Cerebral inflammatory response after fetal asphyxia and hyperoxic resuscitation in newborn sheep

Abstract

Resuscitation with pure oxygen at birth after fetal asphyxia may aggravate brain damage by inducing pro-inflammation. The toll-like receptors (TLRs) may serve a pro-inflammatory role in hyperoxemia during ischemia-reperfusion. Sixteen near-term fetal sheep (132-136 d) were subjected to 10 min of cord occlusion, delivery and mechanical ventilation with 100% O2 (n = 8), or 21% O2 (n = 8) for 30 min followed by normoxemia for 90 min. Eight sheep fetuses were delivered immediately with inspired O2 targeted at normoxemia for 120 min (controls). Levels and distributions of mRNAs for IL-1beta, TNF-alpha, IL-12p40, IL-18, IL-6, IL-10, IFN-gamma, TLR-2, -3 and -4 in cerebral tissue at 2 h after birth were evaluated with real-time polymerase chain reaction (PCR) and in situ hybridization. Expressions of IL-1beta, IL-12p40, TLR-2, and TLR-4 were increased in cortex/subcortex after resuscitation with 100% O2 compared with 21% O2 (all p < 0.05) and to controls (all p < 0.05). Increased cellular expression of IL-1beta was localized to sub-meningeal cortical layers and to sub-cortical white matter. Hyperoxic resuscitation at birth following fetal asphyxia induces a cerebral pro-inflammatory response with an up-regulation of TLR-2 and -4. These may be early events leading to increased tissue damage after exposure to hyperoxemia at birth.