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.
Highlights
Pulmonary hypertension (PH) is a devastating vascular disease characterized by remodeling of the small pulmonary arteries, elevated pulmonary artery pressure, and subsequent development of right heart failure
Circulating monocytes can take on an endothelial-like phenotype once adhering to endothelial cells [89,90]. Both macrophages and hyperproliferative endothelial-like cells were observed in plexiform lesions in pulmonary arterial hypertension (PAH), and they may indicate the conversion of monocytes to endothelial-like cells that contribute to pulmonary vascular remodeling in PAH
bone morphogenetic proteinCells type 2 (BMPR2)+/− mice developed a sustained increase in right ventricular systolic pressure (RVSP), which was coupled with marked perivascular inflammation of the remodeled vessels and a significantly higher expression of chemokine macrophage
Summary
Pulmonary hypertension (PH) is a devastating vascular disease characterized by remodeling of the small pulmonary arteries, elevated pulmonary artery pressure, and subsequent development of right heart failure. The exact role of inflammation and immunity in PAH—and inflammation and immunity in PAH is of academic but more importantly of direct clinical whether or not it is a cause, a promoter, or a downstream bystander of the disease—is poorly understood interest, as a greater understanding of this interaction is expected to facilitate the evolution of new and remains a topic of considerable controversy. We will address these key issues from three angles: We will discuss (A) inflammatory mediators and their effects on pulmonary vascular remodeling; (B) inflammatory/immune cells and their products in PAH; and (C) phenotypic changes in vascular cells and their feedback into the inflammatory and immune responses. Understanding the role of inflammation and immunity in PAH is of academic but more importantly of direct clinical interest, as a greater understanding of this interaction is expected to facilitate the evolution of new targeted therapies for this devastating disease
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