N-acetylcysteine attenuates ventilator-induced diaphragm dysfunction in rats

Introduction

Controlled mechanical ventilation (CMV) results in diaphragmatic dysfunction. Oxidative stress is an important contributor to ventilator-induced diaphragm dysfunction, since 18 hours of CMV lead to increased protein oxidation and increased lipid peroxidation. We hypothesized that administration of an antioxidant, N-acetylcysteine (NAC), would restore the redox balance in the diaphragm and prevent the deleterious effects of CMV.

Methods

Anesthetized rats were submitted for 24 hours to either spontaneous breathing while receiving 150 mg/kg NAC (SBNAC) or saline (SBSAL) or to CMV while receiving 150 mg/kg NAC (MVNAC) or saline (MVSAL).

Results

After 24 hours, diaphragm forces were significantly lower in MVSAL compared with all groups. Administration of NAC completely abolished this decrease such that forces produced in the MVNAC group were comparable with those of both SB groups. Protein oxidation was significantly increased in MVSAL (+53%, P < 0.01) and was restored in MVNAC. Diaphragm caspase-3 activity was significantly increased in MVSAL compared with SBSAL (+279%, P < 0.001). Caspase-3 activity was also increased in the MVNAC group (+158.5%, P < 0.01) but to a significantly lesser extent compared with that of MVSAL. Calpain activity was significantly increased after CMV (+137%, P < 0.001 vs SBSAL), while it was similar to SB groups in the MVNAC group. Significant negative correlation was found between calpain activity and diaphragm tetanic force (r = -0.48, P = 0.02).

Conclusions

These data show that the administration of NAC was able to preserve the diaphragm from the deleterious effects of CMV. NAC inhibits the increase in oxidative stress and proteolysis and reduces the decrease in force generating capacity of the diaphragm.