Delayed Wound Repair in Sepsis Is Associated with Reduced Local Pro-Inflammatory Cytokine Expression

Sepsis is one of the main causes for morbidity and mortality in hospitalized patients. Moreover, sepsis associated complications involving impaired wound healing are common. Septic patients often require surgical interventions that in-turn may lead to further complications caused by impaired wound healing. We established a mouse model to the study delayed wound healing during sepsis distant to the septic focus point. For this reason cecal ligation and puncture (CLP) was combined with the creation of a superficial wound on the mouse ear. Control animals received the same procedure without CPL. Epithelialization was measured every second day by direct microscopic visualization up to complete closure of the wound. As interplay of TNF-alpha, TGF-beta, matrix metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) is important in wound healing in general, TNF-alpha, TGF-beta, MMP7, and TIMP1 were assessed immunohistochemical in samples of wounded ears harvested on days 2, 6, 10 and 16 after wounding. After induction of sepsis, animals showed a significant delay in wound epithelialization from day 2 to 12 compared to control animals. Complete wound healing was attained after mean 12.2 +/- standard deviation (SD) 3.0 days in septic animals compared to 8.7 +/- SD 1.7 days in the control group. Septic animals showed a significant reduction in local pro-inflammatory cytokine level of TNF-alpha on day 2 and day 6 as well as a reduced expression of TGF-beta on day 2 in wounds. A significant lower expression of MMP7 as well as TIMP1 was also observed on day 2 after wounding. The induction of sepsis impairs wound healing distant to the septic focus point. We could demonstrate that expression of important cytokines for wound repair is deregulated after induction of sepsis. Thus restoring normal cytokine response locally in wounds could be a good strategy to enhance wound repair in sepsis.