Lee Tze-Fun, Lu Min, Pasquin Matteo P, Schmölzer Georg M, Cheung Po-Yin
Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
Centre for the Studies of Asphyxia and Resuscitation, University of Alberta, Edmonton, AB, Canada.
Front Pediatr. 2019 Mar 22;7:75. doi: 10.3389/fped.2019.00075. eCollection 2019.
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. 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 ( = 8/group) in a randomized, blinded fashion. Sham-operated piglets ( = 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. 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 < 0.05). These markers were all negatively correlated with urine output. 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.
窒息新生儿常伴有心肌功能障碍和肾功能不全。此前我们在新生仔猪急性缺氧-复氧模型中证实，强力霉素通过抑制基质金属蛋白酶（MMP）-2改善心肾功能。强力霉素对新生儿心肾功能的长期保护作用尚不清楚。因此，我们推测强力霉素的保护作用在存活的个体中持续存在。对新生仔猪进行仪器植入，使其经历1小时的缺氧，然后用21%-25%的氧气进行复氧，并观察4天。在复氧5分钟时，以随机、盲法的方式给予静脉注射强力霉素（30mg/kg）或生理盐水（1mL，生理盐水对照组）（每组n = 8）。假手术仔猪（n = 5）未经历缺氧-复氧。复氧96小时后，用Millar®导管评估左心室功能。通过测量血浆肌酐、尿N-乙酰-D-氨基葡萄糖苷酶活性、肾组织乳酸和MMP-2活性来研究肾损伤。两个缺氧-复氧组的缺氧应激相似，伴有严重乳酸酸中毒和血流动力学恢复。强力霉素治疗的仔猪尿量更高，尿N-乙酰-D-氨基葡萄糖苷酶、血浆肌酐和肾MMP-2活性更低（与生理盐水对照组相比；均P < 0.05）。这些指标均与尿量呈负相关。在经历缺氧-复氧存活的新生仔猪中，我们观察到复苏后给予强力霉素可使肾损伤得到微弱但显著且持续的减轻，并改善恢复情况。
