Host responses to critical illness, such as excessive inflammation and hyperglycemia, trigger detrimental chain reactions that damage cellular proteins and organelles. Such responses to illness contribute to the risk of non-resolving multiple organ dysfunction and adverse outcome. Autophagy is a bulk degradation pathway able to remove toxic protein aggregates and damaged organelles. Morphologically, both liver and muscle of critically ill patients reveal an autophagy-deficiency phenotype. Proteins involved in initiation and elongation steps of autophagy are induced several-fold by critical illness, but mature autophagic vacuole formation is impaired and proteins normally degraded by autophagy accumulate dramatically. Also mitophagy is down-regulated. Artificial nutrition, most specifically the amount of infused amino-acids, appears to be an important factor contributing to suppressed mature autophagy in the critically ill. Although insulin-titrated maintenance of normal blood glucose preserves hepatocytic mitochondrial integrity by prevention of direct damage, the infused insulin may have a downside as it may further impair the autophagic machinery.
Insufficient autophagy in prolonged critical illness may cause inadequate removal of damaged proteins and mitochondria. Such incomplete clearance of cellular damage, inflicted by illness and aggravated by hyperglycemia, could explain lack of recovery from organ failure in prolonged critically ill patients. These novel insights open perspectives for therapies that activate autophagy during critical illness.
30 Apr - 04 May 2011
European Society of Endocrinology