Animal Models Of Inflammation Research Articles

Histological Features of Uterine Myometrial Dysfunction: Possible Involvement of Localized Inflammation.

The latest perspective suggests that elevated levels of inflammation and cytokines are implicated in atonic postpartum hemorrhage. Lipopolysaccharide (LPS) has been widely used to induce inflammation in animal models. Therefore, this study aimed to induce uterine inflammation using LPS to investigate whether local inflammation triggers dysfunction and atrophy in the myometrium, as well as the potential underlying molecular mechanisms involved. In vivo, an animal model was established by intraperitoneal injection of 300 μg/ kg LPS in rats on gestational day 21. Hematoxylin-eosin (H&E) staining and Masson staining were employed to determine morphological changes in the rat uterine smooth muscle. Enzyme-linked immunosorbent assay (ELISA) was used to detect inflammatory cytokines. Immunohistochemistry, tissue fluorescence, and Western blotting were conducted to assess the expression levels of the uterine contraction-related proteins Toll-like receptor 4 (TLR4) and the nuclear factor kappa-B (NF-κB) signaling pathway. In vitro, human uterine smooth muscle cells (HUtSMCs) were exposed to 2 μg/mL LPS to further elucidate the involvement of the TLR4/NF-κB signaling pathway in LPS-mediated inflammation. In this study, LPS induced uterine myometrial dysfunction in rats, leading to a disorganized arrangement, a significant increase in collagen fiber deposition, and widespread infiltration of inflammatory cells. In both in vivo animal models and in vitro HUtSMCs, LPS elevated IL-6, IL-1β, and TNF-α levels while concurrently suppressing the expression of connexin 43 (Cx43) and oxytocin receptor (OXTR). Mechanistically, the LPS-treated group exhibited TLR4 activation, and the phosphorylation levels of p65 and IκBα were notably increased. LPS triggered the TLR4/NF-κB signaling pathway, inducing an inflammatory response in the myometrium and leading to uterine myometrial dysfunction and uterine atony.

Integrated analysis of gut metabolome, microbiome, and exfoliome data in an equine model of intestinal injury

BackgroundThe equine gastrointestinal (GI) microbiome has been described in the context of various diseases. The observed changes, however, have not been linked to host function and therefore it remains unclear how specific changes in the microbiome alter cellular and molecular pathways within the GI tract. Further, non-invasive techniques to examine the host gene expression profile of the GI mucosa have been described in horses but not evaluated in response to interventions. Therefore, the objectives of our study were to (1) profile gene expression and metabolomic changes in an equine model of non-steroidal anti-inflammatory drug (NSAID)-induced intestinal inflammation and (2) apply computational data integration methods to examine host-microbiota interactions.MethodsTwenty horses were randomly assigned to 1 of 2 groups (n = 10): control (placebo paste) or NSAID (phenylbutazone 4.4 mg/kg orally once daily for 9 days). Fecal samples were collected on days 0 and 10 and analyzed with respect to microbiota (16S rDNA gene sequencing), metabolomic (untargeted metabolites), and host exfoliated cell transcriptomic (exfoliome) changes. Data were analyzed and integrated using a variety of computational techniques, and underlying regulatory mechanisms were inferred from features that were commonly identified by all computational approaches.ResultsPhenylbutazone induced alterations in the microbiota, metabolome, and host transcriptome. Data integration identified correlation of specific bacterial genera with expression of several genes and metabolites that were linked to oxidative stress. Concomitant microbiota and metabolite changes resulted in the initiation of endoplasmic reticulum stress and unfolded protein response within the intestinal mucosa.ConclusionsResults of integrative analysis identified an important role for oxidative stress, and subsequent cell signaling responses, in a large animal model of GI inflammation. The computational approaches for combining non-invasive platforms for unbiased assessment of host GI responses (e.g., exfoliomics) with metabolomic and microbiota changes have broad application for the field of gastroenterology.8RW7XWUKiyvANo7PaYZA3nVideo

