Overwhelming Inflammatory Response Research Articles

Possible mechanisms responsible for acute coronary events in COVID-19

The novel coronavirus (SARS-CoV-2) is primarily a respiratory pathogen and its clinical manifestations are dominated by respiratory symptoms, the most severe of which is acute respiratory distress syndrome (ARDS). However, COVID-19 is increasingly recognized to cause an overwhelming inflammatory response and cytokine storm leading to end organ damage. End organ damage to heart is one of the most severe complications of COVID-19 that increases the risk of death. We proposed a two-fold mechanism responsible for causing acute coronary events in patients with COVID-19 infection: Cytokine storm leading to rapid onset formation of new coronary plaques along with destabilization of pre-existing plaques and direct myocardial injury secondary to acute systemic viral infection. A well-coordinated immune response is the first line innate immunity against a viral infection. However, an uncoordinated response and hypersecretion of cytokines and chemokines lead to immune related damage to the human body. Human Coronavirus (HCoV) infection causes infiltration of inflammatory cells that cause excessive production of cytokines, proteases, coagulation factors, oxygen radicals and vasoactive molecules causing endothelial damage, disruption of fibrous cap and initiation of formation of thrombus. Systemic viral infections also cause vasoconstriction leading to narrowing of vascular lumen and stimulation of platelet activation via shear stress. The resultant cytokine storm causes secretion of hypercoagulable tissue factor without consequential increase in counter-regulatory pathways such as AT-III, activated protein C and plasminogen activator type 1. Lastly, influx of CD4+ T-cells in cardiac vasculature results in an increased production of cytokines that stimulate smooth muscle cells to migrate into the intima and generate collagen and other fibrous products leading to advancement of fatty streaks to advanced atherosclerotic lesions. Direct myocardial damage and cytokine storm leading to destabilization of pre-existing plaques and accelerated formation of new plaques are the two instigating mechanisms for acute coronary syndromes in COVID-19.

CD70 contributes to age-associated T cell defects and overwhelming inflammatory responses.

Aging is associated with immune dysregulation, especially T cell disorders, which result in increased susceptibility to various diseases. Previous studies have shown that loss of co-stimulatory receptors or accumulation of co-inhibitory molecules play important roles in T cell aging. In the present study, CD70, which was generally regarded as a costimulatory molecule, was found to be upregulated on CD4+ and CD8+ T cells of elderly individuals. Aged CD70+ T cells displayed a phenotype of over-activation, and expressed enhanced levels of numerous inhibitory receptors including PD-1, 2B4 and LAG-3. CD70+ T cells from elderly individuals exhibited increased susceptibility to apoptosis and high levels of inflammatory cytokines. Importantly, the functional dysregulation of CD70+ T cells associated with aging was reversed by blocking CD70. Collectively, this study demonstrated CD70 as a prominent regulator involved in immunosenescence, which led to defects and overwhelming inflammatory responses of T cells during aging. These findings provide a strong rationale for targeting CD70 to prevent dysregulation related to immunosenescence.

Inhibition of Sphingosine Kinase 1 Attenuates Sepsis-induced Microvascular Leakage via Inhibiting Macrophage NLRP3 Inflammasome Activation in Mice.

