Abstract

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 summarized 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 (MOS) in fact appears to be a central factor in each of these events. Recent studies by our group and others indicate that mitochondrial function is modulated by several signaling molecules including Smad3, STAT3 and FoxO. Mechanical ventilation rapidly activates Smad3 and STAT3, which upregulate MOS. Additional roles may be played by angiotensin II and leaky ryanodine receptors causing elevated calcium levels. We present, here, a hypothetical scaffold for understanding the molecular pathogenesis of VIDD which links together these elements. These pathways harbor several drug targets that could soon move toward testing in clinical trials. We hope that this review will shape a short list of the most promising candidates.

View details for PubMedID 29768017