Traumatic inflammatory response: pathophysiological role and clinical value of cytokines.

Severe trauma is an intractable problem in healthcare. Patients have a widespread immune system response that is complex and vital to survival. Excessive inflammatory response is the main cause of poor prognosis and poor therapeutic effect of medications in trauma patients. Cytokines are signaling proteins that play critical roles in the body's response to injuries, which could amplify or suppress immune responses. Studies have demonstrated that cytokines are closely related to the severity of injuries and prognosis of trauma patients and help present cytokine-based diagnosis and treatment plans for trauma patients. In this review, we introduce the pathophysiological mechanisms of a traumatic inflammatory response and the role of cytokines in trauma patients. Furthermore, we discuss the potential of cytokine-based diagnosis and therapy for post-traumatic inflammatory response, although further clarification to elucidate the underlying mechanisms of cytokines following trauma is warranted.

The role of mtDAMPs in the trauma-induced systemic inflammatory response syndrome.

Systemic inflammatory response syndrome (SIRS) is a non-specific exaggerated defense response caused by infectious or non-infectious stressors such as trauma, burn, surgery, ischemia and reperfusion, and malignancy, which can eventually lead to an uncontrolled inflammatory response. In addition to the early mortality due to the "first hits" after trauma, the trauma-induced SIRS and multiple organ dysfunction syndrome (MODS) are the main reasons for the poor prognosis of trauma patients as "second hits". Unlike infection-induced SIRS caused by pathogen-associated molecular patterns (PAMPs), trauma-induced SIRS is mainly mediated by damage-associated molecular patterns (DAMPs) including mitochondrial DAMPs (mtDAMPs). MtDAMPs released after trauma-induced mitochondrial injury, including mitochondrial DNA (mtDNA) and mitochondrial formyl peptides (mtFPs), can activate inflammatory response through multiple inflammatory signaling pathways. This review summarizes the role and mechanism of mtDAMPs in the occurrence and development of trauma-induced SIRS.

Mitochondrial antioxidant SkQ1 decreases inflammation following hemorrhagic shock by protecting myocardial mitochondria.

Background: Hemorrhagic shock (HS) is a type of hypovolemic shock characterized by hemodynamic instability, tissue hypoperfusion and cellular hypoxia. In pathophysiology, the gradual accumulation of reactive oxygen species (ROS) damages the mitochondria, leading to irreversible cell damage and the release of endogenous damage-associated molecular patterns (DAMPs) including mitochondrial DAMPs (MTDs), eventually triggering the inflammatory response. The novel mitochondria-targeted antioxidant SkQ1 (Visomitin) effectively eliminate excessive intracellular ROS and exhibits anti-inflammatory effects; however, the specific role of SkQ1 in HS has not yet been explicated. Methods and results: A 40% fixed-blood-loss HS rat model was established in this study. Transmission electron microscopy showed that after HS, the myocardial mitochondrial ultrastructure was damaged and the mtDNA release in circulation was increased and the differentially expressed genes were significantly enriched in mitochondrial and ROS-related pathways. Mitochondria-targeted antioxidant SkQ1 attenuated the increased ROS induced by HS in myocardial tissues and by oxygen-glucose deprivation (OGD) in cardiomyocytes. Ultrastructurally, SkQ1 protected the myocardial mitochondrial structure and reduced the release of the peripheral blood mtDNA after HS. RNA-seq transcriptome analysis showed that 56.5% of the inflammation-related genes, which altered after HS, could be significantly reversed after SkQ1 treatment. Moreover, ELISA indicated that SkQ1 significantly reversed the HS-induced increases in the TNF-α, IL-6, and MCP-1 protein levels in rat peripheral blood. Conclusion: HS causes damage to the rat myocardial mitochondrial structure, increases mtDNA release and ROS contents, activates the mitochondrial and ROS-related pathways, and induces systemic inflammatory response. The mitochondrial antioxidant SkQ1 can improve rat myocardial mitochondria ultrastructure, reduce mtDNA and ROS contents, and decrease inflammation by protecting myocardial mitochondria, thereby playing a novel protective role in HS.

Exogenous growth hormone functionally alleviates glucocorticoid-induced longitudinal bone growth retardation in male rats by activating the Ihh/PTHrP signaling pathway.

