Uncontrolled Inflammatory Reaction Research Articles

Neutrophil Extracellular Traps (NETs) in Kidney Disease: Role in Pathogenesis and Possibilities of NET Regulatory Therapy

Excessive uncontrolled inflammatory and immune reactions often lead to the development of acute and chronic forms of damage to various organs, including the kidneys. Neutrophils are the cells of the innate immune system, which are the first cellular effectors in protecting the host from a variety of pathogens, including bacteria, fungi and protozoa. As the most numerous leukocytes present in human blood, neutrophils migrate early to the foci of inflammation or tissue damage, where they play a significant role in the development of inflammation, recruitment of immune cells, removal of pathogens and tissue repair. Neutrophils also produce pro-inflammatory cytokines and release, in a process called netosis, a network of DNA and granular proteins known as neutrophil extracellular traps (NETs). NETs are potentially toxic, contribute to glomerular damage, activate autoimmune processes, cause vascular damage, and promote renal fibrosis. Numerous studies show that an imbalance between NET production and clearance is detrimental to kidney function. Therefore, strategies aimed at modulating the processes associated with NET may have a favorable prognostic effect. The review discusses the role of the netosis in the pathogenesis of kidney diseases, describes the mechanisms of tissue damage associated with NET, and the therapeutic potential of NET regulatory therapy.

Inflammatory reaction and immune response of half-smooth tongue sole (Cynoglossus semilaevis) after infection with Vibrio anguillarum

Frequently occurred bacterial diseases have seriously affected the aquaculture industry of half-smooth tongue sole (Cynoglossus semilaevis). Notably, vibriosis, with Vibrio anguillarum as one of the causative pathogens, is the most severe bacterial disease with severe inflammatory response of the host, leading to high mortality rates. In the present study, we explored the relationship between bacterial concentrations and host mortality, inflammatory reaction, and immune response in half-smooth tongue sole after infection with V. anguillarum at different concentrations (Treatment 1, 6.4 × 105 CFU/mL; Treatment 2, 6.4 × 106 CFU/mL). The mortality of Treatment 2 (77.5%) was significantly higher than that of Treatment 1 (10%), corresponding with bacterial concentrations. Although the number of deaths varies, intensive deaths were observed within 24 h post infection (hpi) in both bacterial concentration groups. Histopathological analyses revealed that fish tissues were most severely damaged at 24 or 48 hpi, and Treatment 2 was more severe than Treatment 1. A qRT-PCR-based detection method with virulence factor gene empA was established to quantify the bacterial loads in various tissues, and the bacterial loads were the highest at 24 hpi in Treatment 2, and at 48 hpi in Treatment 1. Additionally, the expression levels of complement genes (C5a, C3, C5, and C6), inflammatory factors (IL-1β, TNF-α, and IL-10), and other immune-related genes (jak2, NF-κB1, stat3, and tlr3) were increased in various tissues after infection in both treatment groups, with most genes being most expressed at 24 or 48 hpi, and expression levels of inflammatory factors in Treatment 2 were higher than those in Treatment 1. Moreover, the expression of C5a was positively correlated with that of proinflammatory cytokines in both bacterial concentration groups. According to the results of this study, 24–48 hpi was a key node for early vibriosis detection and intervention. Compared with the low mortality of Treatment 1, the mass death of fish in Treatment 2 was suggested to be caused by uncontrolled excessive inflammatory reaction induced by the overactivation of complement system, especially C5a. We believe these results could provide theoretical basis for prevention, evaluation, and treatment of vibrio disease in tongue sole aquaculture, and lay a solid foundation for future functional analyses.

Understanding COVID-19-related myocarditis: pathophysiology, diagnosis, and treatment strategies.

Coronavirus disease 2019 (COVID-19) disease has infected nearly 600 million people, resulting in > 6 million deaths, with many of them dying from cardiovascular diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is caused by a combination of the virus surface spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor. In addition to being highly expressed in the lungs, ACE2 is widely distributed in the heart, mainly in myocardial cells and pericytes. Like other types of viruses, SARS-CoV-2 can cause myocarditis after infecting the myocardial tissue, which is attributed to the direct damage of the virus and uncontrolled inflammatory reactions. Patients with chest tightness, palpitation, abnormal electrocardiogram, and cardiac troponin elevation, should be suspected of myocarditis within 1-3 weeks of COVID-19 infection. When the hemodynamics change rapidly, fulminant myocarditis should be suspected. Cardiac ultrasound, myocardial biopsy, cytokine detection, cardiac magnetic resonance imaging, 18F-fluorodeoxyglucose positron emission tomography, and other examination methods can assist in the diagnosis. Although scientists and clinicians have made concerted efforts to seek treatment and prevention measures, there are no clear recommendations for the treatment of COVID-19-related myocarditis. For most cases of common myocarditis, general symptomatic and supportive treatments are used. For COVID-19-related fulminant myocarditis, it is emphasized to achieve "early identification, early diagnosis, early prediction, and early treatment" based on the "life support-based comprehensive treatment regimen." Mechanical circulatory support therapy can rest the heart, which is a cure for symptoms, and immune regulation therapy can control the inflammatory storms which is a cure for the disease. Furthermore, complications of COVID-19-related myocarditis, such as arrhythmia, thrombosis, and infection, should be actively treated. Herein, we summarized the incidence rate, manifestations, and diagnosis of COVID-19-related myocarditis and discussed in detail the treatment of COVID-19-related myocarditis, especially the treatment strategy of fulminant myocarditis.

Epigenetic regulation of chemokine (CC-motif) ligand 2 in inflammatory diseases.

Appropriate responses to inflammation are conducive to pathogen elimination and tissue repair, while uncontrolled inflammatory reactions are likely to result in the damage of tissues. Chemokine (CC-motif) Ligand 2 (CCL2) is the main chemokine and activator of monocytes, macrophages, and neutrophils. CCL2 played a key role in amplifying and accelerating the inflammatory cascade and is closely related to chronic non-controllable inflammation (cirrhosis, neuropathic pain, insulin resistance, atherosclerosis, deforming arthritis, ischemic injury, cancer, etc.). The crucial regulatory roles of CCL2 may provide potential targets for the treatment of inflammatory diseases. Therefore, we presented a review of the regulatory mechanisms of CCL2. Gene expression is largely affected by the state of chromatin. Different epigenetic modifications, including DNA methylation, post-translational modification of histones, histone variants, ATP-dependent chromatin remodelling, and non-coding RNA, could affect the 'open' or 'closed' state of DNA, and then significantly affect the expression of target genes. Since most epigenetic modifications are proven to be reversible, targeting the epigenetic mechanisms of CCL2 is expected to be a promising therapeutic strategy for inflammatory diseases. This review focuses on the epigenetic regulation of CCL2 in inflammatory diseases.

Ferrous iron-induced formation of glycyrrhizic acid hydrogels for Staphylococcus aureus-infected wound healing

Severe skin wound healing is mainly hindered by bacterial infection and uncontrolled inflammatory reaction. As a wound dressing, multifunctional hydrogel is expected to offer the potential possibility for overcoming current barriers in wound therapeutics. Herein, a natural drug molecule (glycyrrhizic acid, GA) and metal ion (Fe2+) were used to achieve the metal coordination-induced gelation. This as-prepared Fe2+-induced GA hydrogel showed excellent injectability, self-healing property, and sustained release behavior at a relatively lower concentration of GA, thereby reducing the high dose-caused cytotoxicity. In addition to acting as an inducer of gelation, Fe2+ promoted the antibacterial performance of hydrogel against Escherichia coli and Staphylococcus aureus through causing lipid peroxidation, membrane damage, and DNA degradation. Moreover, the released GA from hydrogel significantly accelerated cell migration and inhibited the inflammatory reaction by mediation of NF-κB signaling pathway to downregulate levels of important inflammatory cytokines in lipopolysaccharide-stimulated RAW264.7 cells. Using a mouse skin infected model, we revealed that the Fe2+/GA hydrogel applied to the wound resulted in the rapid wound healing. It is believed that the construction of natural drug molecule-derived hydrogel with antibacterial and anti-inflammatory capabilities may shed a new light to serve as a promising dressing for managing the severe skin wounds.

