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Sample records for chronic inflammation immune

  1. Interleukin-17 and innate immunity in infections and chronic inflammation.

    PubMed

    Isailovic, Natasa; Daigo, Kenji; Mantovani, Alberto; Selmi, Carlo

    2015-06-01

    Interleukin 17 (IL-17) includes several cytokines among which IL-17A is considered as one of the major pro-inflammatory cytokine being central to the innate and adaptive immune responses. IL-17 is produced by unconventional T cells, members of innate lymphoid cells (ILCs), mast cells, as well as typical innate immune cells, such as neutrophils and macrophages located in the epithelial barriers and characterised by a rapid response to infectious agents by recruiting neutrophils as first line of defence and inducing the production of antimicrobial peptides. Th17 responses appear pivotal in chronic and acute infections by bacteria, parasites, and fungi, as well as in autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and psoriatic arthritis. The data discussed in this review cumulatively indicate that innate-derived IL-17 constitutes a major element in the altered immune response against self antigens or the perpetuation of inflammation, particularly at mucosal sites. New drugs targeting the IL17 pathway include brodalumab, ixekizumab, and secukinumab and their use in psoriatic disease is expected to dramatically impact our approach to this systemic condition. PMID:25998834

  2. Role of protein tyrosine phosphatases in regulating the immune system: implications for chronic intestinal inflammation.

    PubMed

    Spalinger, Marianne R; McCole, Declan F; Rogler, Gerhard; Scharl, Michael

    2015-03-01

    Current hypothesis suggests that genetic, immunological, and bacterial factors contribute essentially to the pathogenesis of inflammatory bowel disease. Variations within the gene loci encoding protein tyrosine phosphatases (PTPs) have been associated with the onset of inflammatory bowel disease. PTPs modulate the activity of their substrates by dephosphorylation of tyrosine residues and are critical for the regulation of fundamental cellular signaling processes. Evidence emerges that expression levels of PTPN2, PTPN11, and PTPN22 are altered in actively inflamed intestinal tissue. PTPN2 seems to be critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses and finally for maintaining intestinal homeostasis. These observations have been confirmed in PTPN2 knockout mice in vivo. Those animals are clearly more susceptible to intestinal and systemic inflammation and feature alterations in innate and adaptive immune responses. PTPN22 controls inflammatory signaling in lymphocytes and mononuclear cells resulting in aberrant cytokine secretion pattern and autophagosome formation. PTPN22 deficiency in vivo results in more severe colitis demonstrating the relevance of PTPN22 for intestinal homeostasis in vivo. Of note, loss of PTPN22 promotes mitogen-activated protein kinase-induced cytokine secretion but limits secretion of nuclear factor κB-associated cytokines and autophagy in mononuclear cells. Loss of PTPN11 is also associated with increased colitis severity in vivo. In summary, dysfunction of those PTPs results in aberrant and uncontrolled immune responses that result in chronic inflammatory conditions. This way, it becomes more and more evident that dysfunction of PTPs displays an important factor in the pathogenesis of chronic intestinal inflammation, in particular inflammatory bowel disease. PMID:25581833

  3. Ascorbic acid: its role in immune system and chronic inflammation diseases.

    PubMed

    Sorice, Angela; Guerriero, Eliana; Capone, Francesca; Colonna, Giovanni; Castello, Giuseppe; Costantini, Susan

    2014-05-01

    Ascorbic acid (AA), also known as vitamin C, was initially identified as the factor preventing the scurvy disease, and became very popular for its antioxidant properties. It is an important co-substrate of a large class of enzymes, and regulates gene expression by interacting with important transcription factors. AA is important in all stressful conditions that are linked to inflammatory processes and involve immunity. It has been known for decades that the persistence of an inflammatory stimulus is responsible for the onset of many diseases. AA is essential to stimulate the immune system by increasing the strength and protection of the organism. Therefore, its immunostimulant, antinflammatory, antiviral and antibacterial roles are well known, we have summarized its main functions in different types of diseases related to the immune system and chronic inflammation. We can conclude that AA, due to its effects and diversity of regulated pathways, is suitable for use in various fields of medicine including immunology, toxicology, radiobiology and others. AA is not preferable to be used as an isolated mode of treatment, but it can be co-applied as an adjuvant to regulate immunity, gene expression and other important physiological processes. However, we propose that future studies will take into consideration the research of new combinations of antioxidant natural substances and drugs. PMID:24766384

  4. Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection.

    PubMed

    Hsu, Denise C; Sereti, Irini

    2016-04-01

    In the antiretroviral therapy (ART) era, serious non-AIDS events (SNAEs) have become the major causes of morbidity and mortality in HIV-infected persons. Early ART initiation has the strongest evidence for reducing SNAEs and mortality. Biomarkers of immune activation, inflammation and coagulopathy do not fully normalize despite virologic suppression and persistent immune activation is an important contributor to SNAEs. A number of strategies aimed to reduce persistent immune activation including ART intensification to reduce residual viremia; treatment of co-infections to reduce chronic antigen stimulation; the use of anti-inflammatory agents, reducing microbial translocation as well as interventions to improve immune recovery through cytokine administration and reducing lymphoid tissue fibrosis, have been investigated. To date, there is little conclusive evidence on which strategies beyond treatment of hepatitis B and C co-infections and reducing cardiovascular risk factors will result in clinical benefits in patients already on ART with viral suppression. The use of statins seems to show early promise and larger clinical trials are underway to confirm their efficacy. At this stage, clinical care of HIV-infected patients should therefore focus on early diagnosis and prompt ART initiation, treatment of active co-infections and the aggressive management of co-morbidities until further data are available. PMID:26915027

  5. Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome.

    PubMed

    Rajeevan, Mangalathu S; Dimulescu, Irina; Murray, Janna; Falkenberg, Virginia R; Unger, Elizabeth R

    2015-08-01

    Recent evidence suggests immune and inflammatory alterations are important in chronic fatigue syndrome (CFS). This study was done to explore the association of functionally important genetic variants in inflammation and immune pathways with CFS. Peripheral blood DNA was isolated from 50 CFS and 121 non-fatigued (NF) control participants in a population-based study. Genotyping was performed with the Affymetrix Immune and Inflammation Chip that covers 11K single nucleotide polymorphisms (SNPs) following the manufacturer's protocol. Genotyping accuracy for specific genes was validated by pyrosequencing. Golden Helix SVS software was used for genetic analysis. SNP functional annotation was done using SPOT and GenomePipe programs. CFS was associated with 32 functionally important SNPs: 11 missense variants, 4 synonymous variants, 11 untranslated regulatory region (UTR) variants and 6 intronic variants. Some of these SNPs were in genes within pathways related to complement cascade (SERPINA5, CFB, CFH, MASP1 and C6), chemokines (CXCL16, CCR4, CCL27), cytokine signaling (IL18, IL17B, IL2RB), and toll-like receptor signaling (TIRAP, IRAK4). Of particular interest is association of CFS with two missense variants in genes of complement activation, rs4151667 (L9H) in CFB and rs1061170 (Y402H) in CFH. A 5' UTR polymorphism (rs11214105) in IL18 also associated with physical fatigue, body pain and score for CFS case defining symptoms. This study identified new associations of CFS with genetic variants in pathways including complement activation providing additional support for altered innate immune response in CFS. Additional studies are needed to validate the findings of this exploratory study. PMID:26116897

  6. Immune dysregulation mediated by the oral microbiome: potential link to chronic inflammation and atherosclerosis.

    PubMed

    Slocum, C; Kramer, C; Genco, C A

    2016-07-01

    Cardiovascular disease is an inflammatory disorder characterized by the progressive formation of plaque in coronary arteries, termed atherosclerosis. It is a multifactorial disease that is one of the leading causes of death worldwide. Although a number of risk factors have been associated with disease progression, the underlying inflammatory mechanisms contributing to atherosclerosis remain to be fully delineated. Within the last decade, the potential role for infection in inflammatory plaque progression has received considerable interest. Microbial pathogens associated with periodontal disease have been of particular interest due to the high levels of bacteremia that are observed after routine dental procedures and every day oral activities, such as tooth brushing. Here, we explore the potential mechanisms that may explain how periodontal pathogens either directly or indirectly elicit immune dysregulation and consequently progressive inflammation manifested as atherosclerosis. Periodontal pathogens have been shown to contribute directly to atherosclerosis by disrupting endothelial cell function, one of the earliest indicators of cardiovascular disease. Oral infection is thought to indirectly induce elevated production of inflammatory mediators in the systemic circulation. Recently, a number of studies have been conducted focusing on how disruption of the gut microbiome influences the systemic production of proinflammatory cytokines and consequently exacerbation of inflammatory diseases such as atherosclerosis. It is clear that the immune mechanisms leading to atherosclerotic plaque progression, by oral infection, are complex. Understanding the immune pathways leading to disease progression is essential for the future development of anti-inflammatory therapies for this chronic disease. PMID:26791914

  7. Diet and Inflammation: Possible Effects on Immunity, Chronic Diseases, and Life Span.

    PubMed

    Ricordi, Camillo; Garcia-Contreras, Marta; Farnetti, Sara

    2015-01-01

    Chronic inflammation negatively impacts all physiological functions, causing an array of degenerative conditions including diabetes; cancer; cardiovascular, osteo-articular, and neurodegenerative diseases; autoimmunity disorders; and aging. In particular, there is a growing knowledge of the role that gene transcription factors play in the inflammatory process. Obesity, metabolic syndrome, and diabetes represent multifactorial conditions resulting from improper balances of hormones and gene expression. In addition, these conditions have a strong inflammatory component that can potentially be impacted by the diet. It can reduce pro-inflammatory eicosanoids that can alter hormonal signaling cascades to the modulation of the innate immune system and gene transcription factors. Working knowledge of the impact of how nutrients, especially dietary fatty acids and polyphenols, can impact these various molecular targets makes it possible to develop a general outline of an anti-inflammatory diet that offers a unique, nonpharmacological approach in treating obesity, metabolic syndrome, and diabetes. Several important bioactive dietary components can exert their effect through selected inflammatory pathways that can affect metabolic and genetic changes. In fact, dietary components that can modulate glucose and insulin levels, as well as any other mediator that can activate nuclear factor-kB, can also trigger inflammation through common pathway master switches. PMID:26400428

  8. IL-9 signaling as key driver of chronic inflammation in mucosal immunity.

    PubMed

    Neurath, Markus F; Finotto, Susetta

    2016-06-01

    Recent studies have highlighted a crucial regulatory role of the cytokine IL-9 in driving immune responses in chronic inflammatory and autoimmune diseases at mucosal surfaces. IL-9 activates various types of immune and non-immune cells carrying the membrane bound IL-9R. IL-9 signaling plays a pivotal role in controlling the differentiation and activation of these cells by inducing the Jak/STAT pathway. In particular, IL-9 induces activation of T helper cells and affects the function of various tissue resident cells such as mast cells and epithelial cells in the mucosa. Importantly, recent findings suggest that blockade of IL-9 signaling is effective in treating experimental models of autoimmune and chronic inflammatory diseases such as inflammatory bowel diseases, allergic disorders such as food allergy and asthma. Thus, blockade of IL-9 and IL-9R signaling emerges as potentially novel approach for therapy of inflammatory diseases in the mucosal immune system. PMID:26976761

  9. Quercetin, Inflammation and Immunity

    PubMed Central

    Li, Yao; Yao, Jiaying; Han, Chunyan; Yang, Jiaxin; Chaudhry, Maria Tabassum; Wang, Shengnan; Liu, Hongnan; Yin, Yulong

    2016-01-01

    In vitro and some animal models have shown that quercetin, a polyphenol derived from plants, has a wide range of biological actions including anti-carcinogenic, anti-inflammatory and antiviral activities; as well as attenuating lipid peroxidation, platelet aggregation and capillary permeability. This review focuses on the physicochemical properties, dietary sources, absorption, bioavailability and metabolism of quercetin, especially main effects of quercetin on inflammation and immune function. According to the results obtained both in vitro and in vivo, good perspectives have been opened for quercetin. Nevertheless, further studies are needed to better characterize the mechanisms of action underlying the beneficial effects of quercetin on inflammation and immunity. PMID:26999194

  10. Quercetin, Inflammation and Immunity.

    PubMed

    Li, Yao; Yao, Jiaying; Han, Chunyan; Yang, Jiaxin; Chaudhry, Maria Tabassum; Wang, Shengnan; Liu, Hongnan; Yin, Yulong

    2016-03-01

    In vitro and some animal models have shown that quercetin, a polyphenol derived from plants, has a wide range of biological actions including anti-carcinogenic, anti-inflammatory and antiviral activities; as well as attenuating lipid peroxidation, platelet aggregation and capillary permeability. This review focuses on the physicochemical properties, dietary sources, absorption, bioavailability and metabolism of quercetin, especially main effects of quercetin on inflammation and immune function. According to the results obtained both in vitro and in vivo, good perspectives have been opened for quercetin. Nevertheless, further studies are needed to better characterize the mechanisms of action underlying the beneficial effects of quercetin on inflammation and immunity. PMID:26999194

  11. Effect of Hyssopus officinalis L. on inhibiting airway inflammation and immune regulation in a chronic asthmatic mouse model

    PubMed Central

    MA, XIAOJUAN; MA, XIUMIN; MA, ZHIXING; WANG, JING; SUN, ZHAN; YU, WENYAN; LI, FENGSEN; DING, JIANBING

    2014-01-01

    The Uygur herb, Hyssopus officinalis L., has been demonstrated to affect the levels of a number of cytokines in asthmatic mice, including interleukin-4, -6 and -17 and interferon-γ. In the present study, the effect of Hyssopus officinalis L. on airway immune regulation and airway inflammation was investigated in a mouse model of chronic asthma. A total of 32 BALB/c mice were randomly divided into four groups, which included the normal, chronic asthmatic, dexamethasone treatment and Hyssopus officinalis L.treatment groups. Mice were sensitized and challenged with ovalbumin to establish an asthma model and the ratio of eosinophils (EOS) in the bronchoalveolar lavage fluid (BALF) was determined. In addition, the levels of immunoglobulin (Ig)E and IgG were detected using an enzyme-linked immunosorbent assay. The degree of airway mucus secretion was observed using the periodic acid-Schiff stain method. The results demonstrated that the ratio of EOS in the BALF and the level of serum IgE in the chronic asthmatic and dexamethasone treatment groups increased, while the level of serum IgG decreased, when compared with the normal group. In addition, excessive secretion of airway mucus was observed in these two groups. However, the EOS ratio in the BALF and the levels of serum IgE and IgG in the Hyssopus officinalis L. treatment group were similar to the results observed in the normal group. In conclusion, Hyssopus officinalis L. not only plays an anti-inflammatory role by inhibiting the invasion of EOS and decreasing the levels of IgE, but also affects immune regulation. PMID:25289025

  12. Effect of Hyssopus officinalis L. on inhibiting airway inflammation and immune regulation in a chronic asthmatic mouse model.

    PubMed

    Ma, Xiaojuan; Ma, Xiumin; Ma, Zhixing; Wang, Jing; Sun, Zhan; Yu, Wenyan; Li, Fengsen; Ding, Jianbing

    2014-11-01

    The Uygur herb, Hyssopus officinalis L., has been demonstrated to affect the levels of a number of cytokines in asthmatic mice, including interleukin-4, -6 and -17 and interferon-γ. In the present study, the effect of Hyssopus officinalis L. on airway immune regulation and airway inflammation was investigated in a mouse model of chronic asthma. A total of 32 BALB/c mice were randomly divided into four groups, which included the normal, chronic asthmatic, dexamethasone treatment and Hyssopus officinalis L.treatment groups. Mice were sensitized and challenged with ovalbumin to establish an asthma model and the ratio of eosinophils (EOS) in the bronchoalveolar lavage fluid (BALF) was determined. In addition, the levels of immunoglobulin (Ig)E and IgG were detected using an enzyme-linked immunosorbent assay. The degree of airway mucus secretion was observed using the periodic acid-Schiff stain method. The results demonstrated that the ratio of EOS in the BALF and the level of serum IgE in the chronic asthmatic and dexamethasone treatment groups increased, while the level of serum IgG decreased, when compared with the normal group. In addition, excessive secretion of airway mucus was observed in these two groups. However, the EOS ratio in the BALF and the levels of serum IgE and IgG in the Hyssopus officinalis L. treatment group were similar to the results observed in the normal group. In conclusion, Hyssopus officinalis L. not only plays an anti-inflammatory role by inhibiting the invasion of EOS and decreasing the levels of IgE, but also affects immune regulation. PMID:25289025

  13. Chronic Inflammation in Skin Malignancies

    PubMed Central

    Tang, Lihua

    2016-01-01

    Chronic inflammation is linked to the development and progression of multiple cancers, including those of the lung, stomach, liver, colon, breast and skin. Inflammation not only drives the oncogenic transformation of epithelial cells under the stress of chronic infection and autoimmune diseases, but also promotes the growth, progression and metastatic spread of cancers. Tumor-infiltrating inflammatory cells are comprised of a diverse population of myeloid and immune cell types, including monocytes, macrophages, dendritic cells, T and B cells, and others. Different myeloid and lymphoid cells within tumor microenvironment exert diverse, often contradicting, effects during skin cancer development and progression. The nature of tumor-immune interaction determines the rate of cancer progression and the outcome of cancer treatment. Inflammatory environment within skin tumor also inhibits naturally occurring anti-tumor immunity and limits the efficacy of cancer immunotherapy. In this article we aim to give an overview on the mechanism by which inflammation interferes with the development and therapeutic intervention of cancers, especially those of the skin.

  14. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: innate immune responses in plants.

    PubMed

    Schulze-Lefert, P

    2010-04-01

    Plants rely exclusively upon mechanisms of innate immunity. Current concepts of the plant innate immune system are based largely on two forms of immunity that engage distinct classes of immune receptors. These receptors enable the recognition of non-self structures that are either conserved between members of a microbial class or specific to individual strains of a microbe. One type of receptor comprises membrane-resident pattern recognition receptors (PRRs) that detect widely conserved microbe-associated molecular patterns (MAMPs) on the cell surface. A second type of mainly intracellular immune sensors, designated resistance (R) proteins, recognizes either the structure or function of strain-specific pathogen effectors that are delivered inside host cells. Phytopathogenic microorganisms have evolved a repertoire of effectors, some of which are delivered into plant cells to sabotage MAMP-triggered immune responses. Plants appear to have also evolved receptors that sense cellular injury by the release and perception of endogenous damage-associated molecular patterns (DAMPs). It is possible that the integration of MAMP and DAMP responses is critical to mount robust MAMP-triggered immunity. This signal integration might help to explain why plants are colonized in nature by remarkably diverse and seemingly asymptomatic microbial communities. PMID:20415853

  15. Impact of antiretroviral therapy (ART) timing on chronic immune activation/inflammation and end-organ damage

    PubMed Central

    Rajasuriar, Reena; Wright, Edwina; Lewin, Sharon R.

    2015-01-01

    Purpose of review The purpose of this review was to summarize recent studies on the effect of early antiretroviral therapy (ART) in HIV-infected patients on markers of immune activation/inflammation, viral persistence and serious non-AIDS events. Recent findings Early ART, initiated within days to months of HIV infection, was associated with marked reduction in T-cell activation often reaching levels observed in HIV-uninfected individuals. However, the impact of early ART on markers of innate immune activation, microbial translocation and inflammation/coagulation was less clear. Early ART has also been associated with a significant reduction in the frequency of latently infected cells, which was greater if ART was initiated within days to weeks rather than months following infection. However, few studies have evaluated the relationship between immune activation and viral reservoirs, specifically following early ART. Early ART may potentially reduce serious non-AIDS events and associated mortality, but most of these studies have extrapolated from changes in surrogate markers, such as CD4 : CD8 ratio. Summary Early ART was associated with beneficial effects on multiple markers of immune activation, inflammation and viral persistence. Longer term prospective studies are still needed to determine whether early ART translates to a significant reduction in serious non-AIDS events and mortality. PMID:25415420

  16. The effects of grounding (earthing) on inflammation, the immune response, wound healing, and prevention and treatment of chronic inflammatory and autoimmune diseases

    PubMed Central

    Oschman, James L; Chevalier, Gaétan; Brown, Richard

    2015-01-01

    Multi-disciplinary research has revealed that electrically conductive contact of the human body with the surface of the Earth (grounding or earthing) produces intriguing effects on physiology and health. Such effects relate to inflammation, immune responses, wound healing, and prevention and treatment of chronic inflammatory and autoimmune diseases. The purpose of this report is two-fold: to 1) inform researchers about what appears to be a new perspective to the study of inflammation, and 2) alert researchers that the length of time and degree (resistance to ground) of grounding of experimental animals is an important but usually overlooked factor that can influence outcomes of studies of inflammation, wound healing, and tumorigenesis. Specifically, grounding an organism produces measurable differences in the concentrations of white blood cells, cytokines, and other molecules involved in the inflammatory response. We present several hypotheses to explain observed effects, based on current research results and our understanding of the electronic aspects of cell and tissue physiology, cell biology, biophysics, and biochemistry. An experimental injury to muscles, known as delayed onset muscle soreness, has been used to monitor the immune response under grounded versus ungrounded conditions. Grounding reduces pain and alters the numbers of circulating neutrophils and lymphocytes, and also affects various circulating chemical factors related to inflammation. PMID:25848315

  17. 99th Dahlem Conference on Infection, Inflammation and Chronic Inflammatory Disorders: Immune therapies of type 1 diabetes: new opportunities based on the hygiene hypothesis

    PubMed Central

    Chatenoud, L; You, S; Okada, H; Kuhn, C; Michaud, B; Bach, J-F

    2010-01-01

    Insulin-dependent (type 1) diabetes is a prototypic organ-specific autoimmune disease resulting from the selective destruction of insulin-secreting β cells within pancreatic islets of Langerhans by an immune-mediated inflammation involving autoreactive CD4+ and CD8+ T lymphocytes which infiltrate pancreatic islets. Current treatment is substitutive, i.e. chronic use of exogenous insulin which, in spite of significant advances, is still associated with major constraints (multiple daily injections, risks of hypoglycaemia) and lack of effectiveness over the long term in preventing severe degenerative complications. Finding a cure for autoimmune diabetes by establishing effective immune-based therapies is a real medical health challenge, as the disease incidence increases steadily in industrialized countries. As the disease affects mainly children and young adults, any candidate immune therapy must therefore be safe and avoid a sustained depression of immune responses with the attendant problems of recurrent infection and drug toxicity. Thus, inducing or restoring immune tolerance to target autoantigens, controlling the pathogenic response while preserving the host reactivity to exogenous/unrelated antigens, appears to be the ideal approach. Our objective is to review the major progress accomplished over the last 20 years towards that aim. In addition, we would like to present another interesting possibility to access new preventive strategies based on the ‘hygiene hypothesis’, which proposes a causal link between the increasing incidence of autoimmune diseases, including diabetes, and the decrease of the infectious burden. The underlying rationale is to identify microbial-derived compounds mediating the protective activity of infections which could be developed therapeutically. PMID:20415859

  18. Signaling in Innate Immunity and Inflammation

    PubMed Central

    Newton, Kim; Dixit, Vishva M.

    2012-01-01

    SUMMARY Inflammation is triggered when innate immune cells detect infection or tissue injury. Surveillance mechanisms involve pattern recognition receptors (PRRs) on the cell surface and in the cytoplasm. Most PRRs respond to pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs) by triggering activation of NF-κB, AP1, CREB, c/EBP, and IRF transcription factors. Induction of genes encoding enzymes, chemokines, cytokines, adhesion molecules, and regulators of the extracellular matrix promotes the recruitment and activation of leukocytes, which are critical for eliminating foreign particles and host debris. A subset of PRRs activates the protease caspase-1, which causes maturation of the cytokines IL1β and IL18. Cell adhesion molecules and chemokines facilitate leukocyte extravasation from the circulation to the affected site, the chemokines stimulating G-protein-coupled receptors (GPCRs). Binding initiates signals that regulate leukocyte motility and effector functions. Other triggers of inflammation include allergens, which form antibody complexes that stimulate Fc receptors on mast cells. Although the role of inflammation is to resolve infection and injury, increasing evidence indicates that chronic inflammation is a risk factor for cancer. PMID:22296764

  19. Microbial induction of immunity, inflammation, and cancer.

    PubMed

    Greer, Julia B; O'Keefe, Stephen John

    2011-01-01

    The human microbiota presents a highly active metabolic that influences the state of health of our gastrointestinal tracts as well as our susceptibility to disease. Although much of our initial microbiota is adopted from our mothers, its final composition and diversity is determined by environmental factors. Westernization has significantly altered our microbial function. Extensive experimental and clinical evidence indicates that the westernized diet, rich in animal products and low in complex carbohydrates, plus the overuse of antibiotics and underuse of breastfeeding, leads to a heightened inflammatory potential of the microbiota. Chronic inflammation leads to the expression of certain diseases in genetically predisposed individuals. Antibiotics and a "clean" environment, termed the "hygiene hypothesis," has been linked to the rise in allergy and inflammatory bowel disease, due to impaired beneficial bacterial exposure and education of the gut immune system, which comprises the largest immune organ within the body. The elevated risk of colon cancer is associated with the suppression of microbial fermentation and butyrate production, as butyrate provides fuel for the mucosa and is anti-inflammatory and anti-proliferative. This article will summarize the work to date highlighting the complicated and dynamic relationship between the gut microbiota and immunity, inflammation and carcinogenesis. PMID:21423403

  20. Parainflammation, chronic inflammation and age-related macular degeneration

    PubMed Central

    Chen, Mei; Xu, Heping

    2016-01-01

    Inflammation is an adaptive response of the immune system to noxious insults to maintain homeostasis and restore functionality. The retina is considered an immune privileged tissue due to its unique anatomical and physiological properties. During aging, the retina suffers from a low-grade chronic oxidative insult, which sustains for decades and increases in level with advancing age. As a result, the retinal innate immune system, particularly microglia and the complement system, undergo low levels of activation (para-inflammation). In many cases, this para-inflammatory response can maintain homeostasis in the healthy aging eye. However, in patients with age-related macular degeneration (AMD), this para-inflammatory response becomes dysregulated and contributes to macular damage. Factors contributing to the dysregulation of age-related retinal para-inflammation include genetic predisposition, environmental risk factors and old age. Dysregulated para-inflammation (chronic inflammation) in AMD damages the blood retina barrier (BRB), resulting in the breach of retinal immune privilege leading to the development of retinal lesions. This review discusses the basic principles of retinal innate immune responses to endogenous chronic insults in normal aging and in AMD, and explores the difference between beneficial para-inflammation and the detrimental chronic inflammation in the context of AMD. PMID:26292978

  1. Immune aging, dysmetabolism, and inflammation in neurological diseases

    PubMed Central

    Deleidi, Michela; Jäggle, Madeline; Rubino, Graziella

    2015-01-01

    As we age, the immune system undergoes a process of senescence accompanied by the increased production of proinflammatory cytokines, a chronic subclinical condition named as “inflammaging”. Emerging evidence from human and experimental models suggest that immune senescence also affects the central nervous system and promotes neuronal dysfunction, especially within susceptible neuronal populations. In this review we discuss the potential role of immune aging, inflammation and metabolic derangement in neurological diseases. The discovery of novel therapeutic strategies targeting age-linked inflammation may promote healthy brain aging and the treatment of neurodegenerative as well as neuropsychiatric disorders. PMID:26089771

  2. The role of adipokines in chronic inflammation

    PubMed Central

    Mancuso, Peter

    2016-01-01

    Adipose tissue has traditionally been defined as connective tissue that stores excess calories in the form of triacylglycerol. However, the physiologic functions attributed to adipose tissue are expanding, and it is now well established that adipose tissue is an endocrine gland. Among the endocrine factors elaborated by adipose tissue are the adipokines; hormones, similar in structure to cytokines, produced by adipose tissue in response to changes in adipocyte triacylglycerol storage and local and systemic inflammation. They inform the host regarding long-term energy storage and have a profound influence on reproductive function, blood pressure regulation, energy homeostasis, the immune response, and many other physiologic processes. The adipokines possess pro- and anti-inflammatory properties and play a critical role in integrating systemic metabolism with immune function. In calorie restriction and starvation, proinflammatory adipokines decline and anti-inflammatory adipokines increase, which informs the host of energy deficits and contributes to the suppression of immune function. In individuals with normal metabolic status, there is a balance of pro- and anti-inflammatory adipokines. This balance shifts to favor proinflammatory mediators as adipose tissue expands during the development of obesity. As a consequence, the proinflammatory status of adipose tissue contributes to a chronic low-grade state of inflammation and metabolic disorders associated with obesity. These disturbances are associated with an increased risk of metabolic disease, type 2 diabetes, cardiovascular disease, and many other pathological conditions. This review focuses on the impact of energy homeostasis on the adipokines in immune function. PMID:27529061

  3. The role of adipokines in chronic inflammation.

    PubMed

    Mancuso, Peter

    2016-01-01

    Adipose tissue has traditionally been defined as connective tissue that stores excess calories in the form of triacylglycerol. However, the physiologic functions attributed to adipose tissue are expanding, and it is now well established that adipose tissue is an endocrine gland. Among the endocrine factors elaborated by adipose tissue are the adipokines; hormones, similar in structure to cytokines, produced by adipose tissue in response to changes in adipocyte triacylglycerol storage and local and systemic inflammation. They inform the host regarding long-term energy storage and have a profound influence on reproductive function, blood pressure regulation, energy homeostasis, the immune response, and many other physiologic processes. The adipokines possess pro- and anti-inflammatory properties and play a critical role in integrating systemic metabolism with immune function. In calorie restriction and starvation, proinflammatory adipokines decline and anti-inflammatory adipokines increase, which informs the host of energy deficits and contributes to the suppression of immune function. In individuals with normal metabolic status, there is a balance of pro- and anti-inflammatory adipokines. This balance shifts to favor proinflammatory mediators as adipose tissue expands during the development of obesity. As a consequence, the proinflammatory status of adipose tissue contributes to a chronic low-grade state of inflammation and metabolic disorders associated with obesity. These disturbances are associated with an increased risk of metabolic disease, type 2 diabetes, cardiovascular disease, and many other pathological conditions. This review focuses on the impact of energy homeostasis on the adipokines in immune function. PMID:27529061

  4. The unfolded protein response in immunity and inflammation.

    PubMed

    Grootjans, Joep; Kaser, Arthur; Kaufman, Randal J; Blumberg, Richard S

    2016-08-01

    The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses. PMID:27346803

  5. The Role of Chronic Inflammation in Obesity-Associated Cancers

    PubMed Central

    2013-01-01

    There is a strong relationship between metabolism and immunity, which can become deleterious under conditions of metabolic stress. Obesity, considered a chronic inflammatory disease, is one example of this link. Chronic inflammation is increasingly being recognized as an etiology in several cancers, particularly those of epithelial origin, and therefore a potential link between obesity and cancer. In this review, the connection between the different factors that can lead to the chronic inflammatory state in the obese individual, as well as their effect in tumorigenesis, is addressed. Furthermore, the association between obesity, inflammation, and esophageal, liver, colon, postmenopausal breast, and endometrial cancers is discussed. PMID:23819063

  6. Intestinal immunity and inflammation: recent progress.

    PubMed

    Elson, C O; Kagnoff, M F; Fiocchi, C; Befus, A D; Targan, S

    1986-09-01

    The previous sections illustrate that we are still defining (a) which sets of lymphoid cells are present in the intestine and which are not, (b) which sets are peculiar to the intestine, and (c) how the sets that are there function in the intestinal microenvironment. An understanding of the latter point is going to require knowledge of how these sets communicate with and regulate one another via cell surface molecules such as MHC class I and class II molecules, and via soluble mediators or lymphokines. The recent advances in various technologies make this a particularly exciting time in this field because the tools are now available to address and answer some of these basic and important questions in mucosal immunology. At the same time these advances hold great promise for our eventual understanding of chronic inflammatory diseases of the intestine. As was mentioned at the outset, the immune system has considerable power for both protection and destruction. It remains a puzzle how this latter potential is contained and controlled in the intestine of most individuals, such that they do not have inflammatory disease even in the setting of intense stimulation by substances, such as endotoxin, that are phlogistic elsewhere in the body. An answer to the question of why everyone does not have intestinal inflammation could provide new insights into the mechanisms involved in chronic intestinal inflammatory diseases. The recent advances just detailed, as well as others sure to come, suggest that it is only a matter of time before such questions are answered. PMID:3089867

  7. Parainflammation, chronic inflammation, and age-related macular degeneration.

    PubMed

    Chen, Mei; Xu, Heping

    2015-11-01

    Inflammation is an adaptive response of the immune system to noxious insults to maintain homeostasis and restore functionality. The retina is considered an immune-privileged tissue as a result of its unique anatomic and physiologic properties. During aging, the retina suffers from a low-grade chronic oxidative insult, which sustains for decades and increases in level with advancing age. As a result, the retinal innate-immune system, particularly microglia and the complement system, undergoes low levels of activation (parainflammation). In many cases, this parainflammatory response can maintain homeostasis in the healthy aging eye. However, in patients with age-related macular degeneration, this parainflammatory response becomes dysregulated and contributes to macular damage. Factors contributing to the dysregulation of age-related retinal parainflammation include genetic predisposition, environmental risk factors, and old age. Dysregulated parainflammation (chronic inflammation) in age-related macular degeneration damages the blood retina barrier, resulting in the breach of retinal-immune privilege, leading to the development of retinal lesions. This review discusses the basic principles of retinal innate-immune responses to endogenous chronic insults in normal aging and in age-related macular degeneration and explores the difference between beneficial parainflammation and the detrimental chronic inflammation in the context of age-related macular degeneration. PMID:26292978

  8. Immune Cells and Inflammation in Diabetic Nephropathy

    PubMed Central

    Zheng, Zihan; Zheng, Feng

    2016-01-01

    Diabetic nephropathy (DN) is a serious complication of diabetes. At its core, DN is a metabolic disorder which can also manifest itself in terms of local inflammation in the kidneys. Such inflammation can then drive the classical markers of fibrosis and structural remodeling. As a result, resolution of immune-mediated inflammation is critical towards achieving a cure for DN. Many immune cells play a part in DN, including key members of both the innate and adaptive immune systems. While these cells were classically understood to primarily function against pathogen insult, it has also become increasingly clear that they also serve a major role as internal sensors of damage. In fact, damage sensing may serve as the impetus for much of the inflammation that occurs in DN, in a vicious positive feedback cycle. Although direct targeting of these proinflammatory cells may be difficult, new approaches that focus on their metabolic profiles may be able to alleviate DN significantly, especially since dysregulation of the local metabolic environment may well be responsible for triggering inflammation to begin with. In this review, the authors consider the metabolic profile of several relevant immune types and discuss their respective roles. PMID:26824038

  9. Inflammation, immune activation, and cardiovascular disease in HIV.

    PubMed

    Nou, Eric; Lo, Janet; Grinspoon, Steven K

    2016-06-19

    Cardiovascular disease is one of the leading causes of morbidity and mortality in people living with HIV. Several epidemiological studies have shown an increased risk of myocardial infarction and stroke compared to uninfected controls. Although traditional risk factors contribute to this increased risk of cardiovascular disease, HIV-specific mechanisms likely also play a role. Systemic inflammation has been linked to cardiovascular disease in several populations suffering from chronic inflammation, including people living with HIV. Although antiretroviral therapy reduces immune activation, levels of inflammatory markers remain elevated compared to uninfected controls. The causes of this sustained immune response are likely multifactorial and incompletely understood. In this review, we summarize the evidence describing the relationship between inflammation and cardiovascular disease and discuss potential anti-inflammatory treatment options for cardiometabolic disease in people living with HIV. PMID:27058351

  10. Anemia of Inflammation and Chronic Disease

    MedlinePlus

    ... Disease Organizations (PDF, 270 KB). Alternate Language URL Anemia of Inflammation and Chronic Disease Page Content On ... Nutrition Points to Remember Clinical Trials What is anemia? Anemia is a condition in which a person ...

  11. Inflammation, immunity, and vaccines for Helicobacter pylori infection.

    PubMed

    Velin, Dominique; Straubinger, Kathrin; Gerhard, Markus

    2016-09-01

    The tight control of the innate and adaptive immune responses in the stomach mucosa during chronic Helicobacter pylori infection is of prime importance for the bacteria to persist and for the host to prevent inflammation-driven diseases. This review summarizes recent data on the roles of innate and adaptive immune responses during H. pylori/host interactions. In addition, the latest preclinical developments of H. pylori vaccines are discussed with a special focus on the clinical trial reported by Zeng et al., who provided evidence that oral vaccination significantly reduces the acquisition of natural H. pylori infection in children. PMID:27531535

  12. Can vitamin a mediate immunity and inflammation?

    PubMed

    Spinas, E; Saggini, A; Kritas, S K; Cerulli, G; Caraffa, A; Antinolfi, P; Pantalone, A; Frydas, A; Tei, M; Speziali, A; Saggini, R; Pandolfi, F; Conti, P

    2015-01-01

    Vitamins are natural components of foods and are organic compounds distinct from fat, carbohydrates and proteins. Vitamin A is the generic descriptor for compounds with the qualitative biological activity of retinol. Unlike beta-carotene, vitamin A is not an antioxidant and its benefit is related to possible boosting of immune reactions. The effect of vitamin A on immune function is wide-reaching and its deficiency appears to affect immunity in several ways. Innate and adaptive immune responses are affected in some way by lack of vitamin A. Retinoids seem to act on differentiation of lymphocytes, antibody production, phagocytosis of macrophages, NK, Treg, and T helper cell activity. In addition, in humans, signs of a vitamin A deficiency also include the dysregulation of cytokine/chemokine generation and release. However, excess of vitamin A has been demonstrated to have toxic effects in most species studied. Here we summarize some important effects of vitamin A in immunity and inflammation. PMID:25864736

  13. [Immune granulomatous inflammation as the body's adaptive response].

    PubMed

    Paukov, V S; Kogan, E A

    2014-01-01

    Based on their studies and literature analysis, the authors offer a hypothesis for the adaptive pattern of chronic immune granulomatous inflammation occurring in infectious diseases that are characterized by the development of non-sterile immunity. The authors' proposed hypothesis holds that not every chronic inflammation is a manifestation of failing defenses of the body exposed to a damaging factor. By using tuberculosis and leprosy as an example, the authors show the insolvency of a number of existing notions of the pathogenesis and morphogenesis of epithelioid-cell and leprous granulomas. Thus, the authors consider that resident macrophages in tuberculosis maintain their function to kill mycobacteria; thereby the immune system obtains information on the antigenic determinants of the causative agents. At the same time, by consuming all hydrolases to kill mycobacteria, the macrophage fails to elaborate new lysosomes for the capacity of the pathogens to prevent them from forming. As a result, the lysosome-depleted macrophage transforms into an epithelioid cell that, maintaining phagocytic functions, loses its ability to kill the causative agents. It is this epithelioid cell where endocytobiosis takes place. These microorganisms destroy the epithelioid cell and fall out in the area of caseating granuloma necrosis at regular intervals. Some of them phagocytize epithelioid cells to maintain non-sterile immunity; the others are killed by inflammatory macrophages. The pathogenesis and morphogenesis of leprous granuloma, its tuberculous type in particular, proceed in a fundamentally similar way. Thus, non-sterile immunity required for tuberculosis, leprosy, and, possibly, other mycobacterioses is maintained. PMID:25306624

  14. TLR2-independent induction and regulation of chronic intestinal inflammation.

    PubMed

    Boulard, Olivier; Asquith, Mark J; Powrie, Fiona; Maloy, Kevin J

    2010-02-01

    Interactions between the intestinal microflora and host innate immune receptors play a critical role in intestinal homeostasis. Several studies have shown that TLR2 can modulate inflammatory responses in the gut. TLR2 signals enhance tight junction formation and fortify the epithelial barrier, and may play a crucial role in driving acute inflammatory responses towards intestinal bacterial pathogens. In addition, TLR2 agonists can have direct effects on both Th1 cells and Treg. To define the role of TLR2 in the induction and regulation of chronic intestinal inflammation we examined the effects of TLR2 deletion on several complementary models of inflammatory bowel disease. Our results show that TLR2 signals are not required for the induction of chronic intestinal inflammation by either innate or adaptive immune responses. We further show that TLR2(-/-) mice harbor normal numbers of Foxp3(+) Treg that are able to suppress intestinal inflammation as effectively as their WT counterparts. We also did not find any intrinsic role for TLR2 for pathogenic effector T-cell responses in the gut. Thus, in contrast to their role in acute intestinal inflammation and repair, TLR2 signals may have a limited impact on the induction and regulation of chronic intestinal inflammation. PMID:19950179

  15. Chronic Inflammation and γδ T Cells.

    PubMed

    Fay, Nathan S; Larson, Emily C; Jameson, Julie M

    2016-01-01

    The epithelial tissues of the skin, lungs, reproductive tract, and intestines are the largest physical barriers the body has to protect against infection. Epithelial tissues are woven with a matrix of immune cells programed to mobilize the host innate and adaptive immune responses. Included among these immune cells are gamma delta T lymphocytes (γδ T cells) that are unique in their T cell receptor usage, location, and functions in the body. Stress reception by γδ T cells as a result of traumatic epithelial injury, malignancy, and/or infection induces γδ T cell activation. Once activated, γδ T cells function to repair tissue, induce inflammation, recruit leukocytes, and lyse cells. Many of these functions are mediated via the production of cytokines and growth factors upon γδ T cell activation. Pathogenesis of many chronic inflammatory diseases involves γδ T cells; some of which are exacerbated by their presence, while others are improved. γδ T cells require a delicate balance between their need for acute inflammatory mediators to function normally and the detrimental impact imparted by chronic inflammation. This review will focus on the recent progress made in understanding how epithelial γδ T cells influence the pathogenesis of chronic inflammatory diseases and how a balance between acute and chronic inflammation impacts γδ T cell function. Future studies will be important to understand how this balance is achieved. PMID:27303404

  16. Chronic Inflammation and γδ T Cells

    PubMed Central

    Fay, Nathan S.; Larson, Emily C.; Jameson, Julie M.

    2016-01-01

    The epithelial tissues of the skin, lungs, reproductive tract, and intestines are the largest physical barriers the body has to protect against infection. Epithelial tissues are woven with a matrix of immune cells programed to mobilize the host innate and adaptive immune responses. Included among these immune cells are gamma delta T lymphocytes (γδ T cells) that are unique in their T cell receptor usage, location, and functions in the body. Stress reception by γδ T cells as a result of traumatic epithelial injury, malignancy, and/or infection induces γδ T cell activation. Once activated, γδ T cells function to repair tissue, induce inflammation, recruit leukocytes, and lyse cells. Many of these functions are mediated via the production of cytokines and growth factors upon γδ T cell activation. Pathogenesis of many chronic inflammatory diseases involves γδ T cells; some of which are exacerbated by their presence, while others are improved. γδ T cells require a delicate balance between their need for acute inflammatory mediators to function normally and the detrimental impact imparted by chronic inflammation. This review will focus on the recent progress made in understanding how epithelial γδ T cells influence the pathogenesis of chronic inflammatory diseases and how a balance between acute and chronic inflammation impacts γδ T cell function. Future studies will be important to understand how this balance is achieved. PMID:27303404

  17. IL-17 is not essential for inflammation and chronic pelvic pain development in an experimental model of chronic prostatitis/chronic pelvic pain syndrome.

    PubMed

    Motrich, Ruben D; Breser, María L; Sánchez, Leonardo R; Godoy, Gloria J; Prinz, Immo; Rivero, Virginia E

    2016-03-01

    Pain and inflammation in the absence of infection are hallmarks in chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) patients. The etiology of CP/CPPS is unclear, and autoimmunity has been proposed as a cause. Experimental autoimmune prostatitis (EAP) models have long been used for studying CP/CPPS. Herein, we studied prostate inflammation induction and chronic pelvic pain development in EAP using IL-12p40-KO, IL-4-KO, IL-17-KO, and wild-type (C57BL/6) mice. Prostate antigen (PAg) immunization in C57BL/6 mice induced specific Th1 and Th17 immune responses and severe prostate inflammation and cell infiltration, mainly composed of CD4 T cells and macrophages. Moreover, chronic pelvic pain was evidenced by increased allodynia responses. In immunized IL-17-KO mice, the presence of a prominent PAg-specific Th1 immune response caused similar prostate inflammation and chronic pelvic pain. Furthermore, markedly high PAg-specific Th1 immune responses, exacerbated prostate inflammation, and chronic pelvic pain were detected in immunized IL-4-KO mice. Conversely, immunized IL-12p40-KO mice developed PAg-specific Th2 immune responses, characterized by high IL-4 secretion and neither infiltration nor damage in the prostate. As observed in wild-type control animals, IL12p40-KO mice did not evidence tactile allodynia responses. Our results suggest that, as in patients, chronic pelvic pain is a consequence of prostate inflammation. After PAg immunization, a Th1-associated immune response develops and induces prostate inflammation and chronic pelvic pain. The absence of Th1 or Th2 cytokines, respectively, diminishes or enhances EAP susceptibility. In addition, IL-17 showed not to be essential for pathology induction and chronic pelvic pain development. PMID:26882345

  18. Zinc and its role in immunity and inflammation.

    PubMed

    Bonaventura, Paola; Benedetti, Giulia; Albarède, Francis; Miossec, Pierre

    2015-04-01

    Zinc (Zn) nutritional importance has been known for a long time, but in the last decades its importance in immune modulation has arisen. This review aims at describing the mechanisms involved in the regulation of Zn homeostasis and their effects on the immune response focusing on those which are implicated in the physiopathology of rheumatoid arthritis. Zn functions as a modulator of the immune response through its availability, which is tightly regulated by several transporters and regulators. When this mechanism is disturbed, Zn availability is reduced, altering survival, proliferation and differentiation of the cells of different organs and systems and, in particular, cells of the immune system. Zn deficiency affects cells involved in both innate and adaptive immunity at the survival, proliferation and maturation levels. These cells include monocytes, polymorphonuclear-, natural killer-, T-, and B-cells. T cell functions and the balance between the different T helper cell subsets are particularly susceptible to changes in Zn status. While acute Zn deficiency causes a decrease in innate and adaptive immunity, chronic deficiency increases inflammation. During chronic deficiency, the production of pro-inflammatory cytokines increases, influencing the outcome of a large number of inflammatory diseases, including rheumatoid arthritis. PMID:25462582

  19. Environmental immune disruptors, inflammation and cancer risk

    PubMed Central

    Thompson, Patricia A.; Khatami, Mahin; Baglole, Carolyn J.; Sun, Jun; Harris, Shelley; Moon, Eun-Yi; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Brown, Dustin; Colacci, Annamaria; Mondello, Chiara; Raju, Jayadev; Ryan, Elizabeth; Woodrick, Jordan; Scovassi, Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Salem, Hosni K.; Amedei, Amedeo; Hamid, Roslida A.; Lowe, Leroy; Guarnieri, Tiziana

    2015-01-01

    An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented. PMID:26106141

  20. Environmental immune disruptors, inflammation and cancer risk.

    PubMed

    Thompson, Patricia A; Khatami, Mahin; Baglole, Carolyn J; Sun, Jun; Harris, Shelley A; Moon, Eun-Yi; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Brown, Dustin G; Colacci, Annamaria; Mondello, Chiara; Raju, Jayadev; Ryan, Elizabeth P; Woodrick, Jordan; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Salem, Hosni K; Amedei, Amedeo; Hamid, Roslida A; Lowe, Leroy; Guarnieri, Tiziana; Bisson, William H

    2015-06-01

    An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented. PMID:26106141

  1. CXCR2 inhibition suppresses acute and chronic pancreatic inflammation.

    PubMed

    Steele, Colin W; Karim, Saadia A; Foth, Mona; Rishi, Loveena; Leach, Joshua D G; Porter, Ross J; Nixon, Colin; Jeffry Evans, T R; Carter, C Ross; Nibbs, Robert J B; Sansom, Owen J; Morton, Jennifer P

    2015-09-01

    Pancreatitis is a significant clinical problem and the lack of effective therapeutic options means that treatment is often palliative rather than curative. A deeper understanding of the pathogenesis of both acute and chronic pancreatitis is necessary to develop new therapies. Pathological changes in pancreatitis are dependent on innate immune cell recruitment to the site of initial tissue damage, and on the coordination of downstream inflammatory pathways. The chemokine receptor CXCR2 drives neutrophil recruitment during inflammation, and to investigate its role in pancreatic inflammation, we induced acute and chronic pancreatitis in wild-type and Cxcr2(-/-) mice. Strikingly, Cxcr2(-/-) mice were strongly protected from tissue damage in models of acute pancreatitis, and this could be recapitulated by neutrophil depletion or by the specific deletion of Cxcr2 from myeloid cells. The pancreata of Cxcr2(-/-) mice were also substantially protected from damage during chronic pancreatitis. Neutrophil depletion was less effective in this model, suggesting that CXCR2 on non-neutrophils contributes to the development of chronic pancreatitis. Importantly, pharmacological inhibition of CXCR2 in wild-type mice replicated the protection seen in Cxcr2(-/-) mice in acute and chronic models of pancreatitis. Moreover, acute pancreatic inflammation was reversible by inhibition of CXCR2. Thus, CXCR2 is critically involved in the development of acute and chronic pancreatitis in mice, and its inhibition or loss protects against pancreatic damage. CXCR2 may therefore be a viable therapeutic target in the treatment of pancreatitis. PMID:25950520

  2. Fusobacterium nucleatum, inflammation, and immunity: the fire within human gut.

    PubMed

    Bashir, Arif; Miskeen, Abid Yousuf; Hazari, Younis Mohammad; Asrafuzzaman, Syed; Fazili, Khalid Majid

    2016-03-01

    Fusobacterium nucleatum is an identified proinflammatory autochthonous bacterium implicated in human colorectal cancer. It is also abundantly found in patients suffering from chronic gut inflammation (inflammatory bowel disease), consequently contributing to the pathogenesis of colorectal cancer. Majority of the studies have reported that colorectal tumors/colorectal adenocarcinomas are highly enriched with F. nucleatum compared to noninvolved adjacent colonic tissue. During the course of multistep development of colorectal cancer, tumors have evolved many mechanisms to resist the antitumor immune response. One of such favorite ploy is providing access to pathogenic bacteria, especially F. nucleatum in the colorectal tumor microenvironment, wherein both (colorectal tumors and F. nucleatum) exert profound effect on each other, consequently attracting tumor-permissive myeloid-derived suppressor cells, suppressing cytotoxic CD8+ T cells and inhibiting NK cell-mediated cancer cell killing. In this review, we have primarily focused on how this bug modulates the immune response, consequently rendering the antitumor immune cells inactive. PMID:26718210

  3. Clinical aspects of chronic ENT inflammation in children.

    PubMed

    Mansbach, A L; Brihaye, P; Casimir, G; Dhooghe, I; Gordts, F; Halewyck, S; Hanssens, L; Lemkens, N; Lemkens, P; Leupe, P; Mulier, S; Van Crombrugge, L; Van Der Veken, P; Van Hoecke, H

    2012-01-01

    In children, all ENT cavities are particularly prone to the development of chronic inflammation. This is due to many predisposing factors, of which the most common are unfavourable anatomy, absence of nasal blowing, day care attendance, allergy, immature immunity, gastro-oesophageal reflux and tobacco smoke exposure. The aim of this paper is to outline the most specific paediatric clinical aspects of chronic pharyngo-tonsillitis, rhinosinusitis, otitis media, adenoiditis and laryngotracheitis and the important influence that some of these pathologies exert on the others. PMID:23431613

  4. Heme on innate immunity and inflammation

    PubMed Central

    Dutra, Fabianno F.; Bozza, Marcelo T.

    2014-01-01

    Heme is an essential molecule expressed ubiquitously all through our tissues. Heme plays major functions in cellular physiology and metabolism as the prosthetic group of diverse proteins. Once released from cells and from hemeproteins free heme causes oxidative damage and inflammation, thus acting as a prototypic damage-associated molecular pattern. In this context, free heme is a critical component of the pathological process of sterile and infectious hemolytic conditions including malaria, hemolytic anemias, ischemia-reperfusion, and hemorrhage. The plasma scavenger proteins hemopexin and albumin reduce heme toxicity and are responsible for transporting free heme to intracellular compartments where it is catabolized by heme-oxygenase enzymes. Upon hemolysis or severe cellular damage the serum capacity to scavenge heme may saturate and increase free heme to sufficient amounts to cause tissue damage in various organs. The mechanism by which heme causes reactive oxygen generation, activation of cells of the innate immune system and cell death are not fully understood. Although heme can directly promote lipid peroxidation by its iron atom, heme can also induce reactive oxygen species generation and production of inflammatory mediators through the activation of selective signaling pathways. Heme activates innate immune cells such as macrophages and neutrophils through activation of innate immune receptors. The importance of these events has been demonstrated in infectious and non-infectious diseases models. In this review, we will discuss the mechanisms behind heme-induced cytotoxicity and inflammation and the consequences of these events on different tissues and diseases. PMID:24904418

  5. Current perspectives of molecular pathways involved in chronic inflammation-mediated breast cancer.

    PubMed

    Suman, Shankar; Sharma, Pradeep Kumar; Rai, Girish; Mishra, Sanjay; Arora, Deepika; Gupta, Prachi; Shukla, Yogeshwer

    2016-04-01

    Inflammation has multifaceted role in cancer progression including initiation, promotion and invasion by affecting the immune surveillance and associated signaling pathways. Inflammation facilitates the over-expression of cytokines, chemokines and growth factors involved in progression of different cancers including breast cancer progression. Deregulation of biological processes such as oxidative stress, angiogenesis, and autophagy elicit favorable immune response towards chronic inflammation. Apart from the role in carcinogenesis, chronic inflammation also favors the emergence of drug resistance clones by inducing the growth of breast cancer stem-like cells. Immunomodulation mediated by cytokines, chemokines and several other growth factors present in the tumor microenvironment regulate chronic inflammatory response and alter crosstalk among various signaling pathways such as NF-κB, Nrf-2, JAK-STAT, Akt and MAPKs involved in the progression of breast cancer. In this review, we focused on cellular and molecular processes involved in chronic inflammation, crosstalk among different signaling pathways and their association in breast cancer pathogenesis. PMID:26522220

  6. Therapeutics targeting persistent inflammation in chronic kidney disease.

    PubMed

    Machowska, Anna; Carrero, Juan Jesus; Lindholm, Bengt; Stenvinkel, Peter

    2016-01-01

    Systemic inflammation is a condition intrinsically linked to chronic kidney disease (CKD) and its other typical sequelae, such as acquired immune dysfunction, protein-energy wasting (PEW), and accelerated vascular aging that promote premature cardiovascular disease (CVD) and infections, the two leading causes of death in CKD patients. Inflammation is a major contributor to complications in CKD, and inflammatory markers, such as C-reactive protein and pro- and anti-inflammatory cytokines, correlate with underlying causes and consequences of the inflamed uremic phenotype, such as oxidative stress, endothelial dysfunction, CVD, PEW, and infections, and are sensitive and independent predictors of outcome in CKD. Therefore, inflammation appears to be a logical target for potential preventive and therapeutic interventions in patients with CKD. Putative anti-inflammatory therapy strategies aiming at preventing complications and improving outcomes in CKD span over several areas: (1) dealing with the source of inflammation (such as cardiovascular, gastrointestinal or periodontal disease and depression); (2) providing nonspecific immune modulatory effects by promoting healthy dietary habits and other lifestyle changes; (3) promoting increased use of recognized pharmacologic interventions that have pleiotropic effects; and, (4) introducing novel targeted anticytokine interventions. This review provides a brief update on inflammatory biomarkers and possible therapeutic approaches targeting inflammation and the uremic inflammatory milieu in patients with CKD. PMID:26173187

  7. Pathogenesis of chronic rhinosinusitis: inflammation.

    PubMed

    Van Crombruggen, Koen; Zhang, Nan; Gevaert, Philippe; Tomassen, Peter; Bachert, Claus

    2011-10-01

    Chronic rhinosinusitis (CRS) is a heterogeneous group of inflammatory diseases of the nasal and paranasal cavities either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP and CRSwNP are prevalent medical conditions associated with substantial impaired quality of life, reduced workplace productivity, and serious medical treatment costs. Despite recent research evidence that contributes to further unveiling the pathophysiology of these chronic airway conditions, the cause remains poorly understood and appears to be multifactorial. A diverse spectrum of alterations involving histopathology, inflammatory cell and T-cell patterns, remodeling parameters (eg, TGF-β), eicosanoid and IgE production, microorganisms, and epithelial barrier malfunctions is reported in the search to describe the pathogenesis of this heterogeneous group of upper airway diseases. Furthermore, novel evidence indicates considerable heterogeneity within the CRSwNP subgroup determining the risk of comorbid asthma. The characterization of specific disease subgroups is a challenging scientific and clinical task of utmost importance in the development of diagnostic tools and application of individualized treatments. This review focuses on recent evidence that sheds new light on our current knowledge regarding the inflammatory process of CRS to further unravel its pathogenesis. PMID:21868076

  8. Radiation, Inflammation, and Immune Responses in Cancer

    PubMed Central

    Multhoff, Gabriele; Radons, Jürgen

    2012-01-01

    Chronic inflammation has emerged as one of the hallmarks of cancer. Inflammation also plays a pivotal role in modulating radiation responsiveness of tumors. As discussed in this review, ionizing radiation (IR) leads to activation of several transcription factors modulating the expression of numerous mediators in tumor cells and cells of the microenvironment promoting cancer development. Novel therapeutic approaches thus aim to interfere with the activity or expression of these factors, either in single-agent or combinatorial treatment or as supplements of the existing therapeutic concepts. Among them, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. A great variety of classical or novel drugs including nutraceuticals such as plant phytochemicals have the capacity to interfere with the inflammatory network in cancer and are considered as putative radiosensitizers. Thus, targeting the inflammatory signaling pathways induced by IR offers the opportunity to improve the clinical outcome of radiation therapy by enhancing radiosensitivity and decreasing putative metabolic effects. Since inflammation and sex steroids also impact tumorigenesis, a therapeutic approach targeting glucocorticoid receptors and radiation-induced production of tumorigenic factors might be effective in sensitizing certain tumors to IR. PMID:22675673

  9. Neutrophils come of age in chronic inflammation

    PubMed Central

    Caielli, Simone; Banchereau, Jacques; Pascual, Virginia

    2013-01-01

    Neutrophils have long been known to participate in acute inflammation, but a role in chronic inflammatory and autoimmune diseases is now emerging. These cells are key players in the recognition and elimination of pathogens, but they also sense self components, including nucleic acids and products of sterile tissue damage. While this normally contributes to tissue repair, it can also lead to the release of highly immunogenic products that can trigger and/or amplify autoimmune pathogenic loops. Understanding the mechanisms that underlie neutrophil activation, migration, survival and their various forms of death in health and disease might provide us with new approaches to treat chronic inflammatory conditions. PMID:23127555

  10. Perspectives for Monocyte/Macrophage-Based Diagnostics of Chronic Inflammation

    PubMed Central

    Kzhyshkowska, Julia; Gudima, Alexandru; Moganti, Kondaiah; Gratchev, Alexei; Orekhov, Alexander

    2016-01-01

    Summary Low-grade chronic inflammation underlies the development of the most dangerous cardiometabolic disorders including type 2 diabetes and its vascular complications. In contrast to acute inflammation induced by bacteria and viruses, chronic inflammation can be driven by abnormal reaction to endogenous factors, including Th2 cytokines, metabolic factors like advanced glycation end products (AGEs), modified lipoproteins, or hyperglycemia. The key innate immune cells that recognize these factors in blood circulation are monocytes. Inflammatory programming of monocytes which migrate into tissues can, in turn, result into generation of tissue macrophages with pathological functions. Therefore, determination of the molecular and functional phenotype of circulating monocytes is a very promising diagnostic tool for the identification of hidden inflammation, which can precede the development of the pathology. Here we propose a new test system for the identification of inflammatory programming of monocytes: surface biomarkers and ex vivo functional system. We summarize the current knowledge about surface biomarkers for monocyte subsets, including CD16, CCR2, CX3CR1, CD64, stabilin-1 and CD36, and their association with inflammatory human disorders. Furthermore, we present the design of an ex vivo monocyte-based test system with minimal set of parameters as a potential diagnostic tool for the identification of personalized inflammatory responses. PMID:27226789

  11. Perspectives for Monocyte/Macrophage-Based Diagnostics of Chronic Inflammation.

    PubMed

    Kzhyshkowska, Julia; Gudima, Alexandru; Moganti, Kondaiah; Gratchev, Alexei; Orekhov, Alexander

    2016-03-01

    Low-grade chronic inflammation underlies the development of the most dangerous cardiometabolic disorders including type 2 diabetes and its vascular complications. In contrast to acute inflammation induced by bacteria and viruses, chronic inflammation can be driven by abnormal reaction to endogenous factors, including Th2 cytokines, metabolic factors like advanced glycation end products (AGEs), modified lipoproteins, or hyperglycemia. The key innate immune cells that recognize these factors in blood circulation are monocytes. Inflammatory programming of monocytes which migrate into tissues can, in turn, result into generation of tissue macrophages with pathological functions. Therefore, determination of the molecular and functional phenotype of circulating monocytes is a very promising diagnostic tool for the identification of hidden inflammation, which can precede the development of the pathology. Here we propose a new test system for the identification of inflammatory programming of monocytes: surface biomarkers and ex vivo functional system. We summarize the current knowledge about surface biomarkers for monocyte subsets, including CD16, CCR2, CX3CR1, CD64, stabilin-1 and CD36, and their association with inflammatory human disorders. Furthermore, we present the design of an ex vivo monocyte-based test system with minimal set of parameters as a potential diagnostic tool for the identification of personalized inflammatory responses. PMID:27226789

  12. Role of Histomorphology and Chronic Inflammation Score in Chronic Dacryocystitis

    PubMed Central

    Chakrabarti, Sudipta; Banerjee, Manas; Pal, Debashis

    2016-01-01

    Introduction Diseases of lacrimal drainage system account for nearly 3% of visits to eye clinic. Chronic dacryocystitis is a frequently encountered disorder among these patients. Histomorphology of specimens obtained after Dacryocystorhinostomy (DCR) is a pertinent indicator of prognostic outcome. Aim The aim of the study was to evaluate histopathology of specimens obtained after DCR and to elucidate patterns and score of chronic inflammation encountered. Materials and Methods The study was conducted for a period of one year. Total of 50 patients who were clinically diagnosed as Chronic Dacryocystitis and underwent DCR were included. Following DCR, specimens of lacrimal sac, nasal mucous membrane and nasal bone were collected. Histopathological slides were examined for chronic inflammatory cell infiltration, fibrosis and capillary proliferation and were graded according to severity, in each specimen. A Chronic Inflammation Score (CIS) was recorded for each case. Results The average age of patients was 39.04±14.22 years and their age ranged between 13 and 62 years. There were 28 (56%) females and 22 (44%) males in the study group. The nasal bone did not reveal any abnormality in any case. The nasal mucous membrane showed mild chronic inflammatory cell infiltration in 46 (92%) cases and moderate degree in 4 (8%) patients. Chronic inflammation with granulation tissue formation was noted in lacrimal sacs of all patients. The CIS revealed that 14 (28%) cases belonged to “mild” group, 26 (52%) to “moderate” group and 10 (20%) to “severe” category. Conclusion The inclusion of CIS in histomorphological evaluation of DCR specimens is recommended since it is one of the parameters that influence course of the disease.

  13. Immunity, inflammation, and cancer: an eternal fight between good and evil.

    PubMed

    Shalapour, Shabnam; Karin, Michael

    2015-09-01

    Cancer development and its response to therapy are strongly influenced by innate and adaptive immunity, which either promote or attenuate tumorigenesis and can have opposing effects on therapeutic outcome. Chronic inflammation promotes tumor development, progression, and metastatic dissemination, as well as treatment resistance. However, cancer development and malignant progression are also associated with accumulation of genetic alterations and loss of normal regulatory processes, which cause expression of tumor-specific antigens and tumor-associated antigens (TAAs) that can activate antitumor immune responses. Although signals that trigger acute inflammatory reactions often stimulate dendritic cell maturation and antigen presentation, chronic inflammation can be immunosuppressive. This antagonism between inflammation and immunity also affects the outcome of cancer treatment and needs to be considered when designing new therapeutic approaches. PMID:26325032

  14. Chronic Thromboembolic Pulmonary Hypertension Associated with Chronic Inflammation.

    PubMed

    Kuse, Naoyuki; Abe, Shinji; Kuribayashi, Hidehiko; Fukuda, Asami; Kusunoki, Yuji; Narato, Ritsuko; Saito, Hitoshi; Gemma, Akihiko

    2016-01-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the leading causes of severe pulmonary hypertension. According to previously reported studies in the pertinent literature, chronic inflammatory conditions may be implicated in the development of CTEPH. We herein describe the case of a 56-year-old woman who was diagnosed with CTEPH in association with chronic infection. The patient had experienced five episodes of pneumonia in the five years prior to the diagnosis of CTEPH. Blood tests from the previous five years of outpatient follow-up demonstrated that the C-reactive protein level was slightly elevated. This case suggests that a relationship exists between chronic inflammation and CTEPH, and furthermore, may contribute towards elucidating the pathophysiology of CTEPH. PMID:27250055

  15. The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

    PubMed Central

    Huang, Zhi; Rose, Aaron H.

    2012-01-01

    Abstract Dietary selenium (]Se), mainly through its incorporation into selenoproteins, plays an important role in inflammation and immunity. Adequate levels of Se are important for initiating immunity, but they are also involved in regulating excessive immune responses and chronic inflammation. Evidence has emerged regarding roles for individual selenoproteins in regulating inflammation and immunity, and this has provided important insight into mechanisms by which Se influences these processes. Se deficiency has long been recognized to negatively impact immune cells during activation, differentiation, and proliferation. This is related to increased oxidative stress, but additional functions such as protein folding and calcium flux may also be impaired in immune cells under Se deficient conditions. Supplementing diets with above-adequate levels of Se can also impinge on immune cell function, with some types of inflammation and immunity particularly affected and sexually dimorphic effects of Se levels in some cases. In this comprehensivearticle, the roles of Se and individual selenoproteins in regulating immune cell signaling and function are discussed. Particular emphasis is given to how Se and selenoproteins are linked to redox signaling, oxidative burst, calcium flux, and the subsequent effector functions of immune cells. Data obtained from cell culture and animal models are reviewed and compared with those involving human physiology and pathophysiology, including the effects of Se levels on inflammatory or immune-related diseases including anti-viral immunity, autoimmunity, sepsis, allergic asthma, and chronic inflammatory disorders. Finally, the benefits and potential adverse effects of intervention with Se supplementation for various inflammatory or immune disorders are discussed. Antioxid. Redox Signal. 16, 705–743. PMID:21955027

  16. The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury.

    PubMed

    Schwab, Jan M; Zhang, Yi; Kopp, Marcel A; Brommer, Benedikt; Popovich, Phillip G

    2014-08-01

    During the transition from acute to chronic stages of recovery after spinal cord injury (SCI), there is an evolving state of immunologic dysfunction that exacerbates the problems associated with the more clinically obvious neurologic deficits. Since injury directly affects cells embedded within the "immune privileged/specialized" milieu of the spinal cord, maladaptive or inefficient responses are likely to occur. Collectively, these responses qualify as part of the continuum of "SCI disease" and are important therapeutic targets to improve neural repair and neurological outcome. Generic immune suppressive therapies have been largely unsuccessful, mostly because inflammation and immunity exert both beneficial (plasticity enhancing) and detrimental (e.g. glia- and neurodegenerative; secondary damage) effects and these functions change over time. Moreover, "compartimentalized" investigations, limited to only intraspinal inflammation and associated cellular or molecular changes in the spinal cord, neglect the reality that the structure and function of the CNS are influenced by systemic immune challenges and that the immune system is 'hardwired' into the nervous system. Here, we consider this interplay during the progression from acute to chronic SCI. Specifically, we survey impaired/non-resolving intraspinal inflammation and the paradox of systemic inflammatory responses in the context of ongoing chronic immune suppression and autoimmunity. The concepts of systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS) and "neurogenic" spinal cord injury-induced immune depression syndrome (SCI-IDS) are discussed as determinants of impaired "host-defense" and trauma-induced autoimmunity. PMID:25017893

  17. Chronic Lymphocytic Inflammation Specifies the Organ Tropism of Prions

    NASA Astrophysics Data System (ADS)

    Heikenwalder, Mathias; Zeller, Nicolas; Seeger, Harald; Prinz, Marco; Klöhn, Peter-Christian; Schwarz, Petra; Ruddle, Nancy H.; Weissmann, Charles; Aguzzi, Adriano

    2005-02-01

    Prions typically accumulate in nervous and lymphoid tissues. Because proinflammatory cytokines and immune cells are required for lymphoid prion replication, we tested whether inflammatory conditions affect prion pathogenesis. We administered prions to mice with five inflammatory diseases of the kidney, pancreas, or liver. In all cases, chronic lymphocytic inflammation enabled prion accumulation in otherwise prion-free organs. Inflammatory foci consistently correlated with lymphotoxin up-regulation and ectopic induction of FDC-M1+ cells expressing the normal cellular prion protein PrPC. By contrast, inflamed organs of mice lacking lymphotoxin-α or its receptor did not accumulate the abnormal isoform PrPSc, nor did they display infectivity upon prion inoculation. By expanding the tissue distribution of prions, chronic inflammatory conditions may act as modifiers of natural and iatrogenic prion transmission.

  18. Lymphatic Vessels, Inflammation, and Immunity in Skin Cancer

    PubMed Central

    Lund, Amanda W.; Medler, Terry R.; Leachman, Sancy A.; Coussens, Lisa M.

    2015-01-01

    Skin is a highly ordered immune organ that coordinates rapid responses to external insult while maintaining self-tolerance. In healthy tissue, lymphatic vessels drain fluid and coordinate local immune responses; however, environmental factors induce lymphatic vessel dysfunction, leading to lymph stasis and perturbed regional immunity. These same environmental factors drive the formation of local malignancies, which are also influenced by local inflammation. Herein, we discuss clinical and experimental evidence supporting the tenet that lymphatic vessels participate in regulation of cutaneous inflammation and immunity, are important contributors to malignancy and potential biomarkers and targets for immunotherapy. PMID:26552413

  19. Physical Activity Protects the Human Brain against Metabolic Stress Induced by a Postprandial and Chronic Inflammation

    PubMed Central

    Pruimboom, Leo; Raison, Charles L.; Muskiet, Frits A. J.

    2015-01-01

    In recent years, it has become clear that chronic systemic low-grade inflammation is at the root of many, if not all, typically Western diseases associated with the metabolic syndrome. While much focus has been given to sedentary lifestyle as a cause of chronic inflammation, it is less often appreciated that chronic inflammation may also promote a sedentary lifestyle, which in turn causes chronic inflammation. Given that even minor increases in chronic inflammation reduce brain volume in otherwise healthy individuals, the bidirectional relationship between inflammation and sedentary behaviour may explain why humans have lost brain volume in the last 30,000 years and also intelligence in the last 30 years. We review evidence that lack of physical activity induces chronic low-grade inflammation and, consequently, an energy conflict between the selfish immune system and the selfish brain. Although the notion that increased physical activity would improve health in the modern world is widespread, here we provide a novel perspective on this truism by providing evidence that recovery of normal human behaviour, such as spontaneous physical activity, would calm proinflammatory activity, thereby allocating more energy to the brain and other organs, and by doing so would improve human health. PMID:26074674

  20. HIV-associated chronic immune activation

    PubMed Central

    Paiardini, Mirko; Müller-Trutwin, Michaela

    2013-01-01

    Summary Systemic chronic immune activation is considered today as the driving force of CD4+ T-cell depletion and acquired immunodeficiency syndrome (AIDS). A residual chronic immune activation persists even in HIV-infected patients in which viral replication is successfully inhibited by antiretroviral therapy, with the extent of this residual immune activation being associated with CD4+ T-cell loss. Unfortunately, the causal link between chronic immune activation and CD4+ T-cell loss has not been formally established. This article provides first a brief historical overview on how the perception of the causative role of immune activation has changed over the years and lists the different kinds of immune activation that have been observed to be characteristic for human immunodeficiency virus (HIV) infection. The mechanisms proposed to explain the chronic immune activation are multiple and are enumerated here, as well as the mechanisms proposed on how chronic immune activation could lead to AIDS. In addition, we summarize the lessons learned from natural hosts that know how to ‘show AIDS the door’, and discuss how these studies informed the design of novel immune modulatory interventions that are currently being tested. Finally, we review the current approaches aimed at targeting chronic immune activation and evoke future perspectives. PMID:23772616

  1. Microvascular remodelling in chronic airway inflammation in mice.

    PubMed

    Thurston, G; Maas, K; Labarbara, A; Mclean, J W; McDonald, D M

    2000-10-01

    1. Chronic inflammation is associated with blood vessel remodelling, including vessel proliferation and enlargement, and changes in vessel phenotype. We sought to characterize these changes in chronic airway inflammation and to determine whether corticosteroids that inhibit inflammation, such as dexamethasone, can also reduce microvascular remodelling. 2. Chronic airway inflammation was induced in C3H mice by infection with Mycoplasmapulmonis and the tracheal vessels treatment also decreased the immunoreactivity for P-selectin and the number of adherent leucocytes (595 +/- 203 vs 2,024 +/- 393 cells/ mm2 in treated and non-treated infected mice, respectively). 6. We conclude that microvascular enlargement and changes in vessel phenotype are features of some types of chronic inflammation and, furthermore, that dexamethasone reverses the microvascular enlargement, changes in vessel phenotype and leucocyte influx associated with chronic inflammatory airway disease. PMID:11022979

  2. Gut inflammation in chronic fatigue syndrome.

    PubMed

    Lakhan, Shaheen E; Kirchgessner, Annette

    2010-01-01

    Chronic fatigue syndrome (CFS) is a debilitating disease characterized by unexplained disabling fatigue and a combination of accompanying symptoms the pathology of which is incompletely understood. Many CFS patients complain of gut dysfunction. In fact, patients with CFS are more likely to report a previous diagnosis of irritable bowel syndrome (IBS), a common functional disorder of the gut, and experience IBS-related symptoms. Recently, evidence for interactions between the intestinal microbiota, mucosal barrier function, and the immune system have been shown to play a role in the disorder's pathogenesis.Studies examining the microecology of the gastrointestinal (GI) tract have identified specific microorganisms whose presence appears related to disease; in CFS, a role for altered intestinal microbiota in the pathogenesis of the disease has recently been suggested. Mucosal barrier dysfunction promoting bacterial translocation has also been observed. Finally, an altered mucosal immune system has been associated with the disease. In this article, we discuss the interplay between these factors in CFS and how they could play a significant role in GI dysfunction by modulating the activity of the enteric nervous system, the intrinsic innervation of the gut.If an altered intestinal microbiota, mucosal barrier dysfunction, and aberrant intestinal immunity contribute to the pathogenesis of CFS, therapeutic efforts to modify gut microbiota could be a means to modulate the development and/or progression of this disorder. For example, the administration of probiotics could alter the gut microbiota, improve mucosal barrier function, decrease pro-inflammatory cytokines, and have the potential to positively influence mood in patients where both emotional symptoms and inflammatory immune signals are elevated. Probiotics also have the potential to improve gut motility, which is dysfunctional in many CFS patients. PMID:20939923

  3. Gut hormones: emerging role in immune activation and inflammation.

    PubMed

    Khan, W I; Ghia, J E

    2010-07-01

    Gut inflammation is characterized by mucosal recruitment of activated cells from both the innate and adaptive immune systems. In addition to immune cells, inflammation in the gut is associated with an alteration in enteric endocrine cells and various biologically active compounds produced by these cells. Although the change in enteric endocrine cells or their products is considered to be important in regulating gut physiology (motility and secretion), it is not clear whether the change plays any role in immune activation and in the regulation of gut inflammation. Due to the strategic location of enteric endocrine cells in gut mucosa, these gut hormones may play an important role in immune activation and promotion of inflammation in the gut. This review addresses the research on the interface between immune and endocrine systems in gastrointestinal (GI) pathophysiology, specifically in the context of two major products of enteric endocrine systems, namely serotonin (5-hydroxytryptamine: 5-HT) and chromogranins (Cgs), in relation to immune activation and generation of inflammation. The studies reviewed in this paper demonstrate that 5-HT activates the immune cells to produce proinflammatory mediators and by manipulating the 5-HT system it is possible to modulate gut inflammation. In the case of Cgs the scenario is more complex, as this hormone has been shown to play both proinflammatory and anti-inflammatory functions. It is also possible that interaction between 5-HT and Cgs may play a role in the modulation of immune and inflammatory responses. In addition to enhancing our understanding of immunoendocrine interaction in the gut, the data generated from the these studies may have implications in understanding the role of gut hormone in the pathogenesis of both GI and non-GI inflammatory diseases which may lead ultimately to improved therapeutic strategies in inflammatory disorders. PMID:20408856

  4. The immune system and inflammation in breast cancer

    PubMed Central

    Jiang, Xinguo; Shapiro, David J.

    2016-01-01

    During different stages of tumor development the immune system can either identify and destroy tumors, or promote their growth. Therapies targeting the immune system have emerged as a promising treatment modality for breast cancer, and immunotherapeutic strategies are being examined in preclinical and clinical models. However, our understanding of the complex interplay between cells of the immune system and breast cancer cells is incomplete. In this article, we review recent findings showing how the immune system plays dual host-protective and tumor-promoting roles in breast cancer initiation and progression. We then discuss estrogen receptor α (ERα)-dependent and ERα-independent mechanisms that shield breast cancers from immunosurveillance and enable breast cancer cells to evade immune cell induced apoptosis and produce an immunosuppressive tumor microenvironment. Finally, we discuss protumorigenic inflammation that is induced during tumor progression and therapy, and how inflammation promotes more aggressive phenotypes in ERα positive breast cancers. PMID:23791814

  5. Bioactive lipids as modulators of immunity, inflammation and emotions.

    PubMed

    Chiurchiù, Valerio; Maccarrone, Mauro

    2016-08-01

    Lipids are not only constituents of cellular membranes but also key signaling mediators, thus acting as 'bioactive lipids'. Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation and maintenance of homeostasis. Accumulated evidence indicates the existence of a bidirectional relationship between immune and nervous systems, whereby inflammatory mediators can directly modulate emotions that, in turn, can strongly influence immune responses, thus affecting health. This review summarizes current knowledge on the ability of several families of bioactive lipids to regulate immunity and inflammation (through pro-inflammatory or anti-inflammatory effects), as well as to control emotions and mood-related manifestations, advocating these substances as an attractive interface between 'mind' and 'body', and as a potential target to treat inflammatory/immune-mediated mood disorders. PMID:27372887

  6. Chronic Inflammation-Related HPV: A Driving Force Speeds Oropharyngeal Carcinogenesis

    PubMed Central

    Liu, Xin; Ma, Xiangrui; Lei, Zhengge; Feng, Hao; Wang, Shasha; Cen, Xiao; Gao, Shiyu; Jiang, Yaping; Jiang, Jian; Chen, Qianming; Tang, Yajie; Tang, Yaling; Liang, Xinhua

    2015-01-01

    Oropharyngeal squamous cell carcinoma (OPSCC) has been known to be a highly aggressive disease associated with human papilloma virus (HPV) infection. To investigate the relationship between HPV and chronic inflammation in oropharyngeal carcinogenesis, we collected 140 oral mucous fresh specimens including 50 OPSCC patients, 50 cancer in situ, 30 precancerous lesions, and 10 normal oral mucous. Our data demonstrated that there was a significantly higher proportion of severe chronic inflammation in dysplastic epithelia in comparison with that in normal tissues (P<0.001). The positive rate of HPV 16 was parallel with the chronic inflammation degrees from mild to severe inflammation (P<0.05). The positive rate of HPV 16 was progressively improved with the malignant progression of oral mucous (P<0.05). In addition, CD11b+ LIN- HLA-DR-CD33+ MDSCs were a critical cell population that mediates inflammation response and immune suppression in HPV-positive OPSCC. These indicated that persistent chronic inflammation-related HPV infection might drive oropharyngeal carcinogenesis and MDSCs might pay an important role during this process. Thus, a combination of HPV infection and inflammation expression might become a helpful biomedical marker to predict oropharyngeal carcinogenesis. PMID:26193368

  7. Effects of exercise training on chronic inflammation in obesity : current evidence and potential mechanisms.

    PubMed

    You, Tongjian; Arsenis, Nicole C; Disanzo, Beth L; Lamonte, Michael J

    2013-04-01

    Chronic, systemic inflammation is an independent risk factor for several major clinical diseases. In obesity, circulating levels of inflammatory markers are elevated, possibly due to increased production of pro-inflammatory cytokines from several tissues/cells, including macrophages within adipose tissue, vascular endothelial cells and peripheral blood mononuclear cells. Recent evidence supports that adipose tissue hypoxia may be an important mechanism through which enlarged adipose tissue elicits local tissue inflammation and further contributes to systemic inflammation. Current evidence supports that exercise training, such as aerobic and resistance exercise, reduces chronic inflammation, especially in obese individuals with high levels of inflammatory biomarkers undergoing a longer-term intervention. Several studies have reported that this effect is independent of the exercise-induced weight loss. There are several mechanisms through which exercise training reduces chronic inflammation, including its effect on muscle tissue to generate muscle-derived, anti-inflammatory 'myokine', its effect on adipose tissue to improve hypoxia and reduce local adipose tissue inflammation, its effect on endothelial cells to reduce leukocyte adhesion and cytokine production systemically, and its effect on the immune system to lower the number of pro-inflammatory cells and reduce pro-inflammatory cytokine production per cell. Of these potential mechanisms, the effect of exercise training on adipose tissue oxygenation is worth further investigation, as it is very likely that exercise training stimulates adipose tissue angiogenesis and increases blood flow, thereby reducing hypoxia and the associated chronic inflammation in adipose tissue of obese individuals. PMID:23494259

  8. Age-Related Macular Degeneration in the Aspect of Chronic Low-Grade Inflammation (Pathophysiological ParaInflammation)

    PubMed Central

    Nita, Małgorzata; Ascaso, Francisco J.; Huerva, Valentín

    2014-01-01

    The products of oxidative stress trigger chronic low-grade inflammation (pathophysiological parainflammation) process in AMD patients. In early AMD, soft drusen contain many mediators of chronic low-grade inflammation such as C-reactive protein, adducts of the carboxyethylpyrrole protein, immunoglobulins, and acute phase molecules, as well as the complement-related proteins C3a, C5a, C5, C5b-9, CFH, CD35, and CD46. The complement system, mainly alternative pathway, mediates chronic autologous pathophysiological parainflammation in dry and exudative AMD, especially in the Y402H gene polymorphism, which causes hypofunction/lack of the protective complement factor H (CFH) and facilitates chronic inflammation mediated by C-reactive protein (CRP). Microglial activation induces photoreceptor cells injury and leads to the development of dry AMD. Many autoantibodies (antibodies against alpha beta crystallin, alpha-actinin, amyloid, C1q, chondroitin, collagen I, collagen III, collagen IV, elastin, fibronectin, heparan sulfate, histone H2A, histone H2B, hyaluronic acid, laminin, proteoglycan, vimentin, vitronectin, and aldolase C and pyruvate kinase M2) and overexpression of Fcc receptors play role in immune-mediated inflammation in AMD patients and in animal model. Macrophages infiltration of retinal/choroidal interface acts as protective factor in early AMD (M2 phenotype macrophages); however it acts as proinflammatory and proangiogenic factor in advanced AMD (M1 and M2 phenotype macrophages). PMID:25214719

  9. Innate Immune Responses to Engineered Nanomaterials During Allergic Airway Inflammation

    NASA Astrophysics Data System (ADS)

    Shipkowski, Kelly Anne

    The field of nanotechnology is continually advancing, and increasing amounts of consumer goods are being produced using engineered nanomaterials (ENMs). The health risks of occupational and/or consumer exposure to ENMs are not completely understood, although significant research indicates that pulmonary exposure to nanomaterials induces toxic effects in the lungs of exposed animals. Multi-walled carbon nanotubes (MWCNTs) are a specific category of ENMs and consist of sheets of graphene rolled into cylinders that are multiple layers thick in order to strengthen their rigidity. MWCNTs have a fiber-like shape, similar to that of asbestos, which allows for a high aspect ratio and makes them difficult to clear from the lung. Studies with rodent models have demonstrated that pulmonary exposure to ENMs, in particular MWCNTs, results in acute lung inflammation and the subsequent development of chronic fibrosis, suggesting a potential human health risk to individuals involved in the manufacturing of products utilizing these nanomaterials. Induction of IL-1beta secretion via activation of the inflammasome is a prime mechanism of MWCNT-induced inflammation. The inflammasome is a multi-protein scaffold found in a variety of cell types that forms in response to a variety of immune signals, including particulates. Sensitization with allergens, such as house dust mite (HDM), increases levels of the T helper 2 (Th2) cytokines IL-4 and IL-13 in mice and in humans, and there is particular cause for concern in cases of MWCNT exposure in individuals with pre-existing allergic airway disease, such as asthma. MWCNT exposure exacerbates airway inflammation and fibrosis in animal models of pre-existing allergic asthma, suggesting that individuals suffering from asthma are more susceptible to the toxic pulmonary effects of MWCNT exposure. Asthma is an exceptionally prominent human disease, and therefore the goal of this research was to better understand how pre-existing allergic airway

  10. Aging, inflammation, immunity and periodontal disease.

    PubMed

    Ebersole, Jeffrey L; Graves, Christina L; Gonzalez, Octavio A; Dawson, Dolph; Morford, Lorri A; Huja, Pinar Emecen; Hartsfield, James K; Huja, Sarandeep S; Pandruvada, Subramanya; Wallet, Shannon M

    2016-10-01

    The increased prevalence and severity of periodontal disease have long been associated with aging, such that this oral condition affects the majority of the adult population over 50 years of age. Although the immune system is a critical component for maintaining health, aging can be characterized by quantitative and qualitative modifications of the immune system. This process, termed 'immunosenescence', is a progressive modification of the immune system that leads to greater susceptibility to infections, neoplasia and autoimmunity, presumably reflecting the prolonged antigenic stimulation and/or stress responses that occur across the lifespan. Interestingly, the global reduction in the host capability to respond effectively to these challenges is coupled with a progressive increase in the general proinflammatory status, termed 'inflammaging'. Consistent with the definition of immunosenescence, it has been suggested that the cumulative effect of prolonged exposure of the periodontium to microbial challenge is, at least in part, a contributor to the effects of aging on these tissues. Thus, it has also been hypothesized that alterations in the function of resident immune and nonimmune cells of the periodontium contribute to the expression of inflammaging in periodontal disease. Although the majority of aging research has focused on the adaptive immune response, it is becoming increasingly clear that the innate immune compartment is also highly affected by aging. Thus, the phenomenon of immunosenescence and inflammaging, expressed as age-associated changes within the periodontium, needs to be more fully understood in this era of precision and personalized medicine and dentistry. PMID:27501491

  11. Distinct roles of prostaglandin D2 receptors in chronic skin inflammation.

    PubMed

    Matsushima, Yuki; Satoh, Takahiro; Yamamoto, Yoshihiro; Nakamura, Masataka; Yokozeki, Hiroo

    2011-10-01

    Prostaglandin D2 (PGD2) is a prostanoid implicated in allergic inflammation. However, the roles of PGD2 in immune and allergic responses remain controversial. PGD2 exerts its effect through the CRTH2 and DP receptors. To elucidate functional differences of PGD2 and its receptors in chronic skin inflammation, chronic contact hypersensitivity (chronic CHS) and IgE-mediated chronic allergic skin inflammation (IgE-CAI) were induced in mice deficient in the CRTH2 and/or DP genes. DP (-/-) mice and CRTH2 (-/-)/DP (-/-) mice showed exacerbated chronic CHS, and conversely, CRTH2 (-/-) mice exhibited diminished skin responses. Skin responses correlated with local levels of IL-13, CCL11, and CCL22. These phenotypic changes in chronic CHS of mutant mice were similar to those in acute CHS despite the differences in the cytokine milieus; chronic CHS and acute CHS were mediated by Th2 and Th1/Th17 immunity, respectively. However, in IgE-CAI, DP (-/-) mice showed comparable skin responses to wild-type mice. Alleviation of IgE-CAI was observed in CRTH2 (-/-) mice, and as a consequence, CRTH2 (-/-)/DP (-/-) mice exhibited diminished IgE-CAI compared with wild-type mice. IgE-CAI in mutant mice correlated with local IL-4 and CCL22 production. Consistent with these results, a CRTH2-specific antagonist exerted inhibitory effects in both chronic CHS and IgE-CAI. The present study demonstrates that functional roles of PGD2 and its receptors appear to depend on the nature of the inflammation. Nevertheless, tools targeted against PGD2-CRTH2 signals could offer therapeutic potential for both types of chronic skin inflammation. PMID:21943706

  12. Multiple sclerosis and fatigue: A review on the contribution of inflammation and immune-mediated neurodegeneration.

    PubMed

    Patejdl, Robert; Penner, Iris K; Noack, Thomas K; Zettl, Uwe K

    2016-03-01

    Multiple sclerosis (MS) is an immune mediated disease of the central nervous system (CNS) and the leading cause of non-traumatic disability among young and middle-aged adults in the western world. One of its most prevalent and debilitating symptoms is fatigue. Despite the general acceptance of the idea of an immune pathogenesis of MS itself, the role of autoimmunity in the course of MS-fatigue is a matter of debate. Both immune-related processes (acute inflammation, chronic inflammation, immune-mediated neurodegeneration, immune-mediated alterations of endocrine functions related to fatigue) and presumably non-immune-mediated disturbances and factors (sleep disturbances, depression, cognitive alterations, chronic infections, adverse effects of medications) contribute to the clinical picture. Data from in vitro and animal experiments has provided evidence for a role of cytokines as IL-1 and TNF-alpha. This association could not be verified directly in blood samples from humans whereas whole blood stimulation protocols gave some indirect evidence for a role of cytokines in MS-fatigue. MRI being able to detect acute and chronic immune mediated damage to the CNS could depict that global atrophy of gray or white matter does not correlate with fatigue. Rather, distinctive clusters of lesions and atrophy at different locations, mostly bifrontal or in subcortical structures, correlate specifically with fatigue. Regardless of the difficulties in pinpointing the immunogenesis of MS-fatigue, an important role of autoimmunity is strongly supported by an indirect route: A growing amount of data shows that the highly effective immunotherapeutics which have been introduced to MS-treatment over the last years effectively and sustainably stabilize and ameliorate fatigue in parallel to their dampening effects on the neuroinflammatory process. This review summarizes the existing data on the relation between inflammation, patterns of CNS-lesions and the effects of immunotherapeutics

  13. Cigarette smoke exposure exacerbates lung inflammation and compromises immunity to bacterial infection.

    PubMed

    Lugade, Amit A; Bogner, Paul N; Thatcher, Thomas H; Sime, Patricia J; Phipps, Richard P; Thanavala, Yasmin

    2014-06-01

    The detrimental impact of tobacco on human health is clearly recognized, and despite aggressive efforts to prevent smoking, close to one billion individuals worldwide continue to smoke. People with chronic obstructive pulmonary disease are susceptible to recurrent respiratory infections with pathogens, including nontypeable Haemophilus influenzae (NTHI), yet the reasons for this increased susceptibility are poorly understood. Because mortality rapidly increases with multiple exacerbations, development of protective immunity is critical to improving patient survival. Acute NTHI infection has been studied in the context of cigarette smoke exposure, but this is the first study, to our knowledge, to investigate chronic infection and the generation of adaptive immune responses to NTHI after chronic smoke exposure. After chronic NTHI infection, mice that had previously been exposed to cigarette smoke developed increased lung inflammation and compromised adaptive immunity relative to air-exposed controls. Importantly, NTHI-specific T cells from mice exposed to cigarette smoke produced lower levels of IFN-γ and IL-4, and B cells produced reduced levels of Abs against outer-membrane lipoprotein P6, with impaired IgG1, IgG2a, and IgA class switching. However, production of IL-17, which is associated with neutrophilic inflammation, was enhanced. Interestingly, cigarette smoke-exposed mice exhibited a similar defect in the generation of adaptive immunity after immunization with P6. Our study has conclusively demonstrated that cigarette smoke exposure has a profound suppressive effect on the generation of adaptive immune responses to NTHI and suggests the mechanism by which prior cigarette smoke exposure predisposes chronic obstructive pulmonary disease patients to recurrent infections, leading to exacerbations and contributing to mortality. PMID:24752444

  14. The Immune System in Tissue Environments Regaining Homeostasis after Injury: Is "Inflammation" Always Inflammation?

    PubMed

    Kulkarni, Onkar P; Lichtnekert, Julia; Anders, Hans-Joachim; Mulay, Shrikant R

    2016-01-01

    Inflammation is a response to infections or tissue injuries. Inflammation was once defined by clinical signs, later by the presence of leukocytes, and nowadays by expression of "proinflammatory" cytokines and chemokines. But leukocytes and cytokines often have rather anti-inflammatory, proregenerative, and homeostatic effects. Is there a need to redefine "inflammation"? In this review, we discuss the functions of "inflammatory" mediators/regulators of the innate immune system that determine tissue environments to fulfill the need of the tissue while regaining homeostasis after injury. PMID:27597803

  15. MiRNA in innate immune responses: novel players in wound inflammation

    PubMed Central

    Sen, Chandan K.

    2011-01-01

    Chronic wounds represent a major and rising socioeconomic threat affecting over 6.5 million people in the United States costing in excess of US $25 billion annually. Wound healing is a physiological response to injury that is conserved across tissue systems. In humans, wounding is followed by instant response aimed at hemostasis, which in turn provides the foundation for inflammatory processes that closely follow. Inflammation is helpful and a prerequisite for healing as long as it is mounted and resolved in a timely manner. Chronic inflammation derails the healing cascade resulting in impaired wound closure. Disruption of Dicer, the RNase III enzyme that generates functional miRNAs, has a major impact on the overall immune system. Emerging studies indicate that miRNAs, especially miR-21, miR-146a/b, and miR-155, play a key role in regulating several hubs that orchestrate the inflammatory process. Direct evidence from studies addressing wound inflammation being limited, the current work represents a digest of the relevant literature that is aimed at unveiling the potential significance of miRNAs in the regulation of wound inflammation. Such treatment would help establish new paradigms highlighting a central role of miRs in the understanding and management of dysregulated inflammation as noted in conjunction with chronic wounds. PMID:21139022

  16. Cigarette Smoke Exposure Exacerbates Lung Inflammation and Compromises Immunity to Bacterial Infection

    PubMed Central

    Lugade, Amit A.; Bogner, Paul N.; Thatcher, Thomas H.; Sime, Patricia J.; Phipps, Richard P.; Thanavala, Yasmin

    2014-01-01

    The detrimental impact of tobacco on human health is clearly recognized and despite aggressive efforts to prevent smoking, close to one billion individuals worldwide continue to smoke. People with chronic obstructive pulmonary disease (COPD) are susceptible to recurrent respiratory infections with pathogens, including non-typeable Haemophilus influenzae (NTHI), yet the reasons for this increased susceptibility are poorly understood. As mortality rapidly increases with multiple exacerbations, development of protective immunity is critical to improving patient survival. Acute NTHI infection has been studied in the context of cigarette smoke exposure, but this is the first study to investigate chronic infection and the generation of adaptive immune responses to NTHI following chronic smoke exposure. After chronic NTHI infection, mice that had previously been exposed to cigarette smoke developed increased lung inflammation and compromised adaptive immunity relative to air-exposed controls. Importantly, NTHI-specific T cells from mice exposed to cigarette smoke produced lower levels of IFN-γ and IL-4, and B cells produced reduced levels of antibodies against outer membrane lipoprotein P6, with impaired IgG1, IgG2a and IgA class-switching. However, production of IL-17, which is associated with neutrophilic inflammation, was enhanced. Interestingly, cigarette smoke exposed mice exhibited a similar defect in the generation of adaptive immunity following immunization with P6. Our study has conclusively demonstrated that cigarette smoke exposure has a profound suppressive effect on the generation of adaptive immune responses to NTHI and suggests the mechanism by which prior cigarette smoke exposure predisposes COPD patients to recurrent infections, leading to exacerbations and contributing to mortality. PMID:24752444

  17. Expression of epithelial adhesion proteins and integrins in chronic inflammation.

    PubMed Central

    Haapasalmi, K.; Mäkelä, M.; Oksala, O.; Heino, J.; Yamada, K. M.; Uitto, V. J.; Larjava, H.

    1995-01-01

    Epithelial cell behavior in chronic inflammation is poorly characterized. During inflammation of tooth-supporting structures (periodontal disease), increased proliferation of epithelial cells into the inflamed connective tissue stroma is commonly seen. In some areas ulceration and degeneration take place. We studied alterations in the expression of adhesion molecules and integrins during chronic periodontal inflammation. In inflamed tissue, laminin-1 and type IV collagen were still present in the basement membrane and surrounding blood vessels, but they were also found extravascularly in inflamed connective tissue stroma. Type VII collagen and laminin-5 (also known as kalinin, epiligrin, or nicein) were poorly preserved in the basement membrane zone, but both were found in unusual streak-like distributions in the subepithelial connective tissue stroma in inflamed tissue. Both fibronectin and tenascin were substantially decreased in chronically inflamed connective tissue, showing only punctate staining at the basement membrane zone. Integrins of the beta 1 family showed two distinct staining patterns in epithelial cells during chronic inflammation; focal losses of beta 1 integrins (alpha 2 beta 1 and alpha 3 beta 1) were found in most areas, while in other areas the entire pocket epithelium was found to be strongly positive for beta 1 integrins. No members of the alpha v integrin family were found in any epithelia studied. Expression of the alpha 6 beta 4 integrin was high in basal cells of healthy tissue, but weak in epithelium associated with chronic inflammation. Chronic inflammation therefore involves alterations in both adhesion proteins and integrins expressed by epithelial cells. Basement membrane components found at abnormal sites in stroma in chronic inflammation might serve as new adhesive ligands for various cell types in inflamed stroma. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:7541610

  18. Innate Immune Responses to Engineered Nanomaterials During Allergic Airway Inflammation

    NASA Astrophysics Data System (ADS)

    Shipkowski, Kelly Anne

    The field of nanotechnology is continually advancing, and increasing amounts of consumer goods are being produced using engineered nanomaterials (ENMs). The health risks of occupational and/or consumer exposure to ENMs are not completely understood, although significant research indicates that pulmonary exposure to nanomaterials induces toxic effects in the lungs of exposed animals. Multi-walled carbon nanotubes (MWCNTs) are a specific category of ENMs and consist of sheets of graphene rolled into cylinders that are multiple layers thick in order to strengthen their rigidity. MWCNTs have a fiber-like shape, similar to that of asbestos, which allows for a high aspect ratio and makes them difficult to clear from the lung. Studies with rodent models have demonstrated that pulmonary exposure to ENMs, in particular MWCNTs, results in acute lung inflammation and the subsequent development of chronic fibrosis, suggesting a potential human health risk to individuals involved in the manufacturing of products utilizing these nanomaterials. Induction of IL-1beta secretion via activation of the inflammasome is a prime mechanism of MWCNT-induced inflammation. The inflammasome is a multi-protein scaffold found in a variety of cell types that forms in response to a variety of immune signals, including particulates. Sensitization with allergens, such as house dust mite (HDM), increases levels of the T helper 2 (Th2) cytokines IL-4 and IL-13 in mice and in humans, and there is particular cause for concern in cases of MWCNT exposure in individuals with pre-existing allergic airway disease, such as asthma. MWCNT exposure exacerbates airway inflammation and fibrosis in animal models of pre-existing allergic asthma, suggesting that individuals suffering from asthma are more susceptible to the toxic pulmonary effects of MWCNT exposure. Asthma is an exceptionally prominent human disease, and therefore the goal of this research was to better understand how pre-existing allergic airway

  19. A Mouse Model for Pathogen-induced Chronic Inflammation at Local and Systemic Sites

    PubMed Central

    Slocum, Connie S.; Weinberg, Ellen O.; Hua, Ning; Gudino, Cynthia V.; Hamilton, James A.; Genco, Caroline A.

    2014-01-01

    Chronic inflammation is a major driver of pathological tissue damage and a unifying characteristic of many chronic diseases in humans including neoplastic, autoimmune, and chronic inflammatory diseases. Emerging evidence implicates pathogen-induced chronic inflammation in the development and progression of chronic diseases with a wide variety of clinical manifestations. Due to the complex and multifactorial etiology of chronic disease, designing experiments for proof of causality and the establishment of mechanistic links is nearly impossible in humans. An advantage of using animal models is that both genetic and environmental factors that may influence the course of a particular disease can be controlled. Thus, designing relevant animal models of infection represents a key step in identifying host and pathogen specific mechanisms that contribute to chronic inflammation. Here we describe a mouse model of pathogen-induced chronic inflammation at local and systemic sites following infection with the oral pathogen Porphyromonas gingivalis, a bacterium closely associated with human periodontal disease. Oral infection of specific-pathogen free mice induces a local inflammatory response resulting in destruction of tooth supporting alveolar bone, a hallmark of periodontal disease. In an established mouse model of atherosclerosis, infection with P. gingivalis accelerates inflammatory plaque deposition within the aortic sinus and innominate artery, accompanied by activation of the vascular endothelium, an increased immune cell infiltrate, and elevated expression of inflammatory mediators within lesions. We detail methodologies for the assessment of inflammation at local and systemic sites. The use of transgenic mice and defined bacterial mutants makes this model particularly suitable for identifying both host and microbial factors involved in the initiation, progression, and outcome of disease. Additionally, the model can be used to screen for novel therapeutic strategies

  20. Innate immunity and inflammation in ageing: a key for understanding age-related diseases

    PubMed Central

    Licastro, Federico; Candore, Giuseppina; Lio, Domenico; Porcellini, Elisa; Colonna-Romano, Giuseppina; Franceschi, Claudio; Caruso, Calogero

    2005-01-01

    The process of maintaining life for the individual is a constant struggle to preserve his/her integrity. This can come at a price when immunity is involved, namely systemic inflammation. Inflammation is not per se a negative phenomenon: it is the response of the immune system to the invasion of viruses or bacteria and other pathogens. During evolution the human organism was set to live 40 or 50 years; today, however, the immune system must remain active for much a longer time. This very long activity leads to a chronic inflammation that slowly but inexorably damages one or several organs: this is a typical phenomenon linked to ageing and it is considered the major risk factor for age-related chronic diseases. Alzheimer's disease, atherosclerosis, diabetes and even sarcopenia and cancer, just to mention a few – have an important inflammatory component, though disease progression seems also dependent on the genetic background of individuals. Emerging evidence suggests that pro-inflammatory genotypes are related to unsuccessful ageing, and, reciprocally, controlling inflammatory status may allow a better chance of successful ageing. In other words, age-related diseases are "the price we pay" for a life-long active immune system: this system has also the potential to harm us later, as its fine tuning becomes compromised. Our immune system has evolved to control pathogens, so pro-inflammatory responses are likely to be evolutionarily programmed to resist fatal infections with pathogens aggressively. Thus, inflammatory genotypes are an important and necessary part of the normal host responses to pathogens in early life, but the overproduction of inflammatory molecules might also cause immune-related inflammatory diseases and eventually death later. Therefore, low responder genotypes involved in regulation of innate defence mechanisms, might better control inflammatory responses and age-related disease development, resulting in an increased chance of long life survival

  1. Age-Associated Chronic Diseases Require Age-Old Medicine: Role of Chronic Inflammation

    PubMed Central

    Prasad, Sahdeo; Sung, Bokyung; Aggarwal, Bharat B.

    2012-01-01

    Most chronic diseases - such as cancer, cardiovascular disease (CVD), Alzheimer disease, Parkinson disease, arthritis, diabetes and obesity - are becoming leading causes of disability and death all over the world. Some of the most common causes of these age-associated chronic diseases are lack of physical activity, poor nutrition, tobacco use, and excessive alcohol consumption. All the risk factors linked to these chronic diseases have been shown to up-regulate inflammation. Therefore, downregulation of inflammation-associated risk factors could prevent or delay these age-associated diseases. Although modern science has developed several drugs for treating chronic diseases, most of these drugs are enormously expensive and are associated with serious side effects and morbidity. In this review, we present evidence on how chronic inflammation leads to age-associated chronic disease. Furthermore, we discuss diet and lifestyle as solutions for age-associated chronic disease. PMID:22178471

  2. Airway Inflammation and Hypersensitivity Induced by Chronic Smoking

    PubMed Central

    Kou, Yu Ru; Kwong, Kevin; Lee, Lu-Yuan

    2011-01-01

    Airway hypersensitivity, characterized by enhanced excitability of airway sensory nerves, is a prominent pathophysiological feature in patients with airway inflammatory diseases. Although the underlying pathogenic mechanism is not fully understood, chronic airway inflammation is believed to be primarily responsible. Cigarette smoking is known to cause chronic airway inflammation, accompanied by airway hyperresponsiveness. Experimental evidence indicates that enhanced excitability of vagal bronchopulmonary sensory nerves and increased tachykinin synthesis in these nerves resulting from chronic inflammation are important contributing factors to the airway hyperresponsiveness. Multiple inflammatory mediators released from various types of structural and inflammatory cells are involved in the smoking-induced airway inflammation, which is mainly regulated by redox-sensitive signaling pathways and transcription factors. Furthermore, recent studies have reported potent sensitizing and stimulatory effects of these inflammatory mediators such as prostanoids and reactive oxygen species on these sensory nerves. In summary, these studies using cigarette smoking as an experimental approach have identified certain potentially important cell signaling pathways and underlying mechanisms of the airway hypersensitivity induced by chronic airway inflammation. PMID:21397052

  3. Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation

    PubMed Central

    Muralidharan, Sujatha; Mandrekar, Pranoti

    2013-01-01

    Extensive research in the past decade has identified innate immune recognition receptors and intracellular signaling pathways that culminate in inflammatory responses. Besides its role in cytoprotection, the importance of cell stress in inflammation and host defense against pathogens is emerging. Recent studies have shown that proteins in cellular stress responses, including the heat shock response, ER stress response, and DNA damage response, interact with and regulate signaling intermediates involved in the activation of innate and adaptive immune responses. The effect of such regulation by cell stress proteins may dictate the inflammatory profile of the immune response during infection and disease. In this review, we describe the regulation of innate immune cell activation by cell stress pathways, present detailed descriptions of the types of stress response proteins and their crosstalk with immune signaling intermediates that are essential in host defense, and illustrate the relevance of these interactions in diseases characteristic of aberrant immune responses, such as chronic inflammatory diseases, autoimmune disorders, and cancer. Understanding the crosstalk between cellular stress proteins and immune signaling may have translational implications for designing more effective regimens to treat immune disorders. PMID:23990626

  4. Biofilms and Inflammation in Chronic Wounds

    PubMed Central

    Zhao, Ge; Usui, Marcia L.; Lippman, Soyeon I.; James, Garth A.; Stewart, Philip S.; Fleckman, Philip; Olerud, John E.

    2013-01-01

    Significance The incidence, cost, morbidity, and mortality associated with non-healing of chronic skin wounds are dramatic. With the increasing numbers of people with obesity, chronic medical conditions, and an increasing life expectancy, the healthcare cost of non-healing ulcers has recently been estimated at $25 billion annually in the United States. The role played by bacterial biofilm in chronic wounds has been emphasized in recent years, particularly in the context of the prolongation of the inflammatory phase of repair. Recent Advances Rapid high-throughput genomic approaches have revolutionized the ability to identify and quantify microbial organisms from wounds. Defining bacterial genomes and using genetic approaches to knock out specific bacterial functions, then studying bacterial survival on cutaneous wounds is a promising strategy for understanding which genes are essential for pathogenicity. Critical Issues When an animal sustains a cutaneous wound, understanding mechanisms involved in adaptations by bacteria and adaptations by the host in the struggle for survival is central to development of interventions that favor the host. Future Directions Characterization of microbiomes of clinically well characterized chronic human wounds is now under way. The use of in vivo models of biofilm-infected cutaneous wounds will permit the study of the mechanisms needed for biofilm formation, persistence, and potential synergistic interactions among bacteria. A more complete understanding of bacterial survival mechanisms and how microbes influence host repair mechanisms are likely to provide targets for chronic wound therapy. PMID:24527355

  5. Modulation of the immune system during postpartum uterine inflammation.

    PubMed

    Walker, Caroline G; Meier, Susanne; Hussein, Hassan; McDougall, Scott; Burke, Chris R; Roche, John R; Mitchell, Murray D

    2015-04-01

    Postpartum uterine inflammation (endometritis) in the dairy cow is associated with lower fertility at both the time of infection and after the inflammation has resolved. We hypothesized that aberrant DNA methylation may be involved in the subfertility associated with uterine inflammation. The objective of this study was to characterize genome-wide DNA methylation and gene expression in the endometrium of dairy cows with subclinical endometritis (SCE). Endometrial tissues were obtained at 29 days postpartum (n = 12), and microarrays were used to characterize transcription and DNA methylation. Analyses revealed 1,856 probes differentially expressed in animals with SCE (n = 6) compared with controls (CON, n = 6, P < 0.05, Storey Multiple testing correction) and 2,976 probes with significant correlation between gene expression and bacteriology score. No significant associations among DNA methylation and gene expression were detected. Analysis of transcription data using the Database for Annotation, Visualization, and Integrated Discovery and Gene Set Enrichment Analysis identified several pathways and processes enriched in SCE cows, with the majority related to the immune response. Furthermore, the top ontology terms enriched in genes that had expression data correlated to bacteriology score were: Defense response, inflammatory response, and innate immune response. Gene expression profiles in cows with subclinical endometritis in this study indicate that the immune response is activated, potentially resulting in a local proinflammatory environment in the uterus. If this period of inflammation is prolonged it could result in tissue damage or failure to complete involution of the uterus, which may create a suboptimal environment for future pregnancy. PMID:25604124

  6. Fibrocytes: emerging effector cells in chronic inflammation

    PubMed Central

    Reilkoff, Ronald A.; Bucala, Richard; Herzog, Erica L.

    2013-01-01

    Fibrocytes are mesenchymal cells that arise from monocyte precursors. They are present in injured organs and have both the inflammatory features of macrophages and the tissue remodelling properties of fibroblasts. Chronic inflammatory stimuli mediate the differentiation, trafficking and accumulation of these cells in fibