Lung-protective ventilation worsens ventilator-induced diaphragm atrophy and weakness

BACKGROUND: Lung–protective ventilation (LPV) has been found to minimize the risk of ventilator–induced lung injury (VILI). However, whether LPV is able to diminish ventilator–induced diaphragm dysfunction (VIDD) remains unknown. This study was designed to test the hypothesis that LPV protects the diaphragm against VIDD. METHODS: Adult male Wistar rats received either conventional mechanical (tidal volume [V(T)]: 10 ml/kg, positive end–expiratory pressure [PEEP]: 2 cm H(2)O; CV group) or lung-protective (V(T): 5 ml/kg, PEEP: 10 cm H(2)O; LPV group) ventilation for 12 h. Then, diaphragms and lungs were collected for biochemical and histological analyses. Transcriptome sequencing (RNA–seq) was performed to determine the differentially expressed genes in the diaphragms between groups. RESULTS: Our results suggested that LPV was associated with diminished pulmonary injuries and reduced oxidative stress compared with the effects of the CV strategy in rats. However, animals that received LPV showed increased protein degradation, decreased cross–sectional areas (CSAs) of myofibers, and reduced forces of the diaphragm compared with the same parameters in animals receiving CV (p < 0.05). In addition, the LPV group showed a higher level of oxidative stress in the diaphragm than the CV group (p < 0.05). Moreover, RNA–seq and western blots revealed that the peroxisome proliferator–activated receptor γ coactivator–1alpha (PGC–1α), a powerful reactive oxygen species (ROS) inhibitor, was significantly downregulated in the LPV group compared with its expression in the CV group (p < 0.05). CONCLUSIONS: Compared with the CV strategy, the LPV strategy did not protect the diaphragm against VIDD in rats. In contrast, the LPV strategy worsened VIDD by inducing oxidative stress together with the downregulation of PGC–1α in the diaphragm. However, further studies are required to determine the roles of PGC–1α in ventilator-induced diaphragmatic oxidative stress.