Role of Neuropilin 1 in COVID-19 Patients with Acute Ischemic Stroke.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection can trigger the adaptive and innate immune responses, leading to uncontrolled inflammatory reactions and associated local and systematic tissue damage, along with thromboembolic disorders that may increase the risk of acute ischemic stroke (AIS) in COVID-19 patients. The neuropilin (NRP-1) which is a co-receptor for the vascular endothelial growth factor (VEGF), integrins, and plexins, is involved in the pathogenesis of AIS. NRP-1 is also regarded as a co-receptor for the entry of SARS-CoV-2 and facilitates its entry into the brain through the olfactory epithelium. NRP-1 is regarded as a cofactor for binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2), since the absence of ACE2 reduces SARS-CoV-2 infectivity even in presence of NRP-1. Therefore, the aim of the present study was to clarify the potential role of NRP-1 in COVID-19 patients with AIS. SARS-CoV-2 may transmit to the brain through NRP-1 in the olfactory epithelium of the nasal cavity, leading to different neurological disorders, and therefore about 45% of COVID-19 patients had neurological manifestations. NRP-1 has the potential capability to attenuate neuroinflammation, blood–brain barrier (BBB) permeability, cerebral endothelial dysfunction (ED), and neuronal dysfunction that are uncommon in COVID-19 with neurological involvement, including AIS. Similarly, high NRP-1 serum level is linked with ED, oxidative stress, and the risk of pulmonary thrombosis in patients with severe COVID-19, suggesting a compensatory mechanism to overcome immuno-inflammatory disorders. In conclusion, NRP-1 has an important role in the pathogenesis of COVID-19 and AIS, and could be the potential biomarker linking the development of AIS in COVID-19. The present findings cannot provide a final conclusion, and thus in silico, experimental, in vitro, in vivo, preclinical, and clinical studies are recommended to confirm the potential role of NRP-1 in COVID-19, and to elucidate the pharmacological role of NRP-1 receptor agonists and antagonists in COVID-19.

Neonatal Onset of Hemophagocytic Lymphohistiocytosis Due to Prenatal Varicella-Zoster Infection in a Neonate with Griscelli Syndrome Type 2.

Type 2 Griscelli syndrome (Type2 GS) is a primary inborn error of the immune system, classified in the immune dysregulation group.1,2 There are three different types of the disease, with different genetic causes responsible for the autosomal recessive inheritance pattern. Although hypopigmentation is common in all variants, neurological involvement or immunodeficiency with varying severity is seen in different types. Molecular motor protein myosin 5 an (MYo5A) [Type1GS], guanosine Triphosphate (GTP) binding protein (RAB27A) [Type2GS], and mutation in human melanophilin (MLPH) [Type 3GS] which is limited to hypopigmentation are reported as the known genetic defects in GS.3 Severe, ineffective, and uncontrolled inflammatory reactions are referred to as the pathogenesis of Hemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening condition that can be defined as either primary or secondary. Secondary causes happen in the context of autoimmunity, malignancy, spontaneous, or infections.4 Prenatal infections play an important role in causing long-term complications in the fetus. Some of them include toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and other organisms including syphilis, parvovirus, and Varicella zoster, known as TORCH syndrome (5).TORCH has been well described for a long time but there are limited reports of developing HLH in the context of prenatal infections. We described a type 2GS syndrome with neonatal-onset HLH triggered by a prenatal infection.

Hydrogen-rich and hyperoxygenate saline inhibits lipopolysaccharide-induced lung injury through mediating NF-κB/NLRP3 signaling pathway in C57BL/6 mice.

Background: Acute lung injury (ALI) is one kind of frequently occurred emergency in Intensive Care Unite with a high mortality. The underlying causes are uncontrolled inflammatory reactions and intractable hypoxemia, which are difficult to control and improve. In the past 10 years, gas medical studies have found that both hydrogen molecules and oxygen molecules have protective effects on acute lung injury by improving inflammatory reactions and hypoxia, respectively. Oxygen is an oxidant and hydrogen is an antioxidant. In this study, we investigated the combined effect of above two-gas molecular on lipopolysaccharide (LPS) -induced acute lung injury. To clarify whether the combination of hydrogen and oxygen could increase or cancel out the protective effect, an ALI mice model induced by intraperitoneal injection of LPS was established, and the degree of lung tissue and mitochondria damage was evaluated based on the pathological sections, inflammatory factors, wet-dry ratio, bronchoalveolar lavage fluid (BALF). Immunohistochemistry, electron microscopy, western blotting and other detection methods also used to evaluate the therapeutic effect on acute lung injury model. We observed that the combined protective effect of hydrogen and oxygen was superior to their respective protective effects, and the specific molecular mechanisms of the two therapies might be different. Hydrogen plays a more important role in the inflammatory and anti-apoptosis mechanisms, while oxygen improves hypoxia of the body, and thus, its molecular mechanism may be closely associated to the hypoxia pathways.

Role of Colchicine in Management of COVID-19?

CoV-2 disease 2019 (COVID-19) pandemic has exerted a great burden on the health and economic systems worldwide. One of the most important factors that affect the severity and prognosis of COVID-19 is the occurrence of hyperstimulation of the immune system resulting in “cytokine storm”. Similar to SARS-CoV, an intracellular complex called nod like receptor family pyrin domain containing 3 (NLRP3) inflammasome was found to be activated by SARS-CoV-2, then in turn stimulates several interleukins and initiates the inflammatory cascade. In addition, other inflammatory mediators such as interferons e.g., IFN-α, and IFN-γ, interleukins e.g., IL-1β, IL-12, IL-18, tumor necrosis factor-α (TNF- α), and chemokines e.g., CCL2, CXCL10 have been reported in severely ill patients. These mediators represent the corner stone in developing cytokine storm that results in uncontrolled systemic inflammatory reaction with subsequent acute respiratory distress syndrome (ARDS), multiple organ failure and eventually death. Based on its anti-inflammatory effects, colchicine has also gained attention to be utilized in the management of COVID-19 patient. Colchicine exerts its anti-inflammatory effect through inhibition of formation of microtubules which is considered an essential step in several cellular processes such as division, signalling, and migration. Also, colchicine affects the cytokine cascade by inhibiting IL-1β leading to reduction in neutrophils recruitment, free radicles production and inflammasome stimulation. This raises the concerns about the effectiveness of colchicine in COVID-19 treatment and the possibility of providing an improvement of the clinical course of the disease.

Cytokine release syndrome after CAR infusion in pediatric patients with refractory/relapsed B-ALL: is there a role for diclofenac?

Cytokine release syndrome (CRS) is a major complication after chimeric-antigen receptor T-cell treatment, characterized by an uncontrolled systemic inflammatory reaction. We investigated the potential role of diclofenac in the management of CRS in five pediatric patients treated for relapsed/refractory B-lineage acute lymphoblastic leukemia. In case of persistent fever with fever-free intervals shorter than 3 hours, diclofenac continuous infusion was initiated, at the starting dose of 0.5 mg/Kg/day, the lowest effective pediatric dose in our experience, possibly escalated up to 1 mg/Kg/day, as per institutional guidelines. CRS occurred at a median of 20 hours (range 8-27) after tisagenlecleucel infusion. Diclofenac was started at a median of 20 hours (range 13-33) after fever onset. A mean of 3.07 febrile peaks without diclofenac and 0.95 with diclofenac were reported (p = 0.02). Clinical benefit was achieved by hampering the progression of tachypnea and tachycardia. Despite fever control, CRS progressed in four of the five patients, and hypotension requiring vasopressors and fluid retention, as well as hypoxia, occurred. Vasopressors were followed by 1-2 doses of tocilizumab (one in patient 2 and two in patients 3, 4, and 5), plus steroids in patients 4 and 5. Based on a limited number of patients, diclofenac leads to better fever control, which translates into symptom relief and improvement of tachycardia, but could not prevent the progression of CRS.