Monosodium iodoacetate induces Cartilage degradation and inflammation in rats in a dose- and time-dependent manner

Monosodium iodoacetate (MIA) is a widely recognized agent for inducing cartilage degradation and inflammation in animal models. In this study, we systematically investigated the dose- and time-dependent effects of MIA on cartilage degradation in the knees of rats. We evaluated knee diameter, knee bend score, and the levels of pro-inflammatory cytokines (IL-1 and IL-8) and cartilage degradation markers (CTX-II) to gain insights into cartilage damage and inflammation progression. Wistar rats were categorized into groups receiving various doses of MIA via intra-articular injection (0.1 mg, 0.5 mg, 1 mg, 3 mg, and 5 mg) and were observed at multiple time intervals (2, 4, 6, 8, 10, and 12 weeks). We measured knee diameter to gauge joint swelling, assigned knee bend scores to assess functional limitations, and analyzed synovial fluid samples for IL-1β, IL-8, and CTX-II levels. Our data show that low-dose MIA increases pain sensitivity, knee diameter, inflammatory cytokines IL-1β and IL-8, and CTX-II levels, which progress slowly over 12 weeks. On the other hand, higher dosages of MIA caused cartilage deterioration after two weeks, followed by an increase in inflammatory cytokines. This research sheds light on MIA administration's dose- and time-dependent effects on cartilage breakdown and inflammation in rat knee joints. Analyzing knee diameter, knee bend score, IL-1β, IL-8, and CTX-II as evaluation parameters provides a multidimensional perspective of cartilage injury and inflammatory dynamics. These findings help us comprehend cartilage-related illnesses and have implications for future research on therapeutic approaches for cartilage disorders.

Changes in the Serum Metabolome in an Inflammatory Model of Osteoarthritis in Rats.

Osteoarthritis (OA) is a pathology of great impact worldwide. Its physiopathology is not completely known, and it is usually diagnosed by imaging techniques performed at advanced stages of the disease. The aim of this study was to evaluate early serum metabolome changes and identify the main metabolites involved in an inflammatory OA animal model. This study was performed on thirty rats. OA was induced in all animals by intra-articular injection of monoiodoacetate into the knee joint. Blood samples were taken from all animals and analyzed by mass spectrometry before OA induction and 28, 56, and 84 days following induction. Histological evaluation confirmed OA in all samples. The results of this study allow the identification of several changes in 18 metabolites over time, including organic acids, benzenoids, heterocyclic compounds, and lipids after 28 days, organic acids after 56 days, and lipid classes after 84 days. We conclude that OA induces serological changes in the serum metabolome, which could serve as potential biomarkers. However, it was not possible to establish a relationship between the identified metabolites and the time at which the samples were taken. Therefore, these findings should be confirmed in future OA studies.

Cholesterol-modified sphingomyelin chimeric lipid bilayer for improved therapeutic delivery

Cholesterol (Chol) fortifies packing and reduces fluidity and permeability of the lipid bilayer in vesicles (liposomes)-mediated drug delivery. However, under the physiological environment, Chol is rapidly extracted from the lipid bilayer by biomembranes, which jeopardizes membrane stability and results in premature leakage for delivered payloads, yielding suboptimal clinic efficacy. Herein, we report a Chol-modified sphingomyelin (SM) lipid bilayer via covalently conjugating Chol to SM (SM-Chol), which retains membrane condensing ability of Chol. Systemic structure activity relationship screening demonstrates that SM-Chol with a disulfide bond and longer linker outperforms other counterparts and conventional phospholipids/Chol mixture systems on blocking Chol transfer and payload leakage, increases maximum tolerated dose of vincristine while reducing systemic toxicities, improves pharmacokinetics and tumor delivery efficiency, and enhances antitumor efficacy in SU-DHL-4 diffuse large B-cell lymphoma xenograft model in female mice. Furthermore, SM-Chol improves therapeutic delivery of structurally diversified therapeutic agents (irinotecan, doxorubicin, dexamethasone) or siRNA targeting multi-drug resistant gene (p-glycoprotein) in late-stage metastatic orthotopic KPC-Luc pancreas cancer, 4T1-Luc2 triple negative breast cancer, lung inflammation, and CT26 colorectal cancer animal models in female mice compared to respective FDA-approved nanotherapeutics or lipid compositions. Thus, SM-Chol represents a promising platform for universal and improved drug delivery.

