Kinetics of Inflammatory Mediators in the Immune Response to Burn Injury: Systematic Review and Meta-Analysis of Animal Studies.

Burns are often accompanied by a dysfunctional immune response, which can lead to systemic inflammation, shock, and excessive scarring. The objective of this study was to provide insight into inflammatory pathways associated with burn-related complications. Because detailed information on the various inflammatory mediators is scattered over individual studies, we systematically reviewed animal experimental data for all reported inflammatory mediators. Meta-analyses of 352 studies revealed a strong increase in cytokines, chemokines, and growth factors, particularly 19 mediators in blood and 12 in burn tissue. Temporal kinetics showed long-lasting surges of proinflammatory cytokines in blood and burn tissue. Significant time-dependent effects were seen for IL-1ß, IL-6, TGF-ß1, and CCL2. The response of anti-inflammatory mediators was limited. Burn technique had a profound impact on systemic response levels. Large burn size and scalds further increased systemic, but not local inflammation. Animal characteristics greatly affected inflammation, for example, IL-1ß, IL-6, and TNF-α levels were highest in young, male rats. Time-dependent effects and dissimilarities in response demonstrate the importance of appropriate study design. Collectively, this review presents a general overview of the burn-induced immune response exposing inflammatory pathways that could be targeted through immunotherapy for burn patients and provides guidance for experimental set-ups to advance burn research.

Establishing a health-based recommended occupational exposure limit for isoflurane using experimental animal data: a systematic review protocol.

BACKGROUND: Isoflurane is used as an inhalation anesthetic in medical, paramedical, and veterinary practice. Epidemiological studies suggest an increased risk of miscarriages and malformations at birth related to maternal exposure to isoflurane and other inhalation anesthetics. However, these studies cannot be used to derive an occupational exposure level (OEL), because exposure was not determined quantitatively and other risk factors such as co-exposures to other inhalation anesthetics and other work-related factors may also have contributed to the observed adverse outcomes. The aim of this systematic review project is to assess all available evidence on the effects of isoflurane in studies of controlled exposures in laboratory animals to derive a health-based recommended OEL. METHODS: A comprehensive search strategy was developed to retrieve all animal studies addressing isoflurane exposure from PubMed, EMBASE, and Web of Science. Title-abstract screening will be performed by machine learning, and full-text screening by one reviewer. Discrepancies will be resolved by discussion. We will include primary research in healthy, sexually mature (non human) vertebrates of single exposure to isoflurane. Studies describing combined exposure and treatments with > = 1 vol% isoflurane will be excluded. Subsequently, details regarding study identification, study design, animal model, and intervention will be summarized. All relevant exposure characteristics and outcomes will be extracted. The risk of bias will be assessed by two independent reviewers using an adapted version of the SYRCLE's risk of bias tool and an addition of the OHAT tool. For all outcomes for which dose-response curves can be derived, the benchmark dose (BMD) approach will be used to establish a point of departure for deriving a recommended health-based recommended OEL for 8 h (workshift exposure) and for 15 min (short-term exposure). DISCUSSION: Included studies should be sufficiently sensitive to detect the adverse health outcomes of interest. Uncertainties in the extrapolation from animals to humans will be addressed using assessment factor. These factors are justified in accordance with current practice in chemical risk assessment. A panel of experts will be involved to reach consensus decisions regarding significant steps in this project, such as determination of the critical effects and how to extrapolate from animals to humans. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022308978.

The effects of aerobic exercise on neuroimmune responses in animals with traumatic peripheral nerve injury: a systematic review with meta-analyses.

