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

Abstract

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-α, TGF-β, matrix metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) is important in wound healing in general, TNF-α, TGF-β, 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-α on day 2 and day 6 as well as a reduced expression of TGF-β 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.

Burn wound healing and treatment: review and advancements

“…Excessive or prolonged edema and inflammation exacerbate pain and impair wound healing [17, 18]. Interestingly, studies suggest that in the absence of infection, inflammation might not be required for tissue repair [46].…”

СУЧАСНІ УЯВЛЕННЯ ПРО ПАТОГЕНЕЗ ТА ДІАГНОСТИКУ Гнійно-Септичних СТАНІВ У ДІТЕЙ (Частина 1)

“…Відомо, що цитокіни володіють широким спектром біологічних властивостей -взаємодіють між собою, утворюють універсальну мережу, яка запускає і регу-лює каскад запальних, імунних, метаболічних про-цесів -як локальних, так і системних, направлених на нейтралізацію і елімінацію патогенних агентів [14,15]. Так, ендотоксин Грам (-) бактерій стимулює макро-фаги і нейтрофіли до продукції TNF-α, IL-1, -6, -8 і -12, екзотоксини Грам (+) бактерій активують Т клітини і моноцити до продукції IL-1, -2, TNF-α, ІFγ.…”

Inhibitory effects of serum from sepsis patients on epithelial cell migration in vitro: a case control study

“…Disorders in skin function and wound healing during sepsis may lead to blistering and pressure ulcers that, in addition to surgery and invasive cannulations, compromise this defensive barrier [3]. Septic patients are prone to wound healing complications such as infections, delayed wound healing, fascial dehiscence and anastomotic leaks [4–9]. Septic patients’ predisposition to get spontaneous and iatrogenic wounds combined with impaired wound healing can lead to substantial functional and aesthetic, even life threatening problems.…”

“…In our previous studies, skin collagen synthesis is proven to be diminished [10], the restoration of the epidermal barrier function to be delayed and wound blood flow increased in severe sepsis [8]. Wound re-epithelialization is delayed during sepsis, as demonstrated in rodent models [5, 7, 9] and in a human blister wound model [8]. Re-epithelialization is achieved via the migration and proliferation of keratinocytes from the edges of the wound.…”

“…After injury the wound repair process is initiated immediately by the release of growth factors and cytokines from the serum, which bind to receptors expressed by their target cells, and co-ordinate the re-epithelialization [3, 11, 13–16]. However, knowledge about cell migration and proliferation in human systemic sepsis is currently limited; sepsis wound-healing studies have been conducted only in animals [5, 7, 9]. The role of cytokines involved in wound healing in sepsis is somewhat unclear.…”