Sepsis is the overwhelming inflammatory response to infection, in which nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome plays a crucial role. Shingosine-1-phosphate is reported to evoke NLRP3 inflammasome activation. Sphingosine kinase 1 (SphK1) is the major kinase that catalyzes bioactive lipid shingosine-1-phosphate formation and its role in sepsis remains uncertain. The authors hypothesize that SphK1 elicits NLRP3 inflammasome activation and exacerbates sepsis. Peripheral blood mononuclear cells were isolated from septic patients and healthy volunteers to measure messenger RNA (mRNA) expression. In mice, sepsis was induced by cecal ligation and puncture. Bone marrow-derived macrophages were prepared from C57BL/6J wild-type, Casp1, Nlrp3 and SphK1 mice. PF-543 was used as the specific inhibitor of SphK1. Mortality, peripheral perfusion, lung Evan's blue dye index, lung wet/dry ratio, lung injury score, lung myeloperoxidase activity, NLRP3 activation, and function of endothelial adherens junction were measured. SphK1 mRNA expression was higher in cells from septic patients versus healthy volunteers (septic patients vs. healthy volunteers: 50.9 ± 57.0 fold change vs. 1.2 ± 0.1 fold change, P < 0.0001) and was positively correlated with IL-1β mRNA expression in these cells (r = 0.537, P = 0.012) and negatively correlated with PaO2/FIO2 ratios (r = 0.516, P = 0.017). In mice that had undergone cecal ligation and puncture, the 5-day mortality was 30% in PF-543-treated group and 80% in control group (n = 10 per group, P = 0.028). Compared with controls, PF-543-treated mice demonstrated improved peripheral perfusion and alleviated extravascular Evan's blue dye effusion (control vs. PF-543: 25.5 ± 3.2 ng/g vs. 18.2 ± 1.4 ng/g, P < 0.001), lower lung wet/dry ratio (control vs. PF-543: 8.0 ± 0.2 vs. 7.1 ± 0.4, P < 0.0001), descending lung injury score, and weaker lung myeloperoxidase activity. Inhibition of SphK1 suppressed caspase-1 maturation and interleukin-1β release through repressing NLRP3 inflammasome activation, and subsequently stabilized vascular endothelial cadherin through suppressing interleukin-1β-evoked Src-mediated phosphorylation of vascular endothelial cadherin. SphK1 plays a crucial role in NLRP3 inflammasome activation and contributes to lung injury and mortality in mice polymicrobial sepsis.

P38 MAPK inhibition: A promising therapeutic approach for COVID-19

COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1–7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1–7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.

Adipose-derived mesenchymal stromal cells primed by macrophages decrease inflammation and multiple organ lesions improving mice survival after cecal ligation and puncure-induced sepsis

Background & Aim Sepsis is a life-threatening illness and a public health issue due to its high frequency, its high annual cost and the increase of bacterial resistance to antibiotics. Sepsis results from an overwhelming inflammatory host response to infection that can lead to organ failure. Attenuation of the inflammation could be a new therapeutic approach. In the last few years, mesenchymal stromal cells (MSCs) and in particular adipose-derived mesenchymal stromal cells (ASCs) have been considered as a new therapeutic for sepsis. Indeed, ASCs modulate immune response and therefore could decrease general inflammation. Our recent study demonstrated that contact with pro- (M1-MΦ) or anti-inflammatory (M2-MΦ) macrophages modulate the immunosuppressive capacities of MSCs in vitro. Therefore, the objective of this study was to determine the effect of different human MΦ-primed ASCs in a model of sepsis induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Methods, Results & Conclusion Human adipose-derived mesenchymal stromal cells were co-cultivated with human pro-inflammatory (M1-MΦ) or with anti-inflammatory (M2-MΦ) macrophages. After 24 h of co-culture, cells were harvested and ASCs and macrophages were magnetically separated based on CD45 expression. Sepsis is induced by cecal ligation and puncture in C57/BL6 mice and ASCs or MΦ-primed ASCs were injected in the peritoneal cavity right after the ligation. Then, survival is assayed every 6h for 5 days and general and local inflammation were evaluated 24h and 48h post-CLP. The intraperitoneal injection of Mφ-primed ASCs and especially M1-primed ASCs significantly increases the survival rate compared to unprimed-ASCs. Indeed, 70% of the M1-ASCs-treated mice survived 5 days post-CLP whereas 30% survived in the PBS-treated group. Moreover, injection of MΦ-primed ASCs decrease organ damage that is associated with the modification of recruited immune cells in the organs. MΦ-primed ASCs also modified the immune response in the peritoneal cavity, maintaining macrophage population in the cavity. Finally, M1-primed ASCs restore normal plasma level of lactate and decrease general inflammation. Altogether, our results suggest that MΦ-primed ASCs modulated modifies the immune response after sepsis and are more protective than the injection of unprimed ASCs. Therefore, MΦ-primed ASCs, associated to antibiotics, could improve the clinical outcomes in patients with sepsis. Sepsis is a life-threatening illness and a public health issue due to its high frequency, its high annual cost and the increase of bacterial resistance to antibiotics. Sepsis results from an overwhelming inflammatory host response to infection that can lead to organ failure. Attenuation of the inflammation could be a new therapeutic approach. In the last few years, mesenchymal stromal cells (MSCs) and in particular adipose-derived mesenchymal stromal cells (ASCs) have been considered as a new therapeutic for sepsis. Indeed, ASCs modulate immune response and therefore could decrease general inflammation. Our recent study demonstrated that contact with pro- (M1-MΦ) or anti-inflammatory (M2-MΦ) macrophages modulate the immunosuppressive capacities of MSCs in vitro. Therefore, the objective of this study was to determine the effect of different human MΦ-primed ASCs in a model of sepsis induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Human adipose-derived mesenchymal stromal cells were co-cultivated with human pro-inflammatory (M1-MΦ) or with anti-inflammatory (M2-MΦ) macrophages. After 24 h of co-culture, cells were harvested and ASCs and macrophages were magnetically separated based on CD45 expression. Sepsis is induced by cecal ligation and puncture in C57/BL6 mice and ASCs or MΦ-primed ASCs were injected in the peritoneal cavity right after the ligation. Then, survival is assayed every 6h for 5 days and general and local inflammation were evaluated 24h and 48h post-CLP.

