10 Figure 1. Characteristic histlogical changes seen in the pulmaonray

areriesof lungs affected with PAH showing (A) medial hypertrophy, (B) concentric non-laminar intinal fribrosis, (C) eccentric intimal fibrosis, (D) thrombotic lesions, JAK assay (E) concentric laminar intimal … In the absence of targeted therapies the prognosis of these patients is extremely poor. However with the development of therapies targeted on the pulmonary vasculature the survival of these patients has improved. However this benefit is not seen across all the patient groups, with those who suffer with connective tissue disease or scleroderma fairing much worse than those with an idiopathic cause. 9 PAH is multifactorial disease and a number of different mechanisms have been proposed to contribute to its onset and progression. There are a number of risk factors associated with

the disease which relate to the use of drugs such as aminorex, fenfluramine, dexfenfluramine, cocaine, phenylpropanolamine, St. John’s Wort, chemotherapeutic agents, serotonin re-uptake inhibitors amphetamines, methamphetamines and L-tryptophan or exposure to chemicals such as toxic rapeseed oil. 11 In addition, mutations in bonemorphogenic protein receptor 2, systemic sclerosis, HIV infection, portal hypertension, congenital heart disease with left-to-right shunts, recent acute pulmonary embolism and sickle cell disease are all conditions for which PAH is a risk factor. 12 Although potential causative agents and other diseases associated with PAH represent an apparently diverse range of clinical conditions, there is general agreement that at the cellular level the disease is mediated by dysfunction of the endothelial cells that line the pulmonary vasculature. Endothelial regulation of the pulmonary circulation In common with all other surfaces in the body over which the blood flows, a continuous

layer of endothelial cells covers the pulmonary circulation. While all these cells share AV-951 the same phenotypic markers (expression of CD31 and/or von Willebrand factor) they cannot be considered as a homogeneous population of cells. Evidence exists that blood vessels of differing size and anatomical locations respond in specific ways, often determined by their different physiological roles. 13,14 A common feature between endothelial cells is however, the ability to release a range of vasoactive molecules that interact with blood elements and the underlying vascular smooth muscle. These mediators include nitric oxide (NO), prostacyclin and endothelin-1 (ET-1).