Glucocorticoid (GC)-induced longitudinal bone growth retardation is a common and severe adverse effect in pediatric patients receiving GC immunosuppressive therapy. Molecular mechanisms underlying GC-induced growth inhibition are unclear. GC withdrawal following short-term high-dose use is common, including in the immediate post-transplant period. However, whether skeleton growth recovery is sufficient or whether growth-promoting therapy is required following GC withdrawal is unknown. The aim of this study was to investigate the effect of exogenous growth hormone (GH) on growth plate impairment in GC-induced longitudinal bone growth retardation. Here, apoptotic chondrocytes in the hypertrophic layer of growth plates increased whereas Indian Hedgehog (Ihh) and Parathyroid Hormone Related Peptide (PTHrP) protein levels in the growth plate decreased following GC exposure. The hypertrophic zone of the growth plate expanded following GC withdrawal. Subcutaneously injected GH penetrated the growth plate and modified its organization in rats following GC withdrawal. Ihh and PTHrP expression in GC-induced apoptotic chondrocytes decreased in vitro. GH promoted chondrocyte proliferation by activating Ihh/PTHrP signaling. Downregulating Ihh using specific siRNAs increased chondrocyte apoptosis and inhibited PTHrP, Sox9, and type II collagen (Col2a1) protein expression. GH inhibited apoptosis of Ihh-deficient growth plate chondrocytes by upregulating PTHrP, Sox9, and Col2a1 expression. Thus, reversal of the effect of GC on growth plate impairment following its withdrawal is insufficient, and exogenous GH provides growth plate chondral protection and improved longitudinal growth following GC withdrawal by acting on the Ihh/PTHrP pathway.

Tim-3 regulates sepsis-induced immunosuppression by inhibiting the NF-κB signaling pathway in CD4 T cells.

Immunosuppression in response to severe sepsis remains a serious human health concern. Evidence of sepsis-induced immunosuppression includes impaired T lymphocyte function, T lymphocyte depletion or exhaustion, increased susceptibility to opportunistic nosocomial infection, and imbalanced cytokine secretion. CD4 T cells play a critical role in cellular and humoral immune responses during sepsis. Here, using an RNA sequencing assay, we found that the expression of T cell-containing immunoglobulin and mucin domain-3 (Tim-3) on CD4 T cells in sepsis-induced immunosuppression patients was significantly elevated. Furthermore, the percentage of Tim-3+ CD4 T cells from sepsis patients was correlated with the mortality of sepsis-induced immunosuppression. Conditional deletion of Tim-3 in CD4 T cells and systemic Tim-3 deletion both reduced mortality in response to sepsis in mice by preserving organ function. Tim-3+ CD4 T cells exhibited reduced proliferative ability and elevated expression of inhibitory markers compared with Tim-3-CD4 T cells. Colocalization analyses indicated that HMGB1 was a ligand that binds to Tim-3 on CD4 T cells and that its binding inhibited the NF-κB signaling pathway in Tim-3+ CD4 T cells during sepsis-induced immunosuppression. Together, our findings reveal the mechanism of Tim-3 in regulating sepsis-induced immunosuppression and provide a novel therapeutic target for this condition.

A Functional Variant of CXCL16 Is Associated With Predisposition to Sepsis and MODS in Trauma Patients: Genetic Association Studies.

