Experimental study of the effect of combined elastase inhibition and angiotensin-2-receptor blockade on ventilator-induced neonatal lung injury in newborn mice

• Applicant: Dr. Stefanie Preuß
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 221703638

Mechanical ventilation with O2-supplemented gas (MV-O2) offers life-saving treatment for respiratory failure, but also promotes lung injury, which in neonates translates to defective alveolar septation and angiogenesis resulting in lung growth arrest, as seen in bronchopulmonary dysplasia (BPD). The overall goal of this project is to test novel treatment strategies designed to promote the formation of alveoli and micro-vessels in developing lungs exposed to long-term MV-O2. This proposal derives from studies showing that proteolytic activity and TGF¿- signaling are increased in the lungs of infants with BPD and in animal models of this disease - and that blocking these responses during MV-O2 of newborn mice prevented or reduced lung injury and enabled lung growth. Recent studies discovered that intrapulmonary treatment with the serine elastase inhibitor Elafin prevented degradation and dispersion of lung elastin, but failed to protect the lung microcirculation during MV-O2 leading to loss of lung micro-vessels and lung growth arrest. An explanation for the apparent failure of Elafin is that mechanical stretch may directly activate TGF-β. Recent Studies showed that Losartan, an angiotensin-2 type 1 receptor antagonist has been used effectively to treat conditions linked to increased TGFβ-signaling. For that reason Losartan might be an excellent drug for prophylaxis of lung injury related to increased TGFβ-signaling. The aim of this project is to determine if inhibition of excess TGFβ-signaling with Elafin and the angiotensin-2 receptor blocker Losartan preserves normal lung septation and angiogenesis in newborn mice during MV-40%O2. This therapeutic approach could provide important insights into therapeutic options for promoting a physiologic lung development in preterm babies at risk of BPD.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Richard D. Bland