Dysregulated Inflammatory Response Research Articles

Novel Mechanisms for Resolution of Liver Inflammation: Therapeutic Implications.

Traditional concepts have classically viewed resolution of inflammation as a passive process yet insight into the pathways by which inflammation is resolved has challenged this idea. Resolution has been revealed as a highly dynamic and active event that is essential to counteract the dysregulated inflammatory response that drives diverse disease states. Abrogation of the hepatic inflammatory response through the stimulation of proresolving mechanisms represents a new paradigm in the setting of chronic inflammatory-driven liver diseases. Elucidation of the role of different cells of the innate and adaptive immune system has highlighted the interplay between them as an important orchestrator of liver repair. A finely tuned interaction between neutrophils and macrophages has risen as revolutionary mechanism that drives the restoration of hepatic function and architecture. Specialized proresolving mediators have also been shown to act as stop signals of the inflammatory response and promote resolution as well as tissue regeneration. In this review, we discuss the discovery and understanding of the mechanisms by which inflammation is resolved and highlight novel proresolving pathways that represent promising therapeutic strategies.

Environmental, Metabolic, and Inflammatory Factors Converge in the Pathogenesis of Moderate Acute Malnutrition in Children: An Observational Cohort Study.

ABSTRACTAcute malnutrition affects more than 50 million children worldwide. These children are at an increased risk of morbidity and mortality from infectious disease. However, the pathogenesis of acute malnutrition and mechanisms underlying the increased risk and poor outcomes from infection are not well understood. Our objective was to identify differences in inflammation and inflammatory responses between children with moderate acute malnutrition (MAM) and healthy controls (HCs), and search for environmental, pathophysiological, and metabolic factors that may influence this response. Sixteen children with MAM and 16 HCs aged 18–36 months were studied in Nairobi, Kenya. None of the children had symptoms of an infectious disease (fever, diarrhea, or cough) in the 2 weeks before enrollment and sample collection. Demographic and health data were provided by their primary caregivers. Blood samples were collected to measure various biomarkers and the response to an inflammatory stimulus. Children with MAM were more frequently from households with contaminated water, crowding, and unstable income sources. They also had increases in basal inflammation, circulating bacterial lipopolysaccharide (LPS), markers of intestinal damage, and an exaggerated whole blood inflammatory response to LPS. Metabolic changes in children with MAM led to increased plasma levels of long-chain fatty acids, which were found to contribute to the pro-inflammatory state. These exploratory findings suggest convergence of multiple factors to promote dysregulated inflammatory responses and prompt several mechanistic hypotheses that can be pursued to better understand the pathogenesis of MAM.

Immunophenotyping of Peripheral Blood Mononuclear Cells in Septic Shock Patients With High-Dimensional Flow Cytometry Analysis Reveals Two Subgroups With Differential Responses to Immunostimulant Drugs

Sepsis is associated with a dysregulated inflammatory response to infection. Despite the activation of inflammation, an immune suppression is often observed, predisposing patients to secondary infections. Therapies directed at restoration of immunity may be considered but should be guided by the immune status of the patients. In this paper, we described the use of a high-dimensional flow cytometry (HDCyto) panel to assess the immunophenotype of patients with sepsis. We then isolated peripheral blood mononuclear cells (PBMCs) from patients with septic shock and mimicked a secondary infection by stimulating PBMCs for 4 h in vitro with lipopolysaccharide (LPS) with or without prior exposure to either IFN-γ, or LAG-3Ig. We evaluated the response by means of flow cytometry and high-resolution clustering cum differential analysis and compared the results to PBMCs from healthy donors. We observed a heterogeneous immune response in septic patients and identified two major subgroups: one characterized by hypo-responsiveness (Hypo) and another one by hyper-responsiveness (Hyper). Hypo and Hyper groups showed significant differences in the production of cytokines/chemokine and surface human leukocyte antigen-DR (HLA-DR) expression in response to LPS stimulation, which were observed across all cell types. When pre-treated with either interferon gamma (IFN-γ) or lymphocyte-activation gene 3 (LAG)-3 recombinant fusion protein (LAG-3Ig) prior to LPS stimulation, cells from the Hypo group were shown to be more responsive to both immunostimulants than cells from the Hyper group. Our results demonstrate the importance of patient stratification based on their immune status prior to any immune therapies. Once sufficiently scaled, this approach may be useful for prescribing the right immune therapy for the right patient at the right time, the key to the success of any therapy.

103 Periodontal Health and Sarcopenia: Cross-Sectional Evidence From A Cohort of 2040 Twin Volunteers

Abstract Introduction Periodontitis is a chronic inflammatory disease affecting the periodontium, ultimately leading to looseness and/or loss of teeth. Sarcopenia refers to age-related reduction in muscle mass and strength. Similar to periodontitis, chronic low-grade inflammation is thought to play a key role in its development. In addition, both increase in prevalence with advancing age. Despite known associations with other diseases involving a dysregulated inflammatory response, for example rheumatoid arthritis,, the relationship between periodontitis and sarcopenia, and whether they could be driven by similar processes, remains uncertain. The aim of this study was to explore the association between periodontitis and sarcopenia. Methods Observational study of 2040 adult volunteers [age 67.18 (12.17)] enrolled in the TwinsUK cohort study. Presence of tooth mobility and number of teeth lost were used to assess periodontal health. A binary variable was created to define periodontitis. Measurements of muscle strength, muscle quality/quantity and physical performance were used to assess sarcopenia. A categorical variable was created according to the European Working Group on Sarcopenia in Older People (EWGSOP2) consensus, to define sarcopenia (1: probable; 2: positive; 3: severe). Generalised linear mixed model analysis used on complete cases and age-matched (n = 1,288) samples to ascertain associations between periodontitis and sarcopenia. Results No significant association was found between periodontitis and sarcopenia in both the complete cases analysis and age-matched analysis. Results were consistent when analysis was adjusted for potential confounders including body mass index, frailty index, Mini Mental State Examination smoking, nutritional status and educational level. Conclusions This study found no significant association between periodontitis and sarcopenia in a cohort of 2040 adults. Although both periodontitis and sarcopenia have been linked to a dysregulated immune response and demonstrate an increase in prevalence with increasing age, our work is inconclusive due to the plethora of possible aetiopathogenetic pathways.

NK Cell-Derived IL-10 Supports Host Survival during Sepsis.

The dysregulated sepsis-induced cytokine storm evoked during systemic infection consists of biphasic and interconnected pro- and anti-inflammatory responses. The contrasting inflammatory cytokine responses determine the severity of the septic event, lymphopenia, host survival, and the ensuing long-lasting immunoparalysis state. NK cells, because of their capacity to elaborate pro- (i.e., IFN-γ) and anti-inflammatory (i.e., IL-10) responses, exist at the inflection of sepsis-induced inflammatory responses. Thus, NK cell activity could be beneficial or detrimental during sepsis. In this study, we demonstrate that murine NK cells promote host survival during sepsis by limiting the scope and duration of the cytokine storm. Specifically, NK cell-derived IL-10, produced in response to IL-15, is relevant to clinical manifestations in septic patients and critical for survival during sepsis. This role of NK cells demonstrates that regulatory mechanisms of classical inflammatory cells are beneficial and critical for controlling systemic inflammation, a notion relevant for therapeutic interventions during dysregulated infection-induced inflammatory responses.

Dysregulated Monocyte and Neutrophil Functional Phenotype in Infants With Neonatal Encephalopathy Requiring Therapeutic Hypothermia.

