Potent Anti-inflammatory Mediator Research Articles

Roseburia intestinalis-derived extracellular vesicles ameliorate colitis by modulating intestinal barrier, microbiome, and inflammatory responses.

Inflammatory bowel disease (IBD) is a chronic disorder characterized by recurrent gastrointestinal inflammation, lacking a precise aetiology and definitive cure. The gut microbiome is vital in preventing and treating IBD due to its various physiological functions. In the interplay between the gut microbiome and human health, extracellular vesicles secreted by gut bacteria (BEVs) are key mediators. Herein, we explore the role of Roseburia intestinalis (R)-derived EVs (R-EVs) as potent anti-inflammatory mediators in treating dextran sulfate sodium-induced colitis. R was selected as an optimal BEV producer for IBD treatment through ANCOM analysis. R-EVs with a 76nm diameter were isolated from R using a tangential flow filtration system. Orally administered R-EVs effectively accumulated in inflamed colonic tissues and increased the abundance of Bifidobacterium on microbial changes, inhibiting colonic inflammation and prompting intestinal recovery. Due to the presence of Ile-Pro-Ile in the vesicular structure, R-EVs reduced the DPP4 activity in inflamed colonic tissue and increased the active GLP-1, thereby downregulating the NFκB and STAT3 via the PI3K pathway. Our results shed light on the impact of BEVs on intestinal recovery and gut microbiome alteration in treating IBD.

High-Dose Vitamin B6 (Pyridoxine) Displays Strong Anti-Inflammatory Properties in Lipopolysaccharide-Stimulated Monocytes.

Vitamin B6 is shown to have anti-inflammatory properties, which makes it an interesting nutraceutical agent. Vitamin B6 deficiency is well established as a contributor to inflammatory-related conditions, whilst B6 supplementation can reverse these inflammatory effects. There is less information available regarding the effects of high-dose vitamin B6 supplementation as a therapeutic agent. This study set out to examine the effects of high-dose vitamin B6 on an LPS-stimulated monocyte/macrophage cell population via an analysis of protein and gene expression using an RT2 profiler PCR array for Human Innate and Adaptive Immune responses. It was identified that high-dose vitamin B6 has a global anti-inflammatory effect on lipopolysaccharide-induced inflammation in monocyte/macrophage cells by downregulating the key broad-spectrum inflammatory mediators CCL2, CCL5, CXCL2, CXCL8, CXCL10, CCR4, CCR5, CXCR3, IL-1β, IL-5, IL-6, IL-10, IL-18, IL-23-a, TNF-α, CSF2, DDX58, NLRP3, NOD1, NOD2, TLR-1 -2 -4 -5 -7 -8 -9, MYD88, C3, FOXP3, STAT1, STAT3, STAT6, LYZ, CASP-1, CD4, HLA-E, MAPK1, MAPK8 MPO, MX-1, NF-κβ, NF-κβ1A, CD14, CD40, CD40LG, CD86, Ly96, ICAM1, IRF3, ITGAM, and IFCAM2. The outcomes of this study show promise regarding vitamin B6 within the context of a potent broad-spectrum anti-inflammatory mediator and could prove useful as an adjunct treatment for inflammatory-related diseases.

The effect of the NLRP1 inflammasome on methamphetamine-induced cognitive impairment in rats

