Imatinib in pulmonary arterial hypertension: c-Kit inhibition

Samar Farha, Raed Dweik, Franck Rahaghi, Raymond Benza, Paul Hassoun, Robert Frantz, Fernando Torres, Deborah A. Quinn, Suzy Comhair, Serpil Erzurum, Kewal Asosingh

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 ofaction ofimatinib in PAH and suggest that tryptase is a potential biomarker of response to therapy.

Original languageEnglish (US)
Pages (from-to)452-455
Number of pages4
JournalPulmonary Circulation
Volume4
Issue number3
DOIs
StatePublished - Sep 1 2014

Fingerprint

Pulmonary Hypertension
Mast Cells
Tryptases
Stem Cells
Pulmonary Artery
Biomarkers
Right Ventricular Hypertrophy
Therapeutics
Hematopoietic Stem Cells
Imatinib Mesylate
Vascular Resistance
Protein-Tyrosine Kinases
Blood Vessels
Homeostasis
Cell Count
Bone Marrow
Placebos
Pressure
Pharmaceutical Preparations

Keywords

  • c-Kit
  • Imatinib
  • Mast cells
  • Progenitor cells
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Farha, S., Dweik, R., Rahaghi, F., Benza, R., Hassoun, P., Frantz, R., ... Asosingh, K. (2014). Imatinib in pulmonary arterial hypertension: c-Kit inhibition. Pulmonary Circulation, 4(3), 452-455. https://doi.org/10.1086/677359

Imatinib in pulmonary arterial hypertension : c-Kit inhibition. / Farha, Samar; Dweik, Raed; Rahaghi, Franck; Benza, Raymond; Hassoun, Paul; Frantz, Robert; Torres, Fernando; Quinn, Deborah A.; Comhair, Suzy; Erzurum, Serpil; Asosingh, Kewal.

In: Pulmonary Circulation, Vol. 4, No. 3, 01.09.2014, p. 452-455.

Research output: Contribution to journalArticle

Farha, S, Dweik, R, Rahaghi, F, Benza, R, Hassoun, P, Frantz, R, Torres, F, Quinn, DA, Comhair, S, Erzurum, S & Asosingh, K 2014, 'Imatinib in pulmonary arterial hypertension: c-Kit inhibition', Pulmonary Circulation, vol. 4, no. 3, pp. 452-455. https://doi.org/10.1086/677359
Farha S, Dweik R, Rahaghi F, Benza R, Hassoun P, Frantz R et al. Imatinib in pulmonary arterial hypertension: c-Kit inhibition. Pulmonary Circulation. 2014 Sep 1;4(3):452-455. https://doi.org/10.1086/677359
Farha, Samar ; Dweik, Raed ; Rahaghi, Franck ; Benza, Raymond ; Hassoun, Paul ; Frantz, Robert ; Torres, Fernando ; Quinn, Deborah A. ; Comhair, Suzy ; Erzurum, Serpil ; Asosingh, Kewal. / Imatinib in pulmonary arterial hypertension : c-Kit inhibition. In: Pulmonary Circulation. 2014 ; Vol. 4, No. 3. pp. 452-455.
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