The Shared Pathogenesis of Pulmonary Artery Hypertension

Pulmonary artery hypertension is defined as an increased in pulmonary artery pressure exceeding 25 mmHg with normal pulmonary wedge pressure. The pathogenesis of pulmonary artery hypertension involves interaction among vascular, cellular and biomarker components in the pulmonary tissue; with eventual result is elevated pulmonary artery pressure. Vascular components are remodeling of intimal, medial and adventitial layers. Cellular components are played by apoptosis-resistant endothelial cells, proliferative-prone pulmonary artery smooth muscle cells, fibroblasts and inflammatory cells. The functional biomarkers are produced and mediated by these cellular changes, mainly endothelin-1, thromboxane, serotonin, nitric oxide, and prostacyclin. The pulmonary vascular remodeling in pulmonary artery hypertension are diverse and may present in various severity based on underlying etiology. Understanding the shared pathogenesis in pulmonary artery hypertension is of paramount importance in order to improve the disease management and treatment approach.


INTRODUCTION
Pulmonary artery hypertension is considered to be a progressive disease.It is defined as an increased in pulmonary artery pressure exceeding 25 mmHg with normal pulmonary wedge pressure. 1thogenesis of pulmonary artery hypertension is hallmarked by pulmonary vascular remodeling.
Pulmonary vascular remodeling involves the cellular and molecular modification of the pulmonary vasculature, both reversible or irreversible.All three layers of pulmonary vasculatures, i.e. adventitial, medial and intimal layers, undergo physiological and morphological changes, both consecutively and concomitantly.Thickening of all layers due to cellular growth and proliferation and pathological accumulation of certain cell types and products, such as cytokines, chemokines and matrix componenst, are interplayed in the microenvironment of pulmonary vasculature. 2 addition to structural remodeling from its native vascular cells, perivascular microenvironment played by surrounding cellular components, both from resident cells and migrated cells from remote origin, is supportive in the pathogenesis of pulmonary artery hypertension. 3These components release cellular products or biomarkers, in response to various stimuli.Release of functional biomarkers, mostly those related to maintenance of pulmonary vascular vasoconstriction and vasodilatation, is predominant.Inflammatory cytokines and chemokines, produced by inflammatory cells, are redundantly increased during development toward pulmonary hypertension. 4The aim of this review is to discuss the current shared pathogenesis prevailing in pulmonary artery hypertension.

Pulmonary Vascular Structural Remodeling
Increased pulmonary artery pressure is mainly due to increased resistance in pulmonary vasculature.In normal condition, pulmonary circulation is a high flow and low pressure circulation.The pulmonary arterioles are the main regulator of pulmonary vascular resistance in a whole.These resistance vessels alter their anatomy and perivascular microenvironment in response to increased intraluminal shear stress. 5is pathological shear stress triggers abnormal pulmonary vascular tone, which is is mediated by modulation of endothelial-derived relaxing factor and contracting factors. 2  The adventitia layer of pulmonary artery is compiled by connective tissues that surround the airways and pulmonary arteries.It contains lymphatic vessels and vasa vasorum, therefore a channel for inflammatory cells and rich source of cytokines/chemokines. 4 The adventitial fibroblast is activated under hypoxia, strenuous shear-stress or cytokine/chemokine stimuli. 3is activation produces matrix protein and promotes thickening of adventitial layer.It also produces pro-inflammatory cytokines/ chemokines and recruites macrophages and leukocytes which induce perpetual inflammatory state and neovascularisation which supply inflammatory components in the more inner vascular layers, i.e. medial and intimal layers. 3In addition to inflammation conduit, adventitial layer also an entrance for endothelial progenitor cells and mesenchymal and bone marrow-derived stem cells in which involve in the pathogenesis of pulmonary artery hypertension. 8,9Figure 1 dopicted pulmonary vascular remodeling.

Cellular Activation and Modification
In addition to vascular structural remodeling in the pathogenesis of pulmonary hypertension, cellular activation and subsequent modification are also an integral part of the pathogenesis.The cellular components are Increased chemokines level is identified such as fractalkine, monocyte chemotactic protein and CCL5 (RANTES), which contribute toward developing pulmonary artery hypertension. 12atelet and plasma level of serotonin are increased in pulmonary hypertension.Increased bioavailability of serotonin, a vasocontrictor and profibrotic biomarker, due to increased serotonin release from platelets and endothelial cells is prevailing in pulmonary hypertension. 8The effect of increased serotonin level in pulmonary circulation is hyperplasia and hypertrophy of pulmonary artery smooth muscle cells. 11rotonin transporter (SERT) overexpressed by pulmonary artery smooth muscle cells is responsible for the upregulated mitogenic activity of serotonin by these cells. 8SERT increased expression enhances serotonin transport into pulmonary smooth muscle cells and induces medial thickening and distal muscularisation. 13 patients with idiopathic pulmonary artery hypertension, the expression of SERT is increased which is associated with susceptibility to plasma serotonin mitogenic activity. 11

DISCLOSURE
This article had been presented in Jogja Cardiology Update 2017, Yogyakarta, Indonesia.
Part of the review article had been published in its proceedings.

Figure 3 depicted
the associated biomarkers and pulmonary vascular remodeling.CONCLUSION Pathophysiology of pulmonary artery hypertension involves complex mechanisms consisting delicate interaction among pulmonary vascular structures, cellular modification and biomarker alteration.Understanding each component of mechanisms is of paramount importance in order to improve the disease management and treatment approach.