scholarly journals Predicting Experimental Sepsis Survival with a Mathematical Model of Acute Inflammation

2021 ◽  
Vol 1 ◽  
Author(s):  
Jared Barber ◽  
Amy Carpenter ◽  
Allison Torsey ◽  
Tyler Borgard ◽  
Rami A. Namas ◽  
...  
Keyword(s):  
Immune Response ◽  
Growth Rate ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Initial Conditions ◽  
Mortality Data ◽  
Experimental Sepsis ◽  
Initial Inoculum ◽  
Molecular Pattern ◽  
Parameter Values

Sepsis is characterized by an overactive, dysregulated inflammatory response that drives organ dysfunction and often results in death. Mathematical modeling has emerged as an essential tool for understanding the underlying complex biological processes. A system of four ordinary differential equations (ODEs) was developed to simulate the dynamics of bacteria, the pro- and anti-inflammatory responses, and tissue damage (whose molecular correlate is damage-associated molecular pattern [DAMP] molecules and which integrates inputs from the other variables, feeds back to drive further inflammation, and serves as a proxy for whole-organism health status). The ODE model was calibrated to experimental data from E. coli infection in genetically identical rats and was validated with mortality data for these animals. The model demonstrated recovery, aseptic death, or septic death outcomes for a simulated infection while varying the initial inoculum, pathogen growth rate, strength of the local immune response, and activation of the pro-inflammatory response in the system. In general, more septic outcomes were encountered when the initial inoculum of bacteria was increased, the pathogen growth rate was increased, or the host immune response was decreased. The model demonstrated that small changes in parameter values, such as those governing the pathogen or the immune response, could explain the experimentally observed variability in mortality rates among septic rats. A local sensitivity analysis was conducted to understand the magnitude of such parameter effects on system dynamics. Despite successful predictions of mortality, simulated trajectories of bacteria, inflammatory responses, and damage were closely clustered during the initial stages of infection, suggesting that uncertainty in initial conditions could lead to difficulty in predicting outcomes of sepsis by using inflammation biomarker levels.

scholarly journals A Novel Combination of Vitamin C, Curcumin and Glycyrrhizic Acid Potentially Regulates Immune and Inflammatory Response Associated with Coronavirus Infections: A Perspective from System Biology Analysis

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1193 ◽  
Author(s):  
Liang Chen ◽  
Chun Hu ◽  
Molly Hood ◽  
Xue Zhang ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Vitamin C ◽  
Inflammatory Response ◽  
Signaling Pathways ◽  
System Biology ◽  
Glycyrrhizic Acid ◽  
Inflammatory Responses ◽  
Mapk Signaling ◽  
Gene Target

Novel coronaviruses (CoV) have emerged periodically around the world in recent years. The recurrent spreading of CoVs imposes an ongoing threat to global health and the economy. Since no specific therapy for these CoVs is available, any beneficial approach (including nutritional and dietary approach) is worth investigation. Based on recent advances in nutrients and phytonutrients research, a novel combination of vitamin C, curcumin and glycyrrhizic acid (VCG Plus) was developed that has potential against CoV infection. System biology tools were applied to explore the potential of VCG Plus in modulating targets and pathways relevant to immune and inflammation responses. Gene target acquisition, gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment were conducted consecutively along with network analysis. The results show that VCG Plus can act on 88 hub targets which are closely connected and associated with immune and inflammatory responses. Specifically, VCG Plus has the potential to regulate innate immune response by acting on NOD-like and Toll-like signaling pathways to promote interferons production, activate and balance T-cells, and regulate the inflammatory response by inhibiting PI3K/AKT, NF-κB and MAPK signaling pathways. All these biological processes and pathways have been well documented in CoV infections studies. Therefore, our findings suggest that VCG Plus may be helpful in regulating immune response to combat CoV infections and inhibit excessive inflammatory responses to prevent the onset of cytokine storm. However, further in vitro and in vivo experiments are warranted to validate the current findings with system biology tools. Our current approach provides a new strategy in predicting formulation rationale when developing new dietary supplements.

scholarly journals Selectively caring for the most severe COVID-19 patients delays ICU bed shortages more than increasing hospital capacity

