Preconditioning of physiological cyclic stretch attenuated HMGB1 expression in pathologically mechanical stretch-activated A549 cells and ventilator-induced lung injury rats through inhibition of IL-6/STAT3/SOCS3

•Preconditioning of 5% CS suppresses HMGB1 expression in A549 cells following 20% CS.•Low tidal volume ventilation preconditioning suppresses HMGB1 expression in VILI rats.•The inhibitory effect was mediated by suppressing IL-6/STAT3/SOCS3.•Low tidal volume ventilation preconditioning decreases the severity of VILI.

Previous studies have shown that physiologically cyclic stretch (5% CS) attenuated both oxidative- and LPS-induced increases in HMGB1 expression via STAT3. However, little information exists about the effect of precondition of physiological cyclic stretch (CS) on the expression of HMGB 1, which play a crucial role in ventilator-induced lung injury (VILI). We found that 5% CS-preconditioning significantly inhibited HMGB 1 expression, but not HMGB 1 receptors. 5% CS-preconditioning inhibits the IL-6/STAT3 pathway, and the inhibitory effect on the expression of HMGB 1 induced by 5% CS-preconditioning is abolished by additional treatment of rmIL-6. 5% CS-preconditioning also induces SOCS3 upregulation, and 5% CS-preconditioning fails to inhibit the IL-6/STAT3 pathway in cells transfected with SOCS3 siRNA. Moreover, low tidal volume ventilation preconditioning also decreases the severity of VILI evidenced by the markedly improved pulmonary alveolar-capillary barrier dysfunction, wet/dry weight ratio, and histological analysis. These results suggest that preconditioning of physiological 5% CS can reduce the expression of HMGB 1 induced by pathologically mechanical stretch through IL-6/STAT3 pathway associated with up-regulated SOCS3 expression.