scholarly journals RASAL3 Is a Putative RasGAP Modulating Inflammatory Response by Neutrophils

2021 ◽  
Vol 12 ◽  
Author(s):  
Suguru Saito ◽  
Duo-Yao Cao ◽  
Aaron R. Victor ◽  
Zhenzi Peng ◽  
Hui-Ya Wu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Tissue Injury ◽  
Organ Damage ◽  
Cellular Activity ◽  
Cell Disease ◽  
Disease States ◽  
Inflammatory Conditions ◽  
Gtpase Activating Proteins ◽  
Inflammatory Stimuli ◽  
Lps Activation

As first responder cells in host defense, neutrophils must be carefully regulated to prevent collateral tissue injury. However, the intracellular events that titrate the neutrophil’s response to inflammatory stimuli remain poorly understood. As a molecular switch, Ras activity is tightly regulated by Ras GTPase activating proteins (RasGAP) to maintain cellular active-inactive states. Here, we show that RASAL3, a RasGAP, is highly expressed in neutrophils and that its expression is upregulated by exogenous stimuli in neutrophils. RASAL3 deficiency triggers augmented neutrophil responses and enhanced immune activation in acute inflammatory conditions. Consequently, mice lacking RASAL3 (RASAL3-KO) demonstrate accelerated mortality in a septic shock model via induction of severe organ damage and hyperinflammatory response. The excessive neutrophilic hyperinflammation and increased mortality were recapitulated in a mouse model of sickle cell disease, which we found to have low neutrophil RASAL3 expression upon LPS activation. Thus, RASAL3 functions as a RasGAP that negatively regulates the cellular activity of neutrophils to modulate the inflammatory response. These results demonstrate that RASAL3 could serve as a therapeutic target to regulate excessive inflammation in sepsis and many inflammatory disease states.

scholarly journals The gut microbiome in sickle cell disease: Characterization and potential implications

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255956
Author(s):  
Hassan Brim ◽  
James Taylor ◽  
Muneer Abbas ◽  
Kimberly Vilmenay ◽  
Mohammad Daremipouran ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Gut Microbiome ◽  
Tissue Injury ◽  
Organ Damage ◽  
Composition Analysis ◽  
Cell Disease ◽  
Blood Disorder ◽  
Major Player ◽  
Next Generation Sequencing Ngs

Background Sickle Cell Disease (SCD) is an inherited blood disorder that leads to hemolytic anemia, pain, organ damage and early mortality. It is characterized by polymerized deoxygenated hemoglobin, rigid sickle red blood cells and vaso-occlusive crises (VOC). Recurrent hypoxia-reperfusion injury in the gut of SCD patients could increase tissue injury, permeability, and bacterial translocation. In this context, the gut microbiome, a major player in health and disease, might have significant impact. This study sought to characterize the gut microbiome in SCD. Methods Stool and saliva samples were collected from healthy controls (n = 14) and SCD subjects (n = 14). Stool samples were also collected from humanized SCD murine models including Berk, Townes and corresponding control mice. Amplified 16S rDNA was used for bacterial composition analysis using Next Generation Sequencing (NGS). Pairwise group analyses established differential bacterial groups at many taxonomy levels. Bacterial group abundance and differentials were established using DeSeq software. Results A major dysbiosis was observed in SCD patients. The Firmicutes/Bacteroidetes ratio was lower in these patients. The following bacterial families were more abundant in SCD patients: Acetobacteraceae, Acidaminococcaceae, Candidatus Saccharibacteria, Peptostreptococcaceae, Bifidobacteriaceae, Veillonellaceae, Actinomycetaceae, Clostridiales, Bacteroidacbactereae and Fusobacteriaceae. This dysbiosis translated into 420 different operational taxonomic units (OTUs). Townes SCD mice also displayed gut microbiome dysbiosis as seen in human SCD. Conclusion A major dysbiosis was observed in SCD patients for bacteria that are known strong pro-inflammatory triggers. The Townes mouse showed dysbiosis as well and might serve as a good model to study gut microbiome modulation and its impact on SCD pathophysiology.

scholarly journals Complement factor 3 deficiency attenuates hemorrhagic shock-related hepatic injury and systemic inflammatory response syndrome

2010 ◽  
Vol 299 (5) ◽  
pp. R1175-R1182 ◽  
Author(s):  
Changchun Cai ◽  
Roop Gill ◽  
Hyun-Ae Eum ◽  
Zongxian Cao ◽  
Patricia A. Loughran ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Hemorrhagic Shock ◽  
Complement Activation ◽  
Tissue Injury ◽  
Soft Tissue Injury ◽  
High Mobility ◽  
Organ Damage ◽  
Heme Oxygenase 1 ◽  
Complement Factor ◽  
Wild Type

