Reduced levels of liver kinase B1 in small extracellular vesicles as a predictor for chronic lung allograft dysfunction in cystic fibrosis lung transplant recipients

Abstract

Small extracellular vesicles (sEVs) isolated from plasma of lung transplant recipients (LTRs) with chronic lung allograft dysfunction (CLAD) contain increased levels of lung associated self-antigens, Kα1 tubulin and collagen V, and decreased expression of the tumor suppressor liver kinase B1 (LKB1). In this study, sEVs were isolated from plasma collected from LTRs with or without cystic fibrosis (CF) from multiple centers at the onset of CLAD and 6 and 12 months before clinical diagnosis of CLAD (n = 32) as well as from time-matched stable controls (n = 25). sEVs were analyzed for Kα1 tubulin, collagen V, and LKB1 by western blot. Exoview R200, a functionalized microarray chip was employed to characterize the LKB1 in sEVs. EVs from non-CF LTRs had higher levels of lung self-antigens (p < 0.05) and lower levels of LKB1 (p = 0.024) 12 months before CLAD diagnosis than those from time-matched stable LTRs; however, in CF LTRs, only LKB1 levels were lower (p = 0.0005) 6 months before diagnosis. Further characterization of sEVs 6 months before CLAD in CF LTRs also demonstrated significantly lower numbers of LKB1 and LKB1/CD9 + sEV particles. Reduced LKB1 in circulating sEVs offers a potential biomarker for the risk of CLAD in LTRs with CF.

Keywords: Chronic lung allograft dysfunction; Liver kinase B1; Lung transplant recipient; Lung transplantation; Small extracellular vesicle.