Burn-Induced Gut Barrier Injury Is Attenuated by Phosphodiesterase Inhibition

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-α 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-α. 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.

Inhibition of long myosin light-chain kinase activation alleviates intestinal damage after binge ethanol exposure and burn injury

“…Intestinal damage, characterized by villus blunting and edema as well as intestinal inflammation, commonly occurs after traumatic injury (14,16,48). Six hours after exposure to ethanol and burn injury, ileum morphology begins to change.…”

Vagal nerve stimulation protects against burn-induced intestinal injury through activation of enteric glia cells

“…Male BALB/c mice (8 -12 wk, Jackson Laboratories, Sacramento, CA) were anesthetized with inhaled isoflurane and had their dorsal fur removed. Animals were then placed in a template estimating 30% total body surface area (TBSA) burn and subjected to a steam burn for 7 s as previously described (8). Following burn injury, animals received a subcutaneous injection of 1.5 ml normal saline with buprenorphine for fluid resuscitation and pain control.…”

“…A midline laparotomy was performed 4 h following burn and the distal small intestine identified as previously described (8,9). A 5-cm segment of small intestine was isolated between silk ties prior to intraluminal injection of 25 mg 4.4-kDa FITC-dextran (Sigma, St. Louis, MO) diluted in 200 l phosphate-buffered saline (PBS).…”

“…We have previously studied the intestinal injury associated with severe burn, finding changes in tight junction proteins expression that are associated with increased intestinal permeability at early time points following injury (8,9). The restoration of small intestinal barrier function requires a complex set of events that are initiated within minutes of injury and are characterized by epithelial cell restitution and reassembly of tight junction proteins to close the paracellular space (3).…”

Morphology of the Intestinal Barrier in Different Physiological and Pathological Conditions

“…Burn injury resulted in a marked decrease in the levels of tight junction proteins occludin and ZO-1 at 6 and 24 h following burn analyzed by immunoblotting and immunohistochemistry and seen under confocal microscope [33].…”