Doxycycline Attenuates Renal Injury In A Swine Model Of Neonatal Hypoxia-Reoxygenation

Abstract

Acute kidney injury in asphyxiated neonates is common. The renal protective effects of doxycycline, a known matrix metalloproteinase (MMP) inhibitor, have been demonstrated in rat ischemic-reperfusion models of injury. These effects have not been tested in large-animal models designed to reflect true clinical scenarios of neonatal hypoxia-reoxygenation (H-R). Newborn piglets were surgically instrumented for hemodynamic monitoring and subjected to 2 h of hypoxia followed by 4 h of normoxic reoxygenation. Piglets were blindly randomized to receive i.v. saline or doxycycline (3, 10, or 30 mg/kg) 5 min into reoxygenation (n = 7 per group). Sham-operated piglets (n = 5) received no H-R. Renal injury was investigated by histologic examination and measuring serum creatinine, urinary N-acetyl-D-glucosaminidase activity and renal tissue lactate with enzyme-linked immunosorbent assay. Renal tissue oxidative stress (lipid hydroperoxides) and total MMP-2 activity were measured with enzyme-linked immunosorbent assay and gelatin zymography, respectively. Piglets treated with doxycycline had significantly improved cardiac index, systemic arterial pressure, renal artery blood flow, and oxygen delivery, with no difference observed in heart rate compared with controls. The H-R piglets had significantly higher urinary N-acetyl-D-glucosaminidase activity, renal tissue lipid hydroperoxides, lactate, and MMP-2 activity, which were attenuated to varied degrees in a dose-related manner in piglets treated with doxycycline (P = 0.08 to P < 0.05). Serum creatinine and histologic features of H-R were not different among groups. Postresuscitation administration of doxycycline improved renal perfusion, attenuated renal injury, and reduced tissue oxidative stress and MMP-2 activity in a clinically translatable newborn swine model of H-R.

Attenuation of Acute Renal Injury After the Post-resuscitation Administration of Doxycycline in Surviving Newborn Piglets With Severe Hypoxia-Reoxygenation

“…Its protective effect in neonates against AKI induced by H-R or I-R is largely unknown. Previously, we also demonstrated that post-resuscitation administration of DOX attenuated AKI associated with the inhibition of MMP-2 activity in newborn piglets with severe H-R (18). Despite providing functional and biochemical data for the beneficial effects of DOX in neonatal H-R, the short time course (4 h after reoxygenation) precludes us from understanding if the renal protection of DOX will persist beyond the acute stage.…”

“…Piglets were block-randomized into two treatment groups ( n = 8/group) and subjected to an 1-h period of normocapnic hypoxemia (FiO 2 of 0.11–0.15) followed by a 4-h period of normoxic reoxygenation (FiO 2 of 0.21–0.25). Five minutes into reoxygenation piglets received an intravenous bolus of either 1 mL normal saline (saline-control group) or 30 mg/kg DOX (DOX group), an optimal dose based on our previous study (18), blindly . Five sham-operated piglets underwent surgery with no hypoxia and reoxygenation at a FiO 2 of 0.21–0.25.…”

“…The whole kidney was homogenized. Renal tissue lactate levels were determined by a nicotinamide adenine dinucleotide enzyme coupled colorimetric assay as previously described (18). Gelatinolytic activities of MMP-2 and MMP-9 were quantified using gelatin zymography as previously described (21).…”

Technical Feasibility and Physiological Relevance of Hypoxic Cell Culture Models

“…Humans as well as animals can be exposed to hypobaric (HH) or normobaric hypoxia (NH) in order to study wide variety of diseases, including pulmonary hypertension (20), reoxygenation injury (21), pre-eclampsia (22), hypoxic insult of the brain (23), and diabetic retinopathy (24). While HH, which physically resembles a high-altitude environment, is induced by decreasing atmospheric pressure under 101 325 Pa (1 atm, 760 mm hg) typically in a tightly sealed hypobaric chamber (25), NH exposure is based on the reduction of the partial pressure of oxygen (pO 2 ) at normal atmospheric pressure, which typically occurs through the administration of nitrogen to a face mask (26), hypoxic tent (27), or environmental chamber (22,23).…”

Non Antimicrobial Effects of Antibacterial Agents

“…Sonuçta doksisiklinin renal perfüzyonu arttırdığı, renal hasarı hafiflettiği ve MMP-2 aktivitesini ve doku oksidatif stresi azalttığı gösterilmiştir [57] .…”