Journal article
Cellular, pharmacological, and biophysical evaluation of explanted lungs from a patient with sickle cell disease and severe pulmonary arterial hypertension
Pulmonary circulation, Vol.3(4), pp.936-951
12/01/2013
DOI: 10.1086/674754
PMCID: PMC4070844
PMID: 25006410
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.
Details
- Title: Subtitle
- Cellular, pharmacological, and biophysical evaluation of explanted lungs from a patient with sickle cell disease and severe pulmonary arterial hypertension
- Creators
- Natasha M Rogers - Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMingyi Yao - Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAJohn Sembrat - Heart and Vascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAM. Patricia George - Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAHeather Knupp - Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMark Ross - Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMaryam Sharifi-Sanjani - Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAJadranka Milosevic - Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAClaudette St. Croix - Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USARevathi Rajkumar - Heart and Vascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMaria G Frid - Department of Pediatrics and Cardiovascular Pulmonary Research, University of Colorado, Denver, Colorado, USAKendall S Hunter - Department of Pediatrics and Cardiovascular Pulmonary Research, University of Colorado, Denver, Colorado, USALuciano Mazzaro - Department of Bioengineering, University of Colorado, Denver, Colorado, USAEnrico M Novelli - Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAKurt R Stenmark - Department of Pediatrics and Cardiovascular Pulmonary Research, University of Colorado, Denver, Colorado, USAMark T Gladwin - Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAFerhaan Ahmad - Heart and Vascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAHunter C Champion - Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAJeffrey S Isenberg - Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Resource Type
- Journal article
- Publication Details
- Pulmonary circulation, Vol.3(4), pp.936-951
- DOI
- 10.1086/674754
- PMID
- 25006410
- PMCID
- PMC4070844
- NLM abbreviation
- Pulm Circ
- ISSN
- 2045-8932
- eISSN
- 2045-8940
- Publisher
- University of Chicago Press
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 HL‐108954; DOI: 10.13039/100000968, name: American Heart Association, award: 11BGIA7210001; DOI: 10.13039/100000002, name: National Institutes of Health, award: P01 HL103455, U01 HL108642, 3UL1RR024153; DOI: 10.13039/100000002, name: National Institutes of Health, award: U01 HL108642‐01, R03 HL095401; DOI: 10.13039/100000945, name: Pittsburgh Foundation, award: M2010‐0055
- Language
- English
- Date published
- 12/01/2013
- Academic Unit
- Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984025467002771
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