2020 ◽  
Author(s):  
Miles Roberts ◽  
Helena Duplechin Seymour ◽  
Alexander Dimitrov ◽  
Keyword(s):  
Differential Equations ◽  
Initial Conditions ◽  
Mortality Data ◽  
System Of Differential Equations ◽  
Infection Rates ◽  
Us States ◽  
Hospital Capacity ◽  
Hospital Resources ◽  
Parameter Values ◽  
Implementing Strategies

1AbstractSARS-CoV-2, the virus responsible for COVID-19, has killed hundreds of thousands of Americans. Although physical distancing measures played a key role in slowing COVID-19 spread in early 2020, infection rates are now peaking at record levels across the country. Hospitals in several states are threatened with overwhelming numbers of patients, compounding the death toll of COVID-19. Implementing strategies to minimize COVID-19 hospitalizations will be key to controlling the toll of the disease, but non-physical distancing strategies receive relatively little attention. We present a novel system of differential equations designed to predict the relative effects of hospitalizing fewer COVID-19 patients vs increasing ICU bed availability on delaying ICU bed shortages. This model, which we call SEAHIRD, was calibrated to mortality data on two US states with different peak infection times from mid-March – mid-May 2020. It found that hospitalizing fewer COVID-19 patients generally delays ICU bed shortage more than a comparable increase in ICU bed availability. This trend was consistent across both states and across wide ranges of initial conditions and parameter values. We argue that being able to predict which patients will develop severe COVID-19 symptoms, and thus require hospitalization, should be a key objective of future COVID-19 research, as it will allow limited hospital resources to be allocated to individuals that need them most and prevent hospitals from being overwhelmed by COVID-19 cases.

scholarly journals Metabolic Hormones Modulate Macrophage Inflammatory Responses

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4661
Author(s):  
Matthew J. Batty ◽  
Gwladys Chabrier ◽  
Alanah Sheridan ◽  
Matthew C. Gage
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Innate Immune Response ◽  
Cancer Progression ◽  
Metabolic Diseases ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Metabolic Hormones ◽  
Cancer Types

Macrophages are phagocytotic leukocytes that play an important role in the innate immune response and have established roles in metabolic diseases and cancer progression. Increased adiposity in obese individuals leads to dysregulation of many hormones including those whose functions are to coordinate metabolism. Recent evidence suggests additional roles of these metabolic hormones in modulating macrophage inflammatory responses. In this review, we highlight key metabolic hormones and summarise their influence on the inflammatory response of macrophages and consider how, in turn, these hormones may influence the development of different cancer types through the modulation of macrophage functions.

scholarly journals A Novel Function of Mitochondrial Phosphoenolpyruvate Carboxykinase as a Regulator of Inflammatory Response in Kupffer Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Haibo Dong ◽  
Yue Feng ◽  
Yang Yang ◽  
Yun Hu ◽  
Yimin Jia ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Kupffer Cells ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Inflammatory Responses ◽  
Flow Cytometric Analysis ◽  
Confocal Laser ◽  
Loss Of Function ◽  
Qrt Pcr

Background: There has been a recent appreciation that some metabolic enzymes can profoundly influence the nature of the immune response produced in macrophages. However, the role of mitochondrial phosphoenolpyruvate carboxykinase (PCK2) in immune response remains unknown. This study aims to investigate the role of PCK2 in lipopolysaccharides (LPS)-induced activation in Kupffer cells.Methods: Inflammatory cytokines were determined by real-time quantitative reverse transcription-polymerase chain action (qRT-PCR) and flow cytometric analysis using a cytometric bead array. Western blotting and immunofluorescence staining were used to determine PCK2 expression and subcellular distribution under confocal laser microscopy. qRT-PCR, flow cytometry, and high-performance liquid chromatography (HPLC) were used to determine mitochondrial function. Pharmacological inhibition, knockdown, and overexpression of PCK2 were used to confirm its function. Co-immunoprecipitation (Co-IP) was performed to determine MAPK/NF-κB phosphorylation.Results: Inflammatory response was significantly increased in LPS-treated mice and Kupffer cells. During the inflammatory process, the protein level of PCK2 was significantly upregulated in Kupffer cells. Interestingly, the localization of PCK2 was mainly in cytosol rather than mitochondria after LPS stimulation. Gain-of-function and loss-of-function analyses found that PCK2 overexpression significantly upregulated the levels of inflammation markers, whereas PCK2 knockdown or inhibition significantly mitigated LPS-induced inflammatory response in Kupffer cells. Furthermore, PCK2 promoted protein phosphorylation of NF-κB and AKT/MAPK, the major signaling pathways, controlling inflammatory cascade activation.Conclusion: We identified a novel function of PCK2 in mediating LPS-induced inflammation and provided mechanistic insights into the regulation of inflammatory response in Kupffer cells. Therefore, PCK2 may serve as a novel therapeutic target for the regulation of Kupffer cells-mediated inflammatory responses.

