Serum levels of CD163 and TWEAK in patients with pulmonary arterial hypertension
Introduction
Pulmonary arterial hypertension (PAH) is a rare and progressive disease characterized by fibrotic and proliferative changes in small pulmonary arteries that produce a gradual increase in pulmonary vascular resistance and lead to right-heart failure and premature death. It has been widely described that of the multiple and complex mechanisms contributing to PAH development, endothelial injury, chronic inflammatory state and increased vascular cells proliferation are the major ones involved in the pulmonary vascular remodelling [1].
CD163 is a scavenger receptor exclusively expressed by monocytes and macrophages. It is considered a marker of macrophage population of anti-inflammatory activity. Macrophages are a heterogeneous group of cells activated by various stimuli that can differentiate toward a M1 or a M2 phenotype. The M1 subpopulation produce nitrogen intermediates and pro-inflammatory mediators that promote inflammatory responses. In contrast, the M2 subpopulation secretes predominantly anti-inflammatory cytokines and is also associated with vascularization and tissue repair [2]. Several specific surface receptors are expressed by M2 cells and CD163 scavenger receptor is one of them. It is involved in the clearance of hemoglobin–haptoglobin (Hb–Hp) complexes, protecting tissues from oxidative damage and inflammation [3]. CD163 expression is up-regulated during resolution phase of acute inflammatory response and also in chronic inflammatory diseases possibly reflecting counter-regulatory, adaptation, homeostatic mechanisms. The soluble form (sCD163) is released from the cell surface by proteolysis. The enzymes involved in this process are activated by pro-inflammatory mediators leading to elevated levels of sCD163 in peripheral blood and other tissue fluids during inflammatory diseases. Therefore sCD163 can be considered as a potential biomarker of inflammatory condition, e.g. in autoimmune diseases, asthma or atherosclerosis [4], [5], [6], [7]. Recent studies have revealed that CD163 can also bind soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) [8], which is an inflammatory cytokine belonging to the tumor necrosis factor-alpha (TNF-alpha) superfamily. It modulates multiple biological responses associated with tissue damage and repair, such as proliferation, differentiation, inflammation, apoptosis and angiogenesis [9]. It acts mainly via binding to the fibroblast growth factor-inducible 14 receptor (Fn14), which is rarely expressed on macrophage surface, making CD163 a specific receptor for sTWEAK on monocytes/macrophages [8], [9]. Binding sTWEAK by CD163 leads to neutralization of both molecules, for that reason CD163 seems to act as a “decoy” receptor for sTWEAK [8]. The interaction of sTWEAK with CD163 might be the mechanism that balances inflammatory reactions. Therefore we assume that sTWEAK/sCD163 ratio will better reflect biological activity of sTWEAK.
Recent studies have demonstrated a potential role of sTWEAK in pathogenesis of atherosclerosis as well as prognostic value of this cytokine in chronic heart failure and myocardial infarction [10], [11], [12], [13]. TWEAK/Fn14 pathway plays an important role in regulation of cardiac, and particularly right ventricular, hypertrophy and fibrosis [10], [12]. There is a growing evidence suggesting that sTWEAK may contribute to the pathogenesis of PAH and also have predictive significance [14]. Moreover, these two phenomena very well fit together, as right ventricular function is a major determinant of prognosis in pulmonary arterial hypertension [1].
In this context, the current study aimed at assessment of alterations in the levels of sCD163 and sTWEAK in patients with PAH as potential factors involved in the pathobiology of this disease.
Section snippets
Population
This single-center study included 26 patients with pulmonary arterial hypertension. These subjects made a complete population of PAH patients in north-eastern Poland. The diagnosis of PAH was based on established criteria [1] and confirmed by right-sided heart catheterization, using standard hemodynamic measurements: mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO) and cardiac index (CI). The reference cohort consisted of 24 healthy
Results
The study enrolled 26 stable patients with confirmed diagnosis of PAH, in II–IV WHO functional class and 24 healthy volunteers matched for age, sex and body weight. They were patients with idiopathic PAH (46.2%, n = 12) as well as with PAH associated with connective tissue diseases and congenital heart diseases (26.9%, n = 7 both groups). Of these, 61.5% (n = 16) were prevalent cases, the rest (38.5%, n = 10) were incident cases. Mean age in the study group was 51.1 (±17.8) years vs 47.2 (±13.6) years
Discussion
This is the first study, to our knowledge, that reports significantly elevated serum levels of scavenger receptor, soluble CD163, in patients with PAH. Moreover, we demonstrated for the first time decreased sTWEAK/sCD163 ratio in this group of patients compared to healthy controls.
Numerous studies have documented that patients with idiopathic PAH exhibit higher plasma levels or pulmonary expression of proinflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-alpha, fractalkine and
Conclusions
Patients with PAH present altered serum sTWEAK and sCD163 levels. The sTWEAK/sCD163 ratio appears to be a better indicator of the severity of PAH as compared to sTWEAK or sCD163 alone. The exact role of sCD163 or interaction between CD163 and sTWEAK in the initiation or progression of PAH as well as their potential prognostic significance remains to be established.
Contributions
Malgorzata Jasiewicz: designed and performed research, collected and analyzed data, wrote paper.
Krzysztof Kowal: performed research, collected data, wrote paper.
Otylia Kowal-Bielecka: performed research, wrote paper.
Malgorzata Knapp: performed research, collected data.
Roman Skiepko: performed research, collected data.
Anna Bodzenta-Lukaszyk: analyzed data.
Bozena Sobkowicz: performed research.
Wlodzimierz Jerzy Musial: analyzed data.
Karol Adam Kaminski: designed research, analyzed data, wrote
Acknowledgements
The research was supported by National Science Centre Grant (2011/01/N/NZ5/04361) and statutory activity of Medical University of Bialystok (113-53832L).
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