Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives

Abstract

Clinical and translational research has played a major role in advancing our understanding of pulmonary hypertension (PH), including pulmonary arterial hypertension and other forms of PH with severe vascular remodelling (e.g. chronic thromboembolic PH and pulmonary veno-occlusive disease). However, PH remains an incurable condition with a high mortality rate, underscoring the need for a better transfer of novel scientific knowledge into healthcare interventions. Herein, we review recent findings in pathology (with the questioning of the strict morphological categorisation of various forms of PH into pre- or post-capillary involvement of pulmonary vessels) and cellular mechanisms contributing to the onset and progression of pulmonary vascular remodelling associated with various forms of PH. We also discuss ways to improve management and to support and optimise drug development in this research field.

FIGURE 1

Representative vascular lesions typically detected in lungs of patients with pulmonary arterial hypertension (PAH). a–c) Plexiform lesions. Note that the plexiform core can be in a, b) the para-arterial position, appearing connected to the adventitia, or c) even within the perimeters of the latter, possibly indicating an involvement of the systemic vasculature (vasa vasorum). d) Atypical fibrovascular lesions (also referred to as “SiMFis” (singular millimetric fibrovascular lesions)) of millimetric size (note the scale bar) that can be found in PAH, mostly in its hereditary bone morphogenetic protein receptor type 2-related form. e) Recent thrombotic lesion that shows fresh fibrin at its core and a beginning organising process involving numerous fibroblasts in its periphery (arrows). f) Fully organised thrombotic lesion (“colander-like lesion”) with several recanalisation vessels, vaguely reminiscent of a plexiform lesion. g) Concentric, non-laminar fibrosis of the intima; the media (arrows) is only slightly thickened (note the lymphocyte-rich infiltrate in the lower periphery of the vessel). h) Eccentric, cushion-like fibrosis of the intima, commonly interpreted as an organised thrombotic lesion. i) Hyperplasia of the media and collagen-rich fibrosis of the adventitia (arrows). j) Concentric laminar fibrosis of the intima (“onion-skin lesion”) due to the concentrically arranged multiple fibrous layers that lead to the progressive obstruction of the pulmonary artery.

FIGURE 2

Representative vascular lesions typically detected in the microvasculature, capillaries and post-capillary vessels (pulmonary veins) in lungs of patients with pulmonary arterial hypertension (PAH) or pulmonary veno-occlusive disease (PVOD). a) Microvessels (arteries or venules) presenting some mild inflammatory and fibrous remodelling (patient with PAH). b) Representative image of α-smooth muscle actin immunostaining in lungs of a patient with PVOD, highlighting substantial muscularisation of the pulmonary vasculature. c) Roundish, well-delimited area of interstitial thickening in a patient with PVOD; these areas are distributed in a patchy fashion throughout the lungs of patients with PVOD and probably correspond to typical ground-glass opacities on computed tomography scan. d) At higher magnification, the interstitial thickening in (c) is due to focal multiplication of alveolar capillaries that form multiple layers within the alveolar septa; the term capillary haemangiomatosis-like foci describes this patchy interstitial pattern. e) Muscular hyperplasia and fibrous remodelling in pulmonary septal veins of a patient with PAH. f) Fibrous intima thickening of small septal veins in a patient with PVOD.

FIGURE 3

Impact of hypertrophic systemic vasculature in pulmonary arterial hypertension (PAH): an explanatory approach. The pulmonary artery (top centre, blue) is covered by a systemic vascular plexus, comprising systemic arterial (red) and venous (blue) vessels and microvessels. The systemic plexus anastomoses with the pulmonary artery, the capillary bed and the pulmonary vein (bottom left, red): these bronchopulmonary anastomoses appear to bypass an occlusive PAH lesion, represented by medial thickening and intimal fibrosis (centre). Eventually, the increased systemic blood flow into arterioles, capillaries and the pulmonary vein leads to structural changes of the latter: muscular hyperplasia and focal intimal fibrosis within the pulmonary vein are observed. Reproduced and modified from [4] with permission.

FIGURE 4

Phenotypic signature of dysfunctional pulmonary vascular endothelium in pulmonary arterial hypertension (PAH).

FIGURE 5

Schematic representation of immune disturbance associated with pulmonary arterial hypertension (PAH) and pulmonary vascular remodelling. NK: natural killer; Th: T-helper; Treg: T-regulatory.

FIGURE 6

Cross-talk between transcription factors, epigenetics and metabolism in pulmonary hypertension. Growth factors, ion channels, hormones and cytokines activate the classical signalling pathways and downstream transcriptional factors, which will recruit chromatin-modifying enzymes to local chromatin. On the other hand, nutrient levels and cell metabolism will affect levels of the metabolites, which are required substrates of chromatin-modifying enzymes that use these metabolites to modify both histones and DNA. Variations in these inputs will determine epigenome remodelling and transcription, and subsequently vascular remodelling.

FIGURE 7

Role of transcription factors and transcriptional coregulators in the pathogenesis of pulmonary hypertension (PH). See main text for definitions. Multiple pathological stimuli, such as hypoxia, shear stress, oxidative stress, mitogens and inflammation (cytokines and chemokines), trigger downstream signalling cascades, which modulate the recruitment and activation of transcription factors and transcriptional coregulators that determine the stimulus-specific transcriptional responses in PH.