BACKGROUND: Increasing pre-clinical evidence suggests that aerobic exercise positively modulates neuroimmune responses following traumatic nerve injury. However, meta-analyses on neuroimmune outcomes are currently still lacking. This study aimed to synthesize the pre-clinical literature on the effects of aerobic exercise on neuroimmune responses following peripheral nerve injury. METHODS: MEDLINE (via Pubmed), EMBASE and Web of Science were searched. Controlled experimental studies on the effect of aerobic exercise on neuroimmune responses in animals with a traumatically induced peripheral neuropathy were considered. Study selection, risk of bias assessment and data extraction were performed independently by two reviewers. Results were analyzed using random effects models and reported as standardized mean differences. Outcome measures were reported per anatomical location and per class of neuro-immune substance. RESULTS: The literature search resulted in 14,590 records. Forty studies were included, reporting 139 comparisons of neuroimmune responses at various anatomical locations. All studies had an unclear risk of bias. Compared to non-exercised animals, meta-analyses showed the following main differences in exercised animals: (1) in the affected nerve, tumor necrosis factor-α (TNF-α) levels were lower (p = 0.003), while insulin-like growth factor-1 (IGF-1) (p < 0.001) and Growth Associated Protein 43 (GAP43) (p = 0.01) levels were higher; (2) At the dorsal root ganglia, brain-derived neurotrophic factor (BDNF)/BDNF mRNA levels (p = 0.004) and nerve growth factor (NGF)/NGF mRNA (p < 0.05) levels were lower; (3) in the spinal cord, BDNF levels (p = 0.006) were lower; at the dorsal horn, microglia (p < 0.001) and astrocyte (p = 0.005) marker levels were lower; at the ventral horn, astrocyte marker levels (p < 0.001) were higher, and several outcomes related to synaptic stripping were favorably altered; (4) brainstem 5-HT2A receptor levels were higher (p = 0.001); (5) in muscles, BDNF levels (p < 0.001) were higher and TNF-α levels lower (p < 0.05); (6) no significant differences were found for systemic neuroimmune responses in blood or serum. CONCLUSION: This review revealed widespread positive modulatory effects of aerobic exercise on neuroimmune responses following traumatic peripheral nerve injury. These changes are in line with a beneficial influence on pro-inflammatory processes and increased anti-inflammatory responses. Given the small sample sizes and the unclear risk of bias of the studies, results should be interpreted with caution.

The Effect of Growth Factors on Vaginal Wound Healing: A Systematic Review and Meta-analysis.

Surgical outcomes of pelvic organ prolapse (POP) surgery are poor, resulting in a 20% recurrence risk. Following the hypothesis that impaired wound healing is the main determinant of recurrent POP, growth factors have the potential to promote wound healing and may improve surgical outcomes. In this study, we systematically reviewed the effect of growth factors on vaginal wound healing in both in vitro and animal studies. For each independent comparison, the standardized mean difference and 95% CI were calculated using the Hedges' g correction. Of the 3858 retrieved studies, seven studies were included, of which six were included in meta-analysis (three in vitro studies and four in vivo studies). In vitro, basic fibroblast growth factor (bFGF) promotes proliferation, differentiation, and collagen types I and III production. Epidermal growth factor stimulates proliferation and connective tissue growth factor promotes Tenascin-C expression. These effects, however, are less pronounced in vivo; only bFGF slightly promotes collagen production. The review shows that growth factors, particularly bFGF, are able to promote vaginal wound healing in vitro. The uncertain in vivo findings suggest that preclinical models should be improved. The ultimate goal is to develop effective growth factor-supplemented therapies that improve surgical outcomes for POP.

Application of amniotic membranes in reconstructive surgery of internal organs-A systematic review and meta-analysis.

Amniotic membrane (AM) has great potential as a scaffold for tissue regeneration in reconstructive surgery. To date, no systematic review of the literature has been performed for the applications of AM in wound closure of internal organs. Therefore, in this systematic review and meta-analysis, we summarize the literature on the safety and efficacy of AM for the closure of internal organs. A systematic search was performed in MEDLINE-PubMed database and OVID Embase to retrieve human and controlled animal studies on wound closure of internal organs. The Cochrane Risk of Bias tool for randomized clinical trials and the SYRCLE risk of bias tool for animal studies were used. Meta-analyses (MAs) were conducted for controlled animal studies to assess efficacy of closure, mortality and complications in subjects who underwent surgical wound closure in internal organs with the application of AM. Sixty references containing 26 human experiments and 36 animal experiments were included. The MAs of the controlled animal studies showed comparable results with regard to closure, mortality and complications, and suggested improved mechanical strength and lower inflammation scores after AM application when compared to standard surgical closure techniques. This systematic review and MAs demonstrate that the application of AM to promote wound healing of internal organs appears to be safe, efficacious, and feasible.

The effects of oestrogen on vaginal wound healing: A systematic review and meta-analysis.

AIMS: To determine the effects of oestrogen or oestrogen deprivation on vaginal wound healing. Impaired wound healing following prolapse surgery may increase the risk of recurrent prolapse in the future. Vaginal oestrogen therapy may improve wound healing, hereby possibly improving surgical outcomes. METHODS: A systematic search of OVID MEDLINE, OVID Embase, and Web of Science was conducted up to January 28, 2020. We included original studies comparing wound healing-related outcomes of oestrogen exposed subjects (female animals and women) to hypo-oestrogenic subjects after vaginal surgery. Data on wound healing-related outcome measures were extracted. For each individual comparison, the standardised mean difference (Hedges' g; SMD) and 95% confidence interval (CI) were calculated. RESULTS: Of the 1474 studies reviewed, 14 studies were included for review, and 11 provided data for meta-analysis. Oestrogen improves neovascularisation (SMD: 1.13, 95% CI: 0.67-1.60), microscopic wound closure (SMD: 0.98, 95% CI: 0.66-1.29), collagen synthesis (SMD: 1.08, 95% CI: 0.42-1.74), and tissue strength (SMD: 1.26, 95% CI: 0.53-1.99) in animals. Oestrogen increases granulation (SMD: 1.67, 95% CI: 0.54-2.79) and accelerates macroscopic wound closure (SMD: 1.82, 95% CI: 1.22-2.42) in women and animals. Oestrogen decreases the inflammatory response (SMD: -0.58, 95% CI: -1.14 to -0.02) in women and animals and reduces levels of transforming growth factor (TGF)-ß1 (SMD: -1.68, 95% CI: -2.52 to -0.83) in animals. All results were statistically significant. CONCLUSIONS: Oestrogen therapy has a positive effect on vaginal wound healing. Future studies should determine whether oestrogen therapy has the potential to improve surgical outcomes.

Animal experimental research assessing urogynecologic surgical mesh implants: Outcome measures describing the host response, a systematic review and meta-analysis.

AIM: Before the introduction of new biomaterials for prolapse surgery, animal studies on the host response are required. Unfortunately, large variation in study design hampers obtaining an overview of the safety and efficacy, and translation to clinical practice. Our aim is to systematically review the literature on all outcome measures describing the host response in animal studies assessing the biocompatibility of urogynecologic surgical mesh implants for prolapse surgery. Furthermore, by meta-analysis, we aim to assess the effect of implantation and compare this to control animals receiving sham surgery or native tissue repair. METHODS: We performed a systematic search from inception to August 2020. Since this is an explorative study we included original, controlled, and noncontrolled animal studies describing any host response to the implant. Quantitative outcome measures reported ≥10 times in ≥2 articles were eligible for meta-analysis. RESULTS: Fifty articles were included in the qualitative synthesis and 36 articles were eligible for meta-analysis. In total, 154 outcome measures were defined and classified into (1) histomorphology, (2) biomechanics and, (3) macroscopic morphology. Animals with vaginal implants demonstrated significantly increased M1 and M2 macrophages, MMP-2, neovascularization, TNF-α, and stiffness, and lower vaginal contractility compared to control animals. CONCLUSION: The host response significantly differs in animals after vaginal mesh implantation compared to control animals, both pro- and anti-inflammatory. However, we observed a paucity in the uniformity of reported outcomes. For future animal studies, we propose the development of a core outcome set, which ideally predicts the host response in women.

The effect of macrophage-targeted interventions on blood pressure - a systematic review and meta-analysis of preclinical studies.

