Interrupting Burn-Induced Changes in Serum Acute Response Markers via Connexin 32 Gap Junction Inhibition and Neutralization at the Liver

Author:

McCarty William. J.1,Bohr Stefan1,Yarmush Martin L.1

Affiliation:

1. Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, 51 Blossom St Boston, MA 02114, US

Abstract

Severe burn injuries are associated with chronic hypermetabolism. Through its metabolic, inflammatory, immune, and acute phase functions, the liver plays a central role in the creation and maintenance of prolonged hypermetabolism and ensuing muscle wasting. The objective here was to determine the effects of inhibiting gap junction communication in the liver on the acute phase response and prolonged hypermetabolic state after burn injury in both connexin 32 knockout mice and in wildtype mice dosed with a small molecule connexin 32 inhibitor shortly after burn injury. Male connexin 32 knockout mice received full-thickness 20% total body surface area burns or sham treatments and were euthanized at 24[Formula: see text]h for serum marker profiling and at 14 days for organ and muscle mass analysis. Wildtype mice receiving similar burns or sham treatments were injected 3[Formula: see text]h after injury with connexin 32 gap junction inhibitor 2-aminoethoxydiphenyl borate (2APB) or vehicle control and were euthanized after 24[Formula: see text]h for serum marker profiling. At 24[Formula: see text]h post-burn, lower serum levels of haptoglobin, serum amyloid P component, monocyte chemoattractant protein-1, interleukin-6, and alanine aminotransferase as assessed by ELISA were found in the knockout mice than in the wildtypes. Fourteen days post-burn, the increases in heart, spleen, and liver and decrease in calf muscle mass found in the wildtype mice were significantly mitigated in the knockouts. Further, the post-burn acute phase response was similarly diminished in the wildtype mice after 2APB administration. Interrupting detrimental post-burn hypermetabolism by inhibiting intercellular hepatocyte communication may provide novel therapeutic leverage during the initial systemic inflammatory response and improve clinical outcomes.

Publisher

World Scientific Pub Co Pte Lt

Subject

General Medicine

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