Burn-induced gut barrier injury is attenuated by phosphodiesterase inhibition: effects on tight junction structural proteins.

Abstract

Loss of intestinal barrier function after burn injury allows movement of intraluminal contents across the mucosa, which can lead to the development of distant organ injury and multiple organ failure. Tight junction function is highly regulated by membrane-associated proteins including occludin and zonula occludens protein 1 (ZO-1), which can be modulated by systemic inflammation. We hypothesized that (1) burn injury leads to gut barrier injury, and (2) phosphodiesterase inhibition will attenuate these burn-induced changes. Male balb/c mice undergoing a 30% steam burn were randomized to resuscitation with normal saline or normal saline + pentoxifylline (PTX; 12.5 mg/kg). Intestinal injury was assessed by histological diagnosis and TNF-alpha levels using enzyme-linked immunosorbent assay. Intestinal permeability was assessed by measuring the plasma concentration of fluorescein isothiocyanate-dextran after intraluminal injection in the distal ileum. Occludin and ZO-1 levels were analyzed by immunoblotting and immunohistochemistry. Thirty percent total body surface area (TBSA) burn results in a significant increase in intestinal permeability. Treatment with PTX after burn attenuates intestinal permeability to sham levels. Burn injury resulted in a marked decrease in the levels of tight junction proteins occludin and ZO-1 at 6 and 24 h. The use of PTX after burn significantly decreases the breakdown of occludin and ZO-1. Pentoxifylline also attenuates the burn-induced increase in plasma and intestinal TNF-alpha. Confocal microscopy demonstrates that PTX attenuates the burn-induced reorganization of occludin and ZO-1 away from the tight junction. Pentoxifylline attenuates burn-induced intestinal permeability and decreases the breakdown and reorganization of intestinal occludin and ZO-1. Therefore, phosphodiesterase inhibition may be a useful adjunct strategy in the attenuation of burn-induced gut barrier injury.

• Authors: Todd W Costantini, William H Loomis, James G Putnam, Dana Drusinsky, Jessica Deree, Sunghyuk Choi, Paul Wolf, Andrew Baird, Brian Eliceiri, Vishal Bansal, Raul Coimbra
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 31 Issue 4 Pg. 416-22 (Apr 2009) ISSN: 1540-0514 [Electronic] United States
• PMID: 18791495 (Publication Type: Journal Article)

Chemical References

• Membrane Proteins
• Phosphodiesterase Inhibitors
• Tumor Necrosis Factor-alpha
• Pentoxifylline

Topics

• Animals
• Burns (drug therapy, etiology, pathology, physiopathology)
• Ileum (drug effects, pathology)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Microscopy, Confocal
• Pentoxifylline (pharmacology)
• Permeability (drug effects)
• Phosphodiesterase Inhibitors (therapeutic use)
• Tight Junctions (drug effects, physiology)
• Tumor Necrosis Factor-alpha (metabolism)