Immune dysregulation and endothelial dysfunction in pulmonary arterial hypertension: a complex interplay

A Huertas, F Perros, L Tu, S Cohen-Kaminsky… - Circulation, 2014 - Am Heart Assoc
A Huertas, F Perros, L Tu, S Cohen-Kaminsky, D Montani, P Dorfmüller, C Guignabert
Circulation, 2014Am Heart Assoc
Huertas et al Immune/Endothelial Dysregulation in PAH 1333 comprise pulmonary
transmural inflammatory cell infiltrates with focal vessel wall necrosis and fibrinoid
insudation, a histological pattern that has been etiologically linked with particularly severe
forms of PAH. The histological “inflammatory mark,” which is much more frequent,
corresponds to pulmonary perivascular inflammatory infiltrates, made up primarily of T and B
lymphocytes, mast cells, dendritic cells (DCs), and macrophages13–15 (Figure 1) …
Huertas et al Immune/Endothelial Dysregulation in PAH 1333 comprise pulmonary transmural inflammatory cell infiltrates with focal vessel wall necrosis and fibrinoid insudation, a histological pattern that has been etiologically linked with particularly severe forms of PAH. The histological “inflammatory mark,” which is much more frequent, corresponds to pulmonary perivascular inflammatory infiltrates, made up primarily of T and B lymphocytes, mast cells, dendritic cells (DCs), and macrophages13–15 (Figure 1). Interestingly, it has recently been shown, in an analysis of 62 PAH explanted lungs, that marked perivascular inflammation is present in a high number of PAH lungs and correlates with intima and media remodeling. 16 Despite these data, whether such inflammatory infiltrates are involved in the pathobiology of PAH or whether they are only epiphenomena linked to other pathological mechanisms leading to pulmonary vascular remodeling is still unclear. However, according to the experience gained in our national PH reference center, which gives us access to a large collection of pulmonary samples from severe PAH, inflammatory lesions seem more often to be associated with active and cellular arterial remodeling rather than cicatricial-like fibrotic lesions. 12 Innate responses and effectors such as natural killer (NK) cells may also play an important role in PAH pathogenesis. It has been shown in IPAH and heritable PAH, as well as in animal PH models, that NK cells display an altered and impaired phenotype. 17 Furthermore, cytotoxic T, NK, and NK T cells may contribute to vascular remodeling in different physiological and pathological conditions. We have recently shown that immune regulation of cytotoxic, NK, and NK T cells could contribute differently to the pathophysiology of pulmonary veno-occlusive disease (PVOD) and PAH. We found that in PVOD there was a decrease in populations and subpopulations of cytotoxic and NK T cells but an increase in NK populations. We assessed their function through their capacity to produce granulysin and found that peripheral blood mononuclear cells and explanted lungs display lower levels of GNLY demethylation in PVOD compared with PAH patients. Furthermore, despite the reduced granulysin-containing cells in patients with PVOD, granulysin serum levels were higher, suggesting that these cells were secreting their content. 18 These results suggest that pulmonary vascular remodeling in PAH or PVOD might be linked to alterations of the circulating and pulmonary compartments of immune cells. Although increased inflammatory mediators and cell infiltrates represent a common feature of various forms of PAH, only a small percentage of patients with established PAH respond to anti-inflammatory drugs. Complete reversibility of PAH is rare and appears mostly in the setting of active autoimmune diseases treated with corticosteroids or immunosuppressive agents. In a retrospective study, Sanchez and coworkers19 were able to distinguish a small subgroup of patients with
Am Heart Assoc