Resolution Of Acute Inflammation Research Articles

Examination of Postoperative Changes in Lipid Profile and Glycemic Markers After Coronary Artery Bypass Graft, Percutaneous Intervention Vs Aortic Valve Replacement Demonstrated a Shift in Risk Factors for Coronary Artery Disease.

Surgery-related stress may affect the metabolome, leading to abnormal lipid profiles and ineffective glycemic control. Here, we gauge these changes as they may accelerate atherosclerosis, limiting the benefits of interventions aimed at improving coronary artery disease (CAD) progression. Electronic medical records were queried to identify patients undergoing coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or aortic valve replacement (AVR). 7573 records denoted lipid profile (cholesterol, LDL, HDL, VLDL, triglycerides) and glucose metabolism impairment (HbA1c). Pre-procedure lipid and glucose laboratory values were compared with periods representing acute periprocedural inflammation (1-3 months), resolution of acute inflammation (3-6 months), convalescence (6-12 months), and medium- (1-2 years), and long-term periods (2-5 years). Baseline values differed between groups (AVR: Cholesterol↑↓, LDL↓↑, HDL↓, Triglycerides↑, HbA1c↓; CABG: Cholesterol↓, LDL↓, HDL↓, Triglycerides↓, HbA1c↓; PCI: Cholesterol↑↓, LDL↑↓, HDL↑↓, Triglycerides↓, HbA1c↓). Interestingly, total cholesterol and LDL had opposite trajectories after CABG vs AVR even five years after surgical procedure and the effects were moderate as denoted by d-Cohen statistics. HDL declined acutely after CABG and AVR but not after PCI. Triglycerides were elevated for 2 years after AVR but depressed after CABG and PCI. HbA1c remained depressed for up to 5 years after any studied procedure. Our data suggest surgical procedures result in prolonged lipid profile and glycemic metabolism disturbances, particularly after aortic valve replacement, indicating more aggressive post-surgical treatment of these metabolic abnormalities may be warranted.

Proresolving Lipid Mediators in the Respiratory System.

Lung inflammation, infection, and injury can lead to critical illness and death. The current means to pharmacologically treat excessive uncontrolled lung inflammation needs improvement because many treatments are or will become immunosuppressive. The inflammatory response evolved to protect the host from microbes, injury, and environmental insults. This response brings phagocytes from the bloodstream to the tissue site to phagocytize and neutralize bacterial invaders and enables airway antimicrobial functions. This physiologic response is ideally self-limited with initiation and resolution phases. Polyunsaturated essential fatty acids are precursors to potent molecules that govern both phases. In the initiation phase, arachidonic acid is converted to prostaglandins and leukotrienes that activate leukocytes to transmigrate from postcapillary venules. The omega-3 fatty acids (e.g., DHA and EPA) are precursors to resolvins, protectins, and maresins, which are families of chemically distinct mediators with potent functions in resolution of acute and chronic inflammation in the respiratory system.

Potential immunomodulatory effects of CAS+IMD monoclonal antibody cocktail in hospitalized patients with COVID-19

Passive administration of SARS-CoV-2 neutralizing monoclonal antibodies (mAbs), such as CAS+IMD (Casirivimab+Imdevimab) antibody cocktail demonstrated beneficial effects on clinical outcomes in hospitalized patients with COVID-19 who were seronegative at baseline and outpatients. However, little is known about their impact on the host immunophenotypes. We conducted an immunoprofiling study in 46 patients from a single site of a multi-site trial of CAS+IMD in hospitalized patients. We collected longitudinal samples during October 2020∼April 2021, prior to the emergence of the Delta and Omicron variants and the use of COVID-19 vaccines. All collected samples were analyzed without exclusion and post-hoc statistical analysis was performed. We examined the dynamic interplay of CAS+IMD with host immunity applying dimensional reduction approach on plasma proteomics and high dimensional flow cytometry data. Using an unbiased clustering method, we identified unique immunophenotypes associated with acute inflammation and disease resolution. Compared to placebo group, administration of CAS+IMD accelerated the transition from an acute inflammatory immunophenotype, to a less inflammatory or "resolving" immunophenotype, as characterized by reduced tissue injury, proinflammatory markers and restored lymphocyte/monocyte imbalance independent of baseline serostatus. Moreover, CAS+IMD did not impair the magnitude or the quality of host T cell immunity against SARS-CoV-2 spike protein. Our results identified immunophenotypic changes indicative of a possible SARS-CoV-2 neutralizing antibodies-induced anti-inflammatory effect, without an evident impairment of cellular antiviral immunity, suggesting that further studies of Mabs effects on SAS-CoV-2 or other viral mediated inflammation are warranted. Regeneron Pharmaceuticals Inc and federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority, under OT number: HHSO100201700020C.