PURPOSE: CXC chemokines are mediators which mediate immune cells migration to sites of inflammation and injury. Chemokine C-X-C motif ligand 16 (CXCL16) plays an important role in the occurrence and development of sepsis through leukocyte chemotaxis, leukocyte adhesion and endotoxin clearance. In this study, we selected a set of tagging single nucleotide polymorphisms (tag SNPs) in the CXCL16 gene and investigated their clinical relevance to the development of sepsis and multiple organ dysfunction syndrome (MODS) in patients with major trauma in three independent Chinese Han populations. METHODS: A total of 1,620 major trauma patients were enrolled in this study. Among these patients, 920 came from Chongqing in western China, 350 came from Zhejiang Province in eastern China, and 350 came from Guizhou Province in southwestern China. The improved multiplex ligation detection reaction (iMLDR) method was employed in the genotyping and genetic association analyses to determine the associations between CXCL16 haplotypes and sepsis morbidity rate and higher MOD scores in three cohorts. RESULTS: Only CXCL16 T123V181 haplotype was associated with an increased risk for sepsis morbidity and higher MOD scores in the three cohorts (OR = 1.89, P = 0.001 for the Chongqing cohort; OR = 1.76, P = 0.004 for the Zhejiang cohort; OR = 1.55, P = 0.012 for the Guizhou cohort). The effect of T123V181 haplotype on the chemotaxis, migration and endotoxin clearance of immune cells were further observed. Protein modeling analysis showed that T123 and V181 might alter the structure of the CXCL16 active center. Thus it enhanced the chemotaxis and adhesion ability of immunocytes. CONCLUSION: We demonstrate the mechanism of CXCL16 T123V181 haplotype which regulates the sepsis morbidity rate and thus provide a new biomarker for early diagnosis of sepsis and MODS. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT01713205 (https://www.clinicaltrials.gov/ct2/results?cond=&term=+NCT01713205&cntry=&state=&city=&dist=).

The Value of Interleukin-10 in the Early Diagnosis of Neonatal Sepsis: A Meta-Analysis.

OBJECTIVES: Interleukin-10 is a significant marker in neonatal sepsis. This meta-analysis evaluated the accuracy of interleukin-10 expression in the diagnosis of neonatal sepsis. DATA SOURCE: Summary of literature review. STUDY SELECTION: A literature search strategy was developed, including PubMed, EMBASE, Web of Science, MEDLINE, and the Cochrane Library. All publications published till October 1, 2020, were retrieved; the key words were "sepsis" and "interleukin-10." DATA EXTRACTION: The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were used to evaluate the data, and the heterogeneity of the combined results was tested according to the I2 value. DATA SYNTHESIS: A total of six articles involving 879 newborns were included in the study. The combined sensitivity was 0.82 (95% CI, 0.78-0.86), the specificity was 0.79 (95% CI, 0.75-0.82), the positive likelihood ratio was 4.17 (95% CI, 2.6-6.69), and the negative likelihood ratio was 0.25 (95% CI, 0.16-0.39). The area under the summary receiver operating characteristic curve was 0.88 (95% CI, 0.86-0.91), and the Q index was 0.81. The combined diagnostic odds ratio was 17.52 (95% CI, 8.95-34.29). CONCLUSIONS: Based on the results of the meta-analysis, interleukin-10 is a useful biomarker in the early diagnosis of neonatal sepsis. Its sensitivity, specificity, and diagnostic ability are excellent. However, it needs to be combined with clinical history data for comprehensive judgment and should not be used alone for diagnosis.

[Dynamic changes of cellular immune function in trauma patients and its relationship with prognosis].

