University of Giessen Lung Center

Reversed Remodeling in Pulmonary Hypertension

Pulmonary hypertension is a disease of various origins affecting hundreds of millions patients worldwide. As a consequence of chronic right heart load, patients suffering from this devastating disease have poor prognosis. Progression of pulmonary hypertension is associated with increased proliferation and migration of the pulmonary vascular smooth muscle cells. We recently reported about the novel use of TK inhibitors in experimental models of chronic pulmonary hypertension after identifying platelet derived growth factor (PDGF) as the most important promoter of the disease process (Schermuly et al., JCI 2005). Targeted therapy of vascular remodeling with anti-proliferative substances such as the TK inhibitor imatinib represents a change in paradigm versus the current symptomatic treatment with vasodilators. The aim of the current project is to characterize in detail the importance of tyrosine kinases in the course of the disease on the molecular, cellular, preclinical and clinical level. To address these issues, we perform experiments in two independent models of chronic pulmonary hypertension (monocrotaline in rats and hypoxia in genetically modified mice) using different TK inhibitors as well as selected modifiers of molecules involved in further downstream signaling of this pathway. Finally, differential display analysis in human tissue (PH tissue bank core facility Giessen) will be performed and clinical studies using available TK inhibitors will address translation of this approach from the bench to the patient. On the other hand, the NO signaling pathway plays a pivotal role under physiological conditions but also under conditions of disease in the pulmonary circulation. The PDE5 Inhibitor Sildenafil addressing this pathway has proven its efficacy in and was approved for the treatment of PAH. However, there is a considerable proportion of patients irresponsive to this therapy which maybe imminent to alterations of the NO-sGC-cGMP signaling axis. There is good evidence derived from experimental models of pulmonary hypertension that activators and stimulators of the sGC - as they bypass the primary induction of this system by NO – have a more uniform efficacy in the entire patient population suffering from this devastating disease. Even more, several compounds from this group have the ability to reactivate the oxidized and heme free form of sGCs which are substantially present in conditions of oxidative stress and pulmonary hypertension. To prove this concept, investigations on the level of molecular and cellular analyzes, isolated organs, chronic animal models as well as in translation to clinical studies in affected patients will be performed. In addition, detailed expression analysis of sGC subunits in explanted organs of healthy donors and patients with pulmonary hypertension undergoing lung transplantation will further address the proportional contribution of sGCs in the mediation of the disease.