Search

Benzodiazepines increase vulnerability to infection through α1 subunit dependent Υ-amino-butyric-type-A (GABAA) signalling. Immune cell expression of GABAA receptors and the effect of diazepam on influenza infection was investigated. In patients with pneumonia, α1 GABAA subunits were expressed on alveolar macrophages and blood monocytes. In mice, influenza induced dynamic changes in immune cell GABAA subunit expression: α1 subunits decreased on alveolar macrophage, but increased on monocytes, CD4+ and CD8+ T cells. Following influenza viral infection, diazepam delayed weight loss on day 3 but later increased weight loss. Viral load was unaffected but increased bacterial superinfection was noted on day 10.

Benzodiazepines increase vulnerability to infection through α1 subunit dependent Υ-amino-butyric-type-A (GABAA) signalling. Immune cell expression of GABAA receptors and the effect of diazepam on influenza infection was investigated. In patients with pneumonia, α1 GABAA subunits were expressed on alveolar macrophages and blood monocytes. In mice, influenza induced dynamic changes in immune cell GABAA subunit expression: α1 subunits decreased on alveolar macrophage, but increased on monocytes, CD4+ and CD8+ T cells. Following influenza viral infection, diazepam delayed weight loss on day 3 but later increased weight loss. Viral load was unaffected but increased bacterial superinfection was noted on day 10.

Animal models of viral respiratory disease often use weight loss as a marker of disease severity; however, this may relate to dehydration and malnutrition that would be corrected clinically. We tested whether parenteral fluid therapy improved weight loss from influenza infection. BALB/c and C57BL/6 mice were infected with A/X31 (H3N2) influenza and randomized to intraperitoneal fluid therapy. Blood glucose was also measured post-viral infection on day 3 and 6 in BALB/c mice and on day 6 in C57BL/6 mice. Parenteral fluids did not alter weight loss or the immunological response to infection, and glucose levels were not abnormal.

ObjectivesBenzodiazepines are used for treating anxiety, epilepsy, muscle spasm, alcohol withdrawal, palliation, insomnia, and sedation as they allosterically modulate γ-amino-butyric acid type A (GABAA) receptors. Despite widespread use, the importance and mechanism of their immune side-effects are poorly understood. Herein we sought to elucidate the impact and mechanism of benzodiazepine-induced susceptibility to infection at anxiolytic doses in mice.DesignAnimal randomized controlled trial.SettingLaboratory.SubjectsAdult female C57BL/6 and BALB/c mice.InterventionsThe effect of a subsedative, anxiolytic dose of diazepam (2 mg kg intraperitoneal) was investigated in a murine Streptococcus pneumoniae pneumonia model.Measurement and main resultsMortality, bacterial and cytokine load, cell recruitment, and intracellular pH were measured. Diazepam treatment did not affect immune homeostasis in the lung. However, diazepam increased mortality and bacterial load from S. pneumoniae pneumonia. The increases in mortality and bacterial load were reversed by a GABAA antagonist, bicuculline, indicating dependence on GABAA receptor signaling. While cell recruitment was unaltered by diazepam, the cytokine response to infection was affected, suggesting that local responses to the pathogen were perturbed. Macrophage and monocytes expressed benzodiazepine sensitive (α1-γ2) GABAA receptors. Interestingly macrophage GABAA receptor expression was regulated by bacterial toll-like receptor agonists and cytokines indicating an endogenous role in the immune response. Functionally diazepam appeared to counteract the endogenous down-regulation of GABAA signaling during infection. Consistent with augmented GABAA signaling, diazepam provoked intracellular acidosis in macrophage, leading to impaired cytokine production, bacterial phagocytosis and killing. In contrast, selective benzodiazepines that do not target the α1 GABAA subunit did not affect macrophage function ex vivo or increase susceptibility to pneumonia in vivo.ConclusionsOur data highlight the regulation of macrophage function by GABAA receptor signaling and the potential harm of benzodiazepine exposure during pneumonia. Therapeutically, selective drugs may improve the safety profile of benzodiazepines.