OBJECTIVE: To study the dynamic changes of cellular immune function in peripheral blood of trauma patients and its role in the evaluation of traumatic complications. METHODS: A prospective cohort study design was conducted. Patients with blunt trauma admitted to Chongqing Emergency Medical Center from November 2019 to January 2020 were consecutively enrolled. The peripheral blood samples were collected at 1, 3, 5, 7, and 14 days after injury. The expressions of CD64, CD274, and CD279 on the surface of neutrophils, lymphocytes, and monocytes as well as CD3+, CD4+ and CD8+ T lymphocyte subsets were measured by flow cytometry. The trauma patients were divided into different groups according to the injury severity score (ISS) and sepsis within 28 days after injury, respectively. The dynamic changes of cellular immune function in different time points after injury and differences between different groups were compared. Furthermore, the correlation with acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), and ISS were evaluated by Pearson correlation analysis. RESULTS: A total of 42 patients with trauma were finally enrolled, containing 8 severe trauma patients with ISS greater than 25 scores, 17 patients with ISS between 16 and 25 scores, and 17 patients with ISS less than 16 scores. The sepsis morbidity rates were 14.3% (n = 6) within 28 days after injury. CD64 index and CD4+ T lymphocyte subsets were significantly increased at different time points after trauma (H = 15.464, P = 0.004; F = 2.491, P = 0.035). The CD64 index and positive rates of CD279 in neutrophils, lymphocytes, and monocytes were increased with the severity of injury at day 1 and day 3 after injury, respectively. At the first day after injury, CD64 index were 2.81±1.79, 1.77±0.92, 3.49±1.09; positive rate of CD279 in neutrophils were 1.40% (0.32%, 2.04%), 0.95% (0.44%, 2.70%), 12.73% (3.00%, 25.20%); positive rate of CD279 in lymphocytes were 3.77% (3.04%, 5.15%), 4.71% (4.08%, 6.32%), 8.01% (4.59%, 11.59%); positive rate of CD279 in monocytes were 0.57% (0.24%, 1.09%), 0.85% (0.22%, 1.25%), 6.74% (2.61%, 18.94%) from mild to severe injury groups, respectively. The CD64 index in severe injury group was significantly higher than that in moderate group, and the positive rates of CD279 in neutrophils, lymphocytes and monocytes of severe injury patients were higher than those in other two groups (all P < 0.05). At 3rd day after injury, compared to moderate group, severe injury patients had significantly higher CD64 index and positive rate of CD279 in lymphocytes [4.58±2.41 vs. 2.43±1.68, 7.35% (5.90%, 12.28%) vs. 4.63% (3.26%, 6.06%), both P < 0.05]. Compared with the non-sepsis patients, the sepsis patients had significantly higher CD64 index and positive rate of CD279 in monocytes at day 1 after injury [4.06±1.72 vs. 2.36±1.31, 3.29% (1.14%, 12.84%) vs. 0.67% (0.25%, 1.48%), both P < 0.05], and positive rate of CD279 in lymphocytes significantly higher at 3rd day after injury [8.73% (7.52%, 15.82%) vs. 4.67% (3.82%, 6.21%), P < 0.05]. In addition, correlation analysis showed that positive rate of CD279 in lymphocytes was positively correlated with SOFA and ISS, respectively (r values were 0.533 and 0.394, both P < 0.05), positive rate of CD279 in monocytes was positively correlated with APACHE II, SOFA and ISS scores, respectively (r values were 0.579, 0.452 and 0.490, all P < 0.01), positive rate of CD279 in neutrophils was positively correlated with APACHE II and ISS, respectively (r values were 0.358 and 0.388, both P < 0.05). CONCLUSIONS: CD64 index and CD279 expression in neutrophils, lymphocytes, and monocytes are significantly related to the severity and prognosis of trauma. Dynamic monitoring the cellular immune function may be helpful for assessing the prognosis of trauma patients.

Development and prospective validation of a novel risk score for predicting the risk of lower extremity deep vein thrombosis among multiple trauma patients.

INTRODUCTION: Trauma patients have an increased risk of deep vein thrombosis (DVT). Early identification of patients with a high risk of DVT after trauma is crucial for thromboembolism prophylaxis. We aimed to develop and prospectively validate a novel risk score based on a nomogram to predict lower extremity DVT among multiple trauma patients. MATERIALS AND METHODS: Clinical data were collected from 281 multiple trauma patients who were admitted to our trauma center within 24 h of admission from January 2016 to September 2019 to develop a novel DVT risk score. The DVT risk estimates were then calculated prospectively based on the score in a new study cohort from October 2019 to July 2020. The technique of least absolute shrinkage and selection operator (LASSO) was used to select variables for the early prediction of DVT in multiple trauma patients. The DVT risk assessment score (DRAS) was constructed by incorporating related features based on the LASSO analysis and nomogram prediction model. Further, the multiple trauma patients were divided into various risk groups according to the DRAS. The incidence of lower extremity DVT was compared between groups and the discrimination of the DRAS was assessed using the area under the curve (AUC). RESULTS: Based on the LASSO method, seven variables (age, injury severity score, body mass index, lower extremity fracture, D-dimer level, fibrin degradation products, and prothrombin time) were included in the DRAS. A total of 166 multiple trauma patients were enrolled in the prospective study. Increased risk of DVT after trauma was related to higher DRAS. The area under the receiver operating characteristic (ROC) curve for the DRAS was 0.890 (0.841-0.940) in the validation cohort. Moreover, the discriminatory capacity of the DRAS was superior to that of each variable independently and the TESS score (P < 0.05). CONCLUSIONS: We developed and prospectively validated the DRAS as a reliable tool for predicting the risk of lower extremity DVT among patients with multiple trauma. This may help guide trauma surgeons in making sound decisions in the administration of DVT prophylaxis.

Viral sepsis is a complication in patients with Novel Corona Virus Disease (COVID-19).

BACKGROUND: Until June 23th 2020, 9,195,635 laboratory-confirmed cases of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection have been reported worldwide, including 473,127 deaths. Bacterial infection is the main cause of sepsis, however, sepsis caused by virus is often ignored. Increased awareness, early recognition of viral sepsis, rapid administration of appropriate antiviral drugs, and urgent treatment can significantly reduce deaths of viral sepsis. OBJECTIVES: Given the rapid global spread of novel Corona Virus Disease (COVID-19), coupled with the high rate of missed diagnosis of viral sepsis caused by SARS-CoV-2 infection, it is urgent to evaluate the multiple organ failure score and viral sepsis in COVID-19 patients, so as to determine the clinical characteristics of viral sepsis more accurately and reveal the risk factors related to mortality. METHODS: Here we provide a full description of three cases of viral sepsis and subsequent multiple organ dysfunction (MODS) caused by SARS-CoV-2 infection imported to Guiyang from Wuhan. RESULTS: We analyzed complete laboratory examination, imaging data and treatment methods for the patients and assessed Sepsis-related Organ Failure Assessment score (SOFA score) and Multiple organ dysfunction scores (MOD score) daily, aimed to elucidate the clinical feature of viral sepsis and MODS and to attract enough attention by clinicians. CONCLUSIONS: Therefore, we strongly suggest to daily evaluate SOFA score and MOD score in severe and critically-ill COVID-19 patients, so as to early diagnose and prevention of sepsis and MODS.Given the rapid global spread of novel Corona Virus Disease (COVID-19), coupled with the high rate of missed diagnosis of viral sepsis caused by SARS-CoV-2 infection, it is urgent to evaluate the multiple organ failure score and viral sepsis in COVID-19 patients, so as to determine the clinical characteristics of viral sepsis more accurately and reveal the risk factors related to mortality. Here we provide a full description of three cases of viral sepsis and subsequent multiple organ dysfunction (MODS) caused by SARS-CoV-2 infection imported to Guiyang from Wuhan. We analyzed complete laboratory examination, imaging data and treatment methods for the patients and assessed Sepsis-related Organ Failure Assessment score (SOFA score) and Multiple organ dysfunction scores (MOD score) daily, aimed to elucidate the clinical feature of viral sepsis and MODS and to attract enough attention by clinicians. Therefore, we strongly suggest to daily evaluate SOFA score and MOD score in severe and critically-ill COVID-19 patients, so as to early diagnose and prevention of sepsis and MODS.

Host genetic variants in sepsis risk: a field synopsis and meta-analysis.

BACKGROUND: Published data revealed that host genetic variants have a substantial influence on sepsis susceptibility. However, the results have been inconsistent. We aimed to systematically review the published studies and quantitatively evaluate the effects of these variants on the risk of sepsis. METHODS: We searched the PubMed, EMBASE, Medline, Web of Knowledge, and HuGE databases to identify studies that investigated the associations between genetic variants and sepsis risk. Then, we conducted meta-analyses of the associations for genetic variants with at least three study populations and applied the Venice criteria to assess the association result credibility. RESULTS: A literature search identified 349 eligible articles that investigated 405 variants of 172 distinct genes. We performed 204 primary and 185 subgroup meta-analyses for 76 variants of 44 genes. The results showed that 29 variants of 23 genes were significantly associated with the risk of sepsis, including 8 variants of pattern recognition receptors (PRRs), 14 variants of cytokines, one variant of an immune-related gene and 6 variants of other genes. Furthermore, the cumulative epidemiological evidence of a significant association between each variant and the risk of sepsis was classified as strong or moderate for 18 variants. For the 329 variants with fewer than three study populations, 63 variants of 48 genes have been reported to be significantly associated with the risk of sepsis in a systematic review. CONCLUSION: We identified several genetic variants that could influence the susceptibility to sepsis by systematic review and meta-analysis. This study provides a comprehensive overview of the genetic architecture of variants involved in sepsis susceptibility and novel insight that may affect personalized targeted treatment in the future clinical management of sepsis.