Methamphetamine (METH) use disorder has been shown to be in high comorbidity with cognitive deficits. METH-induced cognitive deficits are accompanied by neurotoxicity which could result from neuroinflammation. The potential role of NLRP1 inflammasome (NLRP1) and the downstream signalling pathway in METH-induced cognitive impairment was explored in the current study. Cognitive functions and the changes of NLRP1/Caspase-1/GSDMD signalling pathway were firstly determined in rats receiving daily injections of METH. Subsequently, the effects of aspirin-triggered-lipoxin A4 (ATL), a potent anti-inflammatory mediator, and NLRP1 siRNA was investigated were investigated in both METH-treated rats and HT22 cells. METH induces significant cognitive deficits in rats, using the NOR test. METH-induced cognitive impairment was in line with increased activities of NLRP1, cleaved-Caspase-11, IL-1β and TNF-α and the presence of GSDMD-mediated pyroptosis in the hippocampus of rats. NLRP1 inhibition by ATL significantly attenuated METH-induced cognitive impairment, in conjunction with the decreased activities of NLRP1 and cleaved-Caspase-1, IL-1β and TNF-α. ATL and NLRP1 siRNA also prevented the presence of apoptosis in the hippocampus of METH-treated rats and the cell death in METH-treated HT22 cells. These results reveal a novel role of NLRP1 and the downstream signaling pathways in the complex actions of METH-induced cognitive deficits.

Immune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro

Mesenchymal stromal/stem cells (MSCs) are currently being used in clinical trials as proposed treatments for a large range of genetic, immunological, orthopaedic, cardiovascular, endocrine and neurological disorders. MSCs are potent anti-inflammatory mediators which are considered immune evasive and employ a large range of secreted vesicles to communicate and repair damaged tissue. Despite their prolific use in therapy, sex specific mechanism of action is rarely considered as a potential confounding factor for use. The purpose of this study was to examine the potency and functionality of both female and male adipose derived MSCs in order to gain further insights into donor selection. Methods MSC were expanded to passage 4, secretome was harvested and stored at − 80c. To assess potency MSC were also primed and assessed via functional immune assays, ELISA, multiplex and immunophenotyping. Results Female MSCs (fMSC), consistently suppressed Peripheral blood mononuclear cell (PBMC) proliferation significantly (p < 0.0001) more than male MSC (mMSC). In co-culture mPBMCs, showed 60.7 ± 15.6% suppression with fMSCs compared with 22.5 ± 13.6% suppression with mMSCs. Similarly, fPBMCs were suppressed by 67.9 ± 10.4% with fMSCs compared to 29.4 ± 9.3% with mMSCs. The enhanced immunosuppression of fMSCs was attributed to the production of higher concentrations of the anti-inflammatory mediators such as IDO1 (3301 pg/mL vs 1699 pg/mL) and perhaps others including IL-1RA (1025 pg/mL vs 701 pg/mL), PGE-2 (6142 pg/mL vs 2448 pg/mL) and prolonged expression of VCAM-1 post activation relative to mMSCs. In contrast, mMSCs produces more inflammatory G-CSF than fMSCs (806 pg/mL vs 503 pg/mL). Moreover, IDO1 expression was correlated to immune suppression and fMSCs, but not mMSCs induced downregulation of the IL-2 receptor and sustained expression of the early T cell activation marker, CD69 in PBMCs further highlighting the differences in immunomodulation potentials between the sexes. Conclusion In conclusion, our data shows that female MSC are more potent in vitro than their male counterparts. The inability of male MSC to match female MSC driven immunomodulation and to use the inflammatory microenvironment to their advantage is evident and is likely a red flag when using allogeneic male MSC as a therapeutic for disease states.

The role of mesenchymal stem/stromal cells in the acute clinical setting.

Accumulating evidence supports the use of mesenchymal stem/stromal cells (MSCs), particularly bone marrow derived, as a safe and promising biologic therapy for promoting tissue repair and regeneration in various chronic diseases and disorders. Despite growing evidence that MSCs are potent anti-inflammatory mediators that can provide substantial benefits in acute organ injury, there are limited clinical trials utilizing MSCs in acute care settings, such as in the emergency department (ED) or intensive care unit (ICU). This article reviews the current state of MSC-based therapeutics and further explores the untapped potential role to treat various acute, life-threating injuries in the ED and ICU. All clinical trials using MSCs in acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), sepsis and acute kidney injury (AKI) demonstrated safety. While some also demonstrate clinical efficacy, efficacy data is inconsistent, with some studies limited by sample size, cell integrity and different dosages, necessitating further studies. MSCs are potentially promising novel biologic therapeutics for clinical application in AMI, ARDS, sepsis, AKI and COVID-19 that have demonstrated safety in all clinical trials. More rigorous clinical trials are necessary and warranted to determine the efficacy of MSCs as a novel therapeutic in an acute setting, such as the ED.

Targeting the Heme Oxygenase 1/Carbon Monoxide Pathway to Resolve Lung Hyper-Inflammation and Restore a Regulated Immune Response in Cystic Fibrosis.

In individuals with cystic fibrosis (CF), lung hyper-inflammation starts early in life and is perpetuated by mucus obstruction and persistent bacterial infections. The continuous tissue damage and scarring caused by non-resolving inflammation leads to bronchiectasis and, ultimately, respiratory failure. Macrophages (MΦs) are key regulators of immune response and host defense. We and others have shown that, in CF, MΦs are hyper-inflammatory and exhibit reduced bactericidal activity. Thus, MΦs contribute to the inability of CF lung tissues to control the inflammatory response or restore tissue homeostasis. The non-resolving hyper-inflammation in CF lungs is attributed to an impairment of several signaling pathways associated with resolution of the inflammatory response, including the heme oxygenase-1/carbon monoxide (HO-1/CO) pathway. HO-1 is an enzyme that degrades heme groups, leading to the production of potent antioxidant, anti-inflammatory, and bactericidal mediators, such as biliverdin, bilirubin, and CO. This pathway is fundamental to re-establishing cellular homeostasis in response to various insults, such as oxidative stress and infection. Monocytes/MΦs rely on abundant induction of the HO-1/CO pathway for a controlled immune response and for potent bactericidal activity. Here, we discuss studies showing that blunted HO-1 activation in CF-affected cells contributes to hyper-inflammation and defective host defense against bacteria. We dissect potential cellular mechanisms that may lead to decreased HO-1 induction in CF cells. We review literature suggesting that induction of HO-1 may be beneficial for the treatment of CF lung disease. Finally, we discuss recent studies highlighting how endogenous HO-1 can be induced by administration of controlled doses of CO to reduce lung hyper-inflammation, oxidative stress, bacterial infection, and dysfunctional ion transport, which are all hallmarks of CF lung disease.

Vasoactive Intestinal Peptide Deficiency Is Associated With Altered Gut Microbiota Communities in Male and Female C57BL/6 Mice.

Vasoactive intestinal peptide (VIP) is crucial for gastrointestinal tract (GIT) health. VIP sustains GIT homeostasis through maintenance of the intestinal epithelial barrier and acts as a potent anti-inflammatory mediator that contributes to gut bacterial tolerance. Based on these biological functions by VIP, we hypothesized that its deficiency would alter gut microbial ecology. To this end, fecal samples from male and female VIP+/+, VIP+/–, and VIP–/– littermates (n = 47) were collected and 16S rRNA sequencing was conducted. Our data revealed significant changes in bacterial composition, biodiversity, and weight loss from VIP–/– mice compared to VIP+/+ and VIP+/– littermates, irrespective of sex. The gut bacteria compositional changes observed in VIP–/– mice was consistent with gut microbial structure changes reported for certain inflammatory and autoimmune disorders. Moreover, predicted functional changes by PICRUSt software suggested an energy surplus within the altered microbiota from VIP–/– mice. These data support that VIP plays an important role in maintaining microbiota balance, biodiversity, and GIT function, and its genetic removal results in significant gut microbiota restructuring and weight loss.

Lipoxin A4 Ameliorates Acute Pancreatitis-Associated Acute Lung Injury through the Antioxidative and Anti-Inflammatory Effects of the Nrf2 Pathway.

Acute lung injury (ALI) is a critical event involved in the pathophysiological process of acute pancreatitis (AP). Many methods have been widely used for the treatment of AP-ALI, but few are useful during early inflammation. Lipoxin A4 (LXA4), a potent available anti-inflammatory and novel antioxidant mediator, has been extensively studied in AP-ALI, but its underlying mechanism as a protective mediator is not clear. This research was conducted to identify the possible targets and mechanisms involved in the anti-AP-ALI effect of LXA4. First, we confirmed that LXA4 strongly inhibited AP-ALI in mice. Next, using ELISA, PCR, and fluorescence detection to evaluate different parameters, LXA4 was shown to reduce the inflammatory cytokine production induced by AP and block reactive oxygen species (ROS) generation in vivo and in vitro. In addition, TNF-α treatment activated the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and its downstream gene heme oxygenase-1 (HO-1) in human pulmonary microvascular endothelial cells (HPMECs), and LXA4 further promoted their expression. This study also provided evidence that LXA4 phosphorylates Ser40 and triggers its nuclear translocation to activate Nrf2. Moreover, when Nrf2-knockout (Nrf2−/−) mice and cells were used to further assess the effect of the Nrf2/HO-1 pathway, we found that Nrf2 expression knockdown partially eliminated the effect of LXA4 on the reductions in inflammatory factor levels while abrogating the inhibitory effect of LXA4 on the ROS generation stimulated by AP-ALI. Overall, LXA4 attenuated the resolution of AP-induced inflammation and ROS generation to mitigate ALI, perhaps by modulating the Nrf2/HO-1 pathway. These findings have laid a foundation for the treatment of AP-ALI.

Relationship of Omega-3 fatty acids DHA and EPA with the inflammatory biomarker hs-CRP in children with sickle cell anemia

BackgroundInflammation and vaso-occlusion play key roles in Sickle Cell Disease (SCD) pathophysiology. Lipoxygenase products of the omega-3 fatty acids (O3FAs), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, are potent anti-inflammatory mediators modulating pain. O3FAs decrease episodes of vaso-occlusion in SCD. MethodsWe assessed erythrocyte fatty acid composition in two major cell membrane phospholipids, phosphatidylcholine and phosphatidylethanolamine, in children with SCD HbSS-disease (n = 38) and age/race-matched HbAA-controls (n = 18). Ratio of pro-inflammatory arachidonic acid (AA) to anti-inflammatory DHA and EPA (FA-Ratio), and its relationship to hs-CRP were evaluated. ResultsFA-Ratios were increased in both phosphatidylcholine and phosphatidylethanolamine in HbSS compared to controls. Correlations were noted in HbSS subjects between hs-CRP and FA-Ratios (p = 0.011). FA-Ratios increased with age (p = 0.0007) due to an increase in pro-inflammatory AA with a concomitant decrease in anti-inflammatory DHA. ConclusionsFindings demonstrate relative deficiencies in HbSS of the anti-inflammatory precursor fatty acids DHA and EPA, which correlates positively with hs-CRP.

Annexin-A1: Therapeutic Potential in Microvascular Disease.

Annexin-A1 (ANXA1) was first discovered in the early 1980's as a protein, which mediates (some of the) anti-inflammatory effects of glucocorticoids. Subsequently, the role of ANXA1 in inflammation has been extensively studied. The biology of ANXA1 is complex and it has many different roles in both health and disease. Its effects as a potent endogenous anti-inflammatory mediator are well-described in both acute and chronic inflammation and its role in activating the pro-resolution phase receptor, FPR2, has been described and is now being exploited for therapeutic benefit. In the present mini review, we will endeavor to give an overview of ANXA1 biology in relation to inflammation and functions that mediate pro-resolution that are independent of glucocorticoid induction. We will focus on the role of ANXA1 in diseases with a large inflammatory component focusing on diabetes and microvascular disease. Finally, we will explore the possibility of exploiting ANXA1 as a novel therapeutic target in diabetes and the treatment of microvascular disease.

Anti-inflammatory mechanisms of cannabinoids: an immunometabolic perspective.

A number of studies have implicated cannabinoids as potent anti-inflammatory mediators. However, the exact mechanism by which cannabinoids exert these effects remains to be fully explained. The recent resurgence in interest regarding the metabolic adaptations undergone by activated immune cells has highlighted the intricate connection between metabolism and an inflammatory phenotype. In this regard, evidence suggests that cannabinoids may alter cell metabolism by increasing AMPK activity. In turn, emerging evidence suggests that the activation of AMPK by cannabinoids may mediate an anti-inflammatory effect through a range of processes. First, AMPK may promote oxidative metabolism, which have been shown to play a central role in immune cell polarisation towards a tolerogenic phenotype. AMPK activation may also attenuate anabolic processes which in turn may antagonise immune cell function. Furthermore, AMPK activity promotes the induction of autophagy, which in turn may promote anti-inflammatory effects through various well-described processes. Taken together, these observations implicate cannabinoids to mediate part of their anti-inflammatory effects through alterations in immune cell metabolism and the induction of autophagy.

Expression of CD73 and CD39 on Peripheral Blood Leukocytes in Type II Diabetes Patients

Background: Type II diabetes mellitus (T2D) is one of the most common chronic metabolic diseases. It is associated with a state of chronic inflammation resulting in both microvascular and macrovascular complications. The adinosinergic axis plays an important anti-inflammatory protective role through conversion of ATP (produced as a result of inflammation) into adenosine (a potent anti-inflammatory mediator) through CD39 and CD73. Various peripheral blood leucocytes hold CD39 and CD73 with different degrees. Objective: To determine the expression of CD73 and CD39 on different peripheral blood leukocytes including Treg cells to uncover their inflammatory modulation role in T2D subjects in comparison to normal control ones. The level of their expression will be correlated with various anthropometric and biochemical parameters in diabetic patients. Materials and Methods: Venous blood was collected on EDTA anticoagulated tubes from 45 T2D patients; 15 with early T2D and 30 with complicated T2D with both microvascular and macrovascular complications. Twenty-five normal subjects, with no family history of T2D, were included. Immunophenotyping of the samples were performed on Navios Flow cytometer (Coulter Electronics, USA), using phycoerythrin (PE)-labelled CD39 antibodies, fluorescein isothiocyanate (FITC)-labelled CD4 antibodies, peridinin-chlorophyll-protein complex: CY5.5 conjugate (PerCP-CY5.5)-labelled CD73 and allophycocyanin conjugate (APC)-labelled CD25. Results: CD39 expression was highest in early cases of T2D in comparison to least expression in complicated T2D on peripheral blood total lymphocytes, CD4+ lymphocytes and CD4+CD25+ lymphocytes. Conclusions: The increased expression of CD39 in early non-complicated cases of T2D indicates a state of low-level chronic inflammation owing to their role in production of adenosine; a potent anti-inflammatory mediator. This is reversed when CD39 expression in peripheral blood leucocytes is assessed in complicated T2D patients, which emphasise their role in protecting the patients from diabetic complications.

Expression of CD73 and CD39 on Peripheral Blood Leukocytes in Type II Diabetes Patients

Background: Type II diabetes mellitus (T2D) is one of the most common chronic metabolic diseases. It is associated with a state of chronic inflammation resulting in both microvascular and macrovascular complications. The adinosinergic axis plays an important anti-inflammatory protective role through conversion of ATP (produced as a result of inflammation) into adenosine (a potent anti-inflammatory mediator) through CD39 and CD73. Various peripheral blood leucocytes hold CD39 and CD73 with different degrees. Objective: To determine the expression of CD73 and CD39 on different peripheral blood leukocytes including Treg cells to uncover their inflammatory modulation role in T2D subjects in comparison to normal control ones. The level of their expression will be correlated with various anthropometric and biochemical parameters in diabetic patients. Materials and Methods: Venous blood was collected on EDTA anticoagulated tubes from 45 T2D patients; 15 with early T2D and 30 with complicated T2D with both microvascular and macrovascular complications. Twenty-five normal subjects, with no family history of T2D, were included. Immunophenotyping of the samples were performed on Navios Flow cytometer (Coulter Electronics, USA), using phycoerythrin (PE)-labelled CD39 antibodies, fluorescein isothiocyanate (FITC)-labelled CD4 antibodies, peridinin-chlorophyll-protein complex: CY5.5 conjugate (PerCP-CY5.5)-labelled CD73 and allophycocyanin conjugate (APC)-labelled CD25. Results: CD39 expression was highest in early cases of T2D in comparison to least expression in complicated T2D on peripheral blood total lymphocytes, CD4+ lymphocytes and CD4+CD25+ lymphocytes. Conclusions: The increased expression of CD39 in early non-complicated cases of T2D indicates a state of low-level chronic inflammation owing to their role in production of adenosine; a potent anti-inflammatory mediator. This is reversed when CD39 expression in peripheral blood leucocytes is assessed in complicated T2D patients, which emphasise their role in protecting the patients from diabetic complications.

Epidermal glucocorticoid and mineralocorticoid receptors act cooperatively to regulate epidermal development and counteract skin inflammation

Endogenous and synthetic glucocorticoids (GCs) regulate epidermal development and combat skin inflammatory diseases. GC actions can be mediated through the GC receptor (GR) and/or the mineralocorticoid receptor (MR), highly homologous ligand-activated transcription factors. While the role of GR as a potent anti-inflammatory mediator is well known, that of MR is not as clear, nor is whether these receptors cooperate or antagonize each other in the epidermis. To address this, we generated mice with epidermal-specific loss of both receptors (double knockout, DKO), and analyzed the phenotypical and functional consequences relative to single KOs or controls (CO). At birth, DKO epidermis displayed a phenotype of defective differentiation and inflammation, which was more severe than in either single KO, featuring neutrophil-containing infiltrates, and gene dysregulation characteristic of human psoriatic lesions. This phenotype resolved spontaneously. However, in adulthood, single or combined loss of GC receptors increased susceptibility to inflammation and hyperproliferation triggered by phorbol ester which, different to CO, was not effectively counteracted by GC treatment. Also, DKOs were more susceptible to imiquimod-induced psoriasis than CO showing severe defective epidermal differentiation and microabcesses while single KOs showed an intermediate response. Immortalized DKO keratinocytes featured increased proliferation kinetics and reduced cell size, a unique phenotype relative to single KO cells. The lack of GR and MR in keratinocytes, individual or combined, caused constitutive increases in p38 and ERK activities, which were partially reversed upon reinsertion of receptors into DKO cells. DKO keratinocytes also displayed significant increases in AP-1 and NF-κB transcriptional activities, which were partially rescued by ERK and p38 inhibition, respectively. Reinsertion of GR and MR in DKO keratinocytes resulted in physical and cooperative functional interactions that restored the transcriptional response to GCs. In conclusion, our data have revealed that epidermal GR and MR act cooperatively to regulate epidermal development and counteract skin inflammation.

Resolvin D1 drives establishment of Leishmania amazonensis infection

Previous studies have indicated that the balance between different eicosanoids reflect the intensity of the inflammatory profile in patients with tegumentary leishmaniasis. More recently, pro-resolution lipid mediators have been shown to play critical roles in dampening pathological inflammatory processes to reestablish homeostasis in a diverse range of experimental settings. Among these lipid mediator, resolvins from D series have been described as potent anti-inflammatory and immunomodulatory mediators, and its activities include inhibition of leukocyte chemotaxis and blockage production of proinflammatory cytokines, while increasing the expression of regulatory mediators. Whether resolvins play significant roles in establishment and persistence of Leishmania infection is currently unknown. We addressed this question in the current study by assessing circulating levels of D-series resolvins in tegumentary leishmaniasis patients presenting with localized or diffuse disease. We found heightened expression of resolvin D1 in diffuse cutaneous leishmaniasis which was correlated with expression profile of biomarkers associated with disease pathogenesis. Additional in vitro experiments using primary human macrophages indicated that resolvin D1 may promote intracellular Leishmania amazonensis replication through a mechanism associated with induction of heme oxygenase-1. These results suggest that targeting resolvin D1 could serve as potential strategy for host directed therapy in diffuse cutaneous leishmaniasis.

