Background and aims: Pulmonary vascular and right ventricular myocardial remodeling are key mechanisms in the pathogenesis of Pulmonary Hypertension (PH) and are mainly mediated by inflammatory processes. Preliminary results of our group, derived from gene expression analysis, could identify the following 3 candidate Interleukins (ILs) as potential novel biomarkers in PH: IL-10, IL-17a and IL-22. Although these ILs have been in various pathologies, there is no data describing their role in PH development and progression. Therefore, the current study was aimed to analyze their expression on the protein level in a preclinical rat model of PH.

Methods: Induction of PH in Sprague-Dawley rats was performed by a single injection of monocrotaline. There were three experimental groups: sham-treated controls (CON, n=6), MCT-induced PH (PH, n=10) and MCT-induced PH treated with the dual endothelin receptor antagonist Macitentan (PH_MAC, n=10). All animals underwent echocardiography and right heart catheterization. Lung and cardiac tissue samples were subjected to histological and immunohistochemical analysis for the three aforementioned ILs and their serum levels were quantified using ELISA.

Results: 

Right ventricular systolic pressure (RVPsys) as well as a variety of echocardiographic parameter reflecting right ventricular function, e.g., tricuspid annular plane systolic excursion (TAPSE) showed a significant worsening in the PH compared to the CON group (p<0.01) with partial reversibility in the PH_MAC group (p<0.05). The level of histological damage of lung and right ventricular (RV) tissue was significantly increased in the PH compared to the CON group (p<0.01) with reversibility in lung but not in cardiac tissue in the PH_MAC group. Serum quantification of IL-10, IL-17a and IL-22 by ELISA revealed detectable levels for all three cytokines and elucidated relevant dynamics between the different experimental groups. When comparing the PH with the CON group, there were significantly elevated serum concentrations for IL-17a (p=0.008) and IL-22 (p=0.04). In the PH_MAC group, there was a decrease compared to the PH group for IL-22 (p=0.021) but not IL17a (p=n.s.). Immunohistochemical studies revealed relevant expression levels in lung but not RV tissue for IL-22, in RV but not lung tissue for IL-10 and in both organs for IL17a. IL-22 expression was significantly increased in the lungs of the PH and PH_MAC group (p<0.05). IL-10 in RV showed an elevated expression in PH (p=0.02) but not PH_MAC animals (p=n.s.). For IL17a, significantly increased tissue levels could be demonstrated only in the lungs of the PH (p=0.001) but not the PH_MAC group (p=n.s.) All three interleukins showed a variety of strong correlations to hemodynamic, echocardiographic and histological parameters, e.g., serum IL-22 to histological lung tissue damage (r=0.73, p=0.001) and TAPSE (r=-0.73, p=0.001) or serum IL-17a to histological tissue damage in RV (r=0.71, p=0.001) and right atrial area (r=0.59, p=0.01).

Conclusions: