Dataset Information

Obesity Prolongs the Inflammatory Response in Mice After Severe Trauma and Attenuates the Splenic Response to the Inflammatory Reflex.

ABSTRACT: Thoracic traumas with extra-thoracic injuries result in an immediate, complex host response. The immune response requires tight regulation and can be influenced by additional risk factors such as obesity, which is considered a state of chronic inflammation. Utilizing high-dimensional mass and regular flow cytometry, we define key signatures of obesity-related alterations of the immune system during the response to the trauma. In this context, we report a modification in important components of the splenic response to the inflammatory reflex in obese mice. Furthermore, during the response to trauma, obese mice exhibit a prolonged increase of neutrophils and an early accumulation of inflammation associated CCR2⁺CD62L⁺Ly6C^hi monocytes in the blood, contributing to a persistent inflammatory phase. Moreover, these mice exhibit differences in migration patterns of monocytes to the traumatized lung, resulting in decreased numbers of regenerative macrophages and an impaired M1/M2 switch in traumatized lungs. The findings presented in this study reveal an attenuation of the inflammatory reflex in obese mice, as well as a disturbance of the monocytic compartment contributing to a prolonged inflammation phase resulting in fewer phenotypically regenerative macrophages in the lung of obese mice.

SUBMITTER: Gartner F

PROVIDER: S-EPMC8634681 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Obesity Prolongs the Inflammatory Response in Mice After Severe Trauma and Attenuates the Splenic Response to the Inflammatory Reflex.

Gärtner Fabian F Gihring Adrian A Roth Aileen A Bischof Joachim J Xu Pengfei P Elad Leonard L Wabitsch Martin M Burster Timo T Knippschild Uwe U

Frontiers in immunology 20211115

Thoracic traumas with extra-thoracic injuries result in an immediate, complex host response. The immune response requires tight regulation and can be influenced by additional risk factors such as obesity, which is considered a state of chronic inflammation. Utilizing high-dimensional mass and regular flow cytometry, we define key signatures of obesity-related alterations of the immune system during the response to the trauma. In this context, we report a modification in important components of t ...[more]

PMID: 34867969

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Project description:BackgroundPlasma has been shown to mitigate the endotheliopathy of trauma. Protection of the endothelium may be due in part to fibrinogen and other plasma-derived proteins found in cryoprecipitate; however, the exact mechanisms remain unknown. Clinical trials are underway investigating early cryoprecipitate administration in trauma. In this study, we hypothesize that cryoprecipitate will inhibit endothelial cell (EC) permeability in vitro and will replicate the ability of plasma to attenuate pulmonary vascular permeability and inflammation induced by hemorrhagic shock and trauma (HS/T) in mice.MethodsIn vitro, barrier permeability of ECs subjected to thrombin challenge was measured by transendothelial electrical resistance. In vivo, using an established mouse model of HS/T, we compared pulmonary vascular permeability among mice resuscitated with (1) lactated Ringer's solution (LR), (2) fresh frozen plasma (FFP), or (3) cryoprecipitate. Lung tissue from the mice in all groups was analyzed for markers of vascular integrity, inflammation, and inflammatory gene expression via NanoString messenger RNA quantification.ResultsCryoprecipitate attenuates EC permeability and EC junctional compromise induced by thrombin in vitro in a dose-dependent fashion. In vivo, resuscitation of HS/T mice with either FFP or cryoprecipitate attenuates pulmonary vascular permeability (sham, 297 ± 155; LR, 848 ± 331; FFP, 379 ± 275; cryoprecipitate, 405 ± 207; p < 0.01, sham vs. LR; p < 0.01, LR vs. FFP; and p < 0.05, LR vs. cryoprecipitate). Lungs from cryoprecipitate- and FFP-treated mice demonstrate decreased lung injury, decreased infiltration of neutrophils and activation of macrophages, and preserved pericyte-endothelial interaction compared with LR-treated mice. Gene analysis of lung tissue from cryoprecipitate- and FFP-treated mice demonstrates decreased inflammatory gene expression, in particular, IL-1β and NLRP3, compared with LR-treated mice.ConclusionOur data suggest that cryoprecipitate attenuates the endotheliopathy of trauma in HS/T similar to FFP. Further investigation is warranted on active components and their mechanisms of action.