IL-10 Plays Opposing Roles during Staphylococcus aureus Systemic and Localized Infections.

IL-10 is a potent anti-inflammatory mediator that plays a crucial role in limiting host immunopathology during bacterial infections by controlling effector T cell activation. Staphylococcus aureus has previously been shown to manipulate the IL-10 response as a mechanism of immune evasion during chronic systemic and biofilm models of infection. In the present study, we demonstrate divergent roles for IL-10 depending on the site of infection. During acute systemic S. aureus infection, IL-10 plays an important protective role and is required to prevent bacterial dissemination and host morbidity by controlling effector T cells and the associated downstream hyperactivation of inflammatory phagocytes, which are capable of host tissue damage. CD19+CD11b+CD5+ B1a regulatory cells were shown to rapidly express IL-10 in a TLR2-dependent manner in response to S. aureus, and adoptive transfer of B1a cells was protective during acute systemic infection in IL-10-deficient hosts. In contrast, during localized s.c. infection, IL-10 production plays a detrimental role by facilitating bacterial persistence via the same mechanism of controlling proinflammatory T cell responses. Our findings demonstrate that induction of IL-10 has a major influence on disease outcome during acute S. aureus infection. Too much IL-10 at one end of the scale may suppress otherwise protective T cell responses, thus facilitating persistence of the bacteria, and at the other end, too little IL-10 may tend toward fatal host-mediated pathology through excessive activation of T cells and associated phagocyte-mediated damage.

Aspirin-triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein E-/- mice.

Atherosclerosis is characterized by a chronic non-resolving inflammation in the arterial wall. Aspirin-triggered lipoxin A4 (ATL) is a potent anti-inflammatory mediator, involved in the resolution of inflammation. However, the therapeutic potential of immune targeting by means of ATL in atherosclerosis has not previously been explored. The aim of the present study was to determine the effects of ATL and its receptor Fpr2 on atherosclerosis development and progression in apolipoprotein E deficient (ApoE-/- ) mice. ApoE-/- ×Fpr2+/+ and ApoE-/- ×Fpr2-/- mice were generated. Four-week-old mice fed a high-fat diet for 4weeks and 16-week-old mice fed chow diet received osmotic pumps containing either vehicle or ATL for 4weeks. Atherosclerotic lesion size and cellular composition were measured in the aortic root and thoracic aorta. Lipid levels and leukocyte counts were measured in blood and mRNA was isolated from abdominal aorta and spleen. ATL blocked atherosclerosis progression in the aortic root and thoracic aorta of ApoE-/- mice. In addition, ATL reduced macrophage infiltration and apoptotic cells in atherosclerotic lesions. The mRNA levels of several cytokines and chemokines in the spleen and aorta were reduced by ATL, whereas circulating leukocyte levels were unchanged. The ATL-induced athero-protection was absent in ApoE-/- mice lacking the Fpr2 receptor. ATL blocked atherosclerosis progression by means of an Fpr2-mediated reduced local and systemic inflammation. These results suggest this anti-inflammatory and pro-resolving agent has therapeutic potential for the treatment of atherosclerosis. This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

