Relevant issues in the pathology and pathobiology of pulmonary hypertension

Abstract

Knowledge of the pathobiology of pulmonary hypertension (PH) continues to accelerate. However, fundamental gaps remain in our understanding of the underlying pathological changes in pulmonary arteries and veins in the different forms of this syndrome. Although PH primarily affects the arteries, venous disease is increasingly recognized as an important entity. Moreover, prognosis in PH is determined largely by the status of the right ventricle, rather than the levels of pulmonary artery pressures. It is increasingly clear that although vasospasm plays a role, PH is an obstructive lung panvasculopathy. Disordered metabolism and mitochondrial structure, inflammation, and dysregulation of growth factors lead to a proliferative, apoptosis-resistant state. These abnormalities may be acquired, genetically mediated as a result of mutations in bone morphogenetic protein receptor-2 or activin-like kinase-1, or epigenetically inherited (as a result of epigenetic silencing of genes such as superoxide dismutase-2). There is a pressing need to better understand how the pathobiology leads to severe disease in some patients versus mild PH in others. Recent recognition of a potential role of acquired abnormalities of mitochondrial metabolism in the right ventricular myocytes and pulmonary vascular cells suggests new therapeutic approaches, diagnostic modalities, and biomarkers. Finally, dissection of the role of pulmonary inflammation in the initiation and promotion of PH has revealed a complex yet fascinating interplay with pulmonary vascular remodeling, promising to lead to novel therapeutics and diagnostics. Emerging concepts are also relevant to the pathobiology of PH, including a role for bone marrow and circulating progenitor cells and microribonucleic acids. Continued interest in the interface of the genetic basis of PH and cellular and molecular pathogenetic links should further expand our understanding of the disease.

Keywords: ALK; BMPR2; DC; ER; HIF; IPAH; LHF; PAH; PH; activin receptor-like kinase; bone morphogenetic protein type II receptor; dendritic cell; endoplasmic reticulum; hypoxia inducible factor; idiopathic pulmonary arterial hypertension; inflammation; left heart failure; metabolism; pulmonary arterial hypertension; pulmonary arteries; pulmonary hypertension; pulmonary veins.

Figure 1. Proposed multifactorial factors influencing progression of pulmonary hypertension

In a suitable genetic background, the interplay of epigenetics and pathobiological injurious events may amplify the severity of the disease, often associated with more pronounced remodeling and worse clinical outcome.

Figure 2. Emerging paradigms in pulmonary hypertension research, involving the broad effects of metabolic programming of intima and media pulmonary vascular cells (endothelial and smooth muscle cells) and the immediate perivascular microenvironment

The perivascular region is dominated by fibroblasts and migrating circulating cells, including inflammatory and progenitor cells. Shown in the center are the impact of these factors in the intima and media of pulmonary arteries. The metabolic plasticity involves all cells involved in the PH panvasculopathy and is itself modified by inflammation and infiltrating progenitor cells (these paradigms are examined in more detail in Ref. (100)).