Potential Therapeutic Effects of Natural Plant Compounds in Kidney Disease.

Background: The blockade of the progression or onset of pathological events is essential for the homeostasis of an organism. Some common pathological mechanisms involving a wide range of diseases are the uncontrolled inflammatory reactions that promote fibrosis, oxidative reactions, and other alterations. Natural plant compounds (NPCs) are bioactive elements obtained from natural sources that can regulate physiological processes. Inflammation is recognized as an important factor in the development and evolution of chronic renal damage. Consequently, any compound able to modulate inflammation or inflammation-related processes can be thought of as a renal protective agent and/or a potential treatment tool for controlling renal damage. The objective of this research was to review the beneficial effects of bioactive natural compounds on kidney damage to reveal their efficacy as demonstrated in clinical studies. Methods: This systematic review is based on relevant studies focused on the impact of NPCs with therapeutic potential for kidney disease treatment in humans. Results: Clinical studies have evaluated NPCs as a different way to treat or prevent renal damage and appear to show some benefits in improving OS, inflammation, and antioxidant capacity, therefore making them promising therapeutic tools to reduce or prevent the onset and progression of KD pathogenesis. Conclusions: This review shows the promising clinical properties of NPC in KD therapy. However, more robust clinical trials are needed to establish their safety and therapeutic effects in the area of renal damage.

Clinical Characteristics and Early Interventional Responses in Patients with Severe COVID-19 Pneumonia.

Progressive acute respiratory distress syndrome (ARDS) is the most lethal cause in patients with severe COVID-19 pneumonia due to uncontrolled inflammatory reaction, for which we found that early intervention of combined treatment with methylprednisolone and human immunoglobulin is a highly effective therapy to improve the prognosis of COVID-19-induced pneumonia patients. Objective. Herein, we have demonstrated the clinical manifestations, laboratory, and radiological characteristics of patients with severe Coronavirus Disease-2019 (COVID-19) pneumonia, as well as measures to ensure early diagnosis and intervention for improving clinical outcomes of COVID-19 patients. Summary Background Data. The COVID-19 is a new infection caused by a severe acute respiratory syndrome- (SARS-) like coronavirus that emerged in China in December 2019 and has claimed millions of lives. Methods. We included 37 severe COVID-19 pneumonia patients who were hospitalized at Taizhou Public Health Medical Center in Zhejiang province from January 17, 2020, to February 18, 2020. Demographic, clinical, and laboratory features; imaging characteristics; treatment history; and clinical outcomes of all patients were collected from electronic medical records. Results. The patients' mean age was 54 years (interquartile range, 43−64), with a slightly higher male preponderance (57%). The most common clinical features of COVID-19 pneumonia were fever (29 (78%)), dry cough (28 (76%)), dyspnea (9 (24%)), and fatigue (9 (24%)). Serum interleukin (IL)-6 and IL-10 were elevated in 35 (95%) and 19 (51%) patients, respectively. Chest computerized tomography scan revealed bilateral pneumonia in 35 (95%) patients. Early intervention with a combination of methylprednisolone and human immunoglobulin was highly effective in improving the prognosis of these patients. Conclusions. Progressive acute respiratory distress syndrome is the most common cause of death in patients with severe COVID-19 pneumonia owing to an uncontrolled inflammatory response. Early intervention with methylprednisolone and human immunoglobulin was highly effective in improving their prognosis.

Protective Role of Mytilus edulis Hydrolysate in Lipopolysaccharide-Galactosamine Acute Liver Injury.

