title: A lymphocyte-dependent mode of action for imatinib mesylate in experimental pulmonary hypertension.
abstract: The capacity of imatinib mesylate to reverse established pulmonary arterial hypertension (PAH) has been attributed to a reduction in pulmonary arterial muscularization via inhibition of platelet-derived growth factor receptor-β on vascular smooth muscle cells. However, there is also a significant immunomodulatory component to the action of imatinib that may account for its efficacy in PAH. We found that monocrotaline-induced pulmonary hypertension was associated with a significant decrease in pulmonary natural killer (NK) cells and T lymphocytes and the accumulation of macrophages in the lungs of F344 rats. The prevention of pulmonary hypertension by imatinib blocked these changes in pulmonary leukocyte content and induced elevations in pulmonary interferon-γ, tumor necrosis factor α, and IL-10, corresponding to the enhanced activity of splenic NK cells ex vivo. Treatment with anti-asialo GM1 antiserum (ASGM1), which ablated circulating NK cells and depleted T cells, eliminated the therapeutic benefit of imatinib. ASGM1-treated animals also exhibited significant pulmonary arteriolar muscularization in response to monocrotaline challenge compared with immunocompetent controls despite daily imatinib administration to both groups. In the athymic rat, imatinib decreased right ventricular hypertrophy and pulmonary arteriolar muscularization in monocrotaline-challenged animals versus saline-treated controls but did not prevent pulmonary macrophage accumulation or the development of pulmonary hypertension. These data demonstrate that the immunomodulatory effects of imatinib are critical to its therapeutic action in experimental PAH.
authors.affiliation: Terrence Donnelly Cardiovascular Research Laboratories, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Ormiston
authors.forename: Yupu
authors.initials: Y
authors.lastname: Deng
authors.forename: Natalie
authors.initials: N
authors.lastname: Rundle
authors.forename: Farid
authors.initials: F
authors.lastname: Bendjelloul
authors.forename: James N
authors.initials: JN
authors.lastname: Tsoporis
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Parker
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: David W
authors.initials: DW
authors.lastname: Courtman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D017380:Hypertrophy, Right Ventricular / Q000473:pathology; D000068877:Imatinib Mesylate; D056747:Immunomodulation / Q000187:drug effects; D007958:Leukocyte Count; D008212:Lymphocyte Depletion; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D016686:Monocrotaline; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011923:Rats, Nude
chemical_list: D001549:Benzamides; D016207:Cytokines; D010879:Piperazines; D011743:Pyrimidines; D016686:Monocrotaline; D000068877:Imatinib Mesylate