Endotoxin-induced inflammation in a rodent model up-regulates IL-1a expression and CD45+leukocyte recruitment and increases the rate of reepithelialization and wound closure

Wound healing is traditionally divided into inflammation, proliferation, and remodeling phases. Several inflammatory mediators and cells regulate the inflammation phase. The specific roles for different mediators have not been clearly defined. The effects of inflammation phase modulation on wound healing were evaluated in this study. Rat full-thickness wounds were divided into different experimental groups: (1) sterile hyper-inflammatory wounds/endotoxin (topical endotoxin), (2) sterile hypo-inflammatory/inhibitor group (cocktail of topical COX-1 plus COX-2 plus lipoxygenase inhibitors), and (3) control groups: topical saline or DMSO. After full-thickness wound creation, custom-made titanium chambers enclosed the wound, creating an isolated well-controlled environment. Wound healing was followed over time; tissue biopsies and wound fluid samples were collected on days 1, 4, and 8 postoperatively. The validity of the inflammation model was confirmed by increased IL-1a expression, increased CD45+ leukocytes recruitment in the hyper-inflamed group as compared to the inhibitor and control groups. The reepithelialization percentage was significantly increased in the endotoxin group as compared to the inhibitor group on day 4 (60.75 vs. 22.05, p-value <0.05) and both the inhibitor and the control group on day 8 (control group: 63.2%, inhibitor group: 28.9%, endotoxin group: 84.2%, p-value <0.05). Also, the macroscopic wound closure was increased in the endotoxin group as compared to the inhibitor group and control group both on day 4 (control group: 69.9%, inhibitor group: 62.9%, endotoxin group: 81.9%, p-value <0.05) and on day 8 (control group: 68.5%, inhibitor group: 69.1%, endotoxin group: 83.7%, p-value <0.05). Endotoxin-induced sterile inflammation up-regulates IL-1a expression and CD45+ leukocyte recruitment and results in faster rate of wound reepithelialization and wound closure in full-thickness rodent wounds. Conversely, the wound reepithelialization and wound closure can be significantly delayed on treatment with a combination of cyclooxygenase and lipoxygenase inhibitors.