Topical p38 MAPK inhibition reduces bacterial growth in an in vivo burn wound model.
BACKGROUND
Although the inflammatory response is a prerequisite for wound healing, excessive activation of the innate immune system can induce epithelial cell damage and apoptosis, which may further compromise dermal integrity. In a noninfectious burn wound model, we previously demonstrated that topical inhibition of p38 MAPK, an important inflammatory signaling pathway, attenuated epithelial cell damage and apoptosis. We now question whether attenuating local inflammation would weaken bacterial wound resistance and compromise host defense.


METHODS
Rats received 30% total body surface area burn, and the wound was treated with topical application of a p38 MAPK inhibitor or vehicle. At 24 hours after injury, burn wounds were inoculated with Pseudomonas aeruginosa. At 48 hours postinjury, animals were sacrificed, and the burn wound was analyzed.


RESULTS
Inoculating burn wounds induced significant bacterial growth. Dermal inflammatory changes were markedly accentuated in the inoculated animals. Topical p38 MAPK inhibition reduced the proinflammatory cytokine expression in the burn wounds and neutrophil sequestration with or without bacterial inoculation. Interestingly, the bacterial wound growth was significantly attenuated in animals treated with topical p38 MAPK inhibitor.


CONCLUSIONS
Topical p38 MAPK inhibition attenuated wound inflammation without interfering with bacterial host defense. Attenuation of excessive burn wound inflammatory signaling may prevent secondary damage of the dermal barrier and reduce the growth of opportunistic pathogens.
Ipaktchi
Kyros
K
Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
Mattar
Aladdein
A
Niederbichler
Andreas D
AD
Hoesel
Laszlo M
LM
Vollmannshauser
Sabrina
S
Hemmila
Mark R
MR
Minter
Rebecca M
RM
Su
Grace L
GL
Wang
Stewart C
SC
Arbabi
Saman
S
D000287:Administration, Topical; D000818:Animals; D002056:Burns / Q000150:complications / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000378:metabolism; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000037:antagonists & inhibitors; D003872:Dermatitis / Q000209:etiology / Q000382:microbiology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development*; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D018836:Inflammation Mediators; D011725:Pyridines; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole