34 - The role of myeloperoxidase in hyperoxia-induced bronchopulmonary dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is the most common chronic pulmonary disease of premature neonates. While ventilation with supplemental O2 is required for development and survival of the premature neonate, it increases the risk of BPD. Both hyperoxia-induced oxidative stress and transient hypoxia resulting from apneic events increase recruitment and activation of myeloid cells to the lungs. Activated myeloid cells release myeloperoxidase (MPO), which oxidizes chloride ions to hypochlorous acid causing oxidative damage and cell death. If myeloid cell recruitment, activation, and MPO release contribute to the pathogenesis of BPD, then inhibiting MPO oxidant production should protect against hyperoxia-induced lung injury. N-acetyl lysyltyrosylcysteine amide (KYC) is a tripeptide inhibitor of MPO that prevents the generation of toxic oxidants by shuttling high energy peroxy radicals in the iron-heme active site into the glutathione pathway. In order to test the hypothesis that inhibiting MPO prevents hyperoxia-induced lung damage, Sprague-Dawley neonatal rat pups were exposed to ten days (P1-P10) of hyperoxia (>90% O2) and injected twice daily with either 5 mg/kg KYC or vehicle control (PBS). KYC treatment reduced myeloid cell counts and MPO and Cl-Tyr levels in the lungs of hyperoxic neonatal pups. Additionally, KYC-treated pups had increased microvascular and alveolar complexity as well as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) levels. These data provide evidence that myeloid cell recruitment and activation and MPO-induced oxidative damage are significant contributors to hyperoxia-induced lung injury in the developing lungs, and that KYC is an effective inhibitor of MPO-dependent oxidative damage to neonatal lungs.