Abrasion Curative Using HerboGel

Our project aims to develop a hydrogel-based wound healing formulation utilizing the medicinal properties of three potent herbs: Curcuma longa (turmeric), Ocimumtenuiflorum (holy basil), and Azadirachtaindica (neem). These herbs are renowned for their antimicrobial and anti-inflammatory properties, which are crucial for effective wound management. The hydrogel will serve as a vehicle for delivering the active compounds extracted from these herbs to the site of injury, promoting faster healing and reducing the risk of infection. Through a series of extraction, formulation, and characterization steps, we will optimize the herbal hydrogel for its physical, chemical, and biological properties. In vitro studies will assess its antimicrobial efficacy against common wound pathogens, while in vivo experiments will evaluate its ability to accelerate wound closure and reduce inflammation in animal models. Safety and stability assessments will ensure the viability of the formulation for clinical translation. Ultimately, this research holds promise for the development of a natural, effective, and accessible solution for wound care, addressing a critical need in healthcare.

Chemiluminescent Conjugated Polymer Nanoparticles for Deep-Tissue Inflammation Imaging and Photodynamic Therapy of Cancer.

Deep-tissue optical imaging and photodynamic therapy (PDT) remain a big challenge for the diagnosis and treatment of cancer. Chemiluminescence (CL) has emerged as a promising tool for biological imaging and in vivo therapy. The development of covalent-binding chemiluminescence agents with high stability and high chemiluminescence resonance energy transfer (CRET) efficiency is urgent. Herein, we design and synthesize an unprecedented chemiluminescent conjugated polymer PFV-Luminol, which consists of conjugated polyfluorene vinylene (PFV) main chains and isoluminol-modified side chains. Notably, isoluminol groups with chemiluminescent ability are covalently linked to main chains by amide bonds, which dramatically narrow their distance, greatly improving the CRET efficiency. In the presence of pathologically high levels of various reactive oxygen species (ROS), especially singlet oxygen (1O2), PFV-Luminol emits strong fluorescence and produces more ROS. Furthermore, we construct the PFV-L@PEG-NPs and PFV-L@PEG-FA-NPs nanoparticles by self-assembly of PFV-Luminol and amphiphilic copolymer DSPE-PEG/DSPE-PEG-FA. The chemiluminescent PFV-L@PEG-NPs nanoparticles exhibit excellent capabilities for in vivo imaging in different inflammatory animal models with great tissue penetration and resolution. In addition, PFV-L@PEG-FA-NPs nanoparticles show both sensitive in vivo chemiluminescence imaging and efficient chemiluminescence-mediated PDT for antitumors. This study paves the way for the design of chemiluminescent probes and their applications in the diagnosis and therapy of diseases.

Anti-Inflammatory Effects of a Novel Nuclear Factor-κB Inhibitory Derivative Derived from Pyrazolo[3,4-d]Pyrimidine in Three Inflammation Models.

