Characterization of myofibroblasts in chronic thromboembolic pulmonary hypertension

Maruoka, Masayuki; Sakao, Seiichiro; Kantake, Masashi; Tanabe, Nobuhiro; Kasahara, Yasunori; Kurosu, Katsushi; Takiguchi, Yuichi; Masuda, Masahisa; Yoshino, Ichiro; Voelkel, Norbert F.; Tatsumi, Koichiro

doi:10.1016/j.ijcard.2011.02.037

Cited by 38 publications

(35 citation statements)

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“…As shown previously, a few different cell types were isolated from the endarterectomized tissues in each of the 15 patients with CTEPH (4). One of them was determined morphologically to be the myofibroblast-like cells (spindleshape with cytoplasmic extensions) (4). At the 2nd passage of the myofibroblast-like cells, another cell type that varied in size and shape and was characterized by a large nucleus, was isolated from one patient described in a previous study (4).…”

Section: Resultsmentioning

confidence: 99%

“…at the Chiba Medical Center, Japan. The details of the cell isolation techniques have been described previously (4). The study was approved by the Research Ethics Committee of Chiba University School of Medicine, and written informed consent was given by all subjects.…”

Section: Methodsmentioning

confidence: 99%

“…The cells at passage 4 were seeded at 1x10 5 in 25-cm 2 flasks and were incubated with serum-free medium for the indicated incubation periods. The details of the serum starvation assay techniques have been described previously (4).…”

Section: Brdu-7-amino-actinomycin D Binding Assay the Brdu Flowmentioning

confidence: 99%

“…Recently, the existence of not only myofibroblast-like cells, but also endothelial-like cells, in the endarterectomized tissues from patients with CTEPH has been demonstrated (4)(5)(6). Moreover, our recent study suggested that these myofibroblast-like cells might release substances that promote the endothelial-mesenchymal transition (EnMT) and/or induce EC dysfunction (7).…”

Section: Introductionmentioning

confidence: 95%

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Characterization of sarcoma-like cells derived from endarterectomized tissues from patients with CTEPH and establishment of a mouse model of pulmonary artery intimal sarcoma

Jujo

Sakao

Kantake

et al. 2012

International Journal of Oncology

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Abstract. In general, intravascular thrombus formation in the pulmonary arteries is considered to be the most common cause of chronic thromboembolic pulmonary hypertension (CTEPH). The current mainstay of therapy for patients with CTEPH is pulmonary endarterectomy (PEA). Recently, the existence of myofibroblast-like cells in endarterectomized tissues has been demonstrated. At the 2nd passage of these myofibroblast-like cells, a pleomorphic cell type was isolated. Pulmonary intimal sarcoma is a very uncommon neoplastic tumor thought to originate from subendothelial-mesenchymal cells of the pulmonary vascular wall. Because these pleomorphic cells were isolated from the pulmonary vascular beds, it is believed that the analysis of these cells may contribute to the understanding of pulmonary intimal sarcoma. We isolated cells from the endarterectomized tissue from patients with CTEPH and identified one type as sarcoma-like cells (SCLs). The SCLs were characterized as hyperproliferative, anchorage-independent, invasive and serum-independent. Moreover, C.B-17/lcr-scid/ scidJcl mice injected subcutaneously with SCLs developed solid, undifferentiated tumors at the site of injection, and those injected intravenously with SCLs via the tail vein developed tumors which grew along the intimal surface of the pulmonary vessels, thus, demonstrating the high tumorigenic potential of these cells. The behavior of SCLs indicated that these cells may have a vascular cell-like potential which can affiliate them with the intimal surface of the pulmonary artery, and which may be shared with pulmonary intimal sarcoma. A further investigation of this mouse model with SCLs may elucidate the mechanism(s) underlying the development of pulmonary intimal sarcoma.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Brdu-7-amino-actinomycin D Binding Assay the Brdu Flowmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Characterization of sarcoma-like cells derived from endarterectomized tissues from patients with CTEPH and establishment of a mouse model of pulmonary artery intimal sarcoma

Jujo

Sakao

Kantake

et al. 2012

International Journal of Oncology

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“…For instance, staphylococcal infection delayed thrombus resolution in mice (5), suggesting that bacterial infection could impair thrombus resolution in CTEPH. In addition, enhanced proliferative features have been observed in pulmonary vascular cells harvested from PEA specimens (32,40) and endothelial and mesenchymal progenitor cells have been identified in pulmonary vascular tissue harvested from CTEPH patients during PEA (10,54).…”

