Title
Insufficient activation of autophagy allows cellular damage to accumulate in critically ill patientsInsufficient activation of autophagy allows cellular damage to accumulate in critically ill patients
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Research group
Laboratory of cell biology and histology
Physiopharmacology (PHAR)
Publication type
article
Publication
Baltimore, Md,
Subject
Human medicine
Source (journal)
The journal of clinical endocrinology and metabolism. - Baltimore, Md
Volume/pages
96(2011):4, p. E633-E645
ISSN
0021-972X
ISI
000289242800007
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Context:Responses to critical illness, such as excessive inflammation and hyperglycemia, may trigger detrimental chain reactions that damage cellular proteins and organelles. Such responses to illness contribute to the risk of (nonresolving) multiple organ dysfunction and adverse outcome. Objective:We studied autophagy as a bulk degradation pathway able to remove toxic protein aggregates and damaged organelles and how these are affected by preventing hyperglycemia with insulin during critical illness. Design and Setting:Patients participated in a randomized study, conducted at a university hospital surgical/medical intensive care unit. Patients:We studied adult prolonged critically ill patients vs. controls. Interventions:Tolerating excessive hyperglycemia was compared with intensive insulin therapy targeting normoglycemia. Main Outcome Measures:We quantified (ultra)structural abnormalities and hepatic and skeletal muscle protein levels of key players in autophagy. Results:Morphologically, both liver and muscle revealed an autophagy-deficiency phenotype. Proteins involved in initiation and elongation steps of autophagy were induced 1.3- to 6.5-fold by critical illness (P ≤ 0.01), but mature autophagic vacuole formation was 62% impaired (P = 0.05) and proteins normally degraded by autophagy accumulated up to 97-fold (P ≤ 0.03). Mitophagy markers were unaltered or down-regulated (P = 0.05). Although insulin preserved hepatocytic mitochondrial integrity (P = 0.05), it further reduced the number of autophagic vacuoles by 80% (P = 0.05). Conclusions: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 data open perspectives for therapies that activate autophagy during critical illness.
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