CD70 contributes to age-associated T cell defects and overwhelming inflammatory responses

Abstract Aging is associated with immune dysregulation, especially T cell disorders, which result in increased susceptibility to various diseases. Previous studies have shown that loss of co-stimulatory receptors or accumulation of co-inhibitory receptors play important roles in T cell senescence. In the present study, CD70, which was generally regarded as a costimulatory molecule, was found to be upregulated on CD4+and CD8+ T cells of elderly individuals. Consistent with its contradictory role in T cell activation, which was reported by recent studies, the findings of this study highlighted an important role of CD70 in T cell senescence. CD70+ T cells from elderly individuals displayed phenotypic features of exhaustion by expressing enhanced levels of numerous inhibitory receptors and elevated susceptibility to apoptosis. In contrast, aged CD70+ T cells also produced higher levels of pro-inflammatory cytokines and expressed more intracellular Granzyme B and perforin, which was consistent with an important feature of senescent cells termed the senescence-associated secretory phenotype (SASP). Importantly, their functional dysregulation associated with aging was reversed by blocking CD70. To the best of our knowledge, this is the first evidence for the involvement of CD70 in immunosenescence. Collectively, this study demonstrated CD70 as a prominent regulator involved in immunosenescence, which led to defects and overwhelming inflammatory responses of T cells during aging. These findings provide a strong rationale for targeting CD70 to prevent dysregulation related to immunosenescence.

The synthetic LPS binding peptide 19-2.5 interferes with clotting and prevents degradation of high molecular weight kininogen in plasma

Sepsis and septic shock are life-threatening conditions and remain an important medical problem, emphasizing the need to identify novel therapeutic approaches. Coagulation dysfunction, hypotension, disturbed microcirculation and multiorgan failure occur frequently. These severe conditions result from an overwhelming inflammatory response, induced by pathogen and damage associated molecular patterns (PAMPs and DAMPs) released into the bloodstream. In the present study, we demonstrated that the synthetic Lipopolysaccharid (LPS)-binding peptide 19-2.5 interferes with the activation of the coagulation and contact system. Moreover, binding of LPS to high molecular weight kininogen (HK), one of the major LPS carrier in blood, could be prevented by the peptide. Thus, peptide 19-2.5 might represent a promising target in the treatment of endotoxemia and sepsis, not only by its anti-inflammatory potential, but also by the anticoagulant effect, together with its ability to prevent degradation of HK.

