The Signaling Network Resulting in Ventilator-induced Diaphragm Dysfunction

Mechanical ventilation (MV) is a life-saving measure for those incapable of adequately ventilating or oxygenating without assistance. Unfortunately, even brief periods of MV result in diaphragm weakness (i.e., ventilator-induced diaphragm dysfunction [VIDD]) that may render it difficult to wean the ventilator. Prolonged MV is associated with cascading complications and is a strong risk factor for death. Thus, prevention of VIDD may have a dramatic impact on mortality rates. Here, we summarize the current understanding of the pathogenic events underlying VIDD. Numerous alterations have been proven important in both human and animal MV diaphragm. These include protein degradation via the ubiquitin proteasome system, autophagy, apoptosis, and calpain activity—all causing diaphragm muscle fiber atrophy, altered energy supply via compromised oxidative phosphorylation and upregulation of glycolysis, and also mitochondrial dysfunction and oxidative stress. Mitochondrial oxidative stress in fact appears to be a c...