Open AccessCellular, Pharmacological, and Biophysical Evaluation of Explanted Lungs from a Patient with Sickle Cell Disease and Severe Pulmonary Arterial Hypertension
Author(s) -
Rogers Natasha M.,
Yao Mingyi,
Sembrat John,
George M. Patricia,
Knupp Heather,
Ross Mark,
SharifiSanjani Maryam,
Milosevic Jadranka,
Croix Claudette St.,
Rajkumar Revathi,
Frid Maria C.,
Hunter Kendall S.,
Mazzaro Luciano,
Novelli Enrico M.,
Stenmark Kurt R.,
Gladwin Mark T.,
Ahmad Ferhaan,
Champion Hunter C.,
Isenberg Jeffrey S.
Publication year - 2013
Publication title -
pulmonary circulation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.791
H-Index - 40
ISSN - 2045-8940
DOI - 10.1086/674754
Subject(s) - medicine , downregulation and upregulation , pulmonary hypertension , elastin , lung , extracellular matrix , pulmonary artery , hypoxic pulmonary vasoconstriction , vasodilation , pathology , vasoconstriction , cardiology , microbiology and biotechnology , biology , biochemistry , gene
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 •– ) 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 •– 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.