Pulmonary Arterial Hypertension after Childhood Cancer Therapy and Bone Marrow Transplantation

Limsuwan, Alisa; Pakakasama, Samart; Rochanawutanon, Mana; Hongeng, Suradej

doi:10.1159/000091638

Cited by 32 publications

(23 citation statements)

References 30 publications

(26 reference statements)

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“…There is growing evidence that exposure to chemotherapeutic agents or ionizing radiation may cause pulmonary hypertension. Pulmonary vasculopathy may be a rare manifestation of graft-versushost disease after allogeneic stem cell transplantation (35,36), but there are also multiple reports of PAH or pulmonary venoocclusive disease that occurred in the absence of graft-versus-host disease, either in patients who received chemotherapy or radiotherapy alone, or after autologous stem cell transplantation (37)(38)(39)(40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension

Federici¹,

Drake²,

Rigelsky³

et al. 2015

Am J Respir Crit Care Med

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Rationale: Pulmonary arterial hypertension (PAH) is a serious lung condition characterized by vascular remodeling in the precapillary pulmonary arterioles. We and others have demonstrated chromosomal abnormalities and increased DNA damage in PAH lung vascular cells, but their timing and role in disease pathogenesis is unknown.Objectives: We hypothesized that if DNA damage predates PAH, it might be an intrinsic cell property that is present outside the diseased lung.Methods: We measured DNA damage, mutagen sensitivity, and reactive oxygen species (ROS) in lung and blood cells from patients with Group 1 PAH, their relatives, and unrelated control subjects.Measurements and Main Results: Baseline DNA damage was significantly elevated in PAH, both in pulmonary artery endothelial cells (P , 0.05) and peripheral blood mononuclear cells (PBMC) (P , 0.001). Remarkably, PBMC from unaffected relatives showed similar increases, indicating this is not related to PAH treatments. ROS levels were also higher (P , 0.01). DNA damage correlated with ROS production and was suppressed by antioxidants (P , 0.001). PBMC from patients and relatives also showed markedly increased sensitivity to two chemotherapeutic drugs, bleomycin and etoposide (P , 0.001). Results were consistent across idiopathic, heritable, and associated PAH groups.Conclusions: Levels of baseline and mutagen-induced DNA damage are intrinsically higher in PAH cells. Similar results in PBMC from unaffected relatives suggest this may be a genetically determined trait that predates disease onset and may act as a risk factor contributing to lung vascular remodeling following endothelial cell injury. Further studies are required to fully characterize mutagen sensitivity, which could have important implications for clinical management.

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Section: Discussionmentioning

confidence: 99%

Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension

Federici¹,

Drake²,

Rigelsky³

et al. 2015

Am J Respir Crit Care Med

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“…Nadciśnienie płucne jest rzadkim, ale poważnym powikłaniem stosowania niektórych leków przeciwnowotworowych, a także przeszczepienia komórek macierzystych szpiku kostnego [203]. Lek z grupy TKI, imatinib, poprawiał parametry hemodynamiczne u pacjentów z zaawansowanym tętniczym nadciśnieniem płucnym (PAH) [204,205].…”

Section: Patofizjologia I Obraz Klinicznyunclassified

2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines

Zamorano¹,

Lancellotti²,

Muñoz³

et al. 2016

Kardiol Pol

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“…9 Other observations have also identified an association between PAH and BMrelated hematologic disorders 10 : in proliferative disorders of the hematopoietic stem cells such as myeloproliferative cancers, there is an unexplained high incidence of PAH. PAH is now a recognized complication of BM transplantation for leukemia, 11 chronic myeloproliferative disorders, 12 or in the treatment of malignant infantile osteopetrosis. 13 On the other hand, serotonin (5-hydroxytryptamine ) is associated with the pathogenesis of PAH.…”

Section: Introductionmentioning

confidence: 99%

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Launay

Hervé

Crinon

et al. 2012

Blood

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Pulmonary arterial hypertension (PAH) is IntroductionPulmonary arterial hypertension (PAH) is a rare but fatal disease, often of unknown origin, characterized by progressive increase in pulmonary vascular resistance and remodeling associated with vasoconstriction. 1 PAH is histologically characterized by a neomuscularization of small pulmonary arteries with intimal thickening, medial hypertrophy, adventitial proliferation, and abnormal extracellular matrix deposition. The progression of vascular remodeling results in vascular lumen narrowing, increased pulmonary artery resistance, hypoxia, and right heart hypertrophy, although the molecular pathways initiating this remodeling are not clearly established.On the one hand, stem cells, resident or not, may give rise to a significant proportion of differentiating/proliferating smooth muscle cells (SMCs) that contribute to intimal hyperplasia in lung vascular remodeling. 2 Moreover, genetic ablation of the transmembrane tyrosine kinase receptor for stem cell factor/c-kit pathway results in a marked reduction in intimal hyperplasia in animal models of vascular injury; conversely, wild-type (WT) bone marrow (BM) reconstitution in c-kit mutant mice led to intimal hyperplasia comparable with WT animals. 3 Pharmacologic antagonism of the c-kit pathway with STI-571 (imatinib mesylate; Gleevec) also results in a marked reduction in hyperplasia. 3 Mobilization of c-kit expressing cells from BM to blood circulation is a physiologic response to hypoxia. Increasing evidence supports the idea that these progenitor cells of BM origin may also contribute to vascular wall remodeling that is characteristic of PAH. [4][5][6][7][8] However, it is unclear, whether this entry of progenitors represents a protective or a worsening process in the development of PAH. 9 Other observations have also identified an association between PAH and BMrelated hematologic disorders 10 : in proliferative disorders of the hematopoietic stem cells such as myeloproliferative cancers, there is an unexplained high incidence of PAH. PAH is now a recognized complication of BM transplantation for leukemia, 11 chronic myeloproliferative disorders, 12 or in the treatment of malignant infantile osteopetrosis. 13 On the other hand, serotonin (5-hydroxytryptamine ) is associated with the pathogenesis of PAH. 14 Therapeutic drugs with PAH as a side effect, such as the amphetamine derivative and anorexigen dexfenfluramine, are potent 5-HT releasers acting at 5-HT transporter (SERT) and/or agonists at 5-HT receptors (5-HTRs). 15 An over-expression of 5-HT 2B Rs is observed in PAH. 16 Blockade of 5-HT 2B Rs using independent approaches, either genetic (5-HT 2B R knock-out mice; 5-HT 2B Ϫ/Ϫ ) or pharmacologic (5-HT 2B antagonist RS-12744) inactivation, completely prevented the development of hypoxia-induced pulmonary hypertension in mice. 16 By using the monocrotaline (MCT)-induced pulmonary hypertension rat model, recent studies confirmed that other 5-HT 2B antagonists (terguride, PRX-08066, or C-122) significantly reduc...

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Pulmonary Arterial Hypertension after Childhood Cancer Therapy and Bone Marrow Transplantation

Cited by 32 publications

References 30 publications

Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension

Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension

2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

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