Journal
PULMONARY CIRCULATION
Volume 3, Issue 4, Pages 936-951Publisher
SAGE PUBLICATIONS INC
DOI: 10.1086/674754
Keywords
sickle cell disease; pulmonary arterial hypertension; lung transplant; CD47; thrombospondin 1; endothelin 1; superoxide; matrix
Funding
- National Institutes of health (NIH) [R01 HL-108954]
- American Heart Association [11BGIA7210001]
- NIH [P01 HL103455, U01 HL108642, 3UL1RR024153, U01 HL108642-01, R03 HL095401]
- Pitts-burgh Foundation [M2010-0055]
- Pulmonary Hypertension Association Proof of Concept Grant
- Parker B. Francis Foundation
- T32 Vascular Training Fellowship
- AHA Postdoctoral Award [13POST14520003]
- Institute for Transfusion Medicine
- Hemophilia Center of Western Pennsylvania
- Vascular Medicine Institute
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Pulmonary hypertension is recognized as a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). We now report benchtop phenotyping from the explanted lungs of the first successful lung transplant in SCD. Pulmonary artery smooth muscle cells (PASMCs) cultured from the explanted lungs were analyzed for proliferate capacity, superoxide (O-2(center dot-)) production, and changes in key pulmonary arterial hypertension (PAH)-associated molecules and compared with non-PAH PASMCs. Upregulation of several pathologic processes persisted in culture in SCD lung PASMCs in spite of cell passage. SCD lung PASMCs showed growth factor-and serum-independent proliferation, upregulation of matrix genes, and increased O(2)(center dot-)production compared with control cells. Histologic analysis of SCD-associated PAH arteries demonstrated increased and ectopically located extracellular matrix deposition and degradation of elastin fibers. Biomechanical analysis of these vessels confirmed increased arterial stiffening and loss of elasticity. Functional analysis of distal fifth-order pulmonary arteries from these lungs demonstrated increased vasoconstriction to an alpha 1-adrenergic receptor agonist and concurrent loss of both endothelial-dependent and endothelial-independent vasodilation compared with normal pulmonary arteries. This is the first study to evaluate the molecular, cellular, functional, and mechanical changes in endstage SCD-associated PAH.
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