A pro-con debate: current controversies in PAH pathogenesis at the American Thoracic Society International Conference in 2017

Kuebler, Wolfgang M.; Nicolls, Mark R.; Olschewski, Andrea; Abe, Kohtaro; Rabinovitch, Marlene; Stewart, Duncan J.; Chan, Stephen Y.; Morrell, Nicholas W.; Archer, Stephen L.; Spiekerkoetter, Edda

doi:10.1152/ajplung.00150.2018

Cited by 16 publications

(12 citation statements)

References 127 publications

(138 reference statements)

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“…The pulmonary artery endothelial cell is thought by most researchers to represent the initial site of disease in PAH, although this is a topic of significant debate [ 4 , 142 ]. Endothelial cells, under various conditions, can themselves serve as non-professional immune cells, synthesizing and secreting inflammatory mediators, as well as being the local targets of inflammation.…”

Section: Inflammatory Mediators and Their Effects On Vascular Remomentioning

confidence: 99%

Perivascular Inflammation in Pulmonary Arterial Hypertension

Chi

Kuebler

et al. 2020

Cells

142

109

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Perivascular inflammation is a prominent pathologic feature in most animal models of pulmonary hypertension (PH) as well as in pulmonary arterial hypertension (PAH) patients. Accumulating evidence suggests a functional role of perivascular inflammation in the initiation and/or progression of PAH and pulmonary vascular remodeling. High levels of cytokines, chemokines, and inflammatory mediators can be detected in PAH patients and correlate with clinical outcome. Similarly, multiple immune cells, including neutrophils, macrophages, dendritic cells, mast cells, T lymphocytes, and B lymphocytes characteristically accumulate around pulmonary vessels in PAH. Concomitantly, vascular and parenchymal cells including endothelial cells, smooth muscle cells, and fibroblasts change their phenotype, resulting in altered sensitivity to inflammatory triggers and their enhanced capacity to stage inflammatory responses themselves, as well as the active secretion of cytokines and chemokines. The growing recognition of the interaction between inflammatory cells, vascular cells, and inflammatory mediators may provide important clues for the development of novel, safe, and effective immunotargeted therapies in PAH.

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Section: Inflammatory Mediators and Their Effects On Vascular Remomentioning

confidence: 99%

Perivascular Inflammation in Pulmonary Arterial Hypertension

Chi

Kuebler

et al. 2020

Cells

142

109

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“…Several recent studies have extended existing work on interventional strategies to promote lung alveolarization under pathological conditions. Phosphodiesterase 5 (PDE) continues to receive attention as a potential drug target in the management of pulmonary hypertension (205,281,409,443,545), cardiac remodeling, and alveolar simplification that result from oxygen support. One recent study applied the PDE5 inhibitor sildenafil to rats in the room air recovery period after exposure to hyperoxia for the first two weeks of postnatal life (460), where "delayed" sildenafil therapy improved right ventricular hypertrophy (pulmonary hemodynamics were not addressed), but not alveolar simplification.…”

Section: New Interventional Strategies To Drive Alveolarizationmentioning

confidence: 99%

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

Lignelli

Palumbo

Myti

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

111

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Bronchopulmonary dysplasia (BPD) is the most common cause of morbidity and mortality in preterm infants. A key histopathological feature of BPD is stunted late lung development, where the process of alveolarization—the generation of alveolar gas exchange units—is impeded, through mechanisms that remain largely unclear. As such, there is interest in the clarification both of the pathomechanisms at play in affected lungs, and the mechanisms of de novo alveoli generation in healthy, developing lungs. A better understanding of normal and pathological alveolarization might reveal opportunities for improved medical management of affected infants. Furthermore, disturbances to the alveolar architecture are a key histopathological feature of several adult chronic lung diseases, including emphysema and fibrosis, and it is envisaged that knowledge about the mechanisms of alveologenesis might facilitate regeneration of healthy lung parenchyma in affected patients. To this end, recent efforts have interrogated clinical data, developed new—and refined existing—in vivo and in vitro models of BPD, have applied new microscopic and radiographic approaches, and have developed advanced cell-culture approaches, including organoid generation. Advances have also been made in the development of other methodologies, including single-cell analysis, metabolomics, lipidomics, and proteomics, as well as the generation and use of complex mouse genetics tools. The objective of this review is to present advances made in our understanding of the mechanisms of lung alveolarization and BPD over the period 1 January 2017–30 June 2019, a period that spans the 50th anniversary of the original clinical description of BPD in preterm infants.

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“…However, plexiform lesions are as diverse as the disease itself in that activated signaling cascades, endotypes, and phenotypes of cell clusters within the lesions change dynamically over time and differ between lung compartments (7,14). While the exact origins of plexiform lesions are still unknown, compelling evidence suggests that the lesions develop as a result of altered shear forces and as such, reflect a downstream consequence instead of a cause of PAH (8). Furthermore, only 30 -50% of resistance arteries in the lung show highly heterogeneous rather than uniform remodeling.…”

Section: Limitations Of the Cancer Paradigm Of Pahmentioning

confidence: 99%