Mode of action and antiproliferative therapeutic potential of the endogenous serine elastase inhibitor Elafin in pulmonary arterial hypertension

• Applicant: Dr. Jan Kristoff Hennigs
• Subject Area: Pneumology, Thoracic Surgery
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 231840359

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by increased pulmonary vascular resistance and pressure. Impaired pulmonary hemodynamics lead to right ventricular insufficiency and right heart failure, which may cause patients’ death.Malfunction of pulmonary arterial (PA) endothelial (EC) and smooth muscle cell (SMC) signal transduction and its paracrine regulation triggers pathological remodeling of pulmonary arteries. Progressive PA obliteration and vascular stiffness are caused by an inflammatory disequilibrium of apoptosis and proliferation of PA EC & PA SMC as well as defective extracellular matrix (ECM) synthesis resulting in increased PA resistance and pressure. Now, there is emerging evidence in mice and in patients with PAH that these features are related to PA SMC production of neutrophil elastase (NE). Degradation of vascular elastin induces release of mitogens from the ECM, recruits inflammatory cells to the vessel wall and increases the apoptotic susceptibility of PA EC eventually promoting deregulated PA angiogenesis. So far, approved PAH medications mainly cause PA vasodilation - FDA/EMEA approval for primarily antiproliferative therapeutics is pending. In addition, translation of antiproliferative drugs (such as tyrosine kinase inhibitors) into clinical use in PAH has recently experienced some set backs due to unexpected cardiopulmonary side effects in humans.Therefore, it is necessary to (a) thoroughly characterize novel antiproliferative approaches and (b) predict their therapeutic potential in humans. Elafin might be such a new antiproliferative drug. It is an endogenous inhibitor of NE already shown to reverse PAH remodeling in animal models by a yet not fully understood mode of action. The present project is intended to further identify the underlying cellular mechanisms of Elafin in PA EC and PA SMC from PAH patients and to predict its therapeutic potential in humans. Therefore, the effect of Elafin on pulmonary vascular remodeling is studied in a novel inflammatory PAH rat model that closely resembles pathophysiological changes in humans. Secondly, PA EC and PA SMC isolated from PAH patients will be used to further characterize Elafin’s mode of action. Finally, the therapeutic potential of Elafin will be tested in lung organ cultures from PAH patients to preclinically estimate the translational success in order to pave the way for clinical trials in the future.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Marlene Rabinovitch