mentioning

confidence: 99%

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

Wynants

Vengethasamy

Ronisz

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Wynants M, Vengethasamy L, Ronisz A, Meyns B, Delcroix M, Quarck R. NF-B pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 305: L934-L942, 2013. First published October 4, 2013 doi:10.1152/ajplung.00034.2013.-Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of proximal pulmonary arteries. The cellular and molecular mechanisms underlying the pathogenesis remain incompletely understood, although we recently evidenced the potential involvement of the inflammatory marker C-reactive protein (CRP). We aimed to investigate the intracellular mechanisms induced by CRP in proximal pulmonary arterial endothelial cells (PAEC). PAEC were isolated from vascular material obtained during pulmonary endarterectomy. RNA was extracted from CRP-stimulated PAEC, and first-stand cDNA was generated. A RT 2 profiler PCR Array was used to evaluate the expression of 84 key genes related to NF-B-mediated signal transduction. CRP-induced NF-B activation was studied. The effects of pyrrolidine-dithio-carbamate ammonium (PDTC), an inhibitor of the NF-B pathway, were investigated on CRP-induced adhesion of monocytes to PAEC, adhesion molecule expression, endothelin-1 (ET-1), interleukin-6 (IL-6), and von Willebrand factor (vWF) secretion. Compared with nonstimulated PAEC, serotonin receptor 2B was downregulated by 25%, inhibitor of NF-B kinase subunit epsilon (IKBKE) by 30%, and toll-like receptor-4 and -6 by 18 and 39%, respectively, in CRP-stimulated PAEC. The transcription factor FOS was threefold upregulated. CRP induced RelA/NF-Bp65 phosphorylation. PDTC dose dependently inhibited the adhesion of monocytes to CRP-stimulated PAEC. PDTC also inhibited the CRP-induced expression of ICAM-1 at the surface of PAEC. PDTC impaired the secretion of ET-1 by 18% and tended to inhibit the secretion of IL-6 by CRP-stimulated PAEC by 46%. PDTC did not inhibit the CRP-induced secretion of vWF. These results suggest an involvement of the NF-B pathway in mediating different effects of CRP on proximal CTEPH-PAEC. C-reactive protein; endothelial cells; NF-B; chronic thromboembolic pulmonary hypertension CHRONIC THROMBOEMBOLIC PULMONARY hypertension (CTEPH) is a severe cause of pulmonary hypertension characterized by an obliteration of proximal pulmonary arteries by intraluminal thrombi and fibrous stenosis. Pulmonary embolism, either as single or recurrent episodes, is thought to be the initiating event followed by progressive pulmonary vascular remodeling. Vascular disobliteration by pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients (38).Knowledge of the physiopathology of CTEPH remains incomplete. Proximal lesions share similarities with atherosclerotic plaques, including media thickening and neointima formation (1). Risk factors for CTEPH include size of the initial thrombus, elevated factor VIII, circulating phospholipid antibodies, and fibrinogen intrinsic ...

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Chronic Thromboembolic Pulmonary Hypertension

Auger

Fedullo

2015

Diagnosis and Management of Pulmonary Hypertension

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C hronic thromboembolic pulmonary hypertension (CTEPH) has emerged as one of the leading causes of severe pulmonary hypertension. The disease is notoriously underdiagnosed, and the true prevalence is still unclear. CTEPH is characterized by intraluminal thrombus organization and fibrous stenosis or complete obliteration of pulmonary arteries. 1 The consequence is an increased pulmonary vascular resistance resulting in pulmonary hypertension and progressive right heart failure. Vascular disobliteration by pulmonary endarterectomy (PEA) is the preferred treatment for patients with CTEPH, 2 but not all patients are eligible for surgery. Recent research has provided evidence suggesting that the mechanistic view of CTEPH as a disease caused solely by obliteration of central pulmonary arteries due to organized thrombi may have been too simplistic. Pulmonary embolism, either as a single episode or as recurrent episodes, is thought to be the initiating event followed by progressive pulmonary vascular remodeling. This concept explains the clinical observation that CTEPH patients may have severe pulmonary hypertension out of proportion to the pulmonary vascular obliteration seen on a pulmonary angiogram. Thus, treatment of CTEPH often requires a multidisciplinary approach and may involve surgery, medical treatment, or both. However, many aspects of the pathogenesis of CTEPH are poorly understood, the diagnostic approach to these patients has not been standardized, and neither randomized controlled trials nor guidelines have been published in this field.In July 2005, a group of international experts met in Zurich, Switzerland, for a comprehensive discussion of CTEPH. The members of this group are listed in the Appendix (in the online-only Data Supplement). This report will review the issues surrounding CTEPH that were discussed during that meeting: its etiology and pathogenesis, epidemiology, diagnosis, treatment options, and associated prognosis. Current issues, including challenges in assessing surgical candidacy and predicting postoperative outcome, will be introduced. Finally, potential ways of resolving uncertain and controversial issues, such as the role of medical therapy and the requirement for randomized controlled trials, will be discussed. Algorithms for the diagnosis and management of CTEPH will be proposed. EpidemiologyThe true incidence and prevalence of CTEPH are unknown. Originally, it was believed that 0.1% to 0.5% of patients who survive an episode of acute pulmonary embolism develop CTEPH. [3][4][5] However, in a prospective follow-up study of 78 survivors of acute pulmonary embolism, echocardiographic findings suggestive of persistent pulmonary hypertension and/or right ventricular dysfunction were present in 44% of the patients after 1 year. 6 Four patients (5.1%) developed definite CTEPH, and 3 of these subsequently underwent successful PEA. The only identifiable risk factors for persistent pulmonary hypertension were an age Ͼ70 years and a systolic pulmonary artery pressure Ͼ50 mm Hg at the initial p...

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Characterization of myofibroblasts in chronic thromboembolic pulmonary hypertension

Cited by 38 publications

References 42 publications

Characterization of sarcoma-like cells derived from endarterectomized tissues from patients with CTEPH and establishment of a mouse model of pulmonary artery intimal sarcoma

Characterization of sarcoma-like cells derived from endarterectomized tissues from patients with CTEPH and establishment of a mouse model of pulmonary artery intimal sarcoma

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

Chronic Thromboembolic Pulmonary Hypertension

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