Nuclear factor-κB (NF-κB) plays a central role in inflammatory responses, and its physiologic functions are essential for cell survival and proliferation. Currently, drugs targeting NF-κB inhibition have not yet been applied in clinical practice. We investigated the physiologic effect of a novel NF-κB inhibitory compound, 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivative (INH #1), on three inflammatory animal models. The pharmacokinetics were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Acute hepatitis was induced by administrating lipopolysaccharide (LPS) and D-(+)-galactosamine hydrochloride followed by the analysis of survival time and inflammatory mediators. Collagen-induced arthritis (CIA) was induced by immunization with type II collagen (CII), and serum-transfer arthritis (STA) was caused by injecting K/BxN mice serum. Clinical and histologic scores were evaluated in both arthritis models. Immune cell subset analysis, CII-induced interferon-gamma (IFN-γ) production and proliferation, and measurement of anti-CII IgG antibodies were performed in the CIA model. In the acute hepatitis model, INH #1 suppressed tumor necrosis factor-α (TNF-α) production and prevented early death in a dose-dependent manner. INH #1 significantly attenuated arthritis scores and joint inflammation in both arthritis models. Additionally, in the CIA model, dendritic cells (DCs) in the regional lymph nodes were decreased in the treated mice and antigen-induced IFN-γ production and cell proliferation in splenocytes were inhibited, whereas the titers of anti-CII IgG antibodies were comparable regardless of the treatment. Here we revealed that INH #1 exerted anti-inflammatory effects in vivo via inhibition of inflammatory mediators and suppression of cellular immune responses. This compound could be a novel candidate for inhibition of NF-κB in certain inflammatory diseases. SIGNIFICANCE STATEMENT: A novel nuclear factor-κB (NF-κB) inhibitory compound, 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivative (INH #1), which retains physiologically essential NF-κB bioactivity, suppressed inflammation in three different mouse models: the acute hepatitis model, the collagen-induced arthritis model, and the K/BxN serum-transfer arthritis model. These results suggest that this compound could be a novel and potent anti-inflammatory agent.

Diabetic Cardiac Autonomic Neuropathy: A Review of NLRP3 Inflammasome Complicity

Debilitating and often misdiagnosed cardiac autonomic neuropathy affects people with diabetes. Damage to the biggest sympathetic trunk ganglion of autonomic nerve fibers that innervate the heart and blood vessels, the superior cervical ganglion (SCG), is the cause of aberrant heart rate and vascular dynamics in people with diabetic cardiac autonomic neuropathy (DCAN). Mediating host immunological responses to microbial infection and cellular damage, inflammasomes are a class of cytosolic protein complexes that include NLRP3. This review compiled the findings of experimental investigations on DCAN and discussed their connection to the NLRP3 inflammasome’s involvement. SCG P2X7 receptor expression can be boosted by inflammation brought on by hyperglycemia, leading to nerve injury. Unfortunately, there is a lack of research on DCAN-related inflammation in animal models, especially in inflammasome. Currently, only IncRNAUC.360+ shRNA and Schisandrin B, prove to alleviate the pathogenesis. Therefore, more research into the causes and potential remedies for DCAN is necessary.

Macrophage membrane-modified targeted phase-change nanoparticles for multimodal imaging of experimental autoimmune myocarditis.

Myocarditis is an important public health issue due to the high prevalence of sudden death in adolescents and young adults. Nevertheless, the early identification of myocarditis remains a serious problem for clinicians. There is no single non-invasive method to diagnose myocarditis in the currently available clinical guidelines and consensus. Molecular imaging is an effective approach for accurate diagnosis. Poly(lactic acid-glycolic acid) (PLGA) is considered to be the preferred carrier for molecular imaging because of its biosafety and modifiability. Macrophage membrane-modified biomimetic nanoprobes (MM-NPs) possess low immunogenicity and inflammation-directed chemotaxis capabilities and are repeatedly chosen as materials for targeted diagnosis and treatment of inflammatory diseases. In this study, experimental autoimmune myocarditis (EAM) was used as an animal model of inflammation. Previous studies have confirmed that this model is similar to pathological injury caused by acute myocarditis in humans. In multimodal imaging (US/PA/MRI), a phase-change material (PFH) and superparamagnetic iron oxide (SPIO) are used as imaging substances. Early identification of myocardial inflammatory sites was achieved by the tail vein injection of MM/NPs loaded with PFH and SPIO. This probe is expected to be a powerful tool for clinicians to diagnose myocarditis.