Acute liver injury in its terminal phase trigger systemic inflammatory response syndrome with multiple organ failure. An uncontrolled inflammatory reaction is difficult to treat and contributes to high mortality. Therefore, to solve this problem a search for new therapeutic approaches remains urgent. This study aimed to explore the protective effects of M. edulis hydrolysate (N2-01) against Lipopolysaccharide-D-Galactosamine (LPS/D-GalN)-induced murine acute liver injure and the underlying mechanisms. N2-01 analysis, using Liquid Chromatography Mass Spectrometry (LCMS) metabolomic and proteomic platforms, confirmed composition, molecular-weight distribution, and high reproducibility between M. edulis hydrolysate manufactured batches. N2-01 efficiently protected mice against LPS/D-GalN-induced acute liver injury. The most prominent result (100% survival rate) was obtained by the constant subcutaneous administration of small doses of the drug. N2-01 decreased Vascular Cell Adhesion Molecule-1 (VCAM-1) expression from 4.648 ± 0.445 to 1.503 ± 0.091 Mean Fluorescence Intensity (MFI) and Interleukin-6 (IL-6) production in activated Human Umbilical Vein Endothelial Cells (HUVECs) from 7.473 ± 0.666 to 2.980 ± 0.130 ng/ml in vitro. The drug increased Nitric Oxide (NO) production by HUVECs from 27.203 ± 2.890 to 69.200 ± 4.716 MFI but significantly decreased inducible Nitric Oxide Synthase (iNOS) expression from 24.030 ± 2.776 to 15.300 ± 1.290 MFI and NO production by murine peritoneal lavage cells from 6.777 ± 0.373 µm to 2.175 ± 0.279 µm. The capability of the preparation to enhance the endothelium barrier function and to reduce vascular permeability was confirmed in Electrical Cell-substrate Impedance Sensor (ECIS) test in vitro and Miles assay in vivo. These results suggest N2-01 as a promising agent for treating a wide range of conditions associated with uncontrolled inflammation and endothelial dysfunction.

Cytokine Release Syndrome after Tisagenlecleucel Infusion in Pediatric Patients with Refractory/Relapsed B-Lineage Acute Lymphoblastic Leukemia: Is there a Role for Diclofenac?

Background: Cytokine Release Syndrome (CRS) is a major complication after Chimeric-Antigen Receptor (CAR) T cell treatment, characterized by an uncontrolled sistemic inflammatory reaction. The potential role of diclofenac in the management of CRS has been investigated in five pediatric patients treated for relapsed/refractory B-lineage acute lymphoblastic leukemia. Procedure: in case of persistent fever with fever-free intervals shorter than 3 hours, diclofenac continuous infusion was initiated, at the starting dose of 0.5 mg/Kg/day, the lowest effective pediatric dose, in our experience, possibly escalated up to 1 mg/Kg/day, as per institutional guidelines. Vital signs, O2 requirement, SpO2/FiO2 ratio and dosage of diclofenac and vasopressors until CRS resolution were recorded. Results: CRS occurred at a median of 20 hours (range 8-27) after tisagenlecleucel infusion. Diclofenac was started at a median of 20 hours (range 13-33) after fever onset. A mean of 3,07 febrile peaks without diclofenac and 0,95 with diclofenac were reported (p-value 0.02). A clinical benefit was achieved by hampering the progression of tachypnea and, mainly, tachycardia. Despite fever control, CRS progressed in four of the five patients and hypotension requiring vasopressors, fluid retention, besides hypoxia, occurred. Vasopressors were followed by 1-2 doses of tocilizumab (one in patient 2 and two in patients 3, 4, and 5), plus steroids in patients 4 and 5. Conclusion: based on a limited number of patients, diclofenac leads to a better fever control, which translates into symptom relief and improvement of tachycardia, but could not prevent the progression of CRS.

