Comparison of the cytokine and chemokine dynamics of the early inflammatory response in models of burn injury and infection

Abstract

The inflammatory response, and its subsequent resolution, are the result of a very complex cascade of events originating at the site of injury or infection. When the response is severe and persistent, Systemic Inflammatory Response Syndrome can set in, which is associated with a severely debilitating systemic hypercatabolic state. This complex behavior, mediated by cytokines and chemokines, needs to be further explored to better understand its systems properties and potentially identify multiple targets that could be addressed simultaneously. In this context, short term responses of serum cytokines and chemokines were analyzed in two types of insults: rats receiving a “sterile” cutaneous dorsal burn on 20% of the total body surface area (TBSA); rats receiving a cecum ligation and puncture treatment (CLP) to induce infection. Considering the temporal variability observed in the baseline corresponding to the control group, the concept of area under the curve (AUC) was explored to assess the dynamic responses of cytokines and chemokines. MCP-1, GROK/KC, IL-12, IL-18 and IL-10 were observed in both burn and CLP groups. While IL-10 concentration was only increased in the burn group, Eotaxin was only elevated in CLP group. It was also observed that Leptin and IP-1 concentrations were decreased in both CLP and sham-CLP groups. The link between the circulating protein mediators and putative transcription factors regulating the cytokine/chemokine gene expression was explored by searching the promoter regions of cytokine/chemokine genes in order to characterize and differentiate the inflammatory responses based on the dynamic data. Integrating multiple sources together with the bioinformatics tools identified mediators sensitive to type and extent of injury, and provided putative regulatory mechanisms. This is essential to gain a better understanding for the important regulatory points that can be used to modulate the inflammatory state at molecular level.

Long-term dynamic profiling of inflammatory mediators in double-hit burn and sepsis animal models

“…Down regulation of Leptin and IP-10 concentrations were found to be related to surgery and/or infection. IL-18 and MCP-1 were elevated in all groups including previously published single injury models receiving similar treatments [15, 16]. …”

“…However, these studies are limited to one type of insult or a limited number of cytokines’ measurements. In our previous study, we analyzed the short term (24 h) responses of 23 different serum cytokines and chemokines in two types of animal models: rats receiving a “sterile” cutaneous dorsal burn on 20% of the total body surface area (TBSA); rats receiving a cecum ligation and puncture treatment (CLP) to induce infection [15]. We utilized the concept of area under the curve (AUC) method to assess the dynamic responses of cytokines and chemokines considering the temporal variability observed in the baseline corresponding to the control group.…”

“…Quantitative and temporal differences in the secretion of mediators and consequently their signaling patterns result in complex inflammatory responses. We recently identified a number of putative transcription factors of cytokines and chemokines which have been significantly altered following burn injury or sepsis [15]. Some of these transcription factors identified such as NFKB (or NF-κβ), STAT and CEBP have been already well studied in literature and shown to be activated by burn and sepsis in various tissues [13, 17–19].…”

The clinical significance of the MIF homolog d-dopachrome tautomerase (MIF-2) and its circulating receptor (sCD74) in burn

“…According to Orman et al the behavior of cytokines after burn injuries differs significantly from other diseases or traumas ( e.g. such as sepsis to cecal ligation and puncture treatment) [24]. …”

Carbohydrate-derived fulvic acid is a highly promising topical agent to enhance healing of wounds infected with drug-resistant pathogens

“…It is noticeable that CHD-FAYtreated wounds were more primed to proceed toward wound healing in both infection models. For instance, IL-10, one of the most important antiinflammatory cytokines in which its overexpression promotes wound healing, 11,17 was threefold more highly expressed than the untreated control at Day 3, suggesting that CHD-FAYtreated wounds were more likely to progress into the next stage of healing bylessening the severityof inflammation. Therefore, by Day 10 when most genes restored to baseline expression, there were still four genes (inflammatory chemokine CCL12 and CCL7, proinflammatory cytokine IL-6, and matrix metalloproteinase MMP9) highly expressed in the sham control, compared with the CHD-FAYtreated wound.…”