Abstract
Background and Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right ventricular remodeling. Interleukin 9 (IL9) is a pleiotropic cytokine with pro- and anti-inflammatory functions. The aim of this study was to evaluate the therapeutic activity of F8IL9F8 consisting of IL9 fused to the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin, which is abundantly expressed in pulmonary vasculature and right ventricular myocardium in PH. Methods: The efficacy of F8IL9F8 in attenuating PH progression in the monocrotaline mouse model was evaluated in comparison to an endothelin receptor antagonist (ERA) or an IL9 based immunocytokine with irrelevant antibody specificity (KSFIL9KSF). Treatment effects were assessed by right heart catheterization, echocardiography as well as histological and immunohistochemical tissue analyses. Results: Compared to controls, systolic right ventricular pressure (RVPsys) was significantly elevated and a variety of right ventricular echocardiographic parameters were significantly impaired in all MCT-induced PH groups except for the F8IL9F8 group. Both, F8IL9F8 and ERA treatments lead to a significant reduction in RVPsys and an improvement of echocardiographic parameters when compared to the MCT group not observable for the KSFIL9KSF group. Only F8IL9F8 significantly reduced lung tissue damage and displayed a significant decrease of leukocyte and macrophage accumulation in the lungs and right ventricles. Conclusions: Our study provides first pre-clinical evidence for the use of F8IL9F8 as a new therapeutic agent for PH in terms of a disease-modifying concept addressing cardiovascular remodeling.
Highlights
Pulmonary hypertension (PH) is a complex and heterogeneous disorder resulting from a variety of cardiovascular and respiratory diseases
While we are reporting a preliminary study on the therapeutic use of Interleukin 9 (IL9) in PH, our findings suggest that F8IL9F8 is a potential candidate for treatment mild tumor growth delay concept in murineaddressing models of melanoma the F8IL9F8 treatment of PH resulted in termsinof a disease-modifying cardiovascular and colon cancer
The F8IL9F8 and KSFIL9KSF fusion proteins consist of two scFv antibody moieties sequentially fused to the N- and C-termini of the murine interleukin 9, by the meaning of 10 amino acid long linkers
Summary
Pulmonary hypertension (PH) is a complex and heterogeneous disorder resulting from a variety of cardiovascular and respiratory diseases. During PH development and progression, increased vasoconstriction and remodeling of the pulmonary vasculature occurs, resulting in PAP elevation, right ventricular pressure overload and the broad spectrum of clinical manifestations of the disease [2,4]. The cell adhesion modulating protein fibronectin represents an important component of the cardiovascular extracellular matrix and occurs as different molecular variants, which are generated by alternative splicing of the pre-mRNA leading to the inclusion or omission of so-called extra domains (ED) into the final multidomain protein. The latter show a disease-associated re-occurrence while being virtually absent in healthy adult tissues. Results: Compared to controls, systolic right ventricular pressure (RVPsys) was significantly elevated and a variety of right ventricular echocardiographic parameters were significantly impaired in all MCT-induced PH groups except for the F8IL9F8 group
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