Reversal of Idiopathic Pulmonary Arterial Hypertension and Allograft Pneumonectomy After Single Lung Transplantation

Deb, Subrato; Yun, Joon; Burton, Nelson A.; Omron, Edward M.; Thurber, John; Nathan, Steven D.

doi:10.1378/chest.130.1.214

Cited by 25 publications

(15 citation statements)

References 15 publications

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“…Recent data also suggest that concurrent shear stress is required for the development and maintenance of severe occlusive vascular lesions after Sugen-induced pulmonary vascular injury (14). This is also supported by pathological reports of a complete reversal of pulmonary remodeling within the native PAH lung after prolonged normalization of pulmonary hemodynamics after contralateral single lung transplantation (15).…”

supporting

confidence: 60%

Shear Stress Maladaptation in Pulmonary Arterial Hypertension. An Ageless Concept

Bonnet

Provencher

2016

Am J Respir Crit Care Med

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Despite significant improvement in our understanding of mechanisms involved in pulmonary artery remodeling in pulmonary arterial hypertension (PAH), the actual course of events leading to this devastating disease remains enigmatic. Indeed, several conditions have been shown to predispose to PAH, including epigenetic modifications (1, 2), genetic mutations, autoimmune and inflammatory conditions, drugs and toxins, and cardiac defects associated with increased pulmonary blood flow and/or pressure. Importantly, none of them appears to be sufficient on its own to lead to overt PAH, commanding the "multiple hits" theory, triggering and perpetuating the intense pulmonary vasculopathy leading to PAH. Intriguingly, despite highly heterogeneous initial triggers, pulmonary vessels respond very stereotypically in a manner similar to acute respiratory distress syndrome, in which variable initial lung injuries ultimately lead to strikingly homogeneous lung pathology (3). This stereotypic vascular response in PAH includes the formation of complex cellular and fibrotic intimal lesions, smooth muscle cells' proliferation, and apoptosis resistance, as well as adventitial infiltration and thickening (4). During the last decades, our understanding of the mechanisms involved in the endothelial dysfunction and the cancer-like angioproliferation in PAH has increased substantially from genetic, epigenetic, metabolic, and inflammatory abnormalities that contribute to this pulmonary vascular remodeling (5). Interestingly, the role of disturbed pulmonary blood flow and the concomitant shear stress, recognized early on as a risk factor for pulmonary vascular injury and remodeling (6), has now been reacknowledged.In this issue of the Journal, Szulcek and colleagues (pp. 1410-1420) demonstrate that human pulmonary artery endothelial cells (PAEC) isolated from subpleural lung microcirculation of patients with PAH at the time of transplantation or necropsy and submitted to ex vivo high shear stress exhibited delayed morphological adaptation compared with control PAEC (7). Interestingly, proximal PAH-PAEC exhibited normal shear stress-related adaptation, confirming the phenotypic heterogeneity of PAEC within the pulmonary vascular bed in PAH (8). At the microcirculation level, platelet endothelial cell adhesion molecule (PECAM)-1 expression and activation of its signaling mediators (extracellular signal-regulated kinases, SRC, and caveolin 1) were significantly decreased in PAH. PECAM-1 expression was not only reduced but was distributed unevenly, with areas entirely lacking the junctional protein, especially in areas of nonuniform flow. Conversely, PECAM-1 independent shear-responsive kinases and PECAM-1 mRNA were normally expressed in PAH-PAEC, suggesting intact shear stress sensing, but specific alterations in PECAM-1 signaling post-transcriptionally presumably related to caspase-mediated cleavage of PECAM-1. The aberrant morphological adaptation to shear stress was reproduced in control PAEC by silencing of PECAM-1, whereas inhibiting caspa...

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supporting

confidence: 60%

Shear Stress Maladaptation in Pulmonary Arterial Hypertension. An Ageless Concept

Bonnet

Provencher

2016

Am J Respir Crit Care Med

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“…For example, previous studies have shown that transplantation of a rat lung, in which monocrotaline had induced severe pulmonary vascular disease, into a normal rat was sufficient to reverse lung structural abnormalities (40). Regression of severe pulmonary vascular disease has been noted to occur in the original lung that remained in a PAH patient after single-lung transplant (41). However, there is the possibility that the regression may have been induced by immunosuppressive agents rather than by the reduction in PA pressure.…”

Section: Figurementioning

confidence: 99%

Molecular pathogenesis of pulmonary arterial hypertension

Rabinovitch¹

2008

J. Clin. Invest.

575

245

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“…10,11 Two case studies have reported partial regression of idiopathic PAH following single lung transplantation, and one of them histologically demonstrated regression of vascular lesions. 12,13 In rats, regression of arterial changes induced by hypoxia begins within 1 week of normoxia, but is not complete even after 1 month. 14,15 Although prostacyclin does not reverse arterial changes in rats, 16 a variety of other therapies do.…”

Section: Introductionmentioning

confidence: 99%

Persistence of complex vascular lesions despite prolonged prostacyclin therapy of pulmonary arterial hypertension

et al. 2012

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Pogoriler J E, Rich S, Archer S L & Husain A N  (2012) Histopathology 61, 597–609 Persistence of complex vascular lesions despite prolonged prostacyclin therapy of pulmonary arterial hypertension Aims: Continuous infusion of prostacyclin analogues improves survival in advanced pulmonary arterial hypertension. In addition to its vasodilatory effects, prostacyclin has the potential to decrease inflammation, thrombosis, and smooth muscle proliferation. The aim of this retrospective study was to determine whether pathological data support the ability of prostanoids to prevent progression of vascular disease. Methods and results: Twenty‐two autopsied patients with World Health Organization category 1 pulmonary arterial hypertension (primarily idiopathic and connective tissue disease‐associated) were divided into those who received long‐term prostacyclin (n = 12, PG‐long, mean treatment 3.9 years) and those who received 0–1 month of prostacyclin (n = 10, PG‐short). Surprisingly, PG‐long patients had larger plexiform lesions (P < 0.05), with no decrease in medial and intimal thicknesses as compared with PG‐short patients. Plexiform lesion size and density increased with increasing treatment time. Also, PG‐long patients had fewer platelet thrombi and more frequent acute diffuse alveolar haemorrhage. Quantification of macrophages and T cells revealed no differences in inflammatory infiltrates. Conclusions: Although long‐term prostacyclin therapy may have an antithrombotic effect in addition to its vasodilatory actions, it was not associated with the prevention of advanced vascular lesions. The mechanism by which prostacyclin analogues improve survival in pulmonary arterial hypertension remains uncertain.

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Reversal of Idiopathic Pulmonary Arterial Hypertension and Allograft Pneumonectomy After Single Lung Transplantation

Cited by 25 publications

References 15 publications

Shear Stress Maladaptation in Pulmonary Arterial Hypertension. An Ageless Concept

Shear Stress Maladaptation in Pulmonary Arterial Hypertension. An Ageless Concept

Molecular pathogenesis of pulmonary arterial hypertension

Persistence of complex vascular lesions despite prolonged prostacyclin therapy of pulmonary arterial hypertension

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