Multiple strategies of melatonin protecting against cardiovascular injury related to inflammation: A comprehensive overview

The onset and progression of baneful chronic diseases are often accompanied by a torrent of uncontrolled inflammatory reactions. Although inflammation is a natural response to detect, eliminate, and counterpoise the harmful insults to physiological integrity, a persistent inflammation causes tissue damage or more serious disorders, for example, the atherosclerosis and myocardial infarction. Inflammation often occurs in the cardiovascular system, but are also caused by other disorders including metabolic syndrome, autoimmune diseases, AIDS, and cancer that can affect the cardiac health. To effectively treat heart diseases a potent remedy is necessary which not only suppresses the inflammation but also prevents inflammation-associated cardio-pathogenesis. The ubiquitous antioxidant molecule melatonin has both anti-inflammatory and cardioprotective activities. Melatonin executes its anti-inflammatory activity by its antioxidant function or by targeting multiple intracellular signalling cascades such as modulating cytokine profile, blocking inflammasome activation and apoptosis. Lipid dysregulation and endothelial dysfunction that play a crucial role in the pathogenesis of atherosclerosis, insulin resistance, and diabetes are prevented by melatonin. Attenuation of mitochondrial and ER stress by melatonin is also pertinent to its cardioprotective action. Additionally, melatonin by its immuno-stimulatory activity can suppress inflammaging and immuno-senescence in HIV patients and thereby averts chronic inflammation-induced cardiovascular abnormality in these subjects. Modulation of cytokine profile and decrease in MMP-9 secretion by melatonin is beneficial in autoimmune conditions. In addition to its anti-tumour potency, melatonin can reduce chemotherapy-induced cardio-toxicity in cancer patients. This review, therefore, provides a concise summary of the currently available information appertaining to the roles of melatonin in mitigation of chronic inflammation and its effect on cardiovascular integrity.

The sino-nasal warzone: transcriptomic and genomic studies on sino-nasal aspergillosis in dogs

We previously showed that each dog with chronic non-invasive sino-nasal aspergillosis (SNA) was infected with a single genotype of Aspergillus fumigatus. Here, we studied the transcriptome of this fungal pathogen and the canine host within the biofilm resulting from the infection. We describe here transcriptomes resulting from natural infections in animal species with A. fumigatus. The host transcriptome showed high expression of IL-8 and alarmins, uncontrolled inflammatory reaction and dysregulation of the Th17 response. The fungal transcriptome showed in particular expression of genes involved in secondary metabolites and nutrient acquisition. Single-nucleotide polymorphism analysis of fungal isolates from the biofilms showed large genetic variability and changes related with adaptation to host environmental factors. This was accompanied with large phenotypic variability in in vitro stress assays, even between isolates from the same canine patient. Our analysis provides insights in genetic and phenotypic variability of Aspergillus fumigatus in biofilms of naturally infected dogs reflecting in-host adaptation. Absence of a Th17 response and dampening of the Th1 response contributes to the formation of a chronic sino-nasal warzone.

Pulmonary Endothelial Dysfunction and Thrombotic Complications in Patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new strain of a Coronaviridae virus that presents 79% genetic similarity to the severe acute respiratory syndrome coronavirus, has been recently recognized as the cause of a global pandemic by the World Health Organization, implying a major threat to world public health. SARS-CoV-2 infects host human cells by binding through the viral spike proteins to the ACE-2 (angiotensin-converting enzyme 2) receptor, fuses with the cell membrane, enters, and starts its replication process to multiply its viral load. Coronavirus disease (COVID-19) was initially considered a respiratory infection that could cause pneumonia. However, in severe cases, it extends beyond the respiratory system and becomes a multiorgan disease. This transition from localized respiratory infection to multiorgan disease is due to two main complications of COVID-19. On the one hand, it is due to the so-called cytokine storm: an uncontrolled inflammatory reaction of the immune system in which defensive molecules become aggressive for the body itself. On the other hand, it is due to the formation of a large number of thrombi that can cause myocardial infarction, stroke, and pulmonary embolism. The pulmonary endothelium actively participates in these two processes, becoming the last barrier before the virus spreads throughout the body. In this review, we examine the role of the pulmonary endothelium in response to COVID-19, the existence of potential biomarkers, and the development of novel therapies to restore vascular homeostasis and to protect and/or treat coagulation, thrombosis patients. In addition, we review the thrombotic complications recently observed in patients with COVID-19 and its potential threatening sequelae.

