Immune Dysregulation and Endothelial Dysfunction in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) corresponds to a heterogeneous group of severe clinical conditions characterized by precapillary pulmonary hypertension (PH) diagnosed when mean pulmonary artery pressure equals or exceeds 25 mm Hg at rest with normal pulmonary artery wedge pressure (≤15 mm Hg). According to the current clinical classification, PAH can be idiopathic (IPAH), heritable, drug or toxin induced, or associated with other diseases (eg, connective tissue diseases [CTDs], congenital heart diseases, HIV infection, and portal hypertension).1 PAH has a complex and multifactorial pathogenesis in which excessive migration and proliferation of pulmonary vascular cells (ie, endothelial cells [ECs] and smooth muscle cells [SMCs]) and dysregulated immune responses are critical contributors to the inappropriate pulmonary vascular remodeling. PAH is a fatal condition leading to right heart failure and death within 2 to 3 years after diagnosis if left untreated. During the last decade, therapeutic options for the treatment of this disease have improved exercise capacity, quality of life, and long-term outcomes. However, there is currently no cure available, and further insight into the disease pathophysiology is needed to advance drug development and to improve patient management. It is now widely accepted that altered immune mechanisms play a significant role in PAH by recruiting inflammatory cells, remodeling the pulmonary vasculature, and promoting autoimmune responses.2–4 Inflammation is a general term for the local accumulation of fluid, plasma proteins, and white blood cells that is initiated by physical injury, infection, or a local immune response. These phenomena represent the innate immune response. The innate immune response contributes to the activation of adaptive immunity, which is the response of antigen-specific lymphocytes to antigen, including the development of immunologic memory. The unique features of adaptive immunity, based on clonal selection of lymphocytes bearing antigen-specific receptors, provide the ability to recognize all pathogens specifically …