Sickle Cell Lung Disease

Translational-Clinical Research

Mission Statement:

Pulmonary complications of sickle cell disease (SCD) are a major cause of morbidity and mortality. Our laboratory, headed by Dr. Elizabeth Klings, has been studying the two main pulmonary complications of SCD, the acute chest syndrome (ACS) and pulmonary hypertension (PH) for over 10 years in conjunction with the Boston Comprehensive Sickle Cell Center under the guidance of Dr. Martin Steinberg. The etiology of these disorders remains unknown. However, a growing body of knowledge amassed at our institution and others have led to greater insight into disease pathogenesis. We have amassed a group of investigators within the Pulmonary Center, Department of Hematology/Oncology, Center for Human Genetics, the Cardiovascular Proteomics Center and the School of Public Health to apply basic science techniques towards the study of disease pathogenesis with the ultimate goal of affecting treatment for these patients.


Pulmonary complications of SCD are common, affecting approximately 30-40% of patients, and are a major risk factor for mortality.

Over the past 5-6 years, our group has been actively involved in developing several projects devoted to the study of pulmonary hypertension (PH) in SCD. Approximately 30-40% of SCD patients have an elevated tricuspid regurgitant jet velocity on echocardiography with an associated 40% survival over 40 months. Six to eleven percent of SCD adults have pulmonary hypertension diagnosed by right heart catheterization. Often this disease presents asymptomatically. The clinical heterogeneity observed in SCD suggests that factors other than the HBB mutation affect disease pathogenesis. The sickle cell genetics group at Boston University has been studying the role of genetic modulation in the different clinical phenotypes of sickle cell disease. Out group has been working collaboratively with this group of researchers to study the genetics of PH related to SCD. Additionally, we have undertaken other projects evaluating the role of altered nitric oxide and redox biology in the pathogenesis of PH in SCD.

Current projects studying PH of SCD include:

  1. Gene polymorphisms of chronic sickle cell lung disease – Uses a genome-wide approach to evaluate the role of genetic modulation of SCD in PH of SCD
  2. Determination of oxidative post-translational modifications of plasma proteins in patients with PH in SCD – Utilizes proteomic technology to assess the role of oxidative protein modifications within the plasma of patients with PH of SCD
  3. Use of microarray technology to study gene profiles in peripheral blood mononuclear cells and circulating endothelial cells in patients with PH of SCD.
  4. Developing model systems for studying the effect of differential endothelial gene expression on endothelial function in SCD.

Principal Investigators:

  • Elizabeth Klings, MD
  • Martin H. Steinberg, MD, Director, Boston Comprehensive Sickle Cell Center
  • Mark McComb, PhD, Cardiovascular Proteomics Center
  • Surinder Safaya, PhD, Boston Comprehensive Sickle Cell Center
  • Jean-Bosco Tagne, PhD
  • Clinton T. Baldwin, PhD, Center for Genetics and Genomics
  • Paola Sebastiani, PhD, Department of Biostatistics, BU School of Public Health

Selected Publications:

  1. Sebastiani P, Timofeev N, Hartley SW, Milton JN, Gupta M, Riva A, Dworkis DA, Klings ES, Telen MJ, Ashley-Koch A, Garrett ME, Baldwin CT, Steinberg MH. Genetic Modifiers of the Severity of Sickle Cell Anemia Identified Through a Genome-Wide Association Study. Am J Hematol 2010;85:29-35. PMID: 20029952.
  2. Timofeev N, Milton JN, Hartley SW, Sherva R, Sebastiani P, Dworkis DA, Klings ES, Farrer LA, Garrett ME, Ashley-Koch A, Telen MJ, Fucharoen S, Ha SY, Li CK, Chui DHK, Baldwin CT, Steinberg MH. Fetal Hemoglobin in Sickle Cell Anemia: Genome-Wide Association Studies Suggest a Regulatory Region in the 5’Olfactory Receptor Gene Cluster. Blood 2010;115:1815-22. PMID: 20018918.
  3. Dworkis DA, Klings ES, Solovieff N, Li G, Milton JN, Hartley SW, Melista E, Parente J, Sebastiani P, Steinberg MH, Baldwin CT. Role of Tumor Necrosis-Alpha Signaling in Sickle Cell Disease: Elevated Biomarker Levels and Genetic Associations with Disease Severity. Am J Hematol 2011; 86:220-3.
  4. Solovieff N, Hartley SW, Baldwin CT, Klings ES, Gladwin MT, Taylor JG, Kato GJ, Farrer LA, Steinberg MH, Sebastiani P. Ancestry of African Americans with Sickle Cell Disease. Blood, Cells Mol Dis 2011; 47:41-5.
  5. Dworkis DA, Klings ES, Shenouda S, Solovieff N, Melista E, Giovannucci C, Safaya S, Li G, Vita J, Steinberg MH, Baldwin CT. Endothelial response to TNF-α in an ARFGEF2 siRNA knockdown model: Enhanced expression of ICAM1, VCAM1 and Transgelin. 2011 (manuscript under review).
  6. Safaya S, Klings ES, Odhiambo A, Li G, Farber HW, Steinberg MH. Effect of Sodium Butyrate on TNFSF15 (Vascular Endothelial Growth Inhibitor, TL1A) Expression in Lung Endothelium: Cell-Specific and Sequence-Selective Expression of TNFSF15. Cytokine 2009;46:72-78.
  7. Klings ES, Bland DA, Rosenman D, Princeton S, Odhiambo A, Li G, Bernard SA, Steinberg MH, Farber HW. Pulmonary Arterial Hypertension and Left-Sided Heart Disease in Sickle Cell Disease: Clinical Characteristics and Association with Soluble Adhesion Molecule Expression. Am J Hematol 2008 83 (7):547-553.
  8. Morris CR, Suh JH, Larkin S, Bland DA, Steinberg MH, Vichinsky EP, Shigenaga M, Ames B, Kuypers FA, Klings ES. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood 2008 111(1):402-10.
  9. Odhiambo A, Perlman DH, Huang H, Costello CE, Farber HW, Steinberg MH, McComb ME, Klings ES. Identification of oxidative post-translational modification of serum albumin in patients with idiopathic pulmonary arterial hypertension and pulmonary hypertension of sickle cell anemia. Rapid Commun Mass Spectrom 2007; 21:2195-2203.