Identification of robust genetic signatures associated with lipopolysaccharide-induced acute lung injury onset and astaxanthin therapeutic effects by integrative analysis of RNA sequencing data and GEO datasets.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening clinical conditions predominantly arising from uncontrolled inflammatory reactions. It has been found that the administration of astaxanthin (AST) can exert protective effects against lipopolysaccharide (LPS)-induced ALI; however, the robust genetic signatures underlying LPS induction and AST treatment remain obscure. Here we performed a statistical meta-analysis of five publicly available gene expression datasets from LPS-induced ALI mouse models, conducted RNA-sequencing (RNA-seq) to screen differentially expressed genes (DEGs) in response to LPS administration and AST treatment, and integrative analysis to determine robust genetic signatures associated with LPS-induced ALI onset and AST administration. Both the meta-analyses and our experimental data identified a total of 198 DEGs in response to LPS administration, and 11 core DEGs (Timp1, Ly6i, Cxcl13, Irf7, Cxcl5, Ccl7, Isg15, Saa3, Saa1, Tgtp1, and Gbp11) were identified to be associated with AST therapeutic effects. Further, the 11 core DEGs were verified by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC), and functional enrichment analysis revealed that these genes are primarily associated with neutrophils and chemokines. Collectively, these findings unearthed the robust genetic signatures underlying LPS administration and the molecular targets of AST for ameliorating ALI/ARDS which provide directions for further research.

Maresins: anti-inflammatory pro-resolving mediators with therapeutic potential.

Although inflammation is protective of the body, uncontrolled acute inflammatory reactions may inflict tissue damage and lead to chronic inflammation. There is a fast-growing research interest in mechanisms that mediate regression of inflammation and actions of anti-inflammatory factors. Studies of inflammatory and anti-inflammatory mechanisms have uncovered roles for new lipid mediators, including lipoxins, resolvins, protectins, and maresins, collectively referred to as specialized pro-resolving mediators (SPM). Maresins have recently been discovered and are biosynthesized from docosahexaenoic acid (DHA) by macrophages and display strong anti-inflammatory and pro-resolving activities. Here, we summarize the actions and mechanisms of maresins in different diseases and suggest possible therapeutic uses.

Design, Implementation, and Validation of a Pediatric ICU Sepsis Prediction Tool as Clinical Decision Support.

Sepsis is an uncontrolled inflammatory reaction caused by infection. Clinicians in the pediatric intensive care unit (PICU) developed a paper-based tool to identify patients at risk of sepsis. To improve the utilization of the tool, the PICU team integrated the paper-based tool as a real-time clinical decision support (CDS) intervention in the electronic health record (EHR). This study aimed to improve identification of PICU patients with sepsis through an automated EHR-based CDS intervention. A prospective cohort study of all patients admitted to the PICU from May 2017 to May 2019. A CDS intervention was implemented in May 2018. The CDS intervention screened patients for nonspecific sepsis criteria, temperature dysregulation and a blood culture within 6 hours. Following the screening, an interruptive alert prompted nursing staff to complete a perfusion screen to assess for clinical signs of sepsis. The primary alert performance outcomes included sensitivity, specificity, and positive and negative predictive value. The secondary clinical outcome was completion of sepsis management tasks. During the 1-year post implementation period, there were 45.0 sepsis events per 1,000 patient days over 10,805 patient days. The sepsis alert identified 392 of the 436 sepsis episodes accurately with sensitivity of 92.5%, specificity of 95.6%, positive predictive value of 46.0%, and negative predictive value of 99.7%. Examining only patients with severe sepsis confirmed by chart review, test characteristics fell to a sensitivity of 73.3%, a specificity of 92.5%. Prior to the initiation of the alert, 18.6% (13/70) of severe sepsis patients received recommended sepsis interventions. Following the implementation, 34% (27/80) received these interventions in the time recommended, p = 0.04. An EHR CDS intervention demonstrated strong performance characteristics and improved completion of recommended sepsis interventions.