Role of YB-1 in the Early Pathogenesis of Acute Respiratory Distress Syndrome (ARDS) and Associated Renal Damage

Le résumé fourni par la source

Background: Acute respiratory distress syndrome (ARDS) is a life-threatening lung impairment that is associated with a mortality of 25% up to 45%. It is caused by acute inflammation and currently patients with ARDS can only be stabilized by mechanical ventilation and intensive care. Acute kidney injury (AKI) is the most common extrapulmonary organ dysfunction associated with ARDS, affecting more than 35% of the patients. Proteins with alarmin function, such as the highly conserved Y-box binding protein (YB-1), are good candidates for early progression of ARDS and the crosstalk between lung and kidney. YB-1 functions as a translation or transcription factor and is also secreted during inflammation. Methods: Mice were mechanically ventilated in a mouse intensive care unit (MICU). The role of YB-1 in murine ARDS and its effect on the kidneys was evaluated in a two-hit- (intratracheal (i.t.) application of hydrochloric acid & ventilation) and a triple-hit- (hydrochloric acid i.t., lipopolysaccharide (LPS))- i.t. & ventilation) model in heterozygous Yb1-deficient (Yb1+/-)-mice and after i.t.-application of recombinant YB-1 protein. In addition, tracheal secretion, urine and serum from ARDS patients were analyzed for (post-translationally modified) extracellular YB-1 by mass spectrometry. Results: In both models, Yb1+/- mice were protected in terms of pulmonary inflammatory parameters. In the two-hit model, the improved lung function in the Yb1+/- mice deteriorated to wild-type (WT) level by additional i.t. application of recombinant YB-1. Interestingly, however, heterozygous YB-1 deficiency in the kidneys led to more intense inflammatory reactions. YB-1 i.t. (instillation in the absence of lung injury) already triggered nephritis. Extracellular YB-1 in murine and human ARDS was post-translational modified, and mass spectrometric analysis of ARDS patient samples showed a correlation of guanidinylated YB-1 levels in tracheal secretion/serum and disease severity. Conclusions: Taken together, YB-1 expression in ARDS mouse models has opposite effects on the inflammatory process in the primarily damaged lung and the secondarily affected kidney. In addition, the intracellular or extracellular localization of YB-1 also determines its protective or destructive character. Funding: Government Support - Non-U.S.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.