Ekaterina Legchenko, Philippe Chouvarine, Klea Hysko, Fatimunnisa Qadri, Radoslw Wesolowski, Edgar Specker, Silke Glage, Martin Meier, Katharina Schwarz, Joerg Heineke, Gerhard Pohlmann, Mehmet Ramazanoglu, Michael Bader, Georg Hansmann
Hannover Medical School. Heidelberg University Medical Faculty Mannheim. Max-Delbrück-Center for Molecular Medicine. Leibniz-Forschungsinstitut für Molekulare Pharmakologie. Fraunhofer Institute for Toxicology and Experimental Medicine. Max Delbrück Center for Molecular Medicine.University of Lübeck. Friedrich-Alexander-University Erlangen-Nürnberg.
Germany
American Journal of Respiratory Cell and Molecular Biology
Am J Respir Cell Mol Biol 2025;
DOI: 10.1165/rcmb.2024-0365OC
Abstract
Inhaled pharmacotherapies are promising treatment options for patients with pulmonary arterial hypertension (PAH) as they minimize extrapulmonary adverse effects. Recently, we developed a highly specific inhibitor (TPHi) of the serotonin synthesizing enzyme tryptophan hydroxylase 1, TPT-004. We hypothesized that repetitive nose-only inhalation of TPT-004 alleviates PAH and pulmonary vascular remodeling in the Sugen-hypoxia (SuHx) rat model. Male Sprague-Dawley rats were divided into 3 groups: (i) ConNx, control animals kept in room air during the study; (ii) SuHx [rats subcutaneously injected with the VEGFR2-inhibitor SU5416, then exposed to chronic hypoxia (3 weeks), followed by 5.5 weeks of room air]; (iii) SuHx + TPHi [SuHx animals treated with TPHi by inhalation for 4 weeks]. Closed-chest right-left heart catheterization and cardiac MRI were performed in spontaneously breathing rats. Lungs underwent histological and mRNA-seq analysis. SuHx-exposed rats had severe PAH, RV hypertrophy, and RV dilation. In comparison with SuHx-exposed rats, TPHi-treated SuHx rats had significantly lower RV systolic pressure (67.25 vs.51.47mmHg; p<0.0001), normalized RV end-systolic volume (182.6 vs. 105.1µL; p<0.0001) and improved RV ejection fraction by cardiac MRI (47.9 vs. 66.8%; p<0.0001). Inhaled TPT-004 did not affect LV end-diastolic or systemic blood pressure. TPT-004 therapy reversed pulmonary vascular remodeling and alveolar macrophage infiltration. RNA-sequencing unraveled TPHi-induced changes in pulmonary gene expression: 1) increased cell adhesion and reduced cell motility/migration; 2) suppressed extracellular matrix remodeling; 3) modulated immune response; 4) suppressed pulmonary vascular remodeling via modulating proliferation, apoptosis, and homeostasis. Taken together, TPT-004 is an effective therapeutic PAH agent, does not cause any hemodynamic adverse effects in rodents, and thus, should be tested further towards a clinical phase 1b/phase 2 study in PAH patients.
Category
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Diagnostic Testing for Pulmonary Vascular Disease. Non-invasive Testing
Diagnostic Testing for Pulmonary Vascular Disease. Invasive Testing
Pulmonary Vascular Pathology
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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