Background and Aims: Pulmonary Hypertension (PH) as heterogeneous disorder accompanied by impaired prognosis is difficult to diagnose and its clinical management remains challenging. Thus, there is an ongoing clinical need to identify both, novel diagnostic and prognostic biomarkers as well as therapeutic targets. Key steps of PH pathogenesis are, besides pulmonary vascular and right ventricular remodelling as well as thrombosis, complex inflammatory processes including a wide range of cytokines. By real-time RT-PCR based pathway focused gene expression analysis in preclinical animal models, our group could identify several candidate molecules relevantly up-regulated in PH, in particular Interleukin-22 (IL-22), Interleukin-23 (IL-23) and toll-like receptor 7 (TLR-7).  Aim of the current study was to evaluate their potential value in patients suffering from PH of different clinical groups compared to healthy controls.

Methods: Serum levels of IL-22, IL-23 and TLR-7 were quantified using commercially available ELISAs in 92 patients suffering from PH of different clinical groups at the timepoint of initial diagnosis as well as in 30 healthy control subjects. Results were correlated to clinical, laboratory, functional, echocardiographic and hemodynamic parameters.

Results: The mean age of PH patients included in the study was 75 ± 12 years, 70% of patients were female. In contrast to IL-23 and TLR-7, there were significantly increased serum levels of IL-22 in PH patients (14.0 ± 41.1pg/ml) compared to controls (3.0 ± 5.9pg/ml; p<0.001). Thus, the following analyses were performed only for IL-22.

When dividing PH patients into different etiological groups according to current ESC guidelines, the increase of IL-22 in PH patients compared to controls remained significant for all groups (p<0.05).

Correlation analysis revealed, among others, a significant relation between IL-22 and brain natriuretic peptide (BNP) (r=0.367; p<0.001), six minutes’ walk test (r=-0.269; p=0.047), tricuspid annular plane systolic excursion (TAPSE, r=-0.459, p<0.001), right atrial (RA) area (r=0.412, p<0.001), mean pulmonary artery pressure (mPAP, r=0.420, p=0.006) and pulmonary vascular resistance (PVR, r=0.368, p=0.017). 

By logistic regression analysis (backward elimination WALD) including a variety of potentially relevant patients’ characteristics, only IL-22 (OR: 1.649; 95% CI: 1.069 – 2.543; p=0.024) could be identified as independent predictor of the presence of PH.  

Conclusions: Against the background of our results, in particular IL-22 could serve as a promising novel inflammatory biomarker of PH with potential value for initial diagnosis, functional classification or even prognosis estimation. The validation of IL-22 in larger patients’ cohorts including outcome and survival data as well as the question, whether the molecule or its receptors might represent promising therapeutic target structures, remains the object of further studies.