Neonatal encephalopathy (NE) is a significant cause of morbidity and mortality. Persistent inflammation and activation of leukocytes mediate brain injury in NE. The standard of care for NE, therapeutic hypothermia (TH), does not improve outcomes in nearly half of moderate to severe cases, resulting in the need for new adjuvant therapies, and immunomodulation holds promise. Our objective was to explore systemic leukocyte phenotype in infants with NE and healthy controls in response to lipopolysaccharide (LPS). Twenty-four infants with NE (NE II-20; NE III = 4) requiring TH and 17 term neonatal controls were enrolled, and blood samples were analyzed between days 1 and 4 of life at a mean (SD) timepoint of 2.1 (± 0.81) days of postnatal life at the time of the routine phlebotomy. Leukocyte cell surface expression levels of Toll-like receptor 4, NADPH oxidase (NOX2), CD11b, mitochondrial mass, and mitochondrial superoxide production were measured by flow cytometry. Gene expression of TRIF (TIR domain–containing adapter-inducing interferon-β), MyD88 and IRAK4 was measured by reverse transcription–polymerase chain reaction. Infants with NE had significantly lower expression of neutrophil CD11b and NOX2 with LPS stimulation compared to healthy term controls. Mitochondrial mass in neutrophils and monocytes was significantly increased in NE infants with LPS compared to controls, potentially indicating a dysregulated metabolism. Infants with NE had significantly lower IRAK4 at baseline than controls. NE infants display a dysregulated inflammatory response compared to healthy infants, with LPS hyporesponsiveness to CD11b and NOX2 and decreased IRAK4 gene expression. This dysregulated immune profile may indicate an adaptable response to limit hyperinflammation.

MAR1 suppresses inflammatory response in LPS-induced RAW 264.7 macrophages and human primary peripheral blood mononuclear cells via the SIRT1/PGC-1\u03b1/PPAR-\u03b3 pathway

BackgroundSepsis is a complex syndrome characterized by a dysregulated inflammatory response to systemic infection and leads to shock, multiple organ failure and death especially if not recognized early and treated promptly. Previous studies have suggested Maresin 1 (MAR1) can alleviate systemic inflammation in sepsis, but its mechanism has not been clarified.MethodsRAW 264.7 cells and human primary peripheral blood mononuclear cells (hPBMCs) were pretreated with LPS and MAR1. The mRNA expression and supernatant levels of pro-inflammatory cytokines, tumor necrosis factor (TNF-α), interleukin (IL)-1β and IL-6 were evaluated by RT-qPCR and ELISA, respectively. The expression levels of Sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and Peroxisome proliferator-activated receptor gamma (PPAR-γ) were determined by RT-qPCR and Western blot analysis, respectively.ResultsOur results show that LPS-induced inflammation increased the expression and secretion of proinflammatory cytokines TNF-α, IL-1β and IL-6 and induced suppression of SIRT1, PGC-1α, and PPAR-γ expression, which could be reversed by MAR1. And the effect of MAR1 was eliminated by repression of SIRT1/PPAR-γ and enhanced by PGC-1α overexpression.ConclusionsMAR1 suppressed inflammatory response in LPS-induced RAW 264.7 macrophages and hPBMCs via the SIRT1/PGC-1α/PPAR-γ pathway.

Leveraging systems biology for predicting modulators of inflammation in patients with COVID-19.

Dysregulations in the inflammatory response of the body to pathogens could progress toward a hyperinflammatory condition amplified by positive feedback loops and associated with increased severity and mortality. Hence, there is a need for identifying therapeutic targets to modulate this pathological immune response. Here, we propose a single cell-based computational methodology for predicting proteins to modulate the dysregulated inflammatory response based on the reconstruction and analysis of functional cell-cell communication networks of physiological and pathological conditions. We validated the proposed method in 12 human disease datasets and performed an in-depth study of patients with mild and severe symptomatology of the coronavirus disease 2019 for predicting novel therapeutic targets. As a result, we identified the extracellular matrix protein versican and Toll-like receptor 2 as potential targets for modulating the inflammatory response. In summary, the proposed method can be of great utility in systematically identifying therapeutic targets for modulating pathological immune responses.

Abstract PO001: Results from a preclinical study to evaluate the efficacy of polyvalent immunoglobulins on the imbalance of (anti-)inflammatory immune cell responses in clinical colorectal cancer

Abstract Introduction: The purpose of this study was to determine the efficacy of an immunoglobulin concentrate on dysregulated inflammatory responses in patients with colorectal cancer (CRC). Recent findings have shown that CRC is associated with dysbiosis of the gut microbiome and frequently a compromised gut barrier, resulting in prolonged and smoldering endotoxin leakage into the circulation. Subclinical local and systemic microinflammation is suggested to facilitate metastasis formation. Previous studies have pointed to the capacity of polyvalent immunoglobulins to neutralize endotoxins and pathogens on gut epithelial surfaces to abrogate inflammatory responses and thereby tumor recurrence. The effects of KMP01D, a colostrum preparation with a multitude of immunoglobulins against gram-negative/positive bacteria and viruses, on pro-/anti-inflammatory cytokine responses and apoptosis were determined ex vivo. Methods: Peripheral blood and tumor-derived mononuclear cells (MNC) from CRC patients at UICC stages I–IV (n=48) operated at our Center for Operative Medicine/Comprehensive Cancer Center and treated under current guidelines for (neo-)adjuvant therapy were further investigated. Expression of CD14, CD68, Toll-like receptor(TLR) 4, and insulin-like growth factor (IGF)-1 with/without co-incubation of KMP01D as well as immune cell apoptosis was analyzed by flow cytometry, RT PCR, immunohistochemistry, and Elisa in each patient. Results: KMP01D increased interleukin (IL)-10 and IL-13 anti-inflammatory cytokine expression in peripheral blood MNCs (UICC I-III). More interestingly, it likewise decreased secretion of IL-1β, IL-6, IFN-γ, TNF-α, and IL-12 driven inflammation as well as IGF-1. Moreover, CD14/CD68 and TLR4 expression critically involved in endotoxin signaling was downregulated in PBMCs and tumor-infiltrating MNCs. CD14+Fas+/TUNEL+ PBMCs and tumor-derived MNCs indicating apoptosis were likewise enhanced under KMP01D co-incubation. Addition of vitamin D3 known as a regulatory factor in immune responses demonstrated additive anti-inflammatory effects in vitro. Conclusions: Inflammatory immune responses are significantly and stage-dependently upregulated which negatively impacts anti-tumor-specific immune reactivity, immune cell apoptosis and prognosis in CRC patients despite modern adjuvant treatment protocols. KMP01D produced from natural bovine sources and composed of a multitude of immunoglobulin activity (IgG1/2 and Lactoferrin) demonstrates highly ex vivo efficacy on downregulation of inflammatory cytokine responses in PBMCs and normalized immune cell apoptosis in CRC patients. Together with previous clinical data our results strongly suggest that KMP01-mediated endotoxin and pathogen neutralization and thereby mitigated chronic inflammation can be a highly valuable add-on instrument in the treatment of CRC patients to downregulate stage-dependently their local and systemic inflammation and risk for metastasis formation. Citation Format: Martin Gasser, Reinhard Lissner, Li-Li Hsiao, Ana Maria Waaga-Gasser. Results from a preclinical study to evaluate the efficacy of polyvalent immunoglobulins on the imbalance of (anti-)inflammatory immune cell responses in clinical colorectal cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO001.

What's New in Shock, February 2021?

What's New in Shock, February 2021?

COVID-19: should we consider it as a septic shock? (The treatment of COVID-19 patients in the ICU).

The severe acute respiratory syndrome coronavirus 2 associated coronavirus disease 2019 (COVID-19) illness combines a syndrome of viral replication and a host dysregulated inflammatory response. Despite sharing a similar etiology, COVID-19 patients present different patterns from asymptomatic to severely hypoxemic patients. In some patients, patterns of multiorgan failure have been observed similarly to patients with bacterial sepsis. This review aimed to analyze the currently available data on the treatment of COVID-19, specifically the most studied antiviral agents and therapies targeting the immune system including those that have been investigated in sepsis. In the last months, several trials have been conducted worldwide to try to identify optimal antiviral treatments against COVID-19. Antiviral agents such as lopinavir/ritonavir, remdesivir, hydroxychloroquine have been investigated as well as specific and non-specific immunomodulators in order to determine their potential efficacy against SARS-Cov2. To date, the vast majority of the studied antiviral and immunomodulatory agents have failed to improve outcomes of patients with COVID-19 except for dexamethasone. Many other trials are currently underway with new antiviral agents and various immunomodulatory agents with potential clinical benefit for COVID-19 patients. Despite these emerging data, robust controlled clinical trials assessing patient-centered outcomes remain imperative.

Effects of 6-hydroxymelatonin in human macrophage model of inflammasome activation in conditions mimicking sepsis

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated inflammatory host response to infection, characterised by cytokine release and oxidative stress. Caspase-1 activation and interleukin (IL-1β) release are classical indicators of inflammasome activation. 6-hydroxymelatonin (6OHM) is the main metabolite of melatonin and has potent antioxidant and anti-inflammatory activity. However little is known about its mode of action. The aim of this study was to investigate the effects of 6OHM in a human macrophage model of inflammasome activation under conditions mimicking sepsis.

DAMPening Mortality in COVID-19: Therapeutic Insights From Basic Cardiometabolic Studies on S100A8/A9.

DAMPening Mortality in COVID-19: Therapeutic Insights From Basic Cardiometabolic Studies on S100A8/A9.

Longitudinal Single-Cell Transcriptomics Reveals a Role for Serpina3n-Mediated Resolution of Inflammation in a Mouse Colitis Model.

Background & AimsProper resolution of inflammation is essential to maintaining homeostasis, which is important as a dysregulated inflammatory response has adverse consequences, even being regarded as a hallmark of cancer. However, our picture of dynamic changes during inflammation remains far from comprehensive.MethodsHere we used single-cell transcriptomics to elucidate changes in distinct cell types and their interactions in a mouse model of chemically induced colitis.ResultsOur analysis highlights the stromal cell population of the colon functions as a hub with dynamically changing roles over time. Importantly, we found that Serpina3n, a serine protease inhibitor, is specifically expressed in stromal cell clusters as inflammation resolves, interacting with a potential target, elastase. Indeed, genetic ablation of the Serpina3n gene delays resolution of induced inflammation. Furthermore, systemic Serpina3n administration promoted the resolution of inflammation, ameliorating colitis symptoms.ConclusionsThis study provides a comprehensive, single-cell understanding of cell-cell interactions during colorectal inflammation and reveals a potential therapeutic target that leverages inflammation resolution.

From nicotine to the cholinergic anti-inflammatory reflex – Can nicotine alleviate the dysregulated inflammation in COVID-19?

The coronavirus SARS-CoV-2 of 2019 (COVID-19) causes a pandemic that has been diagnosed in more than 70 million people worldwide. Mild-to-moderate COVID-19 symptoms include coughing, fever, myalgia, shortness of breath, and acute inflammatory lung injury (ALI). In contrast, acute respiratory distress syndrome (ARDS) and respiratory failure occur in patients diagnosed with severe COVID-19. ARDS is mediated, at least in part, by a dysregulated inflammatory response due to excessive levels of circulating cytokines, a condition known as the “cytokine-storm syndrome.” Currently, there are FDA-approved therapies that attenuate the dysregulated inflammation that occurs in COVID-19 patients, such as dexamethasone or other corticosteroids and IL-6 inhibitors, including sarilumab, tocilizumab, and siltuximab. However, the efficacy of these treatments have been shown to be inconsistent. Compounds that activate the vagus nerve-mediated cholinergic anti-inflammatory reflex, such as the α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuate ARDS/inflammatory lung injury by decreasing the extracellular levels of high mobility group box-1 (HMGB1) in the airways and the circulation. It is possible that HMGB1 may be an important mediator of the “cytokine-storm syndrome.” Notably, high plasma levels of HMGB1 have been reported in patients diagnosed with severe COVID-19, and there is a significant negative correlation between HMGB1 plasma levels and clinical outcomes. Nicotine can activate the cholinergic anti-inflammatory reflex, which attenuates the up-regulation and the excessive release of pro-inflammatory cytokines/chemokines. Therefore, we hypothesize that low molecular weight compounds that activate the cholinergic anti-inflammatory reflex, such as nicotine or GTS-21, may represent a potential therapeutic approach to attenuate the dysregulated inflammatory responses in patients with severe COVID-19.

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Aims: Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis.Methods: The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (WT) and GzmA-/- mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times.Results: Clinically, elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen and GzmA did not affect bacterial replication in macrophages in vitro, indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα.Conclusions: Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology.

Role of immature platelet fraction (IPF) in sepsis patients: A systematic review.

Sepsis is extremely common amongst critically ill patients and requires early diagnosis. Hence, identifying a biomarker that could acknowledge sepsis at its prior stage is of vital significance. Immature platelets are a percentage of circulating platelets that contain RNA and is a newer parameter that is measured using automated hematology analyzers in diagnosing sepsis. This review article discusses 10 articles that reveal the role of immature platelet fraction in predicting the onset of sepsis and its relationship with mortality in sepsis. Literature search was done using PubMed, Scopus and Google Scholar and words like platelet indices and immature platelet fraction were typed in the search bar. The aim of this review article is to present a precise form of data that talk about immature platelet fraction (IPF) and its association with the severity and mortality of sepsis. Five out of 10 articles suggest that immature platelet fraction can predict the onset of sepsis and eight out of 10 articles suggest that increased IPF values are associated with high mortality.

Glucocorticoid-Induced Leucine Zipper: A Promising Marker for Monitoring and Treating Sepsis.

Sepsis is a clinical syndrome that resulting from a dysregulated inflammatory response to infection that leads to organ dysfunction. The dysregulated inflammatory response transitions from a hyper-inflammatory phase to a hypo-inflammatory or immunosuppressive phase. Currently, no phase-specific molecular-based therapies are available for monitoring the complex immune response and treating sepsis due to individual variations in the timing and overlap of the dysregulated immune response in most patients. Glucocorticoid-induced leucine zipper (GILZ), is broadly present in multiple tissues and circumvent glucocorticoid resistance (GCR) or unwanted side effects. Recently, the characteristics of GILZ downregulation during acute hyperinflammation and GILZ upregulation during the immunosuppressive phase in various inflammatory diseases have been well documented, and the protective effects of GILZ have gained attention in the field of sepsis. However, whether GILZ could be a promising candidate biomarker for monitoring and treating septic patients remains unknown. Here, we discuss the effect of GILZ in sepsis and sepsis-induced immunosuppression.

NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients.

Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure, and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. redundant, triggering, amplifying, and synergistic) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.

Lipid Mediators in Critically Ill Patients: A Step Towards Precision Medicine.

A dysregulated response to systemic inflammation is a common pathophysiological feature of most conditions encountered in the intensive care unit (ICU). Recent evidence indicates that a dysregulated inflammatory response is involved in the pathogenesis of various ICU-related disorders associated with high mortality, including sepsis, acute respiratory distress syndrome, cerebral and myocardial ischemia, and acute kidney injury. Moreover, persistent or non-resolving inflammation may lead to the syndrome of persistent critical illness, characterized by acquired immunosuppression, catabolism and poor long-term functional outcomes. Despite decades of research, management of many disorders in the ICU is mostly supportive, and current therapeutic strategies often do not take into account the heterogeneity of the patient population, underlying chronic conditions, nor the individual state of the immune response. Fatty acid-derived lipid mediators are recognized as key players in the generation and resolution of inflammation, and their signature provides specific information on patients’ inflammatory status and immune response. Lipidomics is increasingly recognized as a powerful tool to assess lipid metabolism and the interaction between metabolic changes and the immune system via profiling lipid mediators in clinical studies. Within the concept of precision medicine, understanding and characterizing the individual immune response may allow for better stratification of critically ill patients as well as identification of diagnostic and prognostic biomarkers. In this review, we provide an overview of the role of fatty acid-derived lipid mediators as endogenous regulators of the inflammatory, anti-inflammatory and pro-resolving response and future directions for use of clinical lipidomics to identify lipid mediators as diagnostic and prognostic markers in critical illness.