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

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 inhibit...

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Veröffentlicht in:American journal of respiratory cell and molecular biology 2021-10, Vol.65 (4), p.403-412
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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 adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: ) spontaneously breathing or ) 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 ( < 0.001) and hippocampal ( < 0.0001) brain regions and accompanied by significant increases in and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice ( < 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 ( < 0.01 and < 0.0001, respectively) and anti-IL-6 receptor antibody ( < 0.05 and < 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.
ISSN:1044-1549
1535-4989
DOI:10.1165/rcmb.2021-0072OC