scholarly journals HSP-Target of Therapeutic Agents in Sepsis Treatment

2019 ◽  
Vol 20 (17) ◽  
pp. 4255
Author(s):  
Anderson Vulczak ◽  
Carlos Henrique Rocha Catalão ◽  
Luiz Alexandre Pedro de Freitas ◽  
Maria José Alves Rocha
Keyword(s):  
Immune Response ◽  
Intensive Care ◽  
Heat Shock ◽  
Inflammatory Response ◽  
Immune Cells ◽  
Therapeutic Agents ◽  
Therapeutic Strategies ◽  
Experimental Designs ◽  
Organ Injury ◽  
Experimental Sepsis

Sepsis is a syndrome characterized by a dysregulated inflammatory response, cellular stress, and organ injury. Sepsis is the main cause of death in intensive care units worldwide, creating need for research and new therapeutic strategies. Heat shock protein (HSP) analyses have recently been developed in the context of sepsis. HSPs have a cytoprotection role in stress conditions, signal to immune cells, and activate the inflammatory response. Hence, HSP analyses have become an important focus in sepsis research, including the investigation of HSPs targeted by therapeutic agents used in sepsis treatment. Many therapeutic agents have been tested, and their HSP modulation showed promising results. Nonetheless, the heterogeneity in experimental designs and the diversity in therapeutic agents used make it difficult to understand their efficacy in sepsis treatment. Therefore, future investigations should include the analysis of parameters related to the early and late immune response in sepsis, HSP localization (intra or extracellular), and time to the onset of treatment after sepsis. They also should consider the differences in experimental sepsis models. In this review, we present the main results of studies on therapeutic agents in targeting HSPs in sepsis treatment. We also discuss limitations and possibilities for future investigations regarding HSP modulators.

scholarly journals MCL Plays an Anti-Inflammatory Role inMycobacterium tuberculosis-Induced Immune Response by Inhibiting NF-κB and NLRP3 Inflammasome Activation

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Qingwen Zhang ◽  
Xinru Jiang ◽  
Weigang He ◽  
Kailin Wei ◽  
Jinxia Sun ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Inhibitory Effect ◽  
Drug Candidate ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Nlrp3 Inflammasome Activation

Mycobacterium tuberculosis(Mtb) remains a significant menace to global health as it induces granulomatous lung lesions and systemic inflammatory responses during active tuberculosis (TB). Micheliolide (MCL), a sesquiterpene lactone, was recently reported to have a function of relieving LPS-induced inflammatory response, but the regulative role of MCL on the immunopathology of TB still remains unknown. In this experiment, we examined the inhibitory effect of MCL on Mtb-induced inflammatory response in mouse macrophage-like cell line Raw264.7 by downregulating the activation of nuclear factor kappa B (NF-κB) and NLRP3 inflammasome. Evidences showed that MCL decreased the secretion of Mtb-induced inflammatory cytokines (IL-1βand TNF-α) in a dose-dependent manner. Meanwhile, MCL dramatically suppressed Mtb-induced activation of iNOS and COX2 as well as subsequent production of NO. Furthermore, MCL inhibited Mtb-induced phosphorylation of Akt (Ser 473) in Raw264.7. According to our results, MCL plays an important role in modulating Mtb-induced inflammatory response through PI3K/Akt/NF-κB pathway and subsequently downregulating the activation of NLRP3 inflammasome. Therefore, MCL may represent as a potential drug candidate in the adjuvant treatment of TB by regulating host immune response.

scholarly journals Inhibition of Anthranilate Synthase Component II, a Novel Protein of S. pneumoniae as a Potential Target for Therapy

2021 ◽  
Vol 11 (2) ◽  
pp. 3586-3597
Keyword(s):  
Immune Response ◽  
Salicylic Acid ◽  
Streptococcus Pneumoniae ◽  
Inflammatory Response ◽  
Respiratory Tract ◽  
Inflammatory Responses ◽  
Primary Immune Response ◽  
Anthranilate Synthase ◽  
Virulent Factor ◽  
Novel Protein

