Topical p38MAPK inhibition reduces dermal inflammation and epithelial apoptosis in burn wounds.
Thermal injury induces dermal inflammatory and proapoptotic signaling. These phenomena extend burn wound size and trigger a systemic inflammatory response, factors known to adversely affect outcomes. p38MAPK is known to trigger inflammatory responses and induce epithelial proapoptotic genes. We hypothesize that topical p38MAPK inhibition will attenuate excessive inflammatory and apoptotic signaling and reduce dermal tissue loss. Rats were given a 30% total body surface area partial thickness burn or sham injury. Some of the animals were treated with a p38MAPK inhibitor or vehicle, which was applied directly to the wound. Dermal inflammation was investigated with enzyme-linked immunosorbent assay, reverse transcriptase polymerase chain reaction, myeloperoxidase assay, and Evans blue extravasation. Apoptotic changes were detected using terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Caspase-3 in situ staining. Burn injury activated dermal p38MAPK and induced a significant rise in dermal IL-6, TNF-alpha, and IL-1beta expression. Neutrophil sequestration, microvascular damage, and hair follicle apoptosis were significantly elevated after injury. Topical p38MAPK inhibition significantly attenuated downstream dermal p38MAPK targets, proinflammatory cytokine expression, neutrophil sequestration, and microvascular injury. A significant reduction in hair follicle apoptosis was seen. This study demonstrates the attenuation of burn-induced cellular stress by topical application of p38MAPK inhibitors. Blunting early excessive inflammatory signaling may be an efficient strategy to improve patient outcomes after burn injury.
Ipaktchi
Kyros
K
Department of Surgery, Burn Center, University of Michigan Medical School, Ann Arbor, MI 48109-0033, USA.
Mattar
Aladdein
A
Niederbichler
Andreas D
AD
Hoesel
Laszlo M
LM
Hemmila
Mark R
MR
Su
Grace L
GL
Remick
Daniel G
DG
Wang
Stewart C
SC
Arbabi
Saman
S
D000287:Administration, Topical; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002056:Burns / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D019743:Chemokines, CXC / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003872:Dermatitis / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D019743:Chemokines, CXC; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D015850:Interleukin-6; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole