In a secondary analysis from a randomised, double-blind placebo-controlled trial Dexmedetomidine blocks cholinergic dysregulation in delirium pathogenesis in patients with major surgery.

Dexmedetomidine is an alpha-2 adrenoreceptor agonist with anti-inflammatory and anti-delirogenic properties. Pathogenesis of postoperative delirium (POD) includes cholinergic dysfunction and deregulated inflammatory response to surgical trauma. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are discussed as biomarkers for both POD and severity in acute inflammation. To show whether there is a link between blood cholinesterase activities and dexmedetomidine, we performed a secondary analysis of a randomised, double-blind, placebo-controlled trial that recently showed a lower incidence of POD in the dexmedetomidine group. Abdominal or cardiac surgical patients aged ≥ 60 years were randomised to receive dexmedetomidine or placebo intra- and postoperatively in addition to standard general anaesthesia. We analysed the course of perioperative cholinesterase activities of 56 patients, measured preoperatively and twice postoperatively. Dexmedetomidine resulted in no change in AChE activity and caused a rapid recovery of BChE activity after an initial decrease, while placebo showed a significant decrease in both cholinesterase activities. There were no significant between-group differences at any point in time. From these data it can be assumed that dexmedetomidine could alleviate POD via altering the cholinergic anti-inflammatory pathway (CAIP). We advocate for further investigations to show the direct connection between dexmedetomidine and cholinesterase activity.

Loss of endothelial CFTR drives barrier failure and edema formation in lung infection and can be targeted by CFTR potentiation.

Pneumonia is the most common cause of the acute respiratory distress syndrome (ARDS). Here, we identified loss of endothelial cystic fibrosis transmembrane conductance regulator (CFTR) as an important pathomechanism leading to lung barrier failure in pneumonia-induced ARDS. CFTR was down-regulated after Streptococcus pneumoniae infection ex vivo or in vivo in human or murine lung tissue, respectively. Analysis of isolated perfused rat lungs revealed that CFTR inhibition increased endothelial permeability in parallel with intracellular chloride ion and calcium ion concentrations ([Cl-]i and [Ca2+]i). Inhibition of the chloride ion-sensitive with-no-lysine kinase 1 (WNK1) protein with tyrphostin 47 or WNK463 replicated the effect of CFTR inhibition on endothelial permeability and endothelial [Ca2+]i, whereas WNK1 activation by temozolomide attenuated it. Endothelial [Ca2+]i transients and permeability in response to inhibition of either CFTR or WNK1 were prevented by inhibition of the cation channel transient receptor potential vanilloid 4 (TRPV4). Mice deficient in Trpv4 (Trpv4-/-) developed less lung edema and protein leak than their wild-type littermates after infection with S. pneumoniae. The CFTR potentiator ivacaftor prevented lung CFTR loss, edema, and protein leak after S. pneumoniae infection in wild-type mice. In conclusion, lung infection caused loss of CFTR that promoted lung edema formation through intracellular chloride ion accumulation, inhibition of WNK1, and subsequent disinhibition of TRPV4, resulting in endothelial calcium ion influx and vascular barrier failure. Ivacaftor prevented CFTR loss in the lungs of mice with pneumonia and may, therefore, represent a possible therapeutic strategy in people suffering from ARDS due to severe pneumonia.