Role of p38 MAPK in burn-induced intestinal barrier breakdown.
BACKGROUND
Severe burn results in intestinal barrier breakdown, which may lead to the generation of a systemic inflammatory response and distant organ injury. Intestinal barrier integrity is regulated, in part, by the tight junction protein myosin light chain kinase (MLCK). Previous studies in cell culture have shown that activation of p38 MAPK plays an important role in modulating intestinal barrier function. We hypothesized that (1) severe burn up-regulates p38 MAPK activation and results in increased intestinal permeability via augmented expression of MLCK, and (2) inhibition of p38 MAPK will prevent the burn-induced increase in MLCK expression, resulting in improved intestinal barrier integrity.


METHODS
Male Balb/c mice were subjected to a 30% total body surface area (TBSA) full thickness steam burn, then randomized to receive an intraperitoneal injection of a p38 MAPK inhibitor (SB203580, 25 mg/kg) or vehicle. In vivo intestinal permeability to 4kDa FITC-Dextran was measured. Expression of phosphorylated p38 MAPK, total p38 MAPK, MLCK, and phosphorylated MLC from intestinal extracts was assessed by immunoblotting.


RESULTS
Severe burn increased intestinal permeability, which was associated with activation of p38 MAPK, and increased expression of MLCK. Treatment with SB203580 significantly attenuated burn-induced intestinal permeability (212 microg/mL versus 81 microg/mL, P<0.05), and decreased expression of intestinal MLCK resulting in decreased phosphorylation of MLC.


CONCLUSIONS
p38 MAPK plays an important role in regulating burn-induced intestinal permeability through activation of MLCK. Inhibition of p38 MAPK may be an important therapeutic target aimed at attenuating intestinal barrier breakdown by preventing the burn-induced alterations in tight junction proteins.
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, CA 92103-8896, USA.
Peterson
Carrie Y
CY
Kroll
Lauren
L
Loomis
William H
WH
Eliceiri
Brian P
BP
Baird
Andrew
A
Bansal
Vishal
V
Coimbra
Raul
R
D000818:Animals; D002056:Burns / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism*; D010539:Permeability; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D018994:Myosin Light Chains; D009219:Myosin-Light-Chain Kinase; D048051:p38 Mitogen-Activated Protein Kinases