Role of toll-like receptor 7 (TLR7) in voluntary alcohol consumption.

Overactivation of neuroimmune signaling has been linked to excessive ethanol consumption. Toll-like receptors (TLRs) are a major component of innate immune signaling and initiate anti- and pro-inflammatory responses via intracellular signal transduction cascades. TLR7 is upregulated in post-mortem brain tissue from humans with alcohol use disorder (AUD) and animals with prior exposure to ethanol. Despite this evidence, the role of TLR7 in the regulation of voluntary ethanol consumption has not been studied. We test the hypothesis that TLR7 activation regulates voluntary ethanol drinking behavior by administering a TLR7 agonist (R848) during an intermittent access drinking procedure in mice. Acute activation of TLR7 reduced ethanol intake, preference, and total fluid intake due, at least in part, to an acute sickness response. However, chronic pre-treatment with R848 resulted in tolerance to the adverse effects of the drug and a subsequent increase in ethanol consumption. To determine the molecular machinery that mediates these behavioral changes, we evaluated gene expression after acute and chronic TLR7 activation. We found that acute TLR7 activation produces brain region specific changes in expression of immune pathway genes, whereas chronic TLR7 activation causes downregulation of TLRs and blunted cytokine induction, suggesting molecular tolerance. Our results demonstrate a novel role for TLR7 signaling in regulating voluntary ethanol consumption. Taken together, our findings suggest TLR7 may be a viable target for development of therapies to treat AUD.

Airway closure and closing pressure during mechanical ventilation.

Six subjects without clinical evidence of lung disease were investigated for airway closure and airway closing pressure before and during fentanyl-thiopentone anesthesia with mechanical ventilation. Airway closure was measured by single breath and FRC by multiple breath nitrogen washout. Airway closing pressure was taken to be the transpulmonary pressure at which airway closure commenced. Airway closure occurred within a normal breath in two out of six subjects breathing spontaneously, but in all during mechanical ventilation. Closing capacity was the same in both the awake and anesthetized states while FRC was reduced by 0.41 when anesthesia was instituted. Transpulmonary pressure FRC was on average 1.5 cmH2O (0.15 kPa) and airway closing pressure 4.5 cmH2O (0.44 kPa) greater during anesthesia than in the awake state. Compliance of the lung, calculated both during a vital capacity maneuver and during a tidal breath, was lower with anesthesia. The results of this study suggest that the airways are less stable during mechanical ventilation. But, since lung compliance is lower during anesthesia, a higher transpulmonary pressure is required to maintain a given lung volume. Hence, airway closure occurs at the same lung volume in the anesthetized compared to the non-anesthetized subject.

Arterial oxygenation during artificial ventilation. The effect of airway closure and of its prevention by positive end-expiratory pressure.

Airway closure and arterial blood gases were measured in 11 healthy subjects both before and during anaesthesia with artificial ventilation, prior to routine surgery. The functional residual capacity was then increased by positive end-expiratory pressure (PEEP), so that ventilation took place at a lung volume where no airway closure was present, and the effect on arterial oxygenation was again investigated. A significant increase in alveolar-arterial oxygen gradient occurred in the group of seven patients in whom airway closure within a tidal breath could be demonstrated during anaesthesia, but there was no significant change in the four patients in whom airway closure could not be demonstrated. There was no improvement in arterial oxygenation on increasing functional residual capacity (FRC) in either group. It may well be that this failure to improve oxygenation was due to a deleterious effect of PEEP on the circulation, even though the PEEP was the minimum required to abolish airway closure.

The effect of thoracic extradural analgesia on pulmonary gas distribution, functional residual capacity and airway closure.

Pulmonary gas distribution, functional residual capacity (FRC), closing capacity (CC), arterial oxygen tension (PaO2) and alveolar-arterial oxygen tension gradient (PAO2-PAO2) were measured in seven subjects before and after the induction of extradural analgesia for routine surgery. It was found that pulmonary gas distribution was within normal limits throughout the study, although there were two patients in whom airway closure occurred consistently within the tidal volume. In both cases this was associated with a low PaO2. CC and FRC were substantially unchanged by the induction of extradural analgesia. Changes in (PAO2-PaO2) and PaO2 were usually not large, and are apparently related to factors other than changes in lung geometry.