Exercise-stimulated Resolvin Biosynthesis in Adipose Tissue is Abrogated by High Fat Diet-induced Adrenergic Deficiency.

Diet-induced white adipose tissue inflammation is associated with insulin resistance and metabolic perturbations. Conversely, exercise (Exe) protects against the development of chronic inflammation and insulin resistance independent of changes in weight; however, the mechanisms remain largely unknown. We have recently shown that, through adrenergic stimulation of macrophages, exercise promotes resolution of acute peritoneal inflammation by enhancing the biosynthesis of specialized pro-resolving lipid mediators (SPMs). In this study, we sought to determine if exercise stimulates pro-resolving pathways in adipose tissue and whether this response is modified by diet. Specifically, we hypothesized that high fat diet feeding disrupts exercise-stimulated resolution by inhibiting adrenergic signaling, priming the development of chronic inflammation in adipose tissue (AT). To explore the dietary dependence of the pro-resolving effects of Exe, mice were fed either a control or high-fat diet (HFD) for 2 weeks prior to, and throughout, a 4 wk period of daily treadmill running. Glucose handling, body weight and composition, and exercise performance were evaluated at the end of the feeding and exercise interventions. Likewise, catecholamines and their biosynthetic enzymes were measured along with AT SPM biosynthesis and macrophage phenotype and abundance. When compared with sedentary controls (Sed), macrophages isolated from mice exposed to 4 wk of exercise display elevated expression of the SPM biosynthetic enzyme Alox15, while whole AT SPM levels and anti-inflammatory CD301+ M2 macrophages increased. These changes were dependent upon diet as 6 wk of feeding with HFD abrogated the pro-resolving effect of exercise when compared with control diet-fed animals. Interestingly, exercise-induced epinephrine production was inhibited by HFD, which diminished expression of the epinephrine biosynthetic enzyme phenylethanolamine N-methyltransferase (PNMT) in adrenal glands. Taken together, these results suggest that a diet high in fat diminishes the pro-resolving effects of exercise in adipose tissue via decreasing the biosynthesis of catecholamines.

Lipid mediators in neutrophil biology: inflammation, resolution and beyond.

Acute inflammation is the body's first defense in response to pathogens or injury. Failure to efficiently resolve the inflammatory insult can severely affect tissue homeostasis, leading to chronic inflammation. Neutrophils play a pivotal role in eradicating infectious pathogens, orchestrating the initiation and resolution of acute inflammation, and maintaining physiological functions. The resolution of inflammation is a highly orchestrated biochemical process, partially modulated by a novel class of endogenous lipid mediators known as specialized pro-resolving mediators (SPMs). SPMs mediate their potent bioactions via activating specific cell-surface G protein-coupled receptors (GPCR). This review focuses on recent advances in understanding the multifaceted functions of SPMs, detailing their roles in expediting neutrophil apoptosis, promoting clearance by macrophages, regulating their excessive infiltration at inflammation sites, orchestrating bone marrow deployment, also enhances neutrophil phagocytosis and tissue repair mechanisms under both physiological and pathological conditions. We also focus on the novel role of SPMs in regulating bone marrow neutrophil functions, differentiation, and highlight open questions about SPMs' functions in neutrophil heterogeneity. SPMs play a pivotal role in mitigating excessive neutrophil infiltration and hyperactivity within pathological milieus, notably in conditions such as sepsis, cardiovascular disease, ischemic events, and cancer. This significant function highlights SPMs as promising therapeutic agents in the management of both acute and chronic inflammatory disorders.

Maresin-1 Attenuates Sepsis-Associated Acute Kidney Injury via Suppressing Inflammation, Endoplasmic Reticulum Stress and Pyroptosis by Activating the AMPK/SIRT3 Pathway.

Sepsis-associated acute kidney injury (SA-AKI) is a common complication in patients with sepsis, triggering high morbidity and mortality. Maresin-1 (MaR1) is a pro-resolution lipid mediator that promotes the resolution of acute inflammation and protects organs from inflammation. In this study, we established an SA-AKI model using cecal ligation and puncture (CLP) and investigated the effect and mechanism of MaR1. The blood and kidneys were harvested 24 hours after surgery. The blood biochemical/routine indicators, renal function, SA-AKI-related pathophysiological processes, and AMPK/SIRT3 signaling in septic mice were observed by histological staining, immunohistochemical staining, Western blot, qPCR, ELISA and TUNEL Assay. MaR1 treatment alleviated kidney injury in septic mice, reflected in improved pathological changes in renal structure and renal function. MaR1 treatment decreased the levels of serum creatinine (sCr) and blood urea nitrogen (BUN) and the expressions of KIM-1, NGAL and TIMP-2, which were related to kidney injury, while inhibited the expressions of inflammatory factors TNF-α, IL-1β and IL-6. The expression of endoplasmic reticulum stress-related indicators p-PERK/PERK, GRP78, p-EIF2α/EIF2α, ATF4, CHOP, and pyroptosis-related indicators Caspase-1, NLRP3, GSDMD, IL-18, and IL-1β also decreased after MaR1 treatment. The mechanism may be related to the activation of the AMPK/SIRT3 signaling pathway, and an AMPK inhibitor (compound C) partially reverses MaR1's protective effects in septic mice. Taken together, these findings suggest that MaR1 may partially ameliorate SA-AKI by activating the AMPK/SIRT3 signaling pathway, providing a potential new perspective for research on SA-AKI.

Age-Related Decline in Pancreas Regeneration Is Associated With an Increased Proinflammatory Response to Injury

Background and AimsThe regenerative capacity of the pancreas diminishes with age. Understanding acinar cell responses to injury and the resolution of regenerative processes is crucial for tissue homeostasis. However, knowledge about the impact of aging on these processes remains limited. MethodsTo investigate the influence of aging on pancreas regeneration, we established a cohort of young (7-14 weeks) and old (18 months) C57bl/6 mice. Experimental pancreatitis was induced using caerulein, and pancreas samples were collected at various timepoints after induction, covering acute damage response, inflammation, peak proliferation, and inflammation resolution. Our analysis involved immunohistochemistry, quantitative imaging, and gene expression analyses.Our study revealed a significant decline in the regenerative capacity of the pancreas in old mice. Despite similar morphology and transcriptional profiles between the pancreas of young and old mice under homeostasis, the aged pancreas is primed to generate an exacerbated proinflammatory reaction in response to injury. Specifically, we observed notable upregulation of Junb expression in acinar cells and aberrant myofibroblast activation in aged pancreas. ConclusionsThe response of acinar cells to injury in the pancreas of aged mice is characterized by an increased susceptibility to inflammation and stromal reactions. Our findings uncover a pre-existing proinflammatory state in aged acinar cells, offering insights into potential strategies to prevent the onset of pancreatic insufficiency and the development of inflammatory conditions. These insights hold implications for preventing conditions such as chronic pancreatitis and pancreatic ductal adenocarcinoma.

Efferocyte-Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1-Mediated Activation of Glycolysis.

Clearance of multiple rounds of apoptotic cells (ACs) through continual efferocytosis is critical in the maintenance of organ function, the resolution of acute inflammation, and tissue repair. To date, little is known about the nature of mechanisms and factors that govern this fundamental process. Herein, the authors reported that breakdown of ACs leads to upregulation of 12-lipoxygenase in macrophages. This enzyme converts docosahexaenoic acid to maresin conjugates in tissue regeneration (MCTRs). The levels of these autacoids are elevated at sites of high apoptotic burden in vivo and in efferocytosing macrophages in vitro. Abrogation of MCTR production using genetic approaches limits the ability of macrophages to perform continual efferocytosis both in vivo and in vitro, an effect that is rescued by add-back of MCTRs. Mechanistically, MCTR-mediated priming of macrophages for continual efferocytosis is dependent on alterations in Rac1 signalling and glycolytic metabolism. Inhibition of Rac1 abolishes the ability of MCTRs to increase glucose uptake and efferocytosis in vitro, whereas inhibition of glycolysis limits the MCTR-mediated increases in efferocytosis and tissue repair. Together, these findings demonstrate that upregulation of MCTRs by efferocytosing macrophages plays a central role in the regulation of continual efferocytosis via the autocrine and paracrine modulation of metabolic pathways.

Non-Pigmenting Fixed Drug Eruption Due to Fluconazole Without Cross-Reactivity to Itraconazole

Fixed drug eruption is an uncommon cutaneous skin reaction that is most frequently attributed to antibiotics, non-steroidal anti-inflammatories, and paracetamol. Localized hyperpigmentation often results after the resolution of acute inflammation. Rarely, do fixed drug eruptions resolve without hyperpigmentation. Non-pigmenting fixed drug eruption (NPFDE) is an uncommon subtype that is characterized by well-demarcated, tender erythematous plaques that resolve without post-inflammatory hyperpigmentation. NPFDE has most frequently been associated with pseudoephedrine and piroxicam, but we report a case of a 48-year-old female with repeated occurrences of fluconazole-induced non-pigmenting fixed drug eruption. Clinical diagnosis of non-pigmenting fixed drug eruption was made based on the correlation of the lesion appearing within 2 hours after fluconazole ingestion, and previous history of similar reactions after fluconazole intake with resolution without residual pigmentation.

Myocardial injury causes changes in the transcriptional and regulatory landscape of adaptive immune cells in the heart

Abstract Background Ischaemic heart disease is a leading cause of heart failure (HF) and despite advanced therapeutic options, morbidity and mortality rates remain high. Acute inflammation after myocardial infarction (MI) has been thoroughly studied in recent years and persistent immune-mediated damage has been suggested as a factor contributing to the development of HF. T and B cells are critical mediators of adaptive immune responses after MI, however a thorough analysis of their transcriptomic phenotypes in the heart at baseline and over time after injury are missing. Purpose Here, we aim to understand the transcriptional activity of B and T cells in the post-MI heart, in order to characterize their role in maintaining post-MI autoreactivity. Methods We obtained single cell RNA sequencing data of mouse and human hearts from Forte et al (2020), Martini et al (2019) and Litviňuková et al (2020) and performed differential expression analysis, gene regulatory inferences and trajectory-based differential expression analysis. Results Myocardial T cells subclustered into CD8+, CD4+, CD20+ and NK lineages with naïve, memory and effector functions (Fig. 1). The B cell population was divided into immature, plasma, memory, collagen-producing and B1 cell subgroups (Fig. 2). At baseline, despite a striking presence of effector populations, both B and T cells are governed by homeostatic and tolerance-promoting transcription factors (Deaf1, Ikzf1 and Nr1h3 for T cells and Spi-B as well as Bcl11 for B cells). Post-MI, the activity of transcription factors concerned with differentiation and proliferation increased. T cells express transcripts for proinflammatory chemokines and cytokines (Ccr7, Ccl5, Ifng and Tnf) as well as granzymes and perforin up until 28 days post-MI (Gzma and Prf1). Surprisingly, B cells upregulate collagen transcript levels 5-7 days post-MI (Col1a, Col5a, and Col4a) and regulon analysis supports that B cells increase the activity of transcription factors necessary for collagen production (Ets-1 and Krox20). Both B and T cells remain persistently activated post MI. 28 days post-MI T cells have increased activity of proinflammatory (Nfkb1) and cytokine producing (Crem and Rel) transcription factors, whereas B cells have increase maturation (Nfkb1), autoantibody production (Stat3 and Rel) and memory (Stat5b) transcription factor activity. Conclusion Collectively, our data shows that there are effector immune cell populations present at baseline, which are governed by homeostatic transcription factors. Post-MI, effector transcription factors are upregulated in both T cells and B cells, which promote proliferation, differentiation, cytokine production and in the case of B cells, collagen production. Even after resolution of acute inflammation, both the T and B cell population do not return fully to baseline but remain at a state of persistent activation, as effector transcription factors remain upregulated.

