title: Cellular, pharmacological, and biophysical evaluation of explanted lungs from a patient with sickle cell disease and severe pulmonary arterial hypertension.
abstract: 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 (O2 (•-)) 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 O2 (•-) 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 α1-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 end-stage SCD-associated PAH.
authors.affiliation: Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Rogers
authors.affiliation: Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Yao
authors.affiliation: Heart and Vascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sembrat
authors.affiliation: Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA ; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: M Patricia
authors.initials: MP
authors.lastname: George
authors.affiliation: Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Knupp
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Ross
authors.affiliation: Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Sharifi-Sanjani
authors.affiliation: Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Jadranka
authors.initials: J
authors.lastname: Milosevic
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Claudette
authors.initials: C
authors.lastname: St Croix
authors.affiliation: Heart and Vascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Revathi
authors.initials: R
authors.lastname: Rajkumar
authors.affiliation: Department of Pediatrics and Cardiovascular Pulmonary Research, University of Colorado, Denver, Colorado, USA.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Frid
authors.affiliation: Department of Pediatrics and Cardiovascular Pulmonary Research, University of Colorado, Denver, Colorado, USA ; Department of Bioengineering, University of Colorado, Denver, Colorado, USA.
authors.forename: Kendall S
authors.initials: KS
authors.lastname: Hunter
authors.affiliation: Department of Bioengineering, University of Colorado, Denver, Colorado, USA.
authors.forename: Luciano
authors.initials: L
authors.lastname: Mazzaro
authors.affiliation: Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Enrico M
authors.initials: EM
authors.lastname: Novelli
authors.affiliation: Department of Pediatrics and Cardiovascular Pulmonary Research, University of Colorado, Denver, Colorado, USA.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
authors.affiliation: Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA ; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.affiliation: Heart and Vascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA ; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.affiliation: Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA ; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Isenberg
keywords: CD47; endothelin 1; lung transplant; matrix; pulmonary arterial hypertension; sickle cell disease; superoxide; thrombospondin 1