Abstract
Background: Asphyxiated neonates often have myocardial dysfunction and renal insufficiency. Previously we demonstrated that doxycycline improved cardio-renal function through matrix metalloproteinase (MMP)-2 inhibition in an acute swine model of neonatal hypoxia-reoxygenation. The prolonged cardio-renal protective effects of doxycycline in neonates still remained unknown. We therefore hypothesized that the protective effects of doxycycline persisted in surviving subjects.Methods: Newborn piglets were instrumented and subjected to 1 h of hypoxia followed by reoxygenation with 21–25% oxygen and observed for 4 days. Intravenous doxycycline (30 mg/kg) or normal saline (1 mL, saline-control group) was given at 5 min of reoxygenation (n = 8/group) in a randomized, blinded fashion. Sham-operated piglets (n = 5) received no hypoxia-reoxygenation. At 96 h after reoxygenation, the left ventricular function was assessed by Millar® catheter. Renal injury was investigated by measuring plasma creatinine, urinary N-acetyl-D-glucosaminidase activity, renal tissue lactate and MMP-2 activity.Results: Both hypoxia-reoxygenation groups had similar hypoxic stress with severe lactate acidosis, and hemodynamic recovery. Doxycycline-treated piglets had higher urine output with lower urine N-acetyl-D-glucosaminidase, plasma creatinine, and renal MMP-2 activity (vs. saline-controls; all p < 0.05). These markers were all negatively correlated with urine output.Conclusions: In newborn piglets surviving hypoxia-reoxygenation, we observed a weak but significant and persistent attenuation of renal injury and improved recovery with the post-resuscitation administration of doxycycline.
Highlights
Despite recent advances in obstetrical care and newborn resuscitation, asphyxia remains a major cause of neonatal mortality and morbidity
We demonstrated that doxycycline improved cardio-renal function through matrix metalloproteinase (MMP)-2 inhibition in an acute swine model of neonatal hypoxia-reoxygenation
Using a surviving model of neonatal H-R, we aimed to examine whether the renal protective effects of intravenous DOX persisted for days after the newborn piglets recovered from HR, which is important in the translation of findings to clinical trials
Summary
Despite recent advances in obstetrical care and newborn resuscitation, asphyxia remains a major cause of neonatal mortality and morbidity. Asphyxiated neonates commonly have multi-organ dysfunction and/or failure [4]. Acute kidney injury (AKI) has been reported to be presented in 30–70% of asphyxiated neonates [4,5,6]. AKI has been shown to be associated with neonatal asphyxia, the outcome and its subsequent neurodevelopment in early childhood [5]. Asphyxiated neonates often have myocardial dysfunction and renal insufficiency. We demonstrated that doxycycline improved cardio-renal function through matrix metalloproteinase (MMP)-2 inhibition in an acute swine model of neonatal hypoxia-reoxygenation. The prolonged cardio-renal protective effects of doxycycline in neonates still remained unknown. We hypothesized that the protective effects of doxycycline persisted in surviving subjects
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