Biosketch

Dr. Mark Gladwin is both a senior investigator with the Critical Care Medicine Department at the NIH Clinical Center and the chief of the Vascular Medicine Branch at NIH’s National, Heart, Lung, and Blood Institute. He is a key coordinator for a collaboration between CCMD and NHLBI that aims to develop a new scientific research program focused on four areas of research, each involving a strong and smooth interaction between bench and bedside investigations.

Dr. Gladwin’s research endeavors focus on understanding the role of lung complications in adults with sickle cell disease and evaluating the role of hydroxyurea (current), nitric oxide (future), and nitrite-based therapies in treating sickle cell disease and other vascular diseases, such as pulmonary hypertension. His laboratory also focuses on the role of nitrite in the regulation of blood flow and cellular responses to injury.

He received his undergraduate degree and medical degree from University of Miami and completed an internship and chief residency in internal medicine at Oregon Health Sciences University. Dr. Gladwin then undertook three fellowships: as a critical care fellow in CCMD at the CC, as a pulmonary-critical care fellow in the Pulmonary Division of University of Washington in Seattle, and as a CCMD senior research fellow when he returned to NIH in 1998. From 1995 to 2000, he was on active duty as a commander in the commissioned corps of the U.S. Public Health Service.

He is the principal or associate investigator on more than twenty concurrent clinical studies researching interventional therapies for the management of the symptoms and complications of sickle cell disease. He has received research grants from the NIH Office of Research in Minority Health and the Bench-to-Bedside and Cooperative Research and Development Agreement programs.

As founder and director of the Unity Healthcare Asthma/Pulmonary Clinic Mission in Washington, D.C., Dr. Gladwin delivers pulmonary subspecialty care to homeless and indigent patients through two community clinics. With the support of ORMH and CCMD, he has established programmatic relationships between minority patients and NIH clinical research protocols.

Honors and Awards

Invited Speaker Nobel Forum, Karolinska Institutet, June 2007; NIH Merit Award (category, science), 2006; NIH Director’s Award (category, mentoring), 2006; elected to membership, American Society of Clinical Investigations (ASCI), 2006; CC Director’s Award (category, science), 2002; Distinguished Mentor Award, NIH Pre-IRTA committee, 2002; Academic Medicine Mentor Award, 2001; American Thoracic Society Travel Award, 2001; American Heart Association Scientific Sessions Travel Award, 2000; American Thoracic Society Travel Award, 2000; NIH Fellows Award for Research Excellence, 2000; Achievement Medal, US Public Health Service, NIH, 1999; Oregon Health Sciences University House Staff Teaching Award, 1993, 1994, and 1995

Scientific Discoveries

Since 1998, Dr. Gladwin’s research activities have led to four major scientific discoveries. The discoveries cited below have resulted in more than 100 published peer-reviewed manuscripts, 20 approved protocols, and more than 1,000 patient protocol enrollments at the NIH Clinical Center.

(1) The discovery that the nitrite anion is a circulating storage pool for NO bioactivity (Gladwin, et al. PNAS 2002)

(2) The discovery of a novel physiological function for hemoglobin as an electronically and allosterically-regulated nitrite reductase (Cosby, et al. Nature Medicine 2003; Huang et al. JCI 2005). These studies reveal that nitrite is a potent vasodilator in humans and is bioactivated by reaction with deoxyhemoglobin (and myoglobin) to generate NO preferentially under hypoxic conditions; they also suggest that hemoglobin has an “enzymatic” property as a nitrite reductase that participates in hypoxic vasodilation.

In related translational studies Dr. Gladwin has demonstrated that inhaled nitrite reverses hypoxic neonatal pulmonary hypertension in sheep (Hunter, et al. Nature Medicine 2004), and that infused nitrite solutions prevent post-subarachnoid hemorrhage-induced vasospasm in primates (Pluta et al. JAMA 2005) and prevent hepatic and cardiac ischemia-reperfusion injury and infarction in mice (Lefer et al. JCI 2005).

(3) The characterization of a novel mechanism of disease, hemolysis-associated endothelial dysfunction (Reiter, et al. Nature 2003; Morris et al. JAMA 2005; Minneci et al. JCI 2005). This work has described a state of resistance to NO in patients with sickle cell disease caused by scavenging of nitric oxide by hemoglobin that is released into plasma during hemolysis.

(4) The mechanistic, clinical, and epidemiological description of a human disease syndrome, hemolysis-associated pulmonary hypertension (Gladwin, et al. NEJM 2004). He has found that pulmonary hypertension occurs in 30% of patients with sickle cell disease, is a major cause of mortality in this population (odds ratio 10:1), and is strongly associated with high hemolytic rate, iron overload, and kidney disease.

