Pulmonary hypertension: the science behind the disease spectrum

Abstract

Pulmonary hypertension (PH) is a complex, multifactorial disorder divided into five major subtypes according to pathological, pathophysiological and therapeutic characteristics. Although there are distinct differences between the PH categories, a number of processes are common to the pathology of all subtypes. Vasoconstriction, as a result of endothelial dysfunction and an imbalance in the levels of vasoactive mediators, is a well-characterised contributory mechanism. Excessive cell proliferation and impaired apoptosis in pulmonary vessels leading to structural remodelling is most evident in pulmonary arterial hypertension (PAH), and several factors have been implicated, including mitochondrial dysfunction and mutations in bone morphogenetic protein receptor type 2. Inflammation plays a key role in the development of PH, with increased levels of many cytokines and chemokines in affected patients. Exciting insights into the role of angiogenesis and bone marrow-derived endothelial progenitor cells in disease progression have also recently been revealed. Furthermore, there is increasing interest in changes in the right ventricle in PH and the role of metabolic abnormalities. Despite considerable progress in our understanding of the molecular mechanisms of PH, further research is required to unravel and integrate the molecular changes into a better understanding of the pathophysiology of PH, particularly in non-PAH, to put us in a better position to use this knowledge for improved treatments.

Figure 1.

The key pathological mechanisms underlying vascular changes in pulmonary hypertension (PH). Potential new therapies for PH are also indicated. AEC: alveolar epithelial cell; vWF: von Willebrand factor; TXA₂: thromboxane A₂; NO: nitric oxide; EPC: endothelial progenitor cell; ET-1: endothelin-1; PGI₂: prostaglandin I₂; sGC: soluble guanylate cyclase; cGMP: cyclic guanosine monophosphate; 5-HT: 5-hydroxytryptamine; VEGF: vascular endothelial growth factor; bFGF: basic fibroblast growth factor; TGF-α: transforming growth factor-α; PDGF: platelet-derived growth factor; HGF: hepatocyte growth factor; PPARγ: peroxisome proliferator-activated receptor-γ; STAT3: signal transducer and activator of transcription 3; NFAT: nuclear factor of activated T-cells; MCP-1: monocyte chemoattractant protein-1; TNF: tumour necrosis factor; IL: interleukin; FKN: fractalkine; CCL: chemokine ligand; cAMP: cyclic adenosine monophosphate. Reproduced from [6] with permission from the publisher.