Interleukin-10 reverses acute detrimental effects of endotoxin-induced inflammation on perinatal cerebral hypoxia-ischemia.
Perinatal brain injuries and the subsequent development of cerebral palsy are closely associated with intrauterine infections and inflammatory response. Antibiotics have proven futile in reducing perinatal brain injuries. We tested whether treatment with the anti-inflammatory cytokine IL-10 could have beneficial effects during a concomitant endotoxin and cerebral hypoxic-ischemic challenge. Thirty-three newborn piglets were randomized to pretreatment with:


METHODS
placebo, Endotoxin: 2 kU/kg bolus and infusion of 1 kU/kg per h of endotoxin, or Endotoxin+IL-10: endotoxin in addition to 50 microg/kg of porcine recombinant IL-10. We induced cerebral hypoxia-ischemia by bilateral clamping of the common carotid arteries and ventilation with 8% oxygen for 20 min followed by 3 h of reoxygenation/reperfusion. Extracellular lactate, pyruvate, glycerol and glutamate, microcirculation and tissue oxygenation were monitored in the striatum by microdialysis, laser Doppler flow and oxygen tension probe, respectively. During and/or after cerebral hypoxia-ischemia, Endotoxin caused marked deterioration of the cerebral metabolic situation with higher lactate/pyruvate ratio (P=0.003), compared to CONTROLS and Endotoxin+IL-10. This was caused mainly by very low levels of pyruvate (P=0.001). During the following reoxygenation, Endotoxin compromised cerebral microcirculation (P=0.038) and tissue oxygenation (P=0.012) compared to CONTROLS and Endotoxin+IL-10. After a period of remission, a secondary energy failure and a new rise in the lactate/pyruvate ratio was seen in Endotoxin (P=0.002), but not in CONTROLS or Endotoxin+IL-10. At the end of observation, only the Endotoxin+IL-10 group had regained their baseline values in all variables. Thus IL-10 counteracts acute effects of endotoxin on cerebral metabolism, microcirculation and oxygen tension during hypoxia-ischemia in the perinatal brain.
Frøen
J Frederik
JF
Department of Pediatric Research, The National Hospital, University of Oslo, N-0027 Oslo, Norway. j.f.froen@klinmed.uio.no
Munkeby
Berit H
BH
Stray-Pedersen
Babill
B
Saugstad
Ola Didrik
OD
D000818:Animals; D000831:Animals, Newborn; D001424:Bacterial Infections / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002547:Cerebral Palsy / Q000378:metabolism* / Q000503:physiopathology; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016753:Interleukin-10 / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D019289:Pyruvic Acid / Q000378:metabolism; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004731:Endotoxins; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019344:Lactic Acid; D019289:Pyruvic Acid