Although complement activation is known to occur in the setting of severe hemorrhagic shock and tissue trauma (HS/T), the extent to which complement drives the initial inflammatory response and end-organ damage is uncertain. In this study, complement factor 3-deficient (C3−/−) mice and wild-type control mice were subjected to 1.5-h hemorrhagic shock, bilateral femur fracture, and soft tissue injury, followed by 4.5-h resuscitation (HS/T). C57BL/6 mice were also given 15 U of cobra venom factor (CVF) or phosphate-buffered saline injected intraperitoneally, followed by HS/T 24 h later. The results showed that HS/T resulted in C3 consumption in wild-type mice and C3 deposition in injured livers. C3−/− mice had significantly lower serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and circulating DNA levels, together with much lower circulating interleukin (IL)-6, IL-10, and high-mobility group box 1 (HMGB1) levels. Temporary C3 depletion by CVF preconditioning also led to reduced transaminases and a blunted cytokine release. C3−/− mice displayed well-preserved hepatic structure. C3−/− mice subjected to HS/T had higher levels of heme oxygenase-1, which has been associated with tissue protection in HS models. Our data indicate that complement activation contributes to inflammatory pathways and liver damage in HS/T. This suggests that targeting complement activation in the setting of severe injury could be useful.

How we treat sickle hepatopathy and liver transplantation in adults

Blood ◽  
2014 ◽  
Vol 123 (15) ◽  
pp. 2302-2307 ◽  
Author(s):  
Kate Gardner ◽  
Abid Suddle ◽  
Pauline Kane ◽  
John O’Grady ◽  
Nigel Heaton ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Sickle Cell ◽  
Liver Dysfunction ◽  
Therapeutic Option ◽  
Organ Damage ◽  
Treatment Modalities ◽  
Cell Disease ◽  
Limited Evidence ◽  
Acute Form ◽  
Future Work

Abstract Sickle cell disease (SCD) has evolved into a debilitating disorder with emerging end-organ damage. One of the organs affected is the liver, causing “sickle hepatopathy,” an umbrella term for a variety of acute and chronic pathologies. Prevalence of liver dysfunction in SCD is unknown, with estimates of 10%. Dominant etiologies include gallstones, hepatic sequestration, viral hepatitis, and sickle cell intrahepatic cholestasis (SCIC). In addition, causes of liver disease outside SCD must be identified and managed. SCIC is an uncommon, severe subtype, with outcome of its acute form having vastly improved with exchange blood transfusion (EBT). In its chronic form, there is limited evidence for EBT programs as a therapeutic option. Liver transplantation may have a role in a subset of patients with minimal SCD-related other organ damage. In the transplantation setting, EBT is important to maintain a low hemoglobin S fraction peri- and posttransplantation. Liver dysfunction in SCD is likely to escalate as life span increases and patients incur incremental transfusional iron overload. Future work must concentrate on not only investigating the underlying pathogenesis, but also identifying in whom and when to intervene with the 2 treatment modalities available: EBT and liver transplantation.

scholarly journals The inflammatory response induced by Pseudomonas aeruginosa in macrophages enhances apoptotic cell removal

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adriana Valeria Jäger ◽  
Paula Arias ◽  
Maria Virginia Tribulatti ◽  
Marcela Adriana Brocco ◽  
Maria Victoria Pepe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pseudomonas Aeruginosa ◽  
Inflammatory Response ◽  
Apoptotic Cell ◽  
Bacterial Pathogen ◽  
Environmental Cues ◽  
Apoptotic Cells ◽  
Phagocytic Function ◽  
Inflammatory Stimulus ◽  
Inflammatory Conditions

AbstractPathogens phagocytosis and the uptake of apoptotic cells (efferocytosis) are essential macrophages tasks, classically considered as mutually exclusive. Macrophages have been observed to polarize into either pro-inflammatory/microbicidal or anti-inflammatory/efferocytic phenotypes. However, macrophage functions have shown to be more complex. Furthermore, little is known about the regulation of efferocytosis under inflammatory conditions. In this study, we elucidate the modulation of the macrophage efferocytic function during an inflammatory stimulus. We find that bone marrow-derived macrophages (BMDM) are very efficient in engulfing both the bacterial pathogen Pseudomonas aeruginosa and apoptotic cells. BMDM showed a high bactericidal capacity unaffected by the concomitant presence of apoptotic material. Plasticity in macrophage programming, in response to changing environmental cues, may modulate efferocytic capability. In this work, we further show that, after phagocyting and processing Pseudomonas aeruginosa, macrophages highly increase their efferocytic capacity without affecting their phagocytic function. Moreover, we demonstrate that Pseudomonas aeruginosa enhances efferocytosis of these phagocytes through the IL-6 signaling pathway. Our results show that the inflammatory response generated by the bacterial processing enhances these macrophages’ capacity to control inflammation through an increased efferocytosis.

scholarly journals Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 296
Author(s):  
Rosa Vona ◽  
Nadia Maria Sposi ◽  
Lorenza Mattia ◽  
Lucrezia Gambardella ◽  
Elisabetta Straface ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Organ Damage ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Antioxidant Agents ◽  
Oxidant Status

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

scholarly journals Targeting pain at its source in sickle cell disease

2018 ◽  
Vol 315 (1) ◽  
pp. R104-R112 ◽  
Author(s):  
Kanika Gupta ◽  
Om Jahagirdar ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Somatosensory System ◽  
Organ Damage ◽  
Mast Cell Activation ◽  
Cell Disease ◽  
Central Nervous Systems

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

scholarly journals In Vitro Effect of Replicated Porous Polymeric Nano-MicroStructured Biointerfaces Characteristics on Macrophages Behavior

Nanomaterials ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1913
Author(s):  
Luminita Nicoleta Dumitrescu ◽  
Madalina Icriverzi ◽  
Anca Bonciu ◽  
Anca Roșeanu ◽  
Antoniu Moldovan ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Photoelectron Spectroscopy ◽  
Polyvinylidene Fluoride ◽  
Surface Characteristics ◽  
Sem Analysis ◽  
Chemical Structures ◽  
Microstructured Surface ◽  
Inflammatory Conditions ◽  
Vitro Effect

In the last decades, optimizing implant properties in terms of materials and biointerface characteristics represents one of the main quests in biomedical research. Modifying and engineering polyvinylidene fluoride (PVDF) as scaffolds becomes more and more attractive to multiples areas of bio-applications (e.g., bone or cochlear implants). Nevertheless, the acceptance of an implant is affected by its inflammatory potency caused by surface-induced modification. Therefore, in this work, three types of nano-micro squared wells like PVDF structures (i.e., reversed pyramidal shape with depths from 0.8 to 2.5 microns) were obtained by replication, and the influence of their characteristics on the inflammatory response of human macrophages was investigated in vitro. FTIR and X-ray photoelectron spectroscopy analysis confirmed the maintaining chemical structures of the replicated surfaces, while the topographical surface characteristics were evaluated by AFM and SEM analysis. Contact angle and surface energy analysis indicated a modification from superhydrophobicity of casted materials to moderate hydrophobicity based on the structure’s depth change. The effects induced by PVDF casted and micron-sized reversed pyramidal replicas on macrophages behavior were evaluated in normal and inflammatory conditions (lipopolysaccharide treatment) using colorimetric, microscopy, and ELISA methods. Our results demonstrate that the depth of the microstructured surface affects the activity of macrophages and that the modification of topography could influence both the hydrophobicity of the surface and the inflammatory response.

scholarly journals Nutritional demands in acute and chronic illness

2003 ◽  
Vol 62 (4) ◽  
pp. 777-781 ◽  
Author(s):  
Rosemary A. Richardson ◽  
H. Isobel M. Davidson
Keyword(s):  
Energy Expenditure ◽  
Inflammatory Response ◽  
Energy Homeostasis ◽  
Negative Energy ◽  
Disease States ◽  
Energy Needs ◽  
Sufficient Energy ◽  
Effective Treatment Modality ◽  
The Individual

Common to both acute and chronic disease are disturbances in energy homeostasis, which are evidenced by quantitative and qualitative changes in dietary intake and increased energy expenditure. Negative energy balance results in loss of fat and lean tissue. The management of patients with metabolically-active disease appears to be simple; it would involve the provision of sufficient energy to promote tissue accretion. However, two fundamental issues serve to prevent nutritional demands in disease being met. The determination of appropriate energy requirements relies on predictive formulae. While equations have been developed for critically-ill populations, accurate energy prescribing in the acute setting is uncommon. Only 25–32% of the patients have energy intakes within 10% of their requirements. Clearly, the variation in energy expenditure has led to difficulties in accurately defining the energy needs of the individual. Second, the acute inflammatory response initiated by the host can have profound effects on ingestive behaviour, but this area is poorly understood by practising clinicians. For example, nutritional targets have been set for specific disease states, i.e. pancreatitis 105–147 KJ (25–35 kcal)/kg; chronic liver disease 147–168 kj (35–40 kcl)/kg, but given the alterations in gut physiology that accompany the acute-phase response, targets are unlikely to be met. In cancer cachexia attenuation of the inflammatory response using eicosapentaenoic acid results in improved nutritional intake and status. This strategy poses an attractive proposition in the quest to define nutritional support as a clinically-effective treatment modality in other disorders.

scholarly journals Systemic inflammatory response syndrome and multiple-organ damage / dysfunction in complicated canine babesiosis

2001 ◽  
Vol 72 (3) ◽  
Author(s):  
C. Welzl ◽  
A.L. Leisewitz ◽  
L.S. Jacobson ◽  
T. Vaughan-Scott ◽  
E. Myburgh
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Systemic Inflammatory Response Syndrome ◽  
Inflammatory Response ◽  
Renal Involvement ◽  
Organ Damage ◽  
Multiple Organ ◽  
Systemic Inflammatory Response ◽  
The Body ◽  
Increased Risk

This study was designed to document the systemic inflammatory response syndrome (SIRS) and multiple-organ dysfunction syndrome (MODS) in dogs with complicated babesiosis, and to assess their impact on outcome. Ninety-one cases were evaluated retro-spectively for SIRS and 56 for MODS. The liver, kidneys, lungs, central nervous system and musculature were assessed. Eighty-seven percent of cases were SIRS-positive. Fifty-two percent of the cases assessed for organ damage had single-organ damage and 48 % had MODS. Outcome was not significantly affected by either SIRS or MODS, but involvement of specific organs had a profound effect. Central nervous system involvement resulted in a 57 times greater chance of death and renal involvement in a 5-fold increased risk compared to all other complications. Lung involvement could not be statistically evaluated owing to co-linearity with other organs, but was associated with high mortality. Liver and muscle damage were common, but did not significantly affect outcome. There are manysimilarities between the observations in this study and previous human and animal studies in related fields, lending additional support to the body of evidence for shared underlying pathophysiological mechanisms in systemic inflammatory states.

scholarly journals Activation of GSDME compensates for GSDMD deficiency in a mouse model of NLRP3 inflammasomopathy

2021 ◽  
Author(s):  
Chun Wang ◽  
Tong Yang ◽  
Jianqiu Xiao ◽  
Canxin Xu ◽  
Yael Alippe ◽  
...  
Keyword(s):  
Inflammatory Disease ◽  
Early Death ◽  
Organ Damage ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Inflammatory Pathway ◽  
Disease Symptoms ◽  
Caspase 1 ◽  
Inflammatory Stimuli

AbstractThe D301N NLRP3 mutation in mice (D303N in humans) causes severe multi-organ damage and early death driven by the constitutively activated NLRP3 (NLRP3ca) inflammasome. Triggered inflammasomes activate caspase-1 to process IL-1 family cytokines and gasdermin D (GSDMD), generating N-terminal fragments, which oligomerize within the plasma membrane to form pores, which cause inflammatory cell death (pyroptosis) and through which IL-1β and IL-18 are secreted. GSDMD activation is central to disease symptoms since spontaneous inflammation in Nlrp3ca;Gsdmd-/- mice is negligible. Unexpectedly, when Nlrp3ca;Gsdmd-/- mice were challenged with LPS or TNF-α, they secreted high amounts of IL-1β and IL-18, suggesting an alternative GSDMD-independent inflammatory pathway. Here we show that GSDMD deficient macrophages subjected to inflammatory stimuli activate caspase-8, -3 and GSDME-dependent cytokine release and pyroptosis. Caspase-8, -3 and GSDME also activated pyroptosis when NLRP3 was stimulated in caspase-1 deficient macrophages. Thus, a salvage caspase-8, -3-GSDME inflammatory pathway is activated following NLRP3 activation when the canonical NLRP3-caspase-1-GSDMD is blocked. Surprisingly, the active metabolite of the GSDMD-inhibitor disulfiram, inhibited not only GSDMD but also GSDME-mediated inflammation in vitro and suppressed severe inflammatory disease symptoms in Nlrp3ca mice, a model for severe neonatal multisystem inflammatory disease. Although disulfiram did not directly inhibit GSDME, it suppressed inflammasome activation in GSDMD-deficient cells. Thus, the combination of inflammatory signals and NLRP3ca overwhelmed the protection provided by GSDMD deficiency, rewiring signaling cascades through caspase-8, -3 and GSDME to propagate inflammation. This functional redundancy suggests that concomitant inhibition of GSDMD and GSDME may be necessary to suppress disease in inflammasomopathy patients.

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