GABAA Immunomodulation & Infection
Author(s)
Sanders, Robert A.
Type
Thesis
Abstract
GABAergic drugs, such as benzodiazepines, are widely used in clinical practice
yet their immune side effects are poorly understood. Preliminary studies have
suggested that immune cells express GABAA receptors indicating that they may
be controlled by GABA signaling. Herein parallel preclinical, translational and
epidemiological approaches are described to help understand the importance of
GABAA immunomodulation. The hypothesis is that GABA signaling acts to reduce
responsiveness to a pathogen and thus that GABAergic drugs will increase
susceptibility to infection. To inform on the clinical importance of this work, data
from a subgroup analysis of the Maximizing Efficacy of Targeted Sedation and
Reducing Neurological Dysfunction (MENDS) trial (where the relative effects of
lorazepam, and dexmedetomidine were compared) are described in septic and
non‐septic patients. Consistent with the hypothesis, avoidance of lorazepam
sedation decreased mortality by 70% in septic patients but did not affect
outcome in non‐septic patients. As preclinical data suggests that
benzodiazepines increase mortality at subsedative doses we next conducted a
population‐based cohort and nested case‐control design analysis of The Health
Improvement Network (THIN), a comprehensive UK general practice database.
Benzodiazepines exposure increased the incidence of community acquired
pneumonia (CAP) and both 30‐day and long‐term mortality from CAP. Based on
these significant accumulating data of the harm of exposure to benzodiazepines
during an infection, animal studies were conducted to understand (i) the
biological plausibility of our findings and (ii) the mechanism of the effect. In a
series of mouse studies the prototypical benzodiazepine, diazepam, increased
mortality from Streptococcus pneumoniae through potentiation of GABAA
signaling. The increased mortality was associated with increased pathogen load
and a delayed cytokine response to the infection. However cellular recruitment
was not affected, indicating that local mechanisms were perturbed. Immune cell
profiling revealed that alveolar macrophage and monocytes abundantly
expressed subunits of the GABAA receptor, compatible with benzodiazepine
sensitivity. Ex vivo studies showed that GABAA receptor activation decreased
cytokine responses, phagocytosis and bacterial killing by alveolar macrophage
likely via inducing an intracellular acidosis. Finally based on the immune cell
profile of GABAA receptors we predicted that benzodiazepines that do not target
the α1 GABAA subunit would lack the immune suppression observed by nonselective
drugs. In accordance with this hypothesis we show that these selective
benzodiazepines do not provoke intracellular acidosis, affect cytokine release or
bacterial killing of macrophage ex vivo. In vivo the selective benzodiazepine did
not increase mortality from infection or increase pathogen load.
yet their immune side effects are poorly understood. Preliminary studies have
suggested that immune cells express GABAA receptors indicating that they may
be controlled by GABA signaling. Herein parallel preclinical, translational and
epidemiological approaches are described to help understand the importance of
GABAA immunomodulation. The hypothesis is that GABA signaling acts to reduce
responsiveness to a pathogen and thus that GABAergic drugs will increase
susceptibility to infection. To inform on the clinical importance of this work, data
from a subgroup analysis of the Maximizing Efficacy of Targeted Sedation and
Reducing Neurological Dysfunction (MENDS) trial (where the relative effects of
lorazepam, and dexmedetomidine were compared) are described in septic and
non‐septic patients. Consistent with the hypothesis, avoidance of lorazepam
sedation decreased mortality by 70% in septic patients but did not affect
outcome in non‐septic patients. As preclinical data suggests that
benzodiazepines increase mortality at subsedative doses we next conducted a
population‐based cohort and nested case‐control design analysis of The Health
Improvement Network (THIN), a comprehensive UK general practice database.
Benzodiazepines exposure increased the incidence of community acquired
pneumonia (CAP) and both 30‐day and long‐term mortality from CAP. Based on
these significant accumulating data of the harm of exposure to benzodiazepines
during an infection, animal studies were conducted to understand (i) the
biological plausibility of our findings and (ii) the mechanism of the effect. In a
series of mouse studies the prototypical benzodiazepine, diazepam, increased
mortality from Streptococcus pneumoniae through potentiation of GABAA
signaling. The increased mortality was associated with increased pathogen load
and a delayed cytokine response to the infection. However cellular recruitment
was not affected, indicating that local mechanisms were perturbed. Immune cell
profiling revealed that alveolar macrophage and monocytes abundantly
expressed subunits of the GABAA receptor, compatible with benzodiazepine
sensitivity. Ex vivo studies showed that GABAA receptor activation decreased
cytokine responses, phagocytosis and bacterial killing by alveolar macrophage
likely via inducing an intracellular acidosis. Finally based on the immune cell
profile of GABAA receptors we predicted that benzodiazepines that do not target
the α1 GABAA subunit would lack the immune suppression observed by nonselective
drugs. In accordance with this hypothesis we show that these selective
benzodiazepines do not provoke intracellular acidosis, affect cytokine release or
bacterial killing of macrophage ex vivo. In vivo the selective benzodiazepine did
not increase mortality from infection or increase pathogen load.
Date Issued
2012-06
Date Awarded
2012-08
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Hussell, Tracy
Maze, Mervyn
Sponsor
Medical Research Council (Great Britain)
Grant Number
G0802353
Publisher Department
National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)