LAUSR

Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by frontal cortex and hippocampal dysfunction. Although interleukin-6 (IL-6) is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model. VILI was simulated in anesthetized adult mice using a 35cc/kg tidal volume mechanical ventilation model. There were two controls groups: 1) spontaneously breathing, or 2) anesthetized and mechanically ventilated with 10cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours prior to inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. Cleaved caspase-3 (CC3), a neuronal apoptosis marker, was significantly increased in the frontal (p<0.001) and hippocampal (p<0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared to controls (p<0.001). These findings were not related to cerebral hypoxia and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (p<0.01 and p<0.0001, respectively), anti-IL-6 receptor antibody (p<0.05 and p<0.0001, respectively) compared to saline VILI mice. VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.