USP14 inhibitor IU1 prevents ventilator-induced lung injury in rats.

The pathophysiology of ventilator-induced lung injury (VILI) involves multiple mechanisms including inflammation. USP14 removes the ubiquitin chain of I-κB, therefore inducing I-κB degradation and increasing cytokine release. The purpose of this study was to examine the protecting roles and mechanisms of USP14 inhibitor on I-κB expression and lung injury induced by high tidal volume ventilation in normal rat lung. Male Sprague-Dawley rats were divided into follows: Two ventilation modalities were used: rats in Groups LD (low volume + DMSO) and LI (low volume + IU1) received ventilation with a tidal volume of 8 ml/kg, while the rats in Groups HD (high volume + DMSO) and HI (high volume + IU1) were ventilated with a tidal volume of 40 ml/kg. The levels of lung wet-to-dry weight ratio were used as indicators of water metabolism in lung tissue; the detection of inflammatory cytokines in bronchoalveolar lavage (BAL) fluid was used to indicate inflammatory response, while lung injury was assessed by injury score and morphological changes under light microscope. The USP14 and I-κB protein level was measured in lung tissue by Western blot. Our results indicated that administration of IU1 alleviated ventilator-induced lung injury which was accompanied by reduced MPO activity, wet-to-dry weight ratio, lower TNF-α, IL-1β, IL-6 and IL-8 levels and increased I-κB expression in lung tissue. IU1 could significantly alleviate ventilator-induced rat lung injury by attenuate intrapulmonary inflammatory response.