Crosstalk Between Microbiota, Microbial Metabolites, and Interferons in the Inflammatory Bowel Disease Gut.

With the prevalence of inflammatory bowel diseases (IBD) continuing to rise in Canada and globally, developing improved therapeutics that successfully treat greater percentages of patients with reduced complications is paramount. A better understanding of pertinent immune pathways in IBD will improve our ability to both successfully dampen inflammation and promote gut healing, beyond just inhibiting specific immune proteins; success of combination therapies supports this approach. Interferons (IFNs) are key cytokines that protect mucosal barrier surfaces, and their roles in regulating gut homeostasis and inflammation differ between the three IFN families (type I, II, and III). Interestingly, the gut microbiota and microbial metabolites impact IFN-signaling, yet how this system is impacted in IBD remains unclear. In this review, we discuss the current knowledge of how gut microbiota directly or indirectly impact IFN levels/responses, and what is known about IFNs differentially regulating gut homeostasis and inflammation in animal models or patients with IBD.

Macrophages polarization in renal inflammation and fibrosis animal models (Review)

Macrophages polarization in renal inflammation and fibrosis animal models (Review)

An antioxidation-responsive SERS-active microneedle for detecting the antioxidant capacity in living organisms

To detect the antioxidant capacity in living organisms, an antioxidation-responsive SERS-active microneedle was fabricated by adsorbing resazurin on miniature SERS substrates, SERS-active microneedles. The SERS intensity ratio of characterized peaks of resazurin and its product, resorufin, was adopted and verified as an indicator of antioxidant capacity. The feasibility of detection of the antioxidant capacity in living organisms was proved by using the fabricated SERS-active microneedles to detect the antioxidant capacity of lipopolysaccharide-induce inflammatory animal models. The fabricated SERS-active microneedles can be inserted into target soft tissues with minimal invasion to detect their antioxidant capacity. The fabricated SERS-active microneedles would be a novel tool to bring the detection of antioxidant capacity from samplings ex vivo and cells to complex tissues to promote the researches on redox biology in living organisms.

The Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of the NLRX1 agonist NX-13 in Active Ulcerative Colitis: Results of a Phase 1b Study.

NX-13 activation of NLRX1 reduces intracellular reactive oxygen species and decreases inflammation in animal models of colitis. A phase 1a trial demonstrated a gut-selective pharmacokinetic (PK) profile with good tolerability. This phase Ib study aimed to evaluate the safety, tolerability, and PK of NX-13 in patients with active ulcerative colitis (UC). We conducted a multicenter, randomized, double-blinded, placebo-controlled trial of NX-13 in patients with active UC. Patients with a Mayo Clinic Score of 4-10 were randomly assigned (3:3:3:1 ratio) to three NX-13 oral dose groups (250mg Immediate Release (IR), 500mg IR, or 500mg Delayed Release (DR) or placebo) once daily for 4 weeks. Safety and PK were the primary and secondary objectives, respectively. Thirty-eight patients (11 females) were recruited and randomized to placebo (5), NX-13 250mg IR (11), NX-13 500mg IR (11), or NX-13 500mg DR (11) and received at least one dose. There were no Serious Adverse Events (SAEs) or deaths during the trial. One patient (500mg DR, 1/11) withdrew for worsening of UC and a second (500mg IR, 1/11) on the last day of treatment after a panic attack associated with atrial fibrillation. In the efficacy population (36 patients), clinical improvement in rectal bleeding and stool frequency scores relative to placebo were seen as early as week 2 and endoscopic response was seen at week 4. NX-13 was generally safe and well tolerated with early signs of rapid symptom and endoscopic improvement. This novel mechanism of action warrants further investigation. ClinicalTrials.gov: NCT04862741.

