77 Review Inflammatory Mediators in Animal Burn Models IL-6, IL-10 and TNF-α were higher in rats than in mice, possibly because rats are larger animals, require a longer healing time and are immunologically more similar to humans than mice [19]. On the contrary, wound tissue levels of IL-1β, IL-10 and TNF-α were higher in mice, demonstrating that blood levels do not necessarily represent or predict levels in wound tissue. IL-6 and blood TNF-α were higher in male animals than in females. Sex chromosome genes and differences in hormonal systems proposedly contribute to differential regulation of immune responses between sexes [53]. For this reason male animals are often preferred over females, which creates bias in the available data [54]. Blood levels of IL-1β and TNF-α were higher in young animals than adults. Other researchers reported reduced levels of TNF-α when macrophages from adult mice were stimulated with LPS, due to reduced toll-like receptor expression and function [55,56]. Contrastingly, induced levels of immune cells are generally higher in adult animals [8]. This could mean that although induced levels of inflammatory mediators are higher in young animals, the cellular immune response can be more intense in adults. The young immune system might be underdeveloped and more tolerant, while the adult immune system is apparently more experienced and differently regulated, possibly due to longterm exposure to pathogens [57,58]. Higher levels of wound IL-10 were found by mRNA analysis than by protein analysis. This finding might be related to delayed or troubled protein synthesis or immediate uptake of IL-10 by immune cells. There is still much uncertainty about the relation between mRNA expression and protein levels, therefore more research is needed to clarify this [59,60]. Collectively, these insights demonstrate the importance of appropriate study model design and accurate interpretation of data [61] and might also be relevant in clinical practice. Although our search strategy led to the inclusion of a large number of studies, this review, like many other reviews, was hurdled by underreporting of relevant study details (intervention and experimental procedures) and omission of data that is essential for meta-analysis (e.g., number of animals, standard deviation) (Osborne et al., 2018; du Sert et al., 2020). Authors were contacted for access to raw data sets or information on study details, but the response rate was low. Furthermore, in several studies the investigated subtype or form of IL-1 (α or β), IL-12 (subunit p40 or p70), IL-17 (A-F), VEGF (A-D) and TGF-β (1-3, latent or free [62]) was not specified, stressing the need for correct use of nomenclature in reporting. Failure to adhere to the ARRIVE guidelines makes a large portion of data unsuitable for reuse in advanced analyses and complicates the assessment of study quality and risk of bias. To improve research quality and reusability, there is a strong demand for sharpened reporting standards and effortless access to raw data [17,63]. In turn, this will lead to reduction, refinement and replacement of animal models and can support healthcare developments [13,64]. 3
RkJQdWJsaXNoZXIy MTk4NDMw