Shifting anaerobic to aerobic metabolism stimulates apoptosis through modulation of redox balance Potential intervention in the pathogenesis of postoperative adhesions

Capsule:
Dichloroacetate modulates redox homeostasis, thus protecting cells against anaerobic metabolism and associated oxidative stress. This may provide targets for therapeutic intervention for treatment of profibrotic disorders, including postoperative adhesions.

Authors:
Nicole M. Fletcher, Ph.D., Awoniyi O. Awonuga, M.D., Bailey R. Neubauer, B.S., Mohammad S. Abusamaan, M.D., Mohammed G. Saed, B.A., Michael P. Diamond, M.D., Ghassan M. Saed, Ph.D.

Volume 104, Issue 4, Pages 1022-1029

Abstract:

Objective:
To compare the effect of shifting anaerobic to aerobic metabolism on key regulators of oxidative stress, including extracellular superoxide dismutase (SOD3), inducible nitric oxide synthase (iNOS), and its product, nitric oxide (NO), as well as mitochondrial potential (Δψm) and apoptosis in fibroblasts established from normal peritoneum and adhesion tissues.

Design:
Prospective, experimental study.

Setting:
University medical center.

Patient(s):
Fibroblasts established from normal peritoneum and adhesion tissues from the same patients.

Intervention(s):
Treatment with dichloroacetate (0, 20, 40, and 80 μg/mL, 24 hours)

Main Outcome Measure(s):
The expression of SOD3, iNOS, and NO levels were measured utilizing real-time reverse transcription–polymerase chain reaction and Greiss assay. The Δψm was evaluated by the JC-1 Mitochondrial Membrane Potential Assay. Apoptosis was determined by caspase-3 activity and TUNEL assays. Data were analyzed using SPSS 19.0. Mixed model repeated-measures analysis of variance was used with a Bonferroni correction. Significant interactions were analyzed with independent sample t tests.

Result(s):
Dichloroacetate increased apoptosis, SOD3 messenger RNA, iNOS messenger RNA, and NO levels in fibroblasts from peritoneum and adhesions. There was enhanced Δψm adhesion as compared with normal peritoneal fibroblasts. Creating oxidative stress by exposure by hypoxia markedly increased Δψm in fibroblasts from normal peritoneum to levels observed in adhesions; dichloroacetate protected against the effects of hypoxia.

Conclusion(s):
Anaerobic metabolism and oxidative stress are associated with the development of the adhesion phenotype, which manifests decreased apoptosis. Dichloroacetate induces adhesion fibroblasts to undergo apoptosis via modulation of redox homeostasis. These findings may provide targets for therapeutic treatment for reduction of profibrotic disorders, including postoperative adhesions.

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