Inflammation and autoimmunity in pulmonary hypertension: is there a role for endothelial adhesion molecules? (2017 Grover Conference Series)

Abstract

While pulmonary hypertension (PH) has traditionally not been considered as a disease that is directly linked to or, potentially, even caused by inflammation, a rapidly growing body of evidence has demonstrated the accumulation of a variety of inflammatory and immune cells in PH lungs, in and around the wall of remodeled pulmonary resistance vessels and in the vicinity of plexiform lesions, respectively. Concomitantly, abundant production and release of various inflammatory mediators has been documented in both PH patients and experimental models of PH. While these findings unequivocally demonstrate an inflammatory component in PH, they have fueled an intense and presently ongoing debate as to the nature of this inflammatory aspect: is it a mere bystander of or response to the actual disease process, or is it a pathomechanistic contributor or potentially even a trigger of endothelial injury, smooth muscle hypertrophy and hyperplasia, and the resulting lung vascular remodeling? In this review, we will discuss the present evidence for an inflammatory component in PH disease with a specific focus on the potential role of the endothelium in this scenario and highlight future avenues of experimental investigation which may lead to novel therapeutic interventions.

Inflammasomes: a novel therapeutic target in pulmonary hypertension?

“…The link between PH and altered immunity is also illustrated by the fact that group 1 PH encompasses PAH associated with both autoimmune disorders such as systemic lupus erythematosus and systemic sclerosis (Bazan et al ., ), as well as human immunodeficiency virus infection (Correale et al ., ). In addition to this, PAH patients and indeed PH patients more generally (Pugliese et al ., ; Kuebler et al ., ) display signs of a chronic inflammatory state even without an associated immune‐related condition, most clearly delineated by elevated circulating cytokine levels and perivascular inflammatory infiltrates (Stacher et al ., ). While it is well established that the pathogenesis, and poor prognosis, of PH is primarily due to the remodelling that occurs in the pulmonary vasculature along with RV dysfunction, it is now becoming evident that this remodelling is not simply a consequence of imbalanced vasoreactivity but may indeed be driven by aberrant immune responses (Rabinovitch et al ., ).…”

Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension?

“…Altered immunity and inflammation are increasingly recognized as core features of PAH, where synergistic interplay between various infiltrating and inflammatory cells such as T and B lymphocytes, dendritic cells (DCs), mast cells, monocytes, and macrophages play a central role in the pathogenesis [ 3 , 11 , 12 , 13 ]. As our current understanding of PAH immunology improves, such advances may pave the way for the ‘next generation’ of therapeutics.…”

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

“…A growing body of evidence has implicated inflammation and altered immunity in the pathogenesis of PAH [190][191][192]. In PAH patients, the size of perivascular inflammatory and immune cell infiltrates correlates with intima + media remodeling and pulmonary artery pressure [193], and abnormally elevated levels of circulating proinflammatory cytokines are predictive of worse outcomes [194,195].…”