Abstract 15709: Antagonist of Growth Hormone-Releasing Hormone Receptor Protects Against Cardiopulmonary Injury Induced by rVSV-SARS-CoV-2-S Virus Through Rag2 Regulation

Background: SARS-CoV-2 (COVID-19) transmits a multi-systemic disease that can lead to acute respiratory distress syndrome. Growth hormone-releasing hormone receptor (GHRH-R) and its splice variant are expressed in murine and human lung and heart. GHRH-R antagonist, MIA-602, has been shown to regulate inflammation in animal models and immune cell responses to bleomycin lung injury. Using a BSL2-compatible recombinant VSV-eGFP-SARS-CoV-2-S virus (rVSV-SARS-CoV-2-S) which mimics native SARS-CoV-2 infection in K18 hACE2tg mice, we tested our hypothesis that MIA-602 attenuates COVID-19-induced cardiopulmonary injury by reducing inflammation. Methods: Male and female K18-hACE2tg mice were infected with SARS-CoV-2/USA-WA1/2020, rVSV-SARS-CoV-2-S, or PBS and lung viral load, weight-loss and histopathology were compared (N=8). Mice infected with rVSV-SARS-CoV-2-S were subject to daily subcutaneous injections of 10 μg MIA-602 or vehicle (control) starting at 24h post-infection. Pulmonary function was measured via whole-body plethysmography on day 0, day 3, and day 5 (n=7). Five days after viral infection mice were sacrificed, and blood and tissues collected for histopathological analyses, H&E staining, RNA and protein work. Heart and lung tissues were used for RNASeq (n=3 per group). T-test or One-way ANOVA-test was used for statistical analysis. Results: SARS-CoV-2 and rVSV-SARS-CoV-2-S presented similar pathology for weight loss, infectivity (~60%) and histopathologic changes. Daily treatment with MIA-602 ameliorated weight loss, reduced lung inflammation, pneumonia and pulmonary dysfunction evidenced by rescued respiratory rate, expiratory parameters, and dysregulated airway parameters (p<.05). MIA-602 normalized the high expression of the inflammatory protein ICAM-1 in heart and lung (p<0.01), and master immune modulator Rag2 in lung (RNA:10-FC; Protein: 2-FC; p<.001). Conclusions: The results indicate a possible role for pulmonary Rag2 in protecting against pulmonary dysfunction and heart/lung inflammation by peptide GHRH-R antagonist MIA-602 in a novel animal model of COVID-19 pneumonia.

Anti-inflammatory potential of a Thai traditional remedy called Prabchompoothaweep in an animal model of acute and sub-acute inflammation

Ethnopharmacological relevancePrabchompoothaweep (PCT) is a Thai remedy which is composed of 23 herbs and has been added onto the National List of Essential Medicines (NLEM) of Thailand. This remedy has been used to treat allergic rhinitis and asthma in Thai traditional medicine for many years. Furthermore, a few studies have reported anti-allergic, anti-malarial, anti-inflammatory and antioxidant activities. Aim of the studyThis study aims to evaluate anti-inflammatory activity of PCT extract in an animal model. Materials and methodsThe animal model of acute inflammation was studied over a 24-h period, utilizing the method of carrageenan-induced paw oedema. In addition, sub-acute inflammation was examined over 7 days, using the formalin-induced paw oedema method. The treatment groups received PCT extracts, via the oral route, at 1-h prior to injection and then the sub plantar of the rat right paw was injected with the named substances to generate paw oedema. The paw thickness was measured by vernier caliper at regular intervals after injection. At the end of experiment, the blood and paw tissues were collected for measurement of pro-inflammatory cytokines and histological examination respectively. ResultsIn acute inflammation, all doses of PCT extract (250, 500 and 1000 mg/kg p.o.) significantly reduced paw thickness after the first 3 h in a dose-dependent manner and the percentage of inhibition was 38.7%, 47.8% and 49.5% respectively. The pro-inflammatory cytokines, including TNF-α and IL-1β, statistically decreased with all doses of the extracts. However, the histological examination did not reveal significant results due to the short time duration. As regards to sub-acute inflammation, all doses of PCT extract significantly reduced paw thickness with 12.78%, 23.64% and 35.78%, in a dose dependent manner. Also, the pro-inflammatory cytokines (TNF-α and IL-1β) significantly decreased at day 7. Interestingly, the histological examination of paw tissue demonstrated reductions of mononuclear infiltrations of inflammatory cells, this was observed in the group receiving PCT extracts, also in a dose-dependent manner. ConclusionTherefore, PCT exerted anti-inflammatory activity in an animal model of acute and sub-acute inflammation, suggesting that it could be used as a new source for treatment of inflammatory diseases.

Exogenous IL-25 ameliorates airway neutrophilia via suppressing macrophage M1 polarization and the expression of IL-12 and IL-23 in asthma

BackgroundSevere asthma is associated with substantial mortality and has unmet therapeutic need. A subset of severe asthma is characterized by neutrophilic airway inflammation. Classically activated (or M1) macrophages which express IL-12 and IL-23 are associated with airway neutrophilia in asthma. Exogenous IL-25 was reported to suppress intestinal inflammation in animal models of inflammatory bowel diseases via suppressing IL-12 and IL-23 production. We hypothesize that IL-25 ameliorates airway neutrophilia via inhibiting macrophage M1 polarization and the expression of IL-12 and IL-23 in asthma.MethodsIn a mouse model of neutrophil-dominant allergic airway inflammation, the effect of mouse recombinant IL-25 on airway inflammation were assessed by H&E staining and bronchoalveolar lavage (BAL) cell counting. The percentage of M1 macrophages in lung tissue and BAL cells were analyzed by flow cytometry. Quantitative PCR and immunostaining were performed to measure the expression of Il12, Il23, and inflammatory cytokines. Mechanistic experiments were performed in primary culture of macrophages from mouse lungs. The expression of IL-12, IL-23 and IL-25 in sputum was analyzed in a cohort of severe asthma and subjects with eosinophilic or non-eosinophilic asthma.ResultsIntranasal administration of IL-25 markedly decreased the number of neutrophils in BAL cells in a murine model of neutrophil-dominant allergic airway inflammation. Moreover, exogenous IL-25 decreased the number of M1 macrophages, and reduced the expression of IL-12, IL-23 in the lungs of the mouse model. Exogenous IL-25 also inhibited the expression of inflammatory cytokines IL-1β, IFN-γ, TNF-α and IL-17 A. In vitro, IL-25 suppressed IL-12 and IL-23 expression in lipopolysaccharide (LPS)-stimulated primary culture of mouse pulmonary macrophages. Mechanistically, IL-25 inhibited LPS-induced c-Rel translocation to nucleus via STAT3-dependent signaling. In a cohort of severe asthma, IL-25 protein levels in sputum were significantly lower than control subjects. The transcript levels of IL-12 and IL-23 were increased whereas IL-25 transcripts were decreased in sputum cells from subjects with non-eosinophilic asthma compared to eosinophilic asthma.ConclusionsIL-25 expression is downregulated in subjects with severe or non-eosinophilic asthma. Exogenous IL-25 ameliorates airway neutrophilia, at least in part, via inhibiting macrophage M1 polarization and the expression of IL-12 and IL-23.

Therapeutic effects of candesartan in inflammatory skin disorders by suppressing Th17 differentiation

As angiotensin II is associated with inflammation, type I angiotensin II receptor blockers (ARBs) exibit anti-inflammatory effects in patients with hypertension as well as inflammatory disease animal models including arthritis models. The present study aimed to investigate whether ARBs exert anti-inflammatory effects in vivo in skin disorders. We tested effects of ARBs on 1-chloro-2,4-dinitrobenzene(CDNB)-induced atopic dermatitis-like and imiquimod-induced psoriasis-like skin models. CDNB-induced atopic dermatitis-like skin lesions were suppressed by administration of candesartan or telmisartan. The suppressive effect of telmisartan was blocked by the presence of GW9662, a selective PPARγ inhibitor, but not that of candesartan. Both ARBs suppressed increases in pro-inflammatory cytokine (IL-4, IL-13, IFN-γ, and IL-17A) levels, and GW9662 inhibited telmisartan-induced suppression but not candesartan. Candesartan significantly inhibited in vitro differentiation of naïve T cells into Th17 cells to a greater extent than telmisartan. In the imiquimod-induced psoriasis model, whose primary etiology is activation of IL-23/IL-17 axis, candesartan significantly suppressed psoriasis-like skin lesions and Th17 cell populations in both lymph nodes and spleens to a greater extent than telmisartan. Overall, certain ARBs may have anti-inflammatory effects in skin diseases. Candesartan may have therapeutic implications in inflammatory skin disorders by suppressing Th17 differentiation, while telmisartan might have therapeutic potential by activating PPARγ.

Revealing the biological mechanism of acupuncture in alleviating excessive inflammatory responses and organ damage in sepsis: a systematic review.

Sepsis is a systemic inflammation caused by a maladjusted host response to infection. In severe cases, it can cause multiple organ dysfunction syndrome (MODS) and even endanger life. Acupuncture is widely accepted and applied in the treatment of sepsis, and breakthroughs have been made regarding its mechanism of action in recent years. In this review, we systematically discuss the current clinical applications of acupuncture in the treatment of sepsis and focus on the mechanisms of acupuncture in animal models of systemic inflammation. In clinical research, acupuncture can not only effectively inhibit excessive inflammatory reactions but also improve the immunosuppressive state of patients with sepsis, thus maintaining immune homeostasis. Mechanistically, a change in the acupoint microenvironment is the initial response link for acupuncture to take effect, whereas PROKR2 neurons, high-threshold thin nerve fibres, cannabinoid CB2 receptor (CB2R) activation, and Ca2+ influx are the key material bases. The cholinergic anti-inflammatory pathway of the vagus nervous system, the adrenal dopamine anti-inflammatory pathway, and the sympathetic nervous system are key to the transmission of acupuncture information and the inhibition of systemic inflammation. In MODS, acupuncture protects against septic organ damage by inhibiting excessive inflammatory reactions, resisting oxidative stress, protecting mitochondrial function, and reducing apoptosis and tissue or organ damage.

An Animal Model for Chronic Meningeal Inflammation and Inflammatory Demyelination of the Cerebral Cortex.

Modeling chronic cortical demyelination allows the study of long-lasting pathological changes observed in multiple sclerosis such as failure of remyelination, chronically disturbed functions of oligodendrocytes, neurons and astrocytes, brain atrophy and cognitive impairments. We aimed at generating an animal model for studying the consequences of chronic cortical demyelination and meningeal inflammation. To induce long-lasting cortical demyelination and chronic meningeal inflammation, we immunized female Lewis rats against myelin oligodendrocyte glycoprotein (MOG) and injected lentiviruses for continuing overexpression of the cytokines TNFα and IFNγ in the cortical brain parenchyma. Immunization with MOG and overexpression of TNFα and IFNγ led to widespread subpial demyelination and meningeal inflammation that were stable for at least 10 weeks. We demonstrate here that immunization with MOG is necessary for acute as well as chronic cortical demyelination. In addition, long-lasting overexpression of TNFα and IFNγ in the brain parenchyma is sufficient to induce chronic meningeal inflammation. Our model simulates key features of chronic cortical demyelination and inflammation, reminiscent of human multiple sclerosis pathology. This will allow molecular, cellular and functional investigations for a better understanding of the adaptation mechanisms of the cerebral cortex in multiple sclerosis.