IL-6 Inhibition Reduces Neuronal Injury in a Murine Model of Ventilator-induced Lung Injury.

Sparrow, Nicklaus A.; Anwar, Faizan; Covarrubias, Ambart E.; Rajput, Padmesh S.; Rashid, Mohammad Harun; Nisson, Peyton L.; Gezalian, Michael M.; Toossi, Shahed; Ayodele, Maranatha O.; Karumanchi, S. Ananth; Ely, E. Wesley; Lahiri, Shouri

Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the 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 adultmice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before 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. CC3 (cleaved caspase-3), 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 with control mice (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) and anti-IL-6 receptor antibody (P, 0.05 and P, 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.

ARTIFICIAL respiration; RESPIRATORY therapy; VENTILATION monitoring; DELIRIUM; COGNITION disorders

American Journal of Respiratory Cell & Molecular Biology, 2021, Vol 65, Issue 4, p403

1044-1549

Academic Journal

10.1165/rcmb.2021-0072OC