Animal Models Of Inflammation Research Articles

Electroacupuncture decreases inflammatory pain through a pro-resolving mechanism involving the peripheral annexin A1-formyl peptide receptor 2/ALX-opioid receptor pathway.

The pro-resolving mechanism is a recently described endogenous process that controls inflammation. The present study evaluated components of this mechanism, including annexin 1 (ANXA1) and the formyl peptide receptor 2/ALX (FPR2/ALX) receptor, in the antihyperalgesic effect induced by electroacupuncture (EA) in an animal model of persistent peripheral inflammation. Male Swiss mice underwent intraplantar (i.pl.) injection with complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed with von Frey monofilaments. Animals were treated with EA (2-10Hz, ST36-SP6) or subcutaneous BML-111 injection (FPR2/ALX agonist) for 5 consecutive days. In a separate set of experiments, on the first and fifth days after CFA injection, animals received i.pl. WRW4 (FPR2/ALX antagonist) or naloxone (non-selective opioid receptor antagonist) before EA or BML-111 injection. Paw protein levels of FPR2/ALX and ANXA1 were evaluated on the second day after CFA injection by western blotting technique. EA and BML-111 reduced mechanical hyperalgesia. I.pl. naloxone or WRW4 prevented the antihyperalgesic effect induced by either EA or BML-111. EA increased ANXA1 but did not alter FPR2/ALX receptor levels in the paw. Furthermore, i.pl. pretreatment with WRW4 prevented the increase of ANXA1 levels induced by EA. This work demonstrates that the EA antihyperalgesic effect on inflammatory pain involves the ANXA1/FPR2/ALX pro-resolution pathway. This effect appears to be triggered by the activation of FPR2/ALX receptors and crosstalk communication with the opioid system.

Modeling Inflammation in Zebrafish for the Development of Anti-inflammatory Drugs.

Dysregulation of the inflammatory response in humans can lead to various inflammatory diseases, like asthma and rheumatoid arthritis. The innate branch of the immune system, including macrophage and neutrophil functions, plays a critical role in all inflammatory diseases. This part of the immune system is well-conserved between humans and the zebrafish, which has emerged as a powerful animal model for inflammation, because it offers the possibility to image and study inflammatory responses in vivo at the early life stages. This review focuses on different inflammation models established in zebrafish, and how they are being used for the development of novel anti-inflammatory drugs. The most commonly used model is the tail fin amputation model, in which part of the tail fin of a zebrafish larva is clipped. This model has been used to study fundamental aspects of the inflammatory response, like the role of specific signaling pathways, the migration of leukocytes, and the interaction between different immune cells, and has also been used to screen libraries of natural compounds, approved drugs, and well-characterized pathway inhibitors. In other models the inflammation is induced by chemical treatment, such as lipopolysaccharide (LPS), leukotriene B4 (LTB4), and copper, and some chemical-induced models, such as treatment with trinitrobenzene sulfonic acid (TNBS), specifically model inflammation in the gastro-intestinal tract. Two mutant zebrafish lines, carrying a mutation in the hepatocyte growth factor activator inhibitor 1a gene (hai1a) and the cdp-diacylglycerolinositol 3-phosphatidyltransferase (cdipt) gene, show an inflammatory phenotype, and they provide interesting model systems for studying inflammation. These zebrafish inflammation models are often used to study the anti-inflammatory effects of glucocorticoids, to increase our understanding of the mechanism of action of this class of drugs and to develop novel glucocorticoid drugs. In this review, an overview is provided of the available inflammation models in zebrafish, and how they are used to unravel molecular mechanisms underlying the inflammatory response and to screen for novel anti-inflammatory drugs.

Oxidative Stress and Lipid Mediators Modulate Immune Cell Functions in Autoimmune Diseases

Autoimmune diseases, including psoriasis, systemic lupus erythematosus (SLE), and rheumatic arthritis (RA), are caused by a combination of environmental and genetic factors that lead to overactivation of immune cells and chronic inflammation. Since oxidative stress is a common feature of these diseases, which activates leukocytes to intensify inflammation, antioxidants could reduce the severity of these diseases. In addition to activating leukocytes, oxidative stress increases the production of lipid mediators, notably of endocannabinoids and eicosanoids, which are products of enzymatic lipid metabolism that act through specific receptors. Because the anti-inflammatory CB2 receptors are the predominant cannabinoid receptors in leukocytes, endocannabinoids are believed to act as anti-inflammatory factors that regulate compensatory mechanisms in autoimmune diseases. While administration of eicosanoids in vitro leads to the differentiation of lymphocytes into T helper 2 (Th2) cells, eicosanoids are also necessary for the different0iation of Th1 and Th17 cells. Therefore, their antagonists and/or the genetic deletion of their receptors abolish inflammation in animal models of psoriasis—RA and SLE. On the other hand, products of non-enzymatic lipid peroxidation, especially acrolein and 4-hydroxynonenal-protein adducts, mostly generated by an oxidative burst of granulocytes, may enhance inflammation and even acting as autoantigens and extracellular signaling molecules in the vicious circle of autoimmune diseases.

Deletion of Arno Reduces Eosinophilic Inflammation and Interleukin-5 Expression in a Murine Model of Rhinitis.

ARF nucleotide-binding site opener (ARNO) is a guanine nucleotide-exchange factor for ADP-ribosylation factor proteins. ARF nucleotide-binding site opener also binds MyD88, and small-molecule inhibition of ARNO reduces inflammation in animal models of inflammatory arthritis and acute inflammation. However, whether genetic deletion of Arno in mice reduces pathologic inflammation has not yet been reported. Furthermore, its role in the nasal cavity has yet to be investigated. To generate Arno knockout mice and to determine whether genetic loss of ARNO reduces eosinophilic inflammation in the ovalbumin (OVA) murine model of rhinitis. Arno knockout mice were generated and wild type and knockout littermates were subjected to the OVA-induced mouse model of rhinosinutitis. Eosinophilic inflammation was assessed through immunofluorescent quantification of EMBP+ eosinophils in the septal mucosa and cytokine expression was assessed by quantitative polymerase chain reaction. Arno knockout mice are viable and fertile without any noted deficits. Arno wild type and knockout mice subjected to the OVA-induced model of rhinitis demonstrated an average of 314.5 and 153.8 EMBP+ cells per mm2 septal tissue, respectively (P < .05). Goblet cells per mm of basal lamina were assessed via Alcian blue and there was no statistically significant difference between Arno wild type and knockout mice. Ovalbumin-induced expression of interleukin-5 (IL-5) was significantly reduced in Arno knockout mice (P < .05). There was no statistically significant reduction in IL-4, IL-13, or eotaxin-1 expression. These data demonstrate that deletion of Arno reduces eosinophilic inflammation and IL-5 expression in an OVA-induced model of rhinitis.

Monosodium Urate Crystals Regulate a Unique JNK-Dependent Macrophage Metabolic and Inflammatory Response

The response of macrophages to monosodium urate crystals (MSUc) is incompletely understood partly due to the use of a toll-like receptor (TLR)-induced priming step in cell lines. Yet, MSUc induce inflammation in vivo without prior priming, raising the possibility of an initial cell-autonomous phase that is TLR-independent. Here, using genome wide transcriptomic analysis and biochemical assays we demonstrate that MSUc alone induce a metabolic-inflammatory transcriptional program in non-primed human and murine macrophages that is markedly distinct to that induced by LPS. Genes uniquely upregulated in response to MSUc belonged to lipid and amino acid metabolism, glycolysis, and SLC transporters. This upregulation led to a metabolic rewiring in sera from individuals and mice with acute gouty arthritis. Mechanistically, the initiating inflammatory-metabolic changes in acute gout flares are regulated through a persistent expression and increased binding of JUN to the promoter of target genes through JNK signaling -but not P38- in a process that is different than after LPS stimulation and unexpectedly independent of inflammasome activation. Finally, pharmacological JNK inhibition limited MSUc-induced inflammation in animal models of acute gouty inflammation. MSUc alone induce a unique strong macrophage activation and distinct phenotype that forces a reconsideration of initiating mechanisms in acute gout flares.

Sirt3 Maintains Microvascular Endothelial Adherens Junction Integrity to Alleviate Sepsis-Induced Lung Inflammation by Modulating the Interaction of VE-Cadherin and β-Catenin.

Inflammatory injury is a hallmark of sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). However, the mechanisms underlying inflammatory injury remain obscure. Here, we developed the novel strategy to suppress lung inflammation through maintaining microvascular endothelial barrier integrity. VE-cadherin is the main adherens junction protein that interacts with β-catenin and forms a complex. We found that lung inflammation was accompanied by decreased VE-cadherin expression and increased β-catenin activity in animal models and human pulmonary microvascular endothelial cells (HPMECs), illuminating the relationship among VE-cadherin/β-catenin complex, microvascular endothelial barrier integrity, and inflammation. Furthermore, we showed that the VE-cadherin/β-catenin complex dissociated upon lung inflammation, while Sirt3 promoted the stability of such a complex. Sirt3 was decreased during lung inflammation in vivo and in vitro. Sirt3 deficiency not only led to the downregulation of VE-cadherin but also enhanced the transcriptional activity of β-catenin that further increased β-catenin target gene MMP-7 expression, thereby promoting inflammatory factor COX-2 expression. Sirt3 overexpression promoted VE-cadherin expression, inhibited β-catenin transcriptional activity, strengthened the stability of the VE-cadherin/β-catenin complex, and suppressed inflammation in HPMECs. Notably, Sirt3 deficiency significantly damaged microvascular endothelial barrier integrity and intensified lung inflammation in animal model. These results demonstrated the role of Sirt3 in modulating microvascular endothelial barrier integrity to inhibit inflammation. Therefore, strategies that aim at enhancing the stability of endothelial VE-cadherin/β-catenin complex are potentially beneficial for preventing sepsis-induced lung inflammation.

Egg white-induced inflammation models: A study of edema profile and histological change of rat's paw.

ABSTRACTThe egg white was used to induce rat paw inflammation, with inadequate references to explain its mechanism. It's contained protein was identified as an allergen was suspected to trigger an inflammatory reaction. This research was aimed to evaluate the use of egg white as an inflammatory inductor in inflammation animal models through edema profile and histological change. Male Wistar rats were divided into three groups, which were given λ-carrageenan, fresh takes of the hen's egg white, and sterile saline solution. Edema was induced by subcutaneous injection of 0.1 ml of λ-carrageenan (1%), egg white, and sterile saline solution as the control in the hind paw of rats. Paw volume was measured before and then at 1, 2, 3, 4, 5, 6, and 24 h after the inductor injection. Paw tissue was taken for evaluation of rats’ paw histological change. The data were analyzed by one-way ANOVA followed by LSD test. The results of the study showed that the egg white could induce rat paw inflammation. Edema formation began in the 1st h and reached the peaks in the 2nd h after the subcutaneous injection of egg white. A number of leukocyte cells were also found in the inflamed paw tissues. Egg white was potential as an edema inductor for animal models of inflammation for the evaluation of new drugs or natural product with anti-inflammation activity.

Different roles for the acyl chain and the amine leaving group in the substrate selectivity of N-Acylethanolamine acid amidase

N-acylethanolamine acid amidase (NAAA) is an N-terminal nucleophile (Ntn) hydrolase that catalyses the intracellular deactivation of the endogenous analgesic and anti-inflammatory agent palmitoylethanolamide (PEA). NAAA inhibitors counteract this process and exert marked therapeutic effects in animal models of pain, inflammation and neurodegeneration. While it is known that NAAA preferentially hydrolyses saturated fatty acid ethanolamides (FAEs), a detailed profile of the relationship between catalytic efficiency and fatty acid-chain length is still lacking. In this report, we combined enzymatic and molecular modelling approaches to determine the effects of acyl chain and polar head modifications on substrate recognition and hydrolysis by NAAA. The results show that, in both saturated and monounsaturated FAEs, the catalytic efficiency is strictly dependent upon fatty acyl chain length, whereas there is a wider tolerance for modifications of the polar heads. This relationship reflects the relative stability of enzyme-substrate complexes in molecular dynamics simulations.

Therapeutic Potential of Rhododendron arboreum Polysaccharides in an Animal Model of Lipopolysaccharide-Inflicted Oxidative Stress and Systemic Inflammation.

Systemic inflammation results in physiological changes, largely mediated by inflammatory cytokines. The present investigation was performed to determine the effect of Rhododendron arboreum (RAP) on inflammatory parameters in the animal model. The RAP (100 and 200 mg/kg) were pre-treated for animals, given orally for one week, followed by lipopolysaccharide (LPS) injection. Body temperature, burrowing, and open field behavioral changes were assessed. Biochemical parameters (AST, ALT, LDH, BIL, CK, Cr, BUN, and albumin) were done in the plasma after 6 h of LPS challenge. Oxidative stress markers SOD, CAT, and MDA were measured in different organs. Levels of inflammatory markers like tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β) and, interleukin-6 (IL-6) as well as VEGF, a specific sepsis marker in plasma, were quantified. The plasma enzymes, antioxidant markers and plasma pro-inflammatory cytokines were significantly restored (p < 0.5) by RAP treatment, thus preventing the multi-organ and tissue damage in LPS induced rats. The protective effect of RAP may be due to its potent antioxidant potential. Thus, RAP can prevent LPS induced oxidative stress, as well as inflammatory and multi-organ damage as reported in histopathological studies in rats when administered to the LPS treated animals. These findings indicate that RAP can benefit in the management of systemic inflammation from LPS and may have implications for a new treatment or preventive therapeutic strategies with an inflammatory component.

Anticancer Activity of Novel NF-kappa B Inhibitor DHMEQ by Intraperitoneal Administration.

There have been great advances in the therapy of cancer and leukemia. However, there are still many neoplastic diseases that are difficult to treat. For example, it is often difficult to find effective therapies for aggressive cancer and leukemia. An NF-κB inhibitor named dehydroxymethylepoxyquinomicin (DHMEQ) was discovered in 2000. This compound was designed based on the structure of epoxyquinomicin isolated from a microorganism. It was shown to be a specific inhibitor that directly binds to and inactivates NF-κB components. Until now, DHMEQ has been used by many scientists in the world to suppress animal models of cancer and inflammation. Especially, it was shown to suppress difficult cancer models, such as hormone-insensitive breast cancer and prostate cancer, cholangiocarcinoma, and multiple myeloma. No toxicity has been reported so far. DHMEQ was administered via the intraperitoneal (IP) route in most of the animal experiments because of its simplicity. In the course of developmental studies, it was found that IP administration never increased the blood concentration of DHMEQ because of the instability of DHMEQ in the blood. It is suggested that inflammatory cells in the peritoneal cavity would be important for cancer progression, and that IP administration, itself, is important for the effectiveness and safety of DHMEQ. In the present review, we describe mechanism of action, its in vivo anticancer activity, and future clinical use of DHMEQ IP therapy.

The Role of Dipeptidyl Peptidase 4 as a Therapeutic Target and Serum Biomarker in Inflammatory Bowel Disease: A Systematic Review.

The roles dipeptidyl peptidase 4 (DPP4), aminopeptidase N (APN), and their substrates in autoimmune diseases are being increasingly recognized. However, their significance in inflammatory bowel diseases (IBD) is not entirely understood. This systematic review aims to discuss the pathophysiological processes related to these ectopeptidases while comparing findings from preclinical and clinical settings. This review was conducted according to the PRISMA guidelines. We performed a literature search in PubMed, SCOPUS, and Web of Science to identify all reports from inception until February 2020. The search included validated animal models of intestinal inflammation and studies in IBD patients. Quality assessment was performed using SYRCLE's risk of bias tool and CASP qualitative and cohort checklists. From the 45 included studies, 36 were performed in animal models and 12 in humans (3 reports included both). Overall, the methodological quality of preclinical studies was acceptable. In animal models, DPP4 and APN inhibition significantly improved intestinal inflammation.Glucagon-like peptide (GLP)-1 and GLP-2 analogs and GLP-2-relase-inducing drugs also showed significant benefits in recovery from inflammatory damage. A nonsignificant trend toward disease remission with the GLP-2 analog teduglutide was observed in the sole interventional human study. All human studies reported an inverse correlation between soluble DPP4/CD26 levels and disease severity, in accordance with the proposal of DPP4 as a biomarker for IBD. The use of DPP4 inhibitors and analogs of its substrates has clear benefits in the treatment of experimentally induced intestinal inflammation. Further research is warranted to validate their potential diagnostic and therapeutic applications in IBD patients.

Antioxidant and Anti-Inflammatory Effects of Genus Gynura: A Systematic Review.

Background: Gynura species have been used traditionally to treat various ailments, such as fever, pain, and to control blood glucose level. This systematic review critically discusses studies regarding Gynura species that exhibited antioxidant and anti-inflammatory effects, thus providing perspectives and instructions for future research of the plants as a potential source of new dietary supplements or medicinal agents. Methods: A literature search from internet databases of PubMed, Scopus, Science Direct, e-theses Online Service, and ProQuest was carried out using a combination of keywords such as “Gynura,” “antioxidant,” “anti-inflammatory,” or other related words. Research articles were included in this study if they were experimental (in vitro and in vivo) or clinical studies on the antioxidant or anti-inflammatory effects of Gynura species and if they were articles published in English. Results: Altogether, 27 studies on antioxidant and anti-inflammatory effects of Gynura species were selected. The antioxidant effects of Gynura species were manifested by inhibition of reactive oxygen species production and lipid peroxidation, modulation of glutathione-related parameters, and enzymatic antioxidant production or activities. The anti-inflammatory effects of Gynura species were through the modulation of inflammatory cytokine production, inhibition of prostaglandin E2 and nitric oxide production, cellular inflammatory-related parameters, and inflammation in animal models. The potential anti-inflammatory signaling pathways modulated by Gynura species are glycogen synthase kinase-3, nuclear factor erythroid 2-related factor 2, PPARγ, MAPK, NF-κB, and PI3K/Akt. However, most reports on antioxidant and anti-inflammatory effects of the plants were on crude extracts, and the chemical constituents contributing to bioactivities were not clearly understood. There is a variation in quality of studies in terms of design, conduct, and interpretation, and in-depth studies on the underlying mechanisms involved in antioxidant and anti-inflammatory effects of the plants are in demand. Moreover, there is limited clinical study on antioxidant and anti-inflammatory effects of Gynura species. Conclusion: This review highlighted antioxidant and anti-inflammatory effects of genus Gynura and supported their traditional uses to treat oxidative stress and inflammatory-related diseases. This review is expected to catalyze further studies on genus Gynura. However, extensive preclinical data need to be generated from toxicity and pharmacokinetic studies before clinical studies can be pursued for their development into clinical medicines to treat oxidative stress and inflammatory conditions.

Meibomian gland dysfunction model induced with complete Freund's adjuvant in C57BL/6 mice.

To establish a new inflammatory animal model of meibomian gland dysfunction (MGD) in C57BL/6 mice. C57BL/6 mice were randomly divided into complete Freund's adjuvant (CFA) group (14 animals, 14 eyes), naphthazolin hydrochloride (NH) group (14 animals, 14 eyes) and control group (14 animals, 14 eyes). In CFA group, CFA was used in eyelid conjunctiva injection; in NH group, NH eye drops were used twice a day; control group was injected with equal dose of saline at the same time point and same site with animals in CFA group. The meibomian gland orifices score (MGOS) was evaluated on a scale of 0 to 3 in the middle five meibomian gland orifices of the upper and lower eyelid using slit lamp. After the successful induction of each animal model, intense pulsed light (IPL) was introduced on each mouse in CFA and NH group. Oil red O (ORO), hematoxylin and eosin (H&E) staining were performed before and after successful induction of CFA, NH and control group. At 12wk after CFA injection, inflammatory cell infiltration and fiber necrosis was observed, with acinar density and duct dilatation significantly lower compared with control group. In NH group, the meibomian gland acini were relatively smaller and deformed compared with control group, the number of meibomian gland acini was also slightly lower. No inflammatory cell or fiber necrosis was observed in NH group. After three times of IPL treatment (5/10 mice in each group, and the other 5 mice served as non-IPL control), MGOS was significantly lower in IPL-treated mice in NH group (P<0.01). After three times of IPL treatment, the MGOS of NH group was significantly lower than that in the CFA group (P<0.01). We develop a novel animal model that studies the role of inflammation in the development of MGD and IPL treatment. This model indicates that persistent inflammatory state may be the cause of MGD and weaken the therapeutic effect of IPL.

Dopaminergic signalling limits suppressive activity and gut homing of regulatory T cells upon intestinal inflammation.

Evidence from inflammatory bowel diseases (IBD) patients and animal models has indicated that gut inflammation is driven by effector CD4+ T-cell, including Th1 and Th17. Conversely, Treg seem to be dysfunctional in IBD. Importantly, dopamine, which is abundant in the gut mucosa under homoeostasis, undergoes a sharp reduction upon intestinal inflammation. Here we analysed the role of the high-affinity dopamine receptor D3 (DRD3) in gut inflammation. Our results show that Drd3 deficiency confers a stronger immunosuppressive potency to Treg, attenuating inflammatory colitis manifestation in mice. Mechanistic analyses indicated that DRD3-signalling attenuates IL-10 production and limits the acquisition of gut-tropism. Accordingly, the ex vivo transduction of wild-type Treg with a siRNA for Drd3 induced a potent therapeutic effect abolishing gut inflammation. Thus, our findings show DRD3-signalling as a major regulator of Treg upon gut inflammation.

Exploring the effects of phenolic compounds to reduce intestinal damage and improve the intestinal barrier integrity: A systematic review of in vivo animal studies

The integrity of the intestinal barrier in the diseased is key to prevent further complications and disease such as sepsis and death, whereas, the role of food bioactive molecules (i. e. phenolic compounds (PCs) on the intestinal barrier, is still unknown. The current aim was to explore the benefits of the oral PC administration on the intestinal barrier integrity in animals. The effects of PCs on the intestinal barrier integrity in invivo animal models of intestinal inflammation were assessed up-to August 2020 from the PubMed, SCOPUS, and Cochrane Library databases under the PRISMA methodology. The risk of bias was assessed from ARRAY and SCYRCLE tools. From 1241 articles, 14 studies were included. In animals, oral resveratrol (n=6) improves the intestinal barrier integrity and reduces intestinal damage. Additionally, grape seed extract (n=2), curcumin (n=1), genistein (n=1), chlorogenic acid (n=1), grape pomace (n=1), olive leaf (n=1) or cranberry extract (n=1) improve the intestinal barrier integrity downregulating various inflammatory molecules (TNF-α, and other interleukins), and increasing the antioxidant enzymes in animals. Furthermore, resveratrol, quercetin, epigallocatechin, and other PCs improve the epithelial barrier integrity and pro-inflammatory molecule expression in the intestinal epithelia. The oral PC administration in animals improves the intestinal barrier integrity and function from three main mechanisms: 1) The reduction of pro-inflammatory molecules, 2) the improvement in tight-junction protein expression, and 3) the improvement of the antioxidant intracellular activity suggesting the potential use of PCs in the management of intestinal injury in humans, particularly for resveratrol, the most studied PC.

Novel selective agonist of GPR18, PSB-KK-1415 exerts potent anti-inflammatory and anti-nociceptive activities in animal models of intestinal inflammation and inflammatory pain.

GPR18 is a recently deorphanized receptor which was reported to act with several endogenous cannabinoid ligands. Here, we aimed to describe the role of GPR18 in intestinal inflammation and inflammatory pain. The anti-inflammatory activity of selective GPR18 agonist, PSB-KK-1415, and antagonist, PSB-CB5, was characterized in semi-chronic and chronic mouse models of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). The extent of inflammation was evaluated based on the macroscopic and microscopic scores, quantification of myeloperoxidase (MPO) activity, and Western blot analyses of tumor necrosis factor-α (TNF-α) and interleukin-6 in colonic tissue. The expression of GPR18 in colonic samples from patients with Crohn's disease (CD) was quantified using real-time PCR. The anti-nociceptive potential of the agonist in intestinal inflammation was evaluated in the mouse model of inflammatory pain. In semi-chronic colitis, PSB-KK-1415 reduced macroscopic score (1.79±0.22 vs. 2.61±0.48), expression of TNF-α (1.89±0.36 vs. 2.83±0.64), and microscopic score (5.00±0.33 vs. 6.45±0.40), all compared to mice with colitis. In chronic colitis, PSB-KK-1415 decreased macroscopic score (3.33±1.26 vs. 4.00±1.32) and MPO activity (32.23±8.51 vs. 41.33±11.64) compared to inflamed mice. In the mouse model of inflammatory pain, PSB-KK-1415 decreased the number of pain-induced behaviors in both, controls (32.60±2.54 vs. 58.00±6.24) and inflamed mice (60.83±2.85 vs. 85.00±5.77) compared to animals without treatment with PSB-KK-1415 (P<0.005 for both). Lastly, we showed an increased expression of GPR18 in CD patients compared to healthy controls (3.77±1.46 vs. 2.38±0.66, p=0.87). We showed that GPR18 is worth considering as a potential treatment target in intestinal inflammation and inflammatory pain.

Amitriptyline Downregulates Chronic Inflammatory Response to Biomaterial in Mice.

Recent data has signaled that in addition to its therapeutic indications as antidepressant and analgesic, amitriptyline (AM) exerts anti-inflammatory effects in humans and experimental animal models of acute inflammation. We tested the hypothesis that this compound could also modulate the chronic inflammatory process induced by synthetic matrix in mice. Polyether-polyurethane sponge disks were implanted subcutaneously in 9-week-old male C57BL/6 mice. The animals received by oral gavage 5.0mg/kg of amitriptyline for seven consecutive days in two treatment regimens. In the first series, the treatment was initiated on the day of surgery and the implants removed at day 7 post-implantation. For the assessment of the effect of amitriptyline on chronic inflammation, the treatment was initiated 7days post-implantation and the sponge discs removed 14 after implantation. The inflammatory markers evaluated, myeloperoxidase - MPO, nitrite content, IL-6, IFN-γ, TNF-α, CXCL1 and CCL2 levels, and NF-κB transcription factor activation were reduced in implants when the treatment began 7days post-implantation (chronic inflammation). In contrast, only mast cell number, MPO activity and activation of NF-κB pathway decreased when the treatment began soon after implantation (sub-acute inflammation) in 7-day old implants. The anti-inflammatory effects of amitriptyline described here, extend its range of actions as a potential agent able to attenuate long-term inflammatory processes.

Anti-inflammatory Plant Polyphenolics and Cellular Action Mechanisms

Background: Polyphenolics, a group of natural substances with a wide distribution in the plant kingdom present a great diversity of biological activities such as anti-oxidative, anti-inflammatory, anti-mutagenic, anti-carcinogenic, modulation of enzyme activity, prevention of CHD, etc. The objective of this review was to describe the relevant aspects of polyphenolics, reporting the different known groups, the probable mechanisms by which they act as anti-inflammatory agents. An attempt was also made to enumerate the possible leads e.g. curcumin, resveratrol, baicalein for further development. Methods: For peer-reviewed research literature we undertook a structured search of bibliographic databases using a focused review question. The quality of retrieved papers was appraised using standard tools. The systemic review consists of research using scientific databases such as PubMed, Scopus, Science Direct, and Google Scholar. Research: Compounds like Quercetin, luteolin, apigenin, fisetin, wogonin, and baicalein showed antiinflammatory activity in-vitro through different cellular mechanisms and these were also reported to possess significant anti-inflammatory activity in animal models of inflammation. Conclusion: It is evident that polyphenolic compounds such as flavonoids, lignans, phloroglucinols, stilbenes, diarylheptanoids, quinones, and phenylpropanoids exhibited significant anti-inflammatory activity in-vivo as well as in-vitro. Although, these active compounds are not drugs per se, however, they deserve further investigation as potential candidates for anti-inflammatory drug development through preclinical and clinical studies.

S3198 Antidepressant Use Is Associated With Poor Clinical Outcomes in the Setting of Inflammatory Bowel Disease

INTRODUCTION: Antidepressant medications (AMs) are frequently used in inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Many AMs are designed to enhance serotonin (5-HT) signaling. Increased 5-HT availability is associated with inflammation in animal models and human studies of IBD. We hypothesized that use of 5-HT-enhancing AMs would be associated with poor clinical outcomes in IBD. METHODS: We performed a retrospective cohort study using the Truven Health Marketscan® commercial claims database between 1/1/06 and 12/31/12. Participants (18–64 years) had at least 2 appropriate ICD-9 diagnoses for IBD, concurrent use of IBD medications, no other auto-inflammatory disease, at least 1 year of continuous enrollment before index diagnosis and 2 years after, during the study period. We identified new prescriptions of AM (includingselective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic, tetracyclics, monoamine oxidase inhibitors and other varieties) using the medication possession ratio (MPR; 80% adherence).Primary outcomes were: corticosteroid use, IBD-related complication (intestinal stricture and/or fistula), hospitalization, emergency room (ER) visit, IBD-related surgery and death within 2 years of IBD diagnosis or starting AM. We performed descriptive statisticsand calculatedadjusted hazard ratios (aHRs) comparing 2 groups (AM use vs. no AM use) for each of the outcomes above (adjusting for age, sex, comorbidity, IBD medication use and clinic visits). We also performed subgroup analyses considering IBD and AM subtype. RESULTS: 117,255 people had IBD (51.3% male; 55.6% UC). 7.1% used at least one AM during the follow-up period [most often a SSRI (4.9%) and/or SNRI (1.1%)]. AM users were younger, more likely female and to have several comorbidities, and used IBD-targeted medications more often (Table 1). Corticosteroid use, hospitalizations, ER visits and death were independently associated with AM use (Table 2).In the UC cohort, AM users were more likely to have complications [aHR = 1.90 (1.42–2.54), P < 0.0001)]. SSRIs were the only group independently associated with death [aHR = 7.93 (3.62–17.36), P < 0.0001]. CONCLUSION: We demonstrated that AM use is independently associated with an increased risk of many poor outcomes in IBD (including death). While further study is warranted, providers should exercise caution when using AM in IBD, particularly SSRIs.Table 1.: Demographic and Clinical Characteristics of Antidepressant Medication Users and Non-Users. AM = antidepressant medication; SD = standard deviation.Table 2.: Cox Proportional Hazards Model Evaluating Clinical Outcomes Associated with Antidepressant Use in the full IBD cohort.

Safety and Pharmacokinetics of Recombinant Human Plasma Gelsolin in Patients Hospitalized for Nonsevere Community-Acquired Pneumonia

There remains an unmet need to address the substantial morbidity and mortality associated with severe community-acquired pneumonia (sCAP). Recombinant human plasma gelsolin (rhu-pGSN) improves disease outcomes in diverse animal models of infectious and noninfectious inflammation. This blinded dose-escalation safety study involved non-intensive care unit (ICU) patients admitted for mild CAP and randomized 3:1 to receive adjunctive rhu-pGSN or placebo intravenously. Thirty-three subjects were treated: 8 in the single-dose phase and 25 in the multidose phase. For the single-dose phase, rhu-pGSN at 6 mg/kg of body weight was administered once. For the multidose phase, a daily rhu-pGSN dose of 6, 12, or 24 mg/kg was given on 3 consecutive days. Adverse events (AEs) were generally mild in both treatment groups irrespective of dose. The only serious AE (SAE) in the single-dose phase was a non-drug-related pneumonia in a rhu-pGSN recipient who died after institution of comfort care. One single-dose placebo recipient had a drug-related AE (maculo-papular rash). In the multidose phase, there were 2 SAEs in 1 placebo recipient, including a fatal pulmonary embolism. In the 18 rhu-pGSN recipients in the multidose phase, there were no serious or drug-related AEs, and nausea and increased blood pressure were each reported in 2 patients. The median rhu-pGSN half-life exceeded 17 h with all dosing regimens, and supraphysiologic levels were maintained throughout the 24-h dosing interval in the 2 highest dosing arms. Rhu-pGSN was well tolerated overall in CAP patients admitted to non-ICU beds, justifying a larger proof-of-concept trial in an ICU population admitted with sCAP. (This study has been registered at ClinicalTrials.gov under identifier NCT03466073.).