An increasing body of evidence shows a role for macrophages and monocytes (as their precursors) in hypertension, but with conflicting results with regard to whether they are protective or harmful. Therefore, we systematically reviewed the effect of macrophage interventions on blood pressure in animal models, to explore which factors determine the blood pressure increasing vs. decreasing effect. A search in PubMED and EMBASE yielded 9620 records, 26 of which were included. Eighteen studies (involving 22 different experiments (k = 22)) performed macrophage depletion, whereas 12 studies specifically deleted certain macrophage proteins. The blood pressure effects of macrophage depletion were highly various and directed toward both directions, as expected, which could not be reduced to differences in animal species or methods of hypertension induction. Prespecified subgroup analysis did reveal a potential role for the route in which the macrophage-depleting agent is being administrated (intraperitoneal vs intravenous subgroup difference of P = 0.07 (k = 22), or P < 0.001 in studies achieving considerable (ie, >50%) depletion (k = 18)). Along with findings from specific macrophage protein deletion studies-showing that deletion of one single macrophage protein (like TonEBP, endothelin-B, EP4, NOX-2 and the angiotensin II type 1 receptor) can alter blood pressure responses to hypertensive stimuli-the indication that each route has its specific depletion pattern regarding targeted tissues and macrophage phenotypes suggests a determinative role for these features. These hypothesis-generating results encourage more detailed depletion characterization of each technique by direct experimental comparisons, providing a chance to obtain more knowledge on which macrophages are beneficial versus detrimental in hypertension development.

A systematic summary and comparison of animal models for chemotherapy induced (peripheral) neuropathy (CIPN).

Despite the large amount of human and experimental studies no effective (prophylactic) treatment exists for chemotherapy induced peripheral neuropathy (CIPN), a disabling side effect of many cancer treatments. One of the underlying reasons for this could be that often the preclinical animal models used are not the best representation of the clinical situation. We therefore present a systematic summary and comparison of all animal models currently described in literature for CIPN focusing on stimulus evoked pain-like behaviour and neurophysiological alterations in nerve function (650 included papers, and a comparison of 183 models), that resulted in a clear overview of the most effective and robust CIPN models using an administration route used in clinical practice. Using our three-step approach (step 1: efficacy; step; 2 robustness and step 3: mimicking the clinical situation) we show that all mice CIPN models treated with either paclitaxel or cisplatin using an administration route used in clinical practice seem suitable models. Three specific models using paclitaxel or cisplatin that stand out are 1) C57BL/6 female mice receiving paclitaxel and 2) CD1 male mice receiving paclitaxel and 3) C57BL/6 male mice receiving cisplatin. This overview may help scientists selecting suitable CIPN models for their research. We hypothesize that by using effective and robust animal models that mimic the clinical situation as much as possible, the translational value of preclinical study results with respect to the potential of identifying promising treatments for CIPN in the future, will prove. The methodology described in this paper, aimed at comparing animal models, is novel and can be used by scientist in other research fields as well.

Facilitating healthcare decisions by assessing the certainty in the evidence from preclinical animal studies.

Laboratory animal studies are used in a wide range of human health related research areas, such as basic biomedical research, drug research, experimental surgery and environmental health. The results of these studies can be used to inform decisions regarding clinical research in humans, for example the decision to proceed to clinical trials. If the research question relates to potential harms with no expectation of benefit (e.g., toxicology), studies in experimental animals may provide the only relevant or controlled data and directly inform clinical management decisions. Systematic reviews and meta-analyses are important tools to provide robust and informative evidence summaries of these animal studies. Rating how certain we are about the evidence could provide important information about the translational probability of findings in experimental animal studies to clinical practice and probably improve it. Evidence summaries and certainty in the evidence ratings could also be used (1) to support selection of interventions with best therapeutic potential to be tested in clinical trials, (2) to justify a regulatory decision limiting human exposure (to drug or toxin), or to (3) support decisions on the utility of further animal experiments. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach is the most widely used framework to rate the certainty in the evidence and strength of health care recommendations. Here we present how the GRADE approach could be used to rate the certainty in the evidence of preclinical animal studies in the context of therapeutic interventions. We also discuss the methodological challenges that we identified, and for which further work is needed. Examples are defining the importance of consistency within and across animal species and using GRADE's indirectness domain as a tool to predict translation from animal models to humans.

A Systematic Review of the Modifying Effect of Anaesthetic Drugs on Metastasis in Animal Models for Cancer.

