According to this rationale, we propose that the protective effects of E2 on HPH are mediated by a metabolite-independent, autophagy-dependent mechanism, and are further enhanced by E2 conversion inhibitors.

Curriculum Vitae

NAME: Tim Lahm
POSITION TITLE: Assistant Professor
DEGREE(S): M.D.

EDUCATION/TRAINING
INSTITUTION AND LOCATION   DEGREE   YEAR(s)   FIELD OF STUDY
University of Heidelberg Medical School, Germany   MD
  1993-2000
  Medicine
University of Heidelberg Medical School, Germany   Internist
  2000-2002
  Anesthesiology/Thoracic
Indiana University, School of Medicine
  Resident
  2002-2005
  Internal Medicine
Indiana University, School of Medicine   Fellowship
  2005-2008
  Pulm/Critical Care Med



Positions and Honors

Positions and Employment:
2008-present - Assistant Professor of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Occupational Medicine, Indiana University School of Medicine and Richard L. Roudebush VA Medical Center

Other Experience and Professional Memberships:
Professional Societies

  • 2005-present American College of Chest Physicians, Affiliate member
  • 2006-present Society of Critical Care Medicine
  • 2007-present American Thoracic Society
  • 2008-present Affiliate Network Steering Committee, American College of Chest Physicians
  • 2009 Methods in Molecular Biology (3 week workshop), Indiana University
  • 2009-present Leadership in Academic Medicine Program, Indiana University School of Medicine

Honors:

  • 2007 Invited speaker, 7th World Summit on Trauma, Shock, Inflammation and Sepsis. Munich, Germany
  • 2007 Indiana University Department of Medicine Fellow Research Competition, Second Place
  • 2008 First place, Indiana University Department of Medicine Fellow Research Competition
  • 2009 Sunrise Seminar: PAH – what do I need to know?, American Thoracic Society International Conference. May 19, San Diego, CA.
  • 2009 Invited speaker, Pulmonary Division Grand Rounds, Stanford University, May 22 (Topic: The Effects of Estrogen on the Pulmonary Vasculature)
  • 2009 Invited speaker, Department of Medicine Grand Rounds, Indiana University, May 1 (Topic: Current and Future Treatment Strategies for Pulmonary Arterial Hypertension)
  • 2009 Invited speaker, Krannert Institute of Cardiology, Indiana University, September 22 (Topic: Emerging Concepts and Treatment Strategies in Pulmonary Hypertension)
  • 2009 Sponsored Participant, American College of Chest Physicians Leadership Development Program
  • 2010 Invited Speaker, Kenneth Moser Memorial Symposium at American Thoracic Society International Conference. May 17, New Orleans, LA (Topic: Normal Cellular Physiology and Development of the Right Ventricle)
  • 2010 Sunrise Seminar: Hormones, Hypoxia, and Inheritance: Mechanisms of Sex Differences in Pulmonary Hypertension, American Thoracic Society International Conference, May 29, New Orleans, LA.

Reviewer Activies

  • 2008-present Editorial Board, Journal of Surgical Research (ad hoc reviewer from 2007-2008)
  • 2009–present Associate Editor; web-based Journal Club, American Thoracic Society Pulmonary Assembly
  • 2009–present ad hoc reviewer for Respiration, Stem Cell International, Clinical Infectious Diseases

Selected peer-reviewed publications (published and submitted in chronological order)

