Burns, inflammation, and intestinal injury: protective effects of an anti-inflammatory resuscitation strategy.
BACKGROUND
Intestinal barrier breakdown after severe burn can lead to intestinal inflammation, which may act as the source of the systemic inflammatory response. In vitro intestinal cell studies have shown that mitogen-activated protein kinase (MAPK) signaling is an important modulator of intestinal inflammation. We have previously observed that pentoxifylline (PTX) attenuates burn-induced intestinal permeability and tight junction breakdown. We hypothesized that PTX would limit intestinal barrier breakdown and attenuate inflammatory signaling via the MAPK pathway.


METHODS
Male balb/c mice underwent 30% total body surface area full-thickness steam burn. Immediately after burn, animals received an intraperitoneal injection of PTX (12.5 mg/kg) in normal saline or normal saline alone. In vivo intestinal permeability to 4 kDa fluorescein isothiocyanate-dextran was measured. Intestinal extracts were obtained to measure interleukin-6 by enzyme-linked immunosorbent assay, and phosphorylated p38 MAPK, p38 MAPK, phosphorylated extracellular signal-related kinase (1/2) (ERK (1/2)), and ERK (1/2) by immunoblotting. Acute lung injury was assessed by histology at 24 hours after burn.


RESULTS
Administration of PTX immediately after injury attenuated burn-induced intestinal permeability. PTX also decreased the burn-induced phosphorylation of p38 MAPK and decreased phosphorylation of ERK (1/2) at 2 hours and 24 hours after injury. Animals given PTX had decreased intestinal interleukin-6 levels. A single dose of PTX also decreased histologic lung injury at 24 hours after burn.


CONCLUSIONS
PTX attenuates burn-induced intestinal permeability and subsequent intestinal inflammation. Use of PTX after burn was also associated with decreased acute lung injury. Because of its compelling anti-inflammatory effects, PTX may be an ideal candidate for use as an immunomodulatory adjunct to resuscitation fluid.
Costantini
Todd W
TW
Division of Trauma, Surgical Critical Care, and Burns, Department of Surgery, University of California-San Diego School of Medicine, San Diego, California, USA.
Peterson
Carrie Y
CY
Kroll
Lauren
L
Loomis
William H
WH
Putnam
James G
JG
Wolf
Paul
P
Eliceiri
Brian P
BP
Baird
Andrew
A
Bansal
Vishal
V
Coimbra
Raul
R
D000818:Animals; D002056:Burns / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010431:Pentoxifylline / Q000494:pharmacology*; D010539:Permeability; D010766:Phosphorylation; D012151:Resuscitation / Q000379:methods*; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D048051:p38 Mitogen-Activated Protein Kinases; D010431:Pentoxifylline