BACKGROUND: Distant metastasis or local recurrence after primary tumour resection remain a major clinical problem. The anaesthetic technique used during oncologic surgery is suggested to influence the metastatic process. While awaiting the results of ongoing randomised controlled trials (RCTs), we have analyzed the evidence regarding the influence of anaesthetic drugs on experimental tumour metastasis in animal studies. METHODS: PubMed and Embase were searched until April 21st, 2015. Studies were included in the systematic review when they 1) assessed the effect of an anaesthetic drug used in clinical practice on the number or incidence of metastasis in animal models with experimental cancer, 2) included an appropriate control group, and 3) presented unique data. RESULTS: 20 studies met the inclusion criteria (published between 1958-2010). Data on number of metastases could be retrieved from 17 studies. These studies described 41 independent comparisons, 33 of which could be included in the meta-analysis (MA). The incidence of metastases was studied in 3 unique papers. From these 3 papers, data on 7 independent comparisons could be extracted and included in the MA. Locally administered local anaesthetics appear to decrease the number of metastases (SMD -6.15 [-8.42; -3.88]), whereas general anaesthetics (RD: 0.136 [0.045, 0.226]), and more specifically volatile anaesthetics (SMD 0.54 [0.24; 0.84]), appear to increase the number and risk of metastases in animal models for cancer. CONCLUSIONS: Anaesthetics influence the number and incidence of metastases in experimental cancer models. Although more high quality experimental research is necessary, based on the currently available evidence from animal studies, there is no indication to suggest that locally administered local anaesthetics are harmful during surgery in cancer patients. Volatile anaesthetics, however, might increase metastasis in animal models and clinical trials investigating this possibly harmful effect should receive priority. The results of our systematic review in animal studies are broadly consistent with clinical reports that anaesthetic technique does seem to affect the tumour metastasis process.

A systematic review and meta-analysis of the ability of analgesic drugs to reduce metastasis in experimental cancer models.

Analgesics are commonly used to manage pain in cancer patients. It has been suggested that there might be a relation between analgesics and the outgrowth of metastases. Opioids might increase and non-steroidal anti-inflammatory drugs decrease the risk of metastasis. Robust analysis of all preclinical evidence, however, has so far been lacking. Therefore, we conducted a systematic review and meta-analysis on the effect of treatment with analgesics on metastasis in experimental animal models. One hundred forty-seven studies met the inclusion criteria. Study characteristics, outcome data on the number, and incidence of metastases were extracted, and methodological quality was assessed. In the meta-analysis, we included 215 (± 4000 animals) and 137 (± 3000 animals) comparisons between analgesic vs control treatment, respectively, on the number and incidence of metastases. Overall, treatment with analgesics significantly decreases the number and risk of metastasis. This effect appears mainly to be the consequence of the efficacy of NSAIDs. Other factors that modify the efficacy are species, type of NSAIDs administered, timing, and duration of treatment. There is no evidence indicating that treatment with any analgesics increases the occurrence of metastases. Our findings appear robust for the various animal models and designs included in this review, which increases our confidence in the result and translatability to the clinical situation.

S-adenosylmethionine and S-adenosylhomocysteine levels in the aging brain of APP/PS1 Alzheimer mice.

Hyperhomocysteinemia and factors of homocysteine metabolism, S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet), may play a role in Alzheimer's disease (AD). With liquid-chromatography-tandem-mass-spectrometry AdoMet and AdoHcy were determined in brains of 8- and 15-month-old APP/PS1 Alzheimer mice, and their possible roles in AD brains investigated. The finding that AdoMet levels do not differ between the genotypes in (young) 8-month-old mice, but are different in (older) 15-month-old APP/PS1 mice compared to their wild-type littermates, suggests that alterations in AdoMet are a consequence of AD pathology rather than a cause. During aging, AdoMet levels decreased in the brains of wild-type mice, whereas AdoHcy levels diminished in both wild type and APP/PS1 mice. The finding that AdoMet levels in APP/PS1 mice are not decreased during aging (in contrast to wild-type mice), is probably related to less demand due to neurodegeneration. No effect of the omega-3 fatty acid docosahexaenoic acid (DHA) or cholesterol-enriched diets on AdoMet or AdoHcy levels were found.