Systemic interleukin-6 inhibition ameliorates acute neuropsychiatric phenotypes in a murine model of acute lung injury.

Abstract

Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury; however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.

• Authors: Faizan Anwar, Nicklaus A Sparrow, Mohammad Harun Rashid, Gena Guidry, Michael M Gezalian, Eric J Ley, Maya Koronyo-Hamaoui, Itai Danovitch, E Wesley Ely, S Ananth Karumanchi, Shouri Lahiri
• Journal: Critical care (London, England) (Crit Care) Vol. 26 Issue 1 Pg. 274 (09 13 2022) ISSN: 1466-609X [Electronic] England
• PMID: 36100846 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Interleukin-6

Topics

• Acute Lung Injury (complications, drug therapy)
• Animals
• Delirium (complications)
• Disease Models, Animal
• Interleukin-6
• Mice
• Phenotype
• Ventilator-Induced Lung Injury (pathology)