Sickle Cell Lung Disease

Clinical/Translational Research Translational-Clinical Research

Sickle Cell Group
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 nearly 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.

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

  1. 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. PH affects approximately 30-40% of SCD patients with an associated survival of approximately 25 months post-diagnosis. 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.

Principal Investigators:
Elizabeth Klings, MD
Martin H. Steinberg, MD, Director, Boston Comprehensive Sickle Cell Center

Graduate Student:
Daniel Dworkis

Technicians/Lab Managers/Research Coordinators:
Guihua Li
Lynda Reid

Links:
Pulmonary Hypertension – Clinical Center
Pulmonary Hypertension – Translational-Clinical Research

Selected Publications:

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.  2009 (manuscript submitted).

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.

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.

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.

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.

Klings ES, Safaya S, Adewoye AH, Odhiambo A, Frampton G, Lenburg M, Gerry N, Sebastiani P, Steinberg MH, Farber HW. Differential Gene Expression in Pulmonary Artery Endothelial Cells Exposed to Sickle Cell Plasma. Physiol Genomics 2005; 21: 293
.

Primary teaching affiliate
of BU School of Medicine