Streptococcus pneumoniae infects the human body primarily through the respiratory tract; however, no evident inflammatory responses are observed upon infection. Even though the inflammatory response is the body's primary immune response, the latency of the inflammatory responses may be attributable to the presence of an anthranilate derivative, quinolone, an isostere of salicylic acid, which acts to suppress inflammation. The reduced immune response promotes the formation of the S. pneumoniae biofilm and increases virulence via quinolone and the derivative, fenamic acid, to elicit different responses. It was found in this study that coumarin binds with good affinity to the binding site of anthranilate synthase component II and also confers a good heme-protectant property. The enzyme anthranilate synthase is a virulent factor of S. pneumoniae and influences the inflammatory response signaling pathways. Inhibition of the anthranilate synthase pathway terminates the virulence of S. pneumoniae and helps prevent the impending severe pathogenesis of infection.

scholarly journals FRI0014 A PUTATIVE ROLE OF IGF-1R ON THE PATHOGENESIS OF GOUT THROUGH BINDING TO TRANSCRIPTION FACTORS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 578.2-578
Author(s):  
R. Liu ◽  
O. Gaal ◽  
V. Klück ◽  
T. Crisan ◽  
S. Fanucchi ◽  
...  
Keyword(s):  
Immune Response ◽  
Uric Acid ◽  
Transcription Factors ◽  
Inflammatory Response ◽  
Cell Surface ◽  
Rna Polymerase ◽  
Inflammatory Responses ◽  
Serum Urate ◽  
Advanced Tumor Stage ◽  
Advanced Tumor

Background:Recent studies showed that SNPs on IGF-1/IGF-1R were highly associated with hyperuricemia and gout [1,2]. It was shown that the IGF-1/IGF-1R signaling pathway played a role in regulating the serum urate level. By modulating the uric acid transporters, IGF-1/IGF-1R influenced the resorption and secretion of uric acid. However, we demonstrated that the increased activation of IGF1R could activate the mTOR pathway, leading to a higher inflammatory response upon pathogen stimulation [3]. This finding indicates that IGF-1/IGF1-R has a role in inflammation, which could results in gout. The IGF-1/IGF-1R pathway may have an overall influence on both urate transporters and inflammatory pathways. it was shown that IGF-1R was not only expressed on the cell surface, but could also internalize into the nucleus and recruit RNA polymerase, regulating the expression of other transcription factors[4]. These transcription factors have been shown to regulate inflammation and have been predicted to bind promoter regions of urate transporters [5]Objectives:To unveil how the IGF-1/IGF1-R associates with hyperuricemia and gout by studying the IGF-1R SNP rs6598541.Methods:To assess the influence of the SNP to IGF1-R, the protein expression of IGF-1R on the cell surface was identified by flow cytometry in different genotypes. Additionally, we measured the in vitro immune response of PBMCs with different genotypes upon exposure to MSU and/or LPS. To estimate the overall influence of the SNP on the immune response, we analyzed the SNP’s function on transcription factors.Results:We observed an enhanced inflammatory response in the homozygous genotype with the risk alleles upon LPS and/or MSU stimulation, indicative of a higher risk for gout. However, the IGF-1R surface expression level was comparable between different genotypes. Furthermore, in epigenetic analysis, we found that rs6598541 located in an enhancer region, which is bound by c-FOS, c-JUN and other transcription factors. In recent years, c-FOS and c-JUN have been shown to regulate inflammatory responses.Conclusion:The risk allele of rs6598541 is associated with a higher inflammatory response, which might be the key factor for gout. Because of the location of the SNP, it might explain the function of IGF-1R in gout, and the pathogenesis might be modulated through transcription factors. According to the recent study, intracellular IGF-1R could act as a transcription factor regulating other transcription factors expression, like c-JUN. Additionally, c-JUN has been shown to regulate inflammatory responses. It is tempting to speculate that IGF-1R regulates transcription factors expression and leads to an overall immune responses, which influence the risk of gout.References:[1]Kottgen, A., et al.,Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.Nat Genet, 2013.45(2): p. 145-54.[2]Mannino, G.C., et al.,The polymorphism rs35767 at IGF1 locus is associated with serum urate levels.Sci Rep, 2018.8(1): p. 12255.[3]Bekkering, S., et al.,Metabolic Induction of Trained Immunity through the Mevalonate Pathway.Cell, 2018.172(1-2): p. 135-146.e9.[4]Aleksic, T., et al.,Nuclear IGF1R Interacts with Regulatory Regions of Chromatin to Promote RNA Polymerase II Recruitment and Gene Expression Associated with Advanced Tumor Stage.Cancer Res, 2018.78(13): p. 3497-3509.[5]Granet, C., W. Maslinski, and P. Miossec,Increased AP-1 and NF-kappaB activation and recruitment with the combination of the proinflammatory cytokines IL-1beta, tumor necrosis factor alpha and IL-17 in rheumatoid synoviocytes.Arthritis Res Ther, 2004.6(3): p. R190-8.Disclosure of Interests:Ruiqi Liu: None declared, Orsi Gaal: None declared, Viola Klück: None declared, Tania Crisan: None declared, Stephanie Fanucchi: None declared, Musa Mhlanga: None declared, Leo Joosten Consultant of: SAB member of Olatec Therapeutics LLC

Atopic dermatitis: new horizons of therapy

2019 ◽  
Vol 1 (7) ◽  
pp. 29-32 ◽  
Author(s):  
L. S. Kruglova ◽  
E. M. Gensler
Keyword(s):  
Blood Pressure ◽  
Immune Response ◽  
Allergic Rhinitis ◽  
Atopic Dermatitis ◽  
Targeted Therapy ◽  
Inflammatory Response ◽  
Bronchial Asthma ◽  
New Horizons ◽  
The Past

Over the past decades, the first breakthrough milestone in the treatment of severe forms of atopic dermatitis (AD) has been targeted therapy aimed at inhibiting IL-4 and IL-13. This was made possible thanks to advances in the understanding of the pathogenesis of AD, the driver of which is the Th2-type immune response, which also underlies such manifestations of atopy as bronchial asthma, allergic rhinitis, and polynosis. In the case of the Th2-type immune response, cytokines IL-4 and IL-13 are secreted, which are the main promoters of the inflammatory response in AD. Inhibition of IL-4 and IL-13 leads to the prevention of inflammation and is an effective approach to therapy. The use of therapy aimed at inhibition of cytokines allows you to effectively cope with the manifestations of severe and moderately severe blood pressure.

scholarly journals Pattern of inflammatory immune response determines the clinical course and outcome of COVID-19: unbiased clustering analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eunyoung Emily Lee ◽  
Kyoung-Ho Song ◽  
Woochang Hwang ◽  
Sin Young Ham ◽  
Hyeonju Jeong ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Clustering Analysis ◽  
Validation Cohort ◽  
Inflammatory Responses ◽  
Clinical Course ◽  
Severe Disease ◽  
Outcome Data ◽  
Inflammatory Immune Response ◽  
Cluster 2

AbstractThe objective of the study was to identify distinct patterns in inflammatory immune responses of COVID-19 patients and to investigate their association with clinical course and outcome. Data from hospitalized COVID-19 patients were retrieved from electronic medical record. Supervised k-means clustering of serial C-reactive protein levels (CRP), absolute neutrophil counts (ANC), and absolute lymphocyte counts (ALC) was used to assign immune responses to one of three groups. Then, relationships between patterns of inflammatory responses and clinical course and outcome of COVID-19 were assessed in a discovery and validation cohort. Unbiased clustering analysis grouped 105 patients of a discovery cohort into three distinct clusters. Cluster 1 (hyper-inflammatory immune response) was characterized by high CRP levels, high ANC, and low ALC, whereas Cluster 3 (hypo-inflammatory immune response) was associated with low CRP levels and normal ANC and ALC. Cluster 2 showed an intermediate pattern. All patients in Cluster 1 required oxygen support whilst 61% patients in Cluster 2 and no patient in Cluster 3 required supplementary oxygen. Two (13.3%) patients in Cluster 1 died, whereas no patient in Clusters 2 and 3 died. The results were confirmed in an independent validation cohort of 116 patients. We identified three different patterns of inflammatory immune response to COVID-19. Hyper-inflammatory immune responses with elevated CRP, neutrophilia, and lymphopenia are associated with a severe disease and a worse outcome. Therefore, targeting the hyper-inflammatory response might improve the clinical outcome of COVID-19.

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