Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Abstract

Pulmonary hypertension (PH) is a debilitating progressive disease characterized by increased pulmonary arterial pressures, leading to right ventricular (RV) failure, heart failure and, eventually, death. Based on the underlying conditions, PH patients can be subdivided into the following five groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) PH due to lung disease, (4) chronic thromboembolic PH (CTEPH), and (5) PH with unclear and/or multifactorial mechanisms. Currently, even with PAH-specific drug treatment, prognosis for PAH and CTEPH patients remains poor, with mean five-year survival rates of 57%–59% and 53%–69% for PAH and inoperable CTEPH, respectively. Therefore, more insight into the pathogenesis of PAH and CTEPH is highly needed, so that new therapeutic strategies can be developed. Recent studies have shown increased presence and activation of innate and adaptive immune cells in both PAH and CTEPH patients. Moreover, extensive biomarker research revealed that many inflammatory and immune markers correlate with the hemodynamics and/or prognosis of PAH and CTEPH patients. Increased evidence of the pathological role of immune cells in innate and adaptive immunity has led to many promising pre-clinical interventional studies which, in turn, are leading to innovative clinical trials which are currently being performed. A combination of immunomodulatory therapies might be required besides current treatment based on vasodilatation alone, to establish an effective treatment and prevention of progression for this disease. In this review, we describe the recent progress on our understanding of the involvement of the individual cell types of the immune system in PH. We summarize the accumulating body of evidence for inflammation and immunity in the pathogenesis of PH, as well as the use of inflammatory biomarkers and immunomodulatory therapy in PAH and CTEPH.

In the eye of the storm: the right ventricle in COVID‐19

“…60 Clinically, elevated levels of IL-6 have been reported in idiopathic PAH patients. 61 Also, a recent study showed an independent inverse relationship between serum IL-6 levels and RV function in PH patients, 63 though the underlying mechanism is unclear.…”

“…59 Inflammatory cytokines and chemokines can contribute to the pathogenesis of PH by recruiting immune cells, activating and proliferating pulmonary arterial smooth muscle cells, and causing endothelial cell dysfunction. Interestingly, direct administration or over-expression of IL-6 can lead to PH, [60][61][62] whereas loss of IL-6 attenuated hypoxia-induced PH and RV hypertrophy. 60 Clinically, elevated levels of IL-6 have been reported in idiopathic PAH patients.…”

Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice

“…In these analyses, we found that the total population of monocytes/macrophages, which have also been implicated in PH pathogenesis [ 28 ], was decreased in saline- or LPS-exposed Tnfaip3 DNGR1-KO mice (14 and 22 percent, respectively) compared to WT control mice (30 and 33 percent, respectively) ( Figure 2 d, see for gating: Supplementary Figure S4a ). The induction of immune activation by LPS in Tnfaip3 DNGR1-KO and WT mice was confirmed by the observation of increased proportions of interstitial macrophages (IM) in the lung [ 29 ] ( Figure 2 d).…”

Cancer and pulmonary hypertension: Learning lessons and real-life interplay

“…A very good example of impaired or suppressed immune system in promoting pulmonary vascular remodeling is human immunodeficiency virus infection, which is associated with increased prevalence of PAH 52 . In addition to class 1 PH (PAH), the importance of inflammation and immunity has been shown in classes 2 (PH due to left heart diseases) 53 , 3 (PH due to hypoxia and lung diseases) 54 , and 4 (CTEPH) 55 PH patients.…”