Selected from a total of 29 publications

1. Lahm T, Meldrum DR. Point:Counterpoint "Release of an endothelium-derived vasoconstrictor and RhoA/Rho kinase-mediated calcium sensitization of smooth muscle cell contraction are/are not the main effectors for full and sustained hypoxic pulmonary vasoconstriction". J Appl Physiol. 2007 May;102(5):2077-8; discussion 2080.
2. Lahm T. Crisostomo PR. Markel TA. Wang M. Lillemoe KD. Meldrum DR. The Critical Role of Vascular Endothelial Growth Factor in Pulmonary Vascular Remodeling Following Lung Injury. Shock. 2007 Jul;28(1):4-14.
3. Lahm T, Patel KM, Crisotomo PR, Markel TA, Wang M, Herring C, Meldrum DR. Endogenous Estrogen Attenuates Pulmonary Artery Vasoconstriction and Hypoxic Pulmonary Vasoconstriction: The Effects of Sex and Menstrual Cycle. Am J Physiol Endo Metab 2007. Am J Physiol Endocrinol Metab. 2007 Sep;293(3):E865-71.
4. Hui U. Wang M. Crisostomo PR. Markel TA. Lahm T. Meldrum KK. Lillemoe KD. Meldrum DR. The effect of chronic exogenous androgen on myocardial function following acute ischemia-reperfusion in hosts with different baseline levels of sex steroids. J Surg Res. 2007 Sep;142(1):113-8.
5. Markel TA, Wairiuko GM, Lahm T, Crisostomo PR, Wang M, Herring CM, Meldrum DR. The Right Heart and Its Distinct Mechanisms of Development, Function, and Failure. J Surg Res. 2008 May 15;146(2):304-13.
6. Patel KM. Crisostomo P. Lahm T. Markel T. Herring C. Wang C. Meldrum KK. Meldrum DR. Mesenchymal stem cells attenuate hypoxic pulmonary vasoconstriction by a paracrine mechanism. J Surg Res. 2007 Dec;143(2):281-5.
7. Lahm T, Crisostomo PR, Markel TA, Wang M, Wang Y, Weil BR, Meldrum DR. Exogenous Estrogen Attenuates Pulmonary Artery Vasoreactivity and Acute Hypoxic Pulmonary Vasoconstriction. Shock 2008 Dec;30(6):660-7.
8. Lahm T, Neese S, Thornburg AT, Ober MD, Sarosi GA, Hage CA. Corticosteroids for Blastomycosis-Induced Acute Respiratory Distress Syndrome: A Report of Two Patients and Review of the Literature. Chest 2008 Jun;133(6):1478-80.
9. Lahm T, Crisostomo PR, Markel TA, Wang M, Weil BR, Novotny NM, Meldrum Dr. The Effects of Estrogen on Pulmonary Artery Vasoreactivity and Hypoxic Pulmonary Vasoconstriction: Potential New Clinical Implications for an Old Hormone (review). Crit Care Med. 2008 Jul; 36(7):2174-83.
10. Ray R, Herring CM, Markel TA, Crisostom PR, Wang M, Weil BR, Lahm T, Meldrum DR. The Deleterious Effects of Endogenous and Exogenous Testosterone on Mesenchymal Stem Cell VEGF Production. Am J Physiol Regul Integr Comp Physiol. 2008 May;294(5):R1495-503.
11. Markel TA, Crisostomo PR, Wang M, Wang Y, Lahm T, Novotny NM, Tan J, Meldrum DR. TNFR1 Signaling Resistance Associated with Female Stem Cell Cytokine Production is Independent of TNFR2 Mediated Pathways. Am J Physiol Regul Integr Comp Physiol. 2008 Oct;295(4):R1124-30.
12. Crisostomo PR, Abarbanell AM, Wang M, Lahm T, Wang Y, Meldrum DR. Embryonic Stem Cells Attenuate Myocardial Dysfunction and Inflammation After Surgical Global Ischemia via Paracrine Actions. Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1726-35.
13. Lahm T, Crisostomo PR, Markel TA, Wang M, Wang Y, Tan J, Meldrum DR. Selective Estrogen Receptor-Alpha And Estrogen Receptor-Beta Agonists Rapidly Decrease Pulmonary Artery Vasoconstriction By A Nitric Oxide Dependent Mechanism. Am J Physiol Regul Integr Comp Physiol. 2008 Nov;295(5):R1486-93.
14. Lahm T. Sex Differences in COPD (Brief communication). Eur Resp J 2009 Jul;34(1):288-9.
15. Lahm T, McCaslin CA, Wozniak TC, Ghumman W, Fadl YF, Obeidat OS, Schwab K, Meldrum DR. Medical and Surgical Treatment of Acute Right Ventricular Failure. J Am Coll Cardiol 2010 (in press).

Research Support

  • 11/2008 – present: Encysive Pharmaceuticals: Effects of Selective Endothelin-A Receptor Antagonist Sitaxsentan on Pulmonary Artery Relaxation and Cytokine Expression Following Endotoxinemia (role: PI)
  • 3/2009 – present: VA Young Investigator Award: Noncanonical Estrogen Mechanisms to Reverse Hypoxia-Induced Pulmonary Endothelial Cell Activation (role: PI)
  • 7/2009 – present: Research Support Funds Grant, Indiana University/Purdue University Indianapolis: In vivo determination of the role of estrogen-receptor beta in estradiol-mediated protection from hypoxic pulmonary hypertension (role: PI)

 

 

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