Gold Clusters Attenuate Inflammation in Rat Mesangial Cells via Inhibiting the Activation of NF-κB Pathway.

Sepsis-induced acute kidney injury (AKI) with high incidence and mortality rates remains a great challenge in the clinic; thus, novel therapies need to be developed urgently. This complication is associated with an overwhelming systemic inflammatory response. The aim of this study was to evaluate the potential effects and possible mechanisms of gold clusters on septic AKI in vitro. Rat mesangial HBZY-1 cells were treated with peptide-templated gold clusters under lipopolysaccharide (LPS) stimulation. The LPS-induced expression of pro-inflammatory cytokines was measured, including tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6). Our data showed that the LPS-induced transcription and secretion of these cytokines were suppressed by pretreatment of gold clusters in a dose-dependent manner. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) also play key roles in septic AKI and both of them are induced upon LPS-stimulation in mesangial cells. Our results further showed that pretreatment with gold clusters dramatically inhibited the LPS-stimulated transcription and expression of COX2 and iNOS, and the subsequent prostaglandin E2 (PGE2) and nitric oxide (NO) production in HBZY-1 cells. Since these factors are involved in the NF-κB pathway upon LPS stimulation, the potential roles of gold clusters on the NF-κB pathway were further determined. We found that LPS-induced NF-κB activation was suppressed in gold clusters-pretreated HBZY-1 cells. These results demonstrated that gold clusters can attenuate LPS-induced inflammation in mesangial cells, probably via inhibiting the activation of the NF-κB pathway, suggesting a potential therapeutic approach for septic AKI.

Substituting Angiotensin-(1-7) to Prevent Lung Damage in SARS-CoV-2 Infection?

Substituting Angiotensin-(1-7) to Prevent Lung Damage in SARS-CoV-2 Infection?

The Potential of Mesenchymal Stem Cells to Treat Systemic Inflammation in Horses.

One hallmark of mesenchymal stem cells (MSCs) is the ability to differentiate into multiple tissue types which assists in tissue regeneration. Another hallmark of MSCs is their potent anti-inflammatory and immunomodulatory properties and the potential to treat inflammatory, immune-mediated, and ischemic conditions. In equine practice, MSCs have shown efficacy in the treatment of musculoskeletal disorders such as tendinopathy, meniscal tears and cartilage injury. However, there are many equine disease processes and conditions that may benefit from the immunomodulatory properties of MSCs. Examples include conditions associated with overwhelming acute inflammatory response such as systemic inflammatory response syndrome to chronic diseases characterized by a prolonged low level of inflammation such as equine asthma and recurrent uveitis. For the acute inflammatory response processes, there is often high morbidity and mortality with no effective immunomodulatory treatment to prevent the overwhelming synthesis of proinflammatory mediators. For chronic inflammatory disease processes, frequently long-term corticosteroid treatment is the therapeutic mainstay, with serious potential complications. Thus, there is an unmet need for alternative anti-inflammatory treatments for both acute and chronic illnesses in horses. While MSCs show promise for such conditions, much research is needed before a clinically safe and effective treatment will be available. Optimal MSC tissue source, patient vs. donor source (autologous vs. allogeneic) and cell growth conditions need to be determined for each problem. For immediate use, allogeneic MSC treatments is preferable, but immune tolerance and adequate safety require further study. MSC collection and cryopreservation from horses before they are injured or ill, whether from umbilical cord tissue, bone marrow or adipose might become more widespread. Once these fundamental approaches to treating specific diseases with MSCs are determined, the route of administration, dose and timing of administration also need to be studied. To provide a framework for development of MSC immunomodulatory treatments, this article reviews the current understanding of equine MSC anti-inflammatory and immunomodulatory properties and proposes how MSC therapy may be further developed to treat acute onset systemic inflammatory processes and chronic inflammatory diseases.

Rolipram Protects Mice from Gram-negative Bacterium Escherichia coli-induced Inflammation and Septic Shock

Sepsis is typically triggered by an overwhelming systemic inflammatory response to pathogens, and may lead to severe organ dysfunction and/or death. Sepsis consequently has a high mortality rate and a high rate of complications for survivors, despite modern medical advances. Therefore, drug identification and validation for the treatment of sepsis is of the utmost importance. As a selective phosphodiesterase-4 inhibitor, rolipram also exhibits the abilities of inhibiting multiple pro-inflammatory cytokines production in macrophages and toxin-induced inflammation in mice. However, this drug has never been studied as a sepsis treatment method. We found that rolipram significantly improves survival in mice challenged with gram-negative bacterium E. coli, CLP, or E. coli derived lipopolysaccharide. We have also found that rolipram inhibits organ damage, pro-inflammatory cytokine production, and intracellular migration of early-stage inflammatory elements. Our results also show that rolipram increases anti-inflammatory cytokine production. The protective effects of rolipram on septic mice may result from inhibition of the MAP kinase and NF-κB signaling pathways. Rolipram may therefore be a potential novel sepsis treatment, one that would bypass the time-consuming and costly drug-discovery process.

Diacylglycerol Kinase ζ Regulates Macrophage Responses in Juvenile Arthritis and Cytokine Storm Syndrome Mouse Models.

Dysregulation of monocyte and macrophage responses are often observed in children with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS), a potentially fatal complication of chronic rheumatic diseases. Both conditions are associated with activation of TLR signaling in monocyte and macrophage lineage cells, leading to overwhelming inflammatory responses. Despite the importance of TLR engagement in activating proinflammatory macrophages, relatively little is known about activation of intrinsic negative regulatory pathways to attenuate excessive inflammatory responses. In this study, we demonstrate that loss of diacylglycerol (DAG) kinase (Dgk) ζ, an enzyme which converts DAG into phosphatidic acid, limits inflammatory cytokine production in an arthritic mouse model dependent on TLR2 signaling and in a CSS mouse model dependent on TLR9 signaling. In vitro, Dgkζ deficiency results in reduced production of TNF-α, IL-6, and IL-1β and in limited M1 macrophage polarization. Mechanistically, Dgkζ deficiency decreases STAT1 and STAT3 phosphorylation. Moreover, Dgkζ levels are increased in macrophages derived from mice with CSS or exposed to plasma from sJIA patients with active disease. Our data suggest that Dgkζ induction in arthritic conditions perpetuates systemic inflammatory responses mediated by macrophages and highlight a potential role of Dgkζ-DAG/phosphatidic acid axis as a modulator of inflammatory cytokine production in sJIA and CSS.

Hemoadsorption treatment with CytoSorb® in patients with extracorporeal life support therapy: A case series.

Extracorporeal life support is an increasingly used technique for respiratory and cardiocirculatory support. Besides primary organ dysfunction, an excessive systemic hyperinflammatory response can be the underlying cause for acute organ failure necessitating extracorporeal life support therapy, or it may be associated with the extracorporeal life support itself. Controlling this overwhelming inflammatory response using CytoSorb® hemoadsorption has been shown to be associated with improved hemodynamics and restored metabolic balance resulting in preserved organ functions. In this retrospective case series, we describe 23 patients undergoing extracorporeal life support therapy and CytoSorb hemoadsorption. Cytokine levels were monitored, hemodynamic and metabolic variables were recorded, and outcome measures such as duration of organ support, intensive care unit mortality, and hospital mortality were noted. CytoSorb treatment was associated with a trend toward a reduction in plasma cytokine levels (first treatment median interleukin-6 pre 595 vs post 350 pg/mL (n.s.); second treatment median interleukin-6 317 vs 108 pg/mL, p < 0.05), a reduced vasoplegic response resulting in a reduction in vasopressor requirements (first treatment median norepinephrine pre 0.15 vs post 0.02 µg/kg/min (n.s.); second treatment median norepinephrine 0.1 vs 0.02 µg/kg/min, p < 0.05) as well as rebalancing of deranged metabolic parameters (first treatment median lactate pre-treatment 6 vs post-treatment median lactate 2 mmol/L, p < 0.05). The hemoperfusion treatment was well tolerated and safe, without the occurrence of any CytoSorb device-related adverse events. Hemoadsorption may offer a potentially promising therapeutic option for critically ill patients undergoing extracorporeal life support therapy, with cytokine reduction and a consecutively mitigated inflammatory response, decreased vasoplegia, and improved organ function as seen in our patients.

Phenolic extracts from whole wheat biofortified bread dampen overwhelming inflammatory response in human endothelial cells and monocytes: major role of VCAM-1 and CXCL-10.

The aim of the study was to evaluate the vascular health properties of extracts from biofortified bread, obtained by adding different durum wheat milling by-products rich in phenolic compounds, by analyzing their effects on overwhelming inflammatory response in endothelial cells and monocytes, two main players of atherogenesis. Human umbilical vein endothelial cells or U937 monocytes were incubated with increasing concentrations (1, 5, 10 μg/mL) of biofortified bread polyphenol extracts or corresponding pure phenolic acids before stimulation with lipopolysaccharide (LPS). We analyzed the endothelial-monocyte adhesion and related endothelial adhesion molecules. The expression of chemokines and pro-inflammatory cytokines was also measured in LPS-stimulated endothelial cells and monocytes as well as intracellular oxidative stress. Biofortified bread extracts inhibited monocyte adhesion to LPS-stimulated endothelial cells, in a concentration-dependent manner by reducing mainly endothelial VCAM-1 expression. Phenolic acid extracts contained in 10 mg biofortified bread downregulated the LPS-induced expression of chemokines MCP-1, M-CSF, and CXCL-10 as well as pro-inflammatory cytokines TNF-α and IL-1β, in endothelial cells and monocytes, with CXCL-10 as the most reduced inflammatory mediator. Among phenolic acids of biofortified bread, ferulic, sinapic, and p-coumaric acids significantly inhibited the LPS-stimulated CXCL-10 expression in vascular cells. The reduced pro-inflammatory response was related to a slightly but significant reduction of intracellular oxidative stress. Our findings suggest the bread biofortified with selected durum wheat milling by-products as a source of phenolic acids with multiple anti-inflammatory and anti-atherosclerotic properties, which could help to counteract or prevent inflammatory vascular diseases.

Sepsis 2019 - New Trends and Their Implications for Multiple Trauma Patients.

In spring 2016, an updated sepsis definition (Sepsis-3) introduced a new explanation for the clinical picture of sepsis. Until then, sepsis had been understood as a "systemic inflammatory response syndrome (SIRS)" resulting from infection. An improved understanding of the molecular mechanisms and broad epidemiological studies of the clinical appearance shifted the focus from the inflammatory response to the multicausal tissue damage resulting in organ dysfunction. This paradigm shift highlights organ failure as a result of a dysregulated response of an organism to infection. Central to the new definition is the understanding that sepsis patients form a heterogeneous group and that the clinical picture requires alternative explanation patterns: e.g. sepsis is insufficiently explained by an overwhelming inflammatory response, it also comprises "immune paralysis" as another important pattern. Furthermore, severity of sepsis reflects the capacity of an organism to adapt and to mitigate the tissue damage through metabolic changes and repair mechanisms. Consistent with the paradigm of the new sepsis definition, adaptation in the presence of infections is crucial for the organism. Seriously injured or multiple trauma patients represent a patient group at particular risk, as sepsis often complicates the courses of these patients due to nosocomial infections. Along with comorbidities, past infections and age, leakage of skin and intestinal barriers as well as impaired defence and repair mechanism predispose trauma patients for a septic course. New pathophysiological insights suggest that the control of extracellular haem is of paramount significance. Haemolysis, transfusion and the consecutive expression of haem binding (such as haemopexin) or haem catabolic pathways (such as haem oxygenase) impair the ability of an organism to adapt, correlate with the prognosis and/or are strongly influenced by the surgical treatment concepts. Established treatment concepts of early causal and supportive therapy (damage control, antibiotic and fluid therapy) contribute to the reduction of mortality, depending on stringent implementation as part of Standard Operating Procedures (SOPs) and quality management. The paradigm shift in sepsis research offers an improved understanding of the underlying pathogenic factors within complex and heterogeneous patient groups, such as nosocomial sepsis following trauma. These novel approaches will allow developing new treatment strategies potentially contributing to a significant reduction in morbidity and mortality of trauma patients.Key messages1) According to the new paradigm, the ability to adapt to the pathogenic load associated with trauma and infection is crucial for an organism.2) Seriously injured or multiple trauma patients are predisposed for septic courses due to impaired adaptation mechanisms.3) Established treatment concepts of early causal and supportive therapy (damage control, antibiotic treatment, restrictive transfusion, and volume resuscitation) reduce mortality, in particular as part of SOPs and quality management strategies.4) Newly emerging treatment concepts that focus on the control of extracellular haem are promising, but require more evidence for translation into clinical practice.

Hemophagocytic Lymphohistiocytosis: Management and Special Consideration in Human Immunodeficiency Virus Positive Patients with Immune Reconstitution Syndrome.

The human body is capable of reacting to multiple aggressors by developing an inflammatory response with the secretion of inflammatory cytokines. The worrisome clinical manifestations occur when this inflammatory response is disproportionate. Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe condition characterized by an overwhelming inflammatory response that may result in end-organ damage and might be fatal. Correspondingly, immune reconstitution inflammatory syndrome (IRIS) is another well-known disorder, seen commonly in human immunodeficiency virus (HIV)-infected patients after the commencement of highly active antiretroviral therapy (HAART). Both entities share a similar clinical presentation and a dismal prognosis. Due to widespread clinical manifestations and laboratory abnormalities, diagnosis is often missed at the time of presentation. There is little consensus on the treatment of secondary HLH, which is usually handled on a case-by-case basis. Rapid curbing of the widespread inflammatory response is the main goal of treatment. To the best of our knowledge, there is scarce literature available on the coexistence of HLH and IRIS; therefore, medical management in the co-occurrence of these two conditions needs to be further investigated.

Selective Recruitment of Lethal Pro-inflammatory Macrophages in Sepsis by MIF but not D-DT (MIF-2)

Abstract Sepsis is a leading cause of mortality with an estimated global incidence of 30 million cases annually. Current paradigms emphasize the role of an overwhelming or dysregulated inflammatory response in sepsis lethality, but to date interventions aimed at particular inflammatory pathways have been unsuccessful. Macrophage migration inhibitory factor (MIF) is of interest because MIF promoter polymorphisms predict mortality in different infections and anti-MIF antibody improves survival in experimental models when administered eight hours after infectious insult. The recent description of a second MIF superfamily member, D-dopachrome tautomerase (D-DT/MIF-2), prompts closer investigation of MIF-dependent responses. This study provides new insight into the pathophysiology of polymicrobial sepsis by revealing a direct role for MIF, but not its close structural homolog D-DT/MIF-2, in activating and recruiting a lethal macrophage subset. We subjected Mif −/− and Mif-2−/− mice to polymicrobial sepsis and observed a survival benefit with Mif but not Mif-2 deficiency. Survival was associated with lower levels of small peritoneal macrophages (SPMs) that, in contrast to large peritoneal macrophages (LPMs), are recruited to site of peritoneal inflammation during sepsis. LPMs produce higher quantities of MIF than SPMs, but SPMs express higher levels of inflammatory cytokines and MIF receptors CD74 and CXCR2. Adoptive transfer of SPMs into Mif −/− hosts abrogated the protective effect of Mif deficiency. Notably, MIF-2 lacks the pseudo-(E)LR motif present in MIF that mediates CXCR2 engagement and SPM migration, supporting MIF’s selective role in the recruitment and accumulation of lethal inflammatory SPMs.

Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential.

Acute respiratory distress syndrome (ARDS) is the often fatal sequelae of a broad range of precipitating conditions. Despite decades of intensive research and clinical trials there remain no therapies in routine clinical practice that target the dysregulated and overwhelming inflammatory response that characterises ARDS. Neutrophils play a central role in the initiation, propagation and resolution of this complex inflammatory environment by migrating into the lung and executing a variety of pro‐inflammatory functions. These include degranulation with liberation of bactericidal proteins, release of cytokines and reactive oxygen species as well as production of neutrophil extracellular traps. Although these functions are advantageous in clearing bacterial infection, the consequence of associated tissue damage, the contribution to worsening acute inflammation and prolonged neutrophil lifespan at sites of inflammation are deleterious. In this review, the importance of the neutrophil will be considered, together with discussion of recent advances in understanding neutrophil function and the factors that influence them throughout the phases of inflammation in ARDS. From a better understanding of neutrophils in this context, potential therapeutic targets are identified and discussed. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Inhibition of autophagy protects against sepsis by concurrently attenuating the cytokine storm and vascular leakage

Sepsis is an overwhelming systemic inflammatory response for which no satisfactory therapeutic drug is available. Previous studies have shown that autophagy is involved in the cytokine storm and vascular leakage that occur during sepsis. Therefore, we aimed to evaluate the therapeutic potential of autophagy inhibitors against bacterial infection-induced sepsis. Cytokine production and phagocytosis of bacteria by human leukocytes and the permeability of endothelial cells were determined after the co-incubation of cells with lipopolysaccharide (LPS) or Escherichia coli in the presence or absence of autophagy inhibitors in vitro. Furthermore, the therapeutic effects of the autophagy inhibitors in E. coli-infected mice were analysed. In the presence of the autophagy inhibitors, the LPS-triggered cytokine secretion of human leucocytes and LPS (or LPS-conditioned medium from leucocytes)-induced endothelial hyperpermeability were significantly reduced. Moreover, the inhibition of autophagy enhanced the clearance of E. coli by leucocytes in vitro. Finally, we demonstrated that post-treatment but not pretreatment with an autophagy inhibitor (hydroxychloroquine) completely protected mice against E. coli infection-induced lethality by simultaneously reducing cytokine production and vascular leakage and enhancing bacterial clearance. These results suggest that autophagy plays an important role in the pathogenesis of sepsis and could serve as a potential therapeutic target for sepsis.

Mortality in Severe Acute Pancreatitis: are we getting better?

Background: Severe acute pancreatitis (SAP) remains one of the more feared and respected acute surgical conditions, given that patients often have signifcant organ failure and require careful management. Published mortality rates of SAP hover about 20% but some of these studies are more than 10 years old. We seek to review our centre's mortality rate in SAP. Methods: We retrospectively reviewed 411 cases of acute pancreatitis from 2008 to 2016 at a single centre, looking at pancreatitis severity and cause of mortality. Results: Of 411 cases, 41 cases were severe. The series had 7 deaths, all of whom had SAP, making the overall mortality rate 1.7% for pancreatitis and 17% for SAP. Four of the 7 died from overwhelming systemic inflammatory response syndrome (SIRS) and multiorgan failure within the first 10 days and 1 from infected pancreatic necrosis on day 29. One passed away from aspiration as a result of intestinal obstruction from a concurrent sigmoid tumour; another was managed successfully and survived (SIRS) and intensive care, but passed away suddenly on day 24 of admission in the rehabiliatation ward from cardiorespiratory cause. As such the actual mortality directly due to SAP is 12%. Conclusion: Mortality rate for SAP in our centre is lower than published data and this likely reflects better clinical management with improved understanding of the pathophysiology of pancreatitis over the years. We believe many other centres will also show improved mortality rates compared to previously established data.