title: Imatinib in pulmonary arterial hypertension: c-Kit inhibition.
abstract: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by severe remodeling of the pulmonary artery resulting in increased pulmonary artery pressure and right ventricular hypertrophy and, ultimately, failure. Bone marrow-derived progenitor cells play a critical role in vascular homeostasis and have been shown to be involved in the pathogenesis of PAH. A proliferation of c-Kit(+) hematopoietic progenitors and mast cells has been noted in the remodeled vessels in PAH. Imatinib, a tyrosine kinase inhibitor that targets c-Kit, has been shown to be beneficial for patients with PAH. Here we hypothesize that the clinical benefit of imatinib in PAH could be related to c-Kit inhibition of progenitor cell mobilization and maturation into mast cells. As a corollary to the phase 3 study using imatinib in PAH, blood samples were collected from 12 patients prior to starting study drug (baseline) and while on treatment at weeks 4 and 24. Eight were randomized to imatinib and 4 to placebo. Circulating c-Kit(+) and CD34(+)CD133(+) hematopoietic progenitors as well as biomarkers of mast cell numbers and activation were measured. Circulating CD34(+)CD133(+) and c-Kit(+) progenitor cells as well as c-Kit(+)/CD34(+)CD133(+) decreased with imatinib therapy (all P < 0.05). In addition, total tryptase, a marker of mast cell load, dropped with imatinib therapy (P = 0.02) and was related to pulmonary vascular resistance (R = 0.7, P = 0.02). The findings support c-Kit inhibition as a potential mechanism of action of imatinib in PAH and suggest that tryptase is a potential biomarker of response to therapy.
authors.affiliation: Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA ; Department of Pathobiology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Samar
authors.initials: S
authors.lastname: Farha
authors.affiliation: Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA ; Department of Pathobiology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Raed
authors.initials: R
authors.lastname: Dweik
authors.affiliation: Department of Allergy and Critical Care Medicine, Cleveland Clinic Florida, Weston, Florida, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Rahaghi
authors.affiliation: Allegheny General Hospital, Pittsburgh, Pennsylvania, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Benza
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Hassoun
authors.affiliation: Division of Cardiovascular Diseases, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Frantz
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Torres
authors.affiliation: Novartis Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Quinn
authors.affiliation: Department of Pathobiology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Suzy
authors.initials: S
authors.lastname: Comhair
authors.affiliation: Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA ; Department of Pathobiology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Serpil
authors.initials: S
authors.lastname: Erzurum
authors.affiliation: Department of Pathobiology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Kewal
authors.initials: K
authors.lastname: Asosingh
keywords: c-Kit; imatinib; mast cells; progenitor cells; pulmonary hypertension