Stimulation of Formyl Peptide Receptor-2 by the New Agonist CMC23 Protects against Endotoxin-Induced Neuroinflammatory Response: A Study in Organotypic Hippocampal Cultures.

A substantial body of evidence demonstrates an association between a malfunction in the resolution of acute inflammation and the development of chronic inflammation. Recently, in this context, the importance of formyl peptide receptor 2 (FPR2) has been underlined. FPR2 activity is modulated by a wide range of endogenous ligands, including specialized pro-resolving mediators (SPMs) (e.g., LXA4 and AT-LXA4) and synthetic ligands. Since SPMs have unfavorable pharmacokinetic properties, we aimed to evaluate the protective and pro-resolving effects of a new potent FPR2 agonist, compound CMC23, in organotypic hippocampal cultures (OHCs) stimulated with lipopolysaccharide (LPS). The protective activity of CMC23 limited the lactate dehydrogenase release in LPS-stimulated cultures. This activity was mediated by the interaction with FPR2 as pretreatment with the FPR2 selective antagonist WRW4 abolished CMC23-induced protection. Furthermore, decreased levels of pro-inflammatory IL-1β and IL-6 were observed after CMC23 administration in LPS-treated OHCs. CMC23 also diminished the LPS-induced increase in IL-17A and both IL-23 subunits p19 and p40 in OHCs. Finally, we demonstrated that CMC23 exerts its beneficial impact via the STAT3/SOCS3 signaling pathway since it attenuated the level of phospho-STAT3 and maintained the LPS-induced SOCS3 levels in OHCs. Collectively, our research implies that the new FPR2 agonist CMC23 has beneficial protective and anti-inflammatory properties in nanomolar doses and FPR2 represents a promising target for the enhancement of inflammation resolution.

Umbilical cord-mesenchymal stem cells induce a memory phenotype in CD4+ T cells.

Inflammation is a physiological state where immune cells evoke a response against detrimental insults. Finding a safe and effective treatment for inflammation associated diseases has been a challenge. In this regard, human mesenchymal stem cells (hMSC), exert immunomodulatory effects and have regenerative capacity making it a promising therapeutic option for resolution of acute and chronic inflammation. T cells play a critical role in inflammation and depending on their phenotype, they can stimulate or suppress inflammatory responses. However, the regulatory effects of hMSC on T cells and the underlying mechanisms are not fully elucidated. Most studies focused on activation, proliferation, and differentiation of T cells. Here, we further investigated memory formation and responsiveness of CD4+ T cells and their dynamics by immune-profiling and cytokine secretion analysis. Umbilical cord mesenchymal stem cells (UC-MSC) were co-cultured with either αCD3/CD28 beads, activated peripheral blood mononuclear cells (PBMC) or magnetically sorted CD4+ T cells. The mechanism of immune modulation of UC-MSC were investigated by comparing different modes of action; transwell, direct cell-cell contact, addition of UC-MSC conditioned medium or blockade of paracrine factor production by UC-MSC. We observed a differential effect of UC-MSC on CD4+ T cell activation and proliferation using PBMC or purified CD4+ T cell co-cultures. UC-MSC skewed the effector memory T cells into a central memory phenotype in both co-culture conditions. This effect on central memory formation was reversible, since UC-MSC primed central memory cells were still responsive after a second encounter with the same stimuli. The presence of both cell-cell contact and paracrine factors were necessary for the most pronounced immunomodulatory effect of UC-MSC on T cells. We found suggestive evidence for a partial role of IL-6 and TGFβ in the UC-MSC derived immunomodulatory function. Collectively, our data show that UC-MSCs clearly affect T cell activation, proliferation and maturation, depending on co-culture conditions for which both cell-cell contact and paracrine factors are needed.

