The role of different strain backgrounds in bacterial endotoxin-mediated sensitization to neonatal hypoxic–ischemic brain damage

摘要

class="kwd-title">Abbreviations: ABC, avidin–biotin conjugate, BSA, bovine serum albumin, DAB, diaminobenzidine, dUTP, deoxyuridine triphosphate, GFAP, glial fibrillary acidic protein, GFAP-IR, GFAP immunoreactivity, HI, hypoxia–ischemia, IL, interleukin, LPS, lipopolysaccharide, MCA, middle cerebral artery, PB, phosphate buffer, PFA, paraformaldehyde, SAL, saline, TNFα, tumor necrosis factor alpha, TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling class="kwd-title">Key words: 129SVJ, BALB/c, C57BL/6, CD1, FVB, hypoxia–ischemia class="head no_bottom_margin" id="idm140529180433168title">AbstractGenetic background is known to influence the outcome in mouse models of human disease, and previous experimental studies have shown strain variability in the neonatal mouse model of hypoxia–ischemia. To further map out this variability, we compared five commonly used mouse strains: C57BL/6, 129SVJ, BALB/c, CD1 and FVB in a pure hypoxic–ischemic setup and following pre-sensitization with lipopolysaccharide (LPS).Postnatal day 7 pups were subjected to unilateral carotid artery occlusion followed by continuous 30 min 8% oxygen exposure at 36 °C. Twelve hours prior, a third of the pups received a single intraperitoneal LPS (0.6 μg/g) or a saline (vehicle) administration, respectively; a further third underwent hypoxia–ischemia alone without preceding injection. Both C57BL/6 and 129SVJ strains showed minimal response to 30 min hypoxia–ischemia alone, BALB/c demonstrated a moderate response, and both CD1 and FVB revealed the highest brain damage. LPS pre-sensitization led to substantial increase in overall brain infarction, microglial and astrocyte response and cell death in four of the five strains, with exception of BALB/c that only showed a significant effect with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Saline administration prior to hypoxia–ischemia resulted in an increase in inflammatory-associated markers, particularly in the astroglial activation of C57BL/6 mice, and in combined microglial activation and neuronal cell loss in FVB mice. Finally, two of the four strongly affected strains – C57BL/6 and CD1 – revealed pronounced contralateral astrogliosis with a neuroanatomical localization similar to that observed on the occluded hemisphere.Overall, the current findings demonstrate strain differences in response to hypoxia–ischemia alone, to stress associated with vehicle injection, and to LPS-mediated pre-sensitization, which partially explains the high variability seen in the neonatal mouse models of hypoxia–ischemia. These results can be useful in future studies of fetaleonatal response to inflammation and reduced oxygen–blood supply.