EFFECT OF FISH OIL ON ALVEOLAR BONE OF RATS WITH INDUCED RHEUMATOID ARTHRITIS

INTRODUCTION: Although rheumatoid arthritis (RA) is primarily a chronic inflammatory autoimmune disease which affects the synovial joints, it has profound effects on bone remodeling characterized by increase osteoclastic activity, and a negative balance of bone formation and resorption. A strong correlation has been reported between RA and periodontitis with subsequent alveolar bone resorption. As a potent anti-inflammatory mediator, fish oil rich in omega-3 polyunsaturated fatty acids (n-3 PUFA) has demonstrated beneficial actions in various inflammatory conditions including RA and cardiovascular disease. High intakes of n-3 PUFA provide symptomatic relief and reduce the doses of anti-inflammatory drugs needed to control the RA symptoms.OBJECTIVES: To evaluate the biological effect of fish oil on alveolar bone of rats with induced rheumatoid arthritis.MATERIALS AND METHODS: Twenty one male albino rats were used in this study. The rats were divided into 3 groups 7 rats each. Group I: control group, Group II: RA induced group and Group III: RA induced group + fish oil. Rheumatoid arthritis induction was done by single subcutaneous injection of Freund's complete adjuvant. Fish oil was orally gavaged daily till the end of the experiment. Laboratory investigations were performed twice, after RA induction and at the end of the experiment. Effect of fish oil on alveolar bone of rats was assessed histologically and ultrastructurely in the different groups.RESULTS: Remarkable improvement in the histology and the ultrastructure of the alveolar bone of rats in Group III was observed. Moreover, hematological values revealed significant decrease in the inflammatory condition of rats with induced RA after fish oil treatment.CONCLUSION: Rheumatoid arthritis is an important risk factor for alveolar bone loss. The treatment of the RA induced rats with fish oil not only prevented the alveolar bone resorption and stimulated new bone formation, but also reduced relatively the level of rheumatoid factor in the blood.

Adenosine: an endogenous mediator in the pathogenesis of psoriasis.

It is known that inflammatory and immune responses protect us from the invasion of micro-organisms and eliminate "wastes" from the injured sites, but they may also be responsible for significant tissue damage. Adenosine, as a purine nucleoside, which is produced in inflamed or injured sites, fulfills its role in limiting tissue damage. Although, it may have a pleiotropic effect, which signals it with a proinflammatory state in certain situations, it can be considered a potent anti-inflammatory mediator. The effects of adenosine, which acts through its receptors on T cell, on mast cell and macrophages, on endothelial cells, on neutrophils and dendritic cells, as they indicate TNF-alpha and cytokines, show that this mediator has a central role in the pathogenesis of psoriasis. The way it acts in psoriasis will be reviewed in this study.

Beneficial effect of annexin A1 in a model of experimental allergic conjunctivitis

Annexin A1 (ANXA1), a 37 kDa glucocorticoid-regulated protein, is a potent anti-inflammatory mediator effective in terminating acute inflammatory response, and its role in allergic settings has been poorly studied. The aim of this investigation was to evaluate the mechanism of action of ANXA1 in intraocular inflammation using a classical model of ovalbumin (OVA)-induced allergic conjunctivitis (AC). OVA-immunised Balb/c mice, wild-type (WT) and ANXA1-deficient (AnxA1−/−), were challenged with eye drops containing OVA on days 14–16 with a subset of WT animals pretreated intraperitoneally with the peptide Ac2-26 (N-terminal region of ANXA1) or dexamethasone (DEX). After 24 h of the last ocular challenge, WT mice treated with Ac2-26 and DEX had significantly reduced clinical signs of conjunctivitis (chemosis, conjunctival hyperaemia, lid oedema and tearing), plasma IgE levels, leukocyte (eosinophil and neutrophil) influx and mast cell degranulation in the conjunctiva compared to WT controls. These anti-inflammatory effects of DEX were associated with high endogenous levels of ANXA1 in the ocular tissues as detected by immunohistochemistry. Additionally, Ac2-26 administration was effective to reduce IL-2, IL-4, IL-10, IL-13, eotaxin and RANTES in the eye and lymph nodes compared to untreated WT animals. The lack of ANXA1 produced an exacerbated allergic response as detected by the density of the inflammatory cell influx to the conjunctiva and the cytokine/chemokine release. These different effects observed for Ac2-26 were correlated with diminished level of activated ERK at 24 h in the ocular tissues compared to untreated OVA group. Our findings demonstrate the protective effect of ANXA1 during the inflammatory allergic response suggesting this protein as a potential target for new ocular inflammation therapies.