In-Vivo fluorescent nanosensor implants based on hydrogel-encapsulation: investigating the inflammation and the foreign-body response

Nanotechnology-enabled sensors or nanosensors are emerging as promising new tools for various in-vivo life science applications such as biosensing, components of delivery systems, and probes for spatial bioimaging. However, as with a wide range of synthetic biomaterials, tissue responses have been observed depending on cell types and various nanocomponent properties. The tissue response is critical for determining the acute and long term health of the organism and the functional lifetime of the material in-vivo. While nanomaterial properties can contribute significantly to the tissue response, it may be possible to circumvent adverse reactions by formulation of the encapsulation vehicle. In this study, five formulations of poly (ethylene glycol) diacrylate (PEGDA) hydrogel-encapsulated fluorescent nanosensors were implanted into SKH-1E mice, and the inflammatory responses were tracked in order to determine the favorable design rules for hydrogel encapsulation and minimization of such responses. Hydrogels with higher crosslinking density were found to allow faster resolution of acute inflammation. Five different immunocompromised mice lines were utilized for comparison across different inflammatory cell populations and responses. Degradation products of the gels were also characterized. Finally, the importance of the tissue response in determining functional lifetime was demonstrated by measuring the time-dependent nanosensor deactivation following implantation into animal models.

A multiscale hybrid model for exploring the effect of Resolvin D1 on macrophage polarization during acute inflammation

Dysregulated inflammation underlies various diseases. Specialized pro-resolving mediators (SPMs) like Resolvin D1 (RvD1) have been shown to resolve inflammation and halt disease progression. Macrophages, key immune cells that drive inflammation, respond to the presence of RvD1 by polarizing to an anti-inflammatory type (M2). However, RvD1’s mechanisms, roles, and utility are not fully understood.This paper introduces a gene-regulatory network (GRN) model that contains pathways for RvD1 and other SPMs and proinflammatory molecules like lipopolysaccharides. We couple this GRN model to a partial differential equation–agent-based hybrid model using a multiscale framework to simulate an acute inflammatory response with and without the presence of RvD1. We calibrate and validate the model using experimental data from two animal models.The model reproduces the dynamics of key immune components and the effects of RvD1 during acute inflammation. Our results suggest RvD1 can drive macrophage polarization through the G protein-coupled receptor 32 (GRP32) pathway. The presence of RvD1 leads to an earlier and increased M2 polarization, reduced neutrophil recruitment, and faster apoptotic neutrophil clearance.These results support a body of literature that suggests that RvD1 is a promising candidate for promoting the resolution of acute inflammation. We conclude that once calibrated and validated on human data, the model can identify critical sources of uncertainty, which could be further elucidated in biological experiments and assessed for clinical use.

Fever integrates antimicrobial defences, inflammation control, and tissue repair in a cold-blooded vertebrate

Multiple lines of evidence support the value of moderate fever to host survival, but the mechanisms involved remain unclear. This is difficult to establish in warm-blooded animal models, given the strict programmes controlling core body temperature and the physiological stress that results from their disruption. Thus, we took advantage of a cold-blooded teleost fish that offered natural kinetics for the induction and regulation of fever and a broad range of tolerated temperatures. A custom swim chamber, coupled to high-fidelity quantitative positional tracking, showed remarkable consistency in fish behaviours and defined the febrile window. Animals exerting fever engaged pyrogenic cytokine gene programmes in the central nervous system, increased efficiency of leukocyte recruitment into the immune challenge site, and markedly improved pathogen clearance in vivo, even when an infecting bacterium grew better at higher temperatures. Contrary to earlier speculations for global upregulation of immunity, we identified selectivity in the protective immune mechanisms activated through fever. Fever then inhibited inflammation and markedly improved wound repair. Artificial mechanical hyperthermia, often used as a model of fever, recapitulated some but not all benefits achieved through natural host-driven dynamic thermoregulation. Together, our results define fever as an integrative host response that regulates induction and resolution of acute inflammation, and demonstrate that this integrative strategy emerged prior to endothermy during evolution.

Cell-Type-Specific Gene Regulatory Networks of Pro-Inflammatory and Pro-Resolving Lipid Mediator Biosynthesis in the Immune System.

Lipid mediators are important regulators in inflammatory responses, and their biosynthetic pathways are targeted by commonly used anti-inflammatory drugs. Switching from pro-inflammatory lipid mediators (PIMs) to specialized pro-resolving (SPMs) is a critical step toward acute inflammation resolution and preventing chronic inflammation. Although the biosynthetic pathways and enzymes for PIMs and SPMs have now been largely identified, the actual transcriptional profiles underlying the immune cell type-specific transcriptional profiles of these mediators are still unknown. Using the Atlas of Inflammation Resolution, we created a large network of gene regulatory interactions linked to the biosynthesis of SPMs and PIMs. By mapping single-cell sequencing data, we identified cell type-specific gene regulatory networks of the lipid mediator biosynthesis. Using machine learning approaches combined with network features, we identified cell clusters of similar transcriptional regulation and demonstrated how specific immune cell activation affects PIM and SPM profiles. We found substantial differences in regulatory networks in related cells, accounting for network-based preprocessing in functional single-cell analyses. Our results not only provide further insight into the gene regulation of lipid mediators in the immune response but also shed light on the contribution of selected cell types in their biosynthesis.

One of the possibilities of optimizing the therapy of a new coronavirus infection in children with the inclusion of an extract from marshmallow root, chamomile flowers, horsetail grass, walnut leaves, yarrow grass, oak bark and dandelion grass: prospective open comparative cohort study

Background. The issue of acute respiratory infections in children remains one of the most urgent. Therefore, in the pandemic due to the new coronavirus SARS-CoV-2, the search for effective treatment regimens for this disease is necessary.
 Aim. To compare the change of clinical symptoms, terms of virus elimination and disease-related economic cost as well as utilization of outpatient healthcare services in children with new coronavirus infection using the herbal medicine Tonsilgon N, oral solution, added to standard therapy.
 Materials and methods. A prospective open comparative cohort study of the effectiveness of coronavirus infection treatment in children using the standard of care alone and the standard of care with Tonsilgon N was conducted. Group 1 children (n=720) received the standard therapy for COVID-19 and Tonsilgon N oral solution for 10 days, and group 2 patients (n=670) only received the standard therapy for COVID-19. Treatment efficacy was evaluated according to the change of clinical symptoms in the observed patients, the results of SARS-CoV-2 coronavirus RNA detection in nasopharyngeal smears by polymerase chain reaction, the utilization of healthcare services, temporary disability of parents, the economic cost of the disease.
 Results. Studied patients of both groups had a typical clinical presentation of mild to moderate severity new coronavirus infection. Fatigue (96.599.7%) and sore throat (93.893.9%) were the most frequent symptoms. Posterior pharynx hyperemia was noted slightly less frequently. Low-grade fever was noted in 85.786.6% of the patients, equally often in patients of both groups. The significant therapeutic effect of the herbal medicine containing extract of marshmallow root, chamomile flowers, horsetail herb, walnut leaf, yarrow herb, oak bark, and dandelion herb includes reducing the time of sore throat relief in 93.2% of main group patients. After 10 days of treatment, sore throat persisted only in 6.8% of group 1 and 68.1% of group 2 patients (p=0.0001). These results indicate that Tonsilgon combined with standard of care is a promising way to improve the quality of life of children with the new coronavirus infection. The addition of Tonsilgon in therapy for new coronavirus infection in children shortens the time of acute inflammation resolution and reduces the duration of inflammatory intoxication. The therapy of new coronavirus infection under the provisional guidelines leads to a reduction in the time for clinical recovery and virus elimination in children and adolescents (p=0.0001) and a decrease in the utilization of outpatient healthcare services are observed: 3/4 of Group 1 patients and 1/2 of Group 2 patients (p=0.0001) applied for medical help twice during the observation period, 14.6% of Group 1 patients and 29.1% of Group 2 parents applied for medical help more than 3 times (p=0.0001). Thus, the direct and indirect economic costs of the disease decreased. The lower economic cost for parents of children in Group 1 was due to less need for medication and a lower reduction in family income due to temporary disability compared to those for parents in Group 2 (p=0.0001). No treatment-related adverse events was reported.
 Conclusion. The above data indicate that Tonsilgon therapy is an affordable way to optimize the treatment of new coronavirus infection in children.

