Document resource
Background Acute respiratory distress syndrome (ARDS) is driven by uncontrolled neutrophilic inflammation in the alveolar space with resultant damage to the epithelial and endothelial barrier, resulting in pulmonary oedema. Baricitinib is a JAK1/2 inhibitor which inhibits inflammation in experimental lung injury in animal models and reduces mortality in COVID related respiratory failure. The effect of baricitinib on human lung injury outside of COVID is unknown.Hypothesis JAK1/2 inhibition with baricitinib reduces LPS (lipopolysaccharide)-induced lung injury in ex vivo perfused and ventilated human lungs.Methods Human lungs unsuitable for transplantation, for which there was consent for use in research, were ventilated and perfused ex vivo, using a modified Toronto protocol. Lungs with intact alveolar fluid clearance at baseline were injured by instilling 6 mg LPS (E coli) into a lobe and adding whole blood to the perfusate at a final concentration of 1/10. Lungs were randomised to receive either baricitinib or placebo in the perfusate (final concentration baricitinib=50ng/ml to correspond with Cmax obtained in healthy volunteers receiving 4 mg/day, the standard dose of baricitinib, and that used in the treatment of COVID in RECOVERY). Bronchoalveolar lavage was carried out at 4 hours after LPS instillation. Total cell count in BAL was measured using an Eve Automated cell counter (NanoEntek) and differential white cell count carried out on cytospins prepared from BAL. Ethical approval was obtained from NRES (REC 14 LO 0250) and Queen’s University of Belfast School of Medicine Ethics Committee (SREC14/08).Results 13 pairs of lungs (26 in total) were obtained. Baseline fluid clearance was impaired in 3 lungs and these were excluded from the study. 12 lungs were randomised to receive placebo and 11 baricitinib. Baricitinib reduced BAL neutrophil count at 4 hours from median 5.76 (IQR 2.74–9.16) x10 4/ml to 2.02 (IQR 1.73–4.73) x104/ml (figure 1), *p=0.0489, Wilcoxon rank-sum test. The effect of baricitinib on markers of permeability, alveolar epithelial and endothelial injury will be measured.Conclusion Baricitinib reduces neutrophil count in the alveolar space in a human EVLP model of LPS-induced lung injury, supporting its potential to inhibit alveolar neutrophilic inflammation in non-COVID related ARDS.