Plexiform Lesions in Pulmonary Arterial Hypertension

Jonigk, Danny; Golpon, Heiko; Bockmeyer, Clemens L.; Maegel, Lavinia; Hoeper, Marius M.; Gottlieb, Jens; Nickel, Nils; Hussein, Kais; Maus, Ulrich A.; Lehmann, Ulrich; Janciauskiene, Sabina; Welte, Tobias; Haverich, Axel; Rische, Johanna; Kreipe, Hans; Laenger, Florian

doi:10.1016/j.ajpath.2011.03.040

Cited by 151 publications

(73 citation statements)

References 49 publications

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“…These changes mimicked those seen in plexiform lesions in human patients with severe pulmonary hypertension (Fig. 3F) [40,47,48]. In contrast, hypertensive animals treated with bosentan had less severe vascular remodeling that was limited to medial hypertrophy with no plexiform lesions being observed (Figs.…”

Section: Resultssupporting

confidence: 60%

“…To further assess the cellular composition of the remodeled pulmonary vasculature of the animals, we immunohistochemically stained 4μm-thick formalin fixed paraffin imbedded slides for CD31 and smooth muscle actin (SMA), essentially as described [40]. The staining patterns/staining intensity were microscopically assessed in at least four different locations of the lung specimens.…”

Section: Methodsmentioning

confidence: 99%

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Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonaryhypertension

Rafikova

Rafikov

Kumar

et al. 2013

Free Radical Biology and Medicine

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Pulmonary arterial hypertension (PH) is a fatal disease marked by excessive pulmonary vascular cell proliferation. Patients with idiopathic PH express endothelin-1 (ET-1) at high levels in their lungs. As the activation of both types of ET-1 receptor (ETA and ETB) leads to increased generation of superoxide and hydrogen peroxide, this may contribute to the severe oxidative stress found in PH patients. As a number of pathways may induce oxidative stress, the particular role of ET-1 remains unclear. The aim of this study was to determine whether inhibition of ET-1 signaling could reduce pulmonary oxidative stress and attenuate the progression of disease in rats with occlusive-angioproliferative PH induced by a single dose of SU5416 (200 mg/kg) and subsequent exposure to hypoxia for 21 days. Using this regimen, animals developed severe PH as evidenced by a progressive increase in right-ventricle (RV) peak systolic pressure (RVPSP), severe RV hypertrophy, and pulmonary endothelial and smooth muscle cell proliferation, resulting in plexiform vasculopathy. PH rats also had increased oxidative stress, correlating with endothelial nitric oxide synthase uncoupling and NADPH oxidase activation, leading to enhanced protein nitration and increases in markers of vascular remodeling. Treatment with the combined ET receptor antagonist bosentan (250 mg/kg/day; day 10 to 21) prevented further increase in RVPSP and RV hypertrophy, decreased ETA/ETB protein levels, reduced oxidative stress and protein nitration, and resulted in marked attenuation of pulmonary vascular cell proliferation. We conclude that inhibition of ET-1 signaling significantly attenuates the oxidative and nitrosative stress associated with PH and prevents its progression.

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Section: Resultssupporting

confidence: 60%

Section: Methodsmentioning

confidence: 99%

Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonaryhypertension

Rafikova

Rafikov

Kumar

et al. 2013

Free Radical Biology and Medicine

Self Cite

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“…Because of the morphology of these lesions, they may represent fibroticthrombotic material with small-vessel recanalization, as observed in fibrotic thrombi in human CTEPH. However, the structure of these lesions is also analogous to human plexiform lesions, 2,20 and further studies using labeled collagen and/or labeled fibrinogen are required to assess the origin of these fibrotic-cellular lesions.…”

Section: Discussionmentioning

confidence: 99%

“…Another transcript upregulated in lung tissue of PE rats was matrix metallopeptidase 9, which has already been associated with pulmonary remodeling and formation of plexiform lesions including sprouting of vascular channels. 20,25 Finally, CTEPH pathology also involves a proliferative cellular compartment; therefore, it is interesting that the 2 downregulated transcripts (heat shock 70 kD protein 1B and heat shock protein 4-like mRNA) have been associated with lung cancer and development.…”

Section: Discussionmentioning

confidence: 99%

Development and Characterization of an Inducible Rat Model of Chronic Thromboembolic Pulmonary Hypertension

Arias-Loza¹,

Jung²,

Abeßer³

et al. 2016

Hypertension

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C hronic thromboembolic pulmonary hypertension (CTEPH)is an important but yet under-researched entity of PH. CTEPH is characterized by nonresolving thrombi that obstruct pulmonary arteries and promote progressive pulmonary vascular remodeling. The chronic increase in pulmonary vascular resistance translates into elevated pulmonary artery pressure and results in right ventricular (RV) hypertrophy, which ultimately causes RV dilatation and failure.2 The treatment of choice is pulmonary endarterectomy that consist in the surgical removal of organized thrombi to an extent that improves pulmonary hemodynamics. However, a relevant number of patients present persistent small-vessel vasculopathy post pulmonary endarterectomy , 3 and many affected individuals are poor candidates for pulmonary endarterectomy because of a predominantly distal surgically inaccessible embolism pattern, high age, or severe comorbidities. Therefore to improve quality of life and eventually survival, numerous CTEPH patients require additional or alternative nonsurgical treatment. However, our understanding of the pathophysiology of CTEPH is limited and an obstacle in the development of new treatment strategies. 4 The pathogenesis of CTEPH is still under debate. According to the local thrombosis hypothesis, CTEPH originates from primary distal pulmonary arteropathy accompanied by secondary in situ thrombosis. However, this hypothesis does not provide a mechanism to explain proximal pulmonary artery thrombosis.5 Thus, the majority of experts in the field favor the embolism hypothesis that attributes CTEPH pathogenesis to a single or recurrent pulmonary embolisms (PE). The latter hypothesis is supported by a history of PE in ≤75% of all CTEPH patients and by the beneficial effects of timely performed pulmonary endarterectomy. 2,6 Finally, several risk factors for CTEPH including specific procoagulation factors such as phospholipid antibodies, protein S and protein C, factor V mutations, malignancy, inflammatory bowel disease, and previous deep vein thrombosis are also risk factors for recurrent PE.6,7 It is not yet understood how PE progresses to CTEPH, and the mechanisms behind thrombi escape to thrombolysis and subsequent fibrotic transformation are still unknown. Consequently, there is a need for simple and reproducible CTEPH animal models that not only permit the analysis of molecular signals involved in the pathology of this disease but also enable the evaluation of new therapeutic strategies to improve the fate of individuals diagnosed with CTEPH.Abstract-Chronic thromboembolic pulmonary hypertension (CTEPH) is an entity of PH that not only limits patients quality of life but also causes significant morbidity and mortality. The treatment of choice is pulmonary endarterectomy. However numerous patients do not qualify for pulmonary endarterectomy or present with residual vasculopathy post pulmonary endarterectomy and require specific vasodilator treatment. Currently, there is no available specific small animal model of CTEPH that could serve a...

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“…MAPK also mediate the increase of ECM deposition in the vessel wall of PAH patients [17,18]. Moreover, PAH is associated with an altered interaction of MAPK with the transforming growth factor β1 (TGF-β1) activated signaling cascades, which are relevant to ECM restructuring [17,19].…”

Section: Introductionmentioning

confidence: 99%

The Interaction of Endothelin-1 and TGF-β1 Mediates Vascular Cell Remodeling

et al. 2013

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BackgroundPulmonary arterial hypertension is characterized by increased thickness of pulmonary vessel walls due to both increased proliferation of pulmonary arterial smooth muscle cell (PASMC) and deposition of extracellular matrix. In patients suffering from pulmonary arterial hypertension, endothelin-1 (ET-1) synthesis is up-regulated and may increase PASMC activity and vessel wall remodeling through transforming growth factor beta-1 (TGF-β1) and connective tissue growth factor.ObjectiveTo assess the signaling pathway leading to ET-1 induced proliferation and extracellular matrix deposition by human PASMC.MethodsPASMC were serum starved for 24 hours before stimulation with either ET-1 and/or TGF-β1. ET-1 was inhibited by Bosentan, ERK1/2 mitogen activated protein kinase (MAPK) was inhibited by U0126 and p38 MAPK was inhibited by SB203580.ResultsET-1 increased PASMC proliferation when combined with serum. This effect involved the mitogen activated protein kinases (MAPK) ERK1/2 MAPK and was abrogated by Bosentan which caused a G1- arrest through activation of p27(Kip). Regarding the contribution of extracellular matrix deposition in vessel wall remodeling, TGF-β1 increased the deposition of collagen type-I and fibronectin, which was further increased when ET-1 was added mainly through ERK1/2 MAPK. In contrast, collagen type-IV was not affected by ET-1. Bosentan dose-dependently reduced the stimulatory effect of ET-1 on collagen type-I and fibronectin, but had no effect on TGF-β1.Conclusion and Clinical RelevanceET-1 alone does not induce PASMC proliferation and extracellular matrix deposition. However, ET-1 significantly up-regulates serum induced proliferation and TGF-β1 induced extracellular matrix deposition, specifically of collagen type-I and fibronectin. The synergistic effects of ET-1 on serum and TGF-β1 involve ERK1/2 MAPK and may thus present a novel mode of action in the pathogenesis of pulmonary arterial hypertension.

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Plexiform Lesions in Pulmonary Arterial Hypertension

Cited by 151 publications

References 49 publications

Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonaryhypertension

Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonaryhypertension

Development and Characterization of an Inducible Rat Model of Chronic Thromboembolic Pulmonary Hypertension

The Interaction of Endothelin-1 and TGF-β1 Mediates Vascular Cell Remodeling

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