Project description:The study was aimed to identify mechanisms linked to complicated courses after severe trauma by a systems biology approach. In severe trauma, overwhelming systemic inflammation can result in adverse events and the development of complications, including sepsis. In a prospective study, RNA samples from circulating leukocytes from patients with multiple injury (injury severity score â¥ 17) were analyzed for dynamic changes in gene expression over a period of 21 days by whole genome screening. Based on their clinical presentation, patients were divided into two subgroups: patients with secondary sepsis after trauma (n=5) and patients with systemic inflammation without infection (n=5). Expression cluster were defined by correlating gene expression data with clinical outcome parameters. Using unsupervised clustering, patients with systemic inflammation only and patients with sepsis showed a distinct expression pattern and the discrimination of clinical presentation was reflected by clustering of the samples. Explorative gene set analysis revealed robust upregulation of genes related to âhemoglobin metabolism/oxygen transportâ and âpathogenic E.coli infectionâ. 10 patients with multi-system trauma (ISS â¥ 17 points) admitted to the Division of Trauma Surgery at the University Hospital Zurich were included. Whole blood from trauma patients was collected within the first 6 h after trauma (day 0) and on days 1, 2, 3, 5, 7, 10, 14, and 21. Total cellular RNA from circulating leukocytes was isolated using PaxGene Blood RNA Kit (PreAnalytix) for transcriptome profiling. RNA from blood of trauma patients was extracted and subjected to microarray analysis for comparison of longitudinal transcriptomic responses of patients. RNA samples of circulating leukocytes covering time points directly after admission (D0) and on the consecutive days (D1-D21) were subject to multifactorial microarray data analysis: Differences in dynamics of transcripts were assessed by contrasting time- and individual-resolved changes for sepsis and systemic inflammation without infection.

Project description:Accumulating evidence has reported that the intestinal microbiota could play important roles in the occurrence and progression of severe trauma. However, the hypothesized potential targeted intestinal microbiota to mediate and regulate the levels of inflammatory cytokines and promote rapid recovery of body after severe trauma remains unclear. This study was aimed to explore the changes and correlation of intestinal microbiota and inflammatory cytokines in rats with severe crush and fracture trauma. The controlled laboratory study design was used, and a crush and fracture severe trauma rat model was established. 16S rRNA high-throughput gene sequencing and ELISA were used to analyze the changes in intestinal microbiota and inflammatory cytokines within one week after trauma. The correlation between intestinal microbiota and inflammatory cytokines was also analyzed. Loss of overall diversity and expansion of intestinal microbiota in the rats due to severe trauma was observed. Specifically, there was a significant increase in the abundance of Muribaculaceae [LDA (Linear Discriminant Analysis)-value = 4.814, P = 0.014] after severe trauma, while Prevotella (LDA-value = 5.235, P = 0.020) and Alloprevotella (LDA-value = 4.443, P = 0.015) were slightly lower in the trauma group than in the control group. The levels of inflammatory cytokines (IL-1α, IL-6, IL-8 and TNF-α) in the trauma group decreased from the first day to the third day and continued to increase until one week after the trauma. Prevotellaceae_UCG_001 was correlated with TNF-a (R = 0.411, P = 0.033); Lactobacillus was negatively correlated with IL-6 (R = - 0.434, P = 0.024) and IL-1α (R = - 0.419, P = 0.030) and positively correlated with IL-8 (R = 0.391, P = 0.045); and Lachnospiraceae_NK4A136_group (R = - 0.559, P = 0.027) and Muribaculaceae (R = - 0.568, P = 0.024) were negatively correlated with IL-8. Severe trauma shows stress-like activities by negatively modulating intestinal microbiota and affecting certain inflammatory cytokines contributing to host health, which implies that the regulation of potentially targeted intestinal microbiota, and further mediating and maintaining the homeostasis of inflammatory cytokines, is expected to promote the accelerating recovery of the body after severe trauma.

Dataset Information

Obesity Prolongs the Inflammatory Response in Mice After Severe Trauma and Attenuates the Splenic Response to the Inflammatory Reflex.

Publications

Obesity Prolongs the Inflammatory Response in Mice After Severe Trauma and Attenuates the Splenic Response to the Inflammatory Reflex.

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