Inhibition of nuclear factor-kappaB and p38 mitogen-activated protein kinase does not always have adverse effects on wound healing.
BACKGROUND
Inflammatory stimuli that activate p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) contribute to inflammation and fibroblast function, which are necessary components of incision and wound healing. Inhibition of these signal transduction pathways may provide novel strategies to prevent sepsis but may interfere with healing. We examined the effects of inhibiting p38 activation and NF-kappaB translation on incision healing in a dorsal slit model.


METHODS
Male MF-1 mice were randomized into three treatment groups: Control (0.1% dimethylsulfoxide [vehicle]); SB-202190 (2.5 mcM/kg), an inhibitor of p38 MAPK; and SN-50 (10 mcg/kg), an inhibitor of the p50 subunit of NF-kappaB. Animals first underwent a dorsal slit incision, which was closed with interrupted non-absorbable sutures. Animals were sacrificed at three or seven days, and the incision sites were excised for histologic examination (hematoxylin and eosin and Van Gieson stains) and assessment of breaking strengths by tensiometry. Blood was collected for cytokine analysis. Analysis of variance was used to interpret the data.


RESULTS
Neither SB202190 nor SN-50 significantly impaired incision strength at day three (control 0.84 +/- 0.2 N vs. SN-50 0.78 +/- 0.2 N and SB-202190 0.93 +/- 0.2 N) or day seven (0.73 +/- 0.2 N vs. 0.66 +/- 0.2 N and 0.66 +/- 0.2 N, respectively). Circulating concentrations of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were low on day three with no significant differences between groups (p = 0.7 and 0.4). On day seven, there were no differences in circulating IL-6 (p = 0.08); however, the blood concentrations of TNF-alpha were significantly higher in the SB-202190-treated group (p = 0.003). Histologic analysis did not demonstrate any differences in inflammatory infiltrate or collagen deposition in the incision sites and correlated with the tensiometry findings.


CONCLUSIONS
Inhibition of p38 and NF-kappaB does not affect healing adversely. These results suggest that these agents do not affect the inflammation required for normal healing and could be used safely for treating inflammatory and septic conditions in clinical practice.
O'Sullivan
Adrian
A
Department of Academic Surgery, University College Cork, Cork, Ireland. awmos@btinternet.com
O'Malley
Diarmuid
D
Coffey
John
J
Wang
Jiang Huai
JH
Redmond
Henry
H
D000818:Animals; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D006651:Histocytochemistry; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008853:Microscopy; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology*; D010455:Peptides / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011897:Random Allocation; D014945:Wound Healing; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology*
D016207:Cytokines; D007093:Imidazoles; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D010455:Peptides; D011725:Pyridines; C118258:SN50 peptide; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole