Focus on Early Events: Pathogenesis of Pulmonary Arterial Hypertension Development

Abstract

Significance: Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vasculature characterized by the proliferation of all vascular wall cell types, including endothelial, smooth muscle, and fibroblasts. The disease rapidly advances into a form with extensive pulmonary vascular remodeling, leading to a rapid increase in pulmonary vascular resistance, which results in right heart failure. Recent Advances: Most current research in the PAH field has been focused on the late stage of the disease, largely due to an urgent need for patient treatment options in clinics. Further, the pathobiology of PAH is multifaceted in the advanced disease, and there has been promising recent progress in identifying various pathological pathways related to the late clinical picture. Critical Issues: Early stage PAH still requires additional attention from the scientific community, and although the survival of patients with early diagnosis is comparatively higher, the disease develops in patients asymptomatically, making it difficult to identify and treat early. Future Directions: There are several reasons to focus on the early stage of PAH. First, the complexity of late stage disease, owing to multiple pathways being activated in a complex system with intra-and intercellular signaling, leads to an unclear picture of the key contributors to the pathobiology. Second, an understanding of early pathophysiological events can increase the ability to identify PAH patients earlier than what is currently possible. Third, the prompt diagnosis of PAH would allow for the therapy to start earlier, which has proved to be a more successful strategy, and it ensures better survival in PAH patients. Antioxid. Redox Signal. 31, 933-953.

Sex-specific stress response and HMGB1 release in pulmonary endothelial cells

“…Thus, the release of damage-associated molecular patterns (DAMPs) from dying cells could induce a strong inflammatory response and immune system activation. High mobility group box 1 (HMGB1) is a DAMP that specifically releases from necrotic but not apoptotic cells [49]. Through its binding to pattern recognition receptors, such as Toll Like Receptor 4 (TLR4) and the receptor of advanced glycation end products (RAGE), HMGB1 activates the NfκB pathway and has been shown to play a critical role in the pathogenesis of PAH [27,50].…”

Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability

“…This, in turn, can attract inflammatory cells and accumulate cytokines and chemokines. We have also shown a strong correlation between lung edema and pulmonary pressure, and the hypoxic environment of vessels surrounding by edema [2]. Moreover, this liquid layer will mechanically reduce the vasodilation of the arteries [36] and increase their stiffness.…”

“…2b and c) that was consistent with the lung weight findings and vascular remodeling. Indeed, we have recently shown a direct correlation between the manifestation of disease and lung edema in both MCT and SU/Hx models [2].…”

“…Pulmonary hypertension (PH) affects vascular circulation in the lungs. Pulmonary vasculature becomes narrowed due to vasoconstriction, proliferation, fibrosis, or thrombosis, leading to increased pressure in the pulmonary circulation and increased workload for the right heart [1][2][3]. Patients with PH die due to the right heart failure.…”

“…Thus, we found that at the beginning of the disease, cells in the lungs significantly change their metabolism, leading to alterations in arginine/nitric oxide pathway, glycolysis, prostaglandin synthesis, glutathione balance, extracellular matrix formation, and activity of inflammatory pathways. Therefore, focusing on early events in the pulmonary circulation can shed light on important mechanisms leading to pathological changes in PH [2].…”