Specialized pro-resolving lipid mediators: A future for conventional endodontics-A review

Human dental pulp is a highly dynamic tissue that plays major roles in the defense against pathogens and during tissue injury. However, the efficiency of these mechanisms during dental pulp inflammation (pulpitis) varies due to anatomical and physiological restrictions. Uncontrolled progressive unresolved inflammation can lead to pulp tissue necrosis and subsequent apical periodontitis or it can develop into chronic inflammation and become a silent killer causing bone destruction. Considering the cause & effect model, the decision to perform pulp extirpation and endodontic treatment is justifiable only by the lack of therapeutic tools that limit the immune/inflammatory process. The resolution of acute inflammation is necessary to avoid the development of chronic inflammation and to promote repair or regeneration. This active process is orchestrated by Specialized Pro-resolving lipid Mediators (SPMs), which include several families of distinct local mediators (lipoxins, resolvins, protectins and Maresins). These immunoresolvents are distinct from immunosuppressive molecules as they not only dampen inflammation but also promote host defense. Experimental application of SPMs has shown promising result in wide range of inflammatory diseases. This article illustrates about the potential use of SPMs in dentistry

IFN-β mediates the anti-osteoclastic effect of bisphosphonates and dexamethasone.

Zoledronic acid (Zol) is a potent bisphosphonate that inhibits the differentiation of monocytes into osteoclasts. It is often used in combination with dexamethasone (Dex), a glucocorticoid that promotes the resolution of inflammation, to treat malignant diseases, such as multiple myeloma. This treatment can result in bone pathologies, namely medication related osteonecrosis of the jaw, with a poor understanding of the molecular mechanism on monocyte differentiation. IFN-β is a pro-resolving cytokine well-known as an osteoclast differentiation inhibitor. Here, we explored whether Zol and/or Dex regulate macrophage osteoclastic differentiation via IFN-β. RAW 264.7 and peritoneal macrophages were treated with Zol and/or Dex for 4-24h, and IFN-β secretion was examined by ELISA, while the IFN stimulated gene (ISG) 15 expression was evaluated by Western blotting. RANKL-induced osteoclastogenesis of RAW 264.7 cells was determined by TRAP staining following treatment with Zol+Dex or IFN-β and anti-IFN-β antibodies. We found only the combination of Zol and Dex increased IFN-β secretion by RAW 264.7 macrophages at 4h and, correspondingly, ISG15 expression in these cells at 24h. Moreover, Zol+Dex blocked osteoclast differentiation to a similar extent as recombinant IFN-β. Neutralizing anti-IFN-β antibodies reversed the effect of Zol+Dex on ISG15 expression and partially recovered osteoclastic differentiation induced by each drug alone or in combination. Finally, we found Zol+Dex also induced IFN-β expression in peritoneal resolution phase macrophages, suggesting these drugs might be used to enhance the resolution of acute inflammation. Altogether, our findings suggest Zol+Dex block the differentiation of osteoclasts through the expression of IFN-β. Revealing the molecular pathway behind this regulation may lead to the development of IFN-β-based therapy to inhibit osteoclastogenesis in multiple myeloma patients.

Interferon-β regulates proresolving lipids to promote the resolution of acute airway inflammation.

Aberrant immune responses, including hyperresponsiveness to Toll-like receptor (TLR) ligands, underlie acute respiratory distress syndrome (ARDS). Type I interferons confer antiviral activities and could also regulate the inflammatory response, whereas little is known about their actions to resolve aberrant inflammation. Here we report that interferon-β (IFN-β) exerts partially overlapping, but also cooperative actions with aspirin-triggered 15-epi-lipoxin A4 (15-epi-LXA4) and 17-epi-resolvin D1 to counter TLR9-generated cues to regulate neutrophil apoptosis and phagocytosis in human neutrophils. In mice, TLR9 activation impairs bacterial clearance, prolongs Escherichia coli-evoked lung injury, and suppresses production of IFN-β and the proresolving lipid mediators 15-epi-LXA4 and resolvin D1 (RvD1) in the lung. Neutralization of endogenous IFN-β delays pulmonary clearance of E. coli and aggravates mucosal injury. Conversely, treatment of mice with IFN-β accelerates clearance of bacteria, restores neutrophil phagocytosis, promotes neutrophil apoptosis and efferocytosis, and accelerates resolution of airway inflammation with concomitant increases in 15-epi-LXA4 and RvD1 production in the lungs. Pharmacological blockade of the lipoxin receptor ALX/FPR2 partially prevents IFN-β-mediated resolution. These findings point to a pivotal role of IFN-β in orchestrating timely resolution of neutrophil and TLR9 activation-driven airway inflammation and uncover an IFN-β-initiated resolution program, activation of an ALX/FPR2-centered, proresolving lipids-mediated circuit, for ARDS.