Perivascular Inflammation in Pulmonary Arterial Hypertension

Abstract

Perivascular inflammation is a prominent pathologic feature in most animal models of pulmonary hypertension (PH) as well as in pulmonary arterial hypertension (PAH) patients. Accumulating evidence suggests a functional role of perivascular inflammation in the initiation and/or progression of PAH and pulmonary vascular remodeling. High levels of cytokines, chemokines, and inflammatory mediators can be detected in PAH patients and correlate with clinical outcome. Similarly, multiple immune cells, including neutrophils, macrophages, dendritic cells, mast cells, T lymphocytes, and B lymphocytes characteristically accumulate around pulmonary vessels in PAH. Concomitantly, vascular and parenchymal cells including endothelial cells, smooth muscle cells, and fibroblasts change their phenotype, resulting in altered sensitivity to inflammatory triggers and their enhanced capacity to stage inflammatory responses themselves, as well as the active secretion of cytokines and chemokines. The growing recognition of the interaction between inflammatory cells, vascular cells, and inflammatory mediators may provide important clues for the development of novel, safe, and effective immunotargeted therapies in PAH.

Keywords: inflammation; pulmonary hypertension; vascular remodeling.

Figure 1

Vascular Remodeling in PAH is driven by inflammation. Pulmonary vascular lesions in PAH patients exist in an extremely inflamed micro-environment. See text for details. Note the changes to each layer of the vessel wall, including neointimal formation, medial hypertrophy, and adventitial expansion. Adventitial fibroblasts become activated and secrete cytokines and chemokines to recruit immune cells to the vessel wall via an expanded vasa vasorum. The activation of these recruited immune cells results in the further recruitment of cellular mediators as well as the secretion of cytokines, autoantibodies, and other soluble molecules. Adapted from Rabinovitch et al. Circulation Research 115: 165–175 (2014). Boxes highlight the actions of macrophage LTB4 (Section 2.2.1) and B cells (Section 2.3.5).

Figure 2

Neutrophil elastase in pulmonary arterial hypertension (PAH). Released from neutrophils, as well as smooth muscle cells, neutrophil elastase influences multiple steps in the pathogenesis of PAH, and it is the subject of significant therapeutic interest. Elastase can degrade the extracellular matrix (ECM), liberating active bone morphogenic protein (BMP9) and transforming growth factor (TGF-β). These cytokines induce phenotypic alterations in smooth muscle cells (SMC), fibroblasts, and macrophages, detailed in the text. Additionally, elastin can cleave and activate interleukin-1β (IL-1β), which is a potent inflammatory cytokine that further stimulates macrophage migration and activation to the pulmonary vasculature. Finally, elastin secretion is involved in the formation of neutrophil extracellular traps (NETs), which themselves can induce endothelial apoptosis, which is a key feature of PAH.

Figure 3

Activated fibroblasts drive PAH pathogenesis. Pulmonary artery adventitial fibroblasts respond to multiple stimuli and then propagate inflammation in PAH. In response to inflammatory cytokines, mechanical stretch, and hypoxia, fibroblasts adopt an activated, pro-inflammatory state. This phenotype is characterized by the overexpression of surface adhesion molecules and other inflammatory surface receptors, and secretion of cytokines and chemokines, importantly IL-6, IL-1β and CCL2. Together, these molecules stimulate both the adhesion and activation of nearby macrophages to propagate the inflammatory response. Activated fibroblasts also alter extracellular matrix homeostasis, secreting ECM proteins, as well as matrix metalloproteinases (MMP) to break down ECM. Finally, fibroblasts themselves proliferate in response to abnormal stimuli encountered in PAH.