Selected Publications

SELECTED BOOKS/BOOK CHAPTERS

Gladwin MT, Trattler W. Clinical Microbiology Made Ridiculously Simple. 1st ed. (1995), 2nd edition (1997), 3rd ed. (2001), 4th edition (2007) Miami (FL): Medmaster, Inc; 1995.

Copeland JR, Gladwin MT, and Shelhamer JH. Nitric oxide, reactive nitrogen species and lipid mediator generation in the lung. In: Therapeutic Targets of Airway Inflammation. N. T. Eissa and D. P. Huston, eds. Marcel Decker, NY. 2003.

Machado RF and Gladwin MT. Hemolytic Anemia Associated Pulmonary Hypertension. In: Pulmonary Vascular Disease. J. Mandell and D. Taichman, eds. Saunders Elsevier, PA. 2006

SELECTED JOURNAL ARTICLES

Gladwin MT, Schechter AN, Shelhamer JH, Pannell LK, Conway DA, Hrinczenko BW, Nichols JS, Pease-Fye ME, Noguchi CT, Rodgers GP, and Ognibene FP. Inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin without affecting oxygen affinity. Journal of Clinical Investigation 1999; 104:937-945.

Gladwin MT, Ognibene FP, Pannell LK, Nichols JS, Pease-Fye ME, Shelhamer JH, and Schechter AN. Relative role of heme nitrosylation and b-cysteine 93 nitrosation in the transport and metabolism of nitric oxide by hemoglobin in the human circulation. Proceedings of the National Academy of Sciences 2000; 97: 9943-9948.

Cannon III RO, Schechter AN, Panza JA, Ognibene FP, Pease-Fye ME, Waclawiw M, Shelhamer JH, and Gladwin MT. Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. Journal of Clinical Investigation 2001; 108: 279-287.

Gladwin MT, Wang X, Reiter C, Yang B, Vivas E, Bonaventura C, and Schechter A. S-nitrosohemoglobin is unstable in the reductive red cell environment and lacks O2/NO-linked allosteric function. Journal of Biological Chemistry 2002; 277:27818-27828.

Reiter CD, Wang X, Tanos-Santos J, Hogg N, Cannon RO,Schechter AN, and Gladwin MT. Cell free hemoglobin limits NO bioavailability in sickle cell disease. Nature Medicine 2002; 8:1383-1389.

Gladwin MT, Schechter AN, Ognibene FP, Coles W, Reiter CD, Schenke WH, Csako G, Waclawiw MA, Panza JA, and Cannon RO. Divergent nitric oxide bioavailability in men and women with sickle cell disease. Circulation 2003; 107:271-278.

Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter C, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter A, Cannon RO, and Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nature Medicine 2003; 9:1498-1505.

Gladwin MT, Sachdev V, Jison M, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder W, Schechter AN, Rodgers GP, Castro O, and Ognibene FP. Pulmonary Hypertension as a Risk Factor for Death in Patients with Sickle Cell Disease. New England Journal of Medicine 2004; 350:886-895.

Duranski MR, Greer JJM, Dejam A, Sathya J, Hogg N, Langston W, Patel RP, Yet S-F, Wang X, Kevil CG, Gladwin MT, and Lefer DJ. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. Journal of Clinical Investigation 2005; 115(5):1232-1240.

Huang Z, Shiva S, Kim-Shapiro DB, Patel RP, Ringwood LA, Irby CE, Huang KT, Ho C, Schechter AN, Hogg N, and Gladwin MT. Enzymatic function of hemoglobin as a nitrite reductase that produces nitric oxide under allosteric control. Journal of Clinical Investigation 2005; 115:2099-2107.

Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen ST, Vichinsky EP, Morris SM Jr. and Gladwin MT. Dysregulated arginine metabolism, hemolysis –associated pulmonary hypertension and mortality in sickle cell disease. Journal of the American Medical Association 2005; 294:81-90.

Machado RF, Anthi A, Steinberg MH, Bonds D, Sachdev V, Kato GJ, Taveira-DaSilva AM, Ballas SK, Blackwelder W, Xu X, Hunter L, Barton B, Waclawiw M, Castro O, Gladwin MT; MSH Investigators. N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. Journal of American Medical Association 2006; 296(3):310-318.

Shiva S, Wang X, Ringwood LA, Xu X, Yuditskaya S, Annavajjhala V, Miyajima H, Hoog N, Harris ZL, Gladwin MT. Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO hemostasis. Nature Chemical Biology. 2006; 2(9):486-483.

Shiva S, Huang Z, Grubina R, Sun J, Ringwood LA, Macarthur PH, Xu X, Murphy E, Darley-Usmar VM, Gladwin MT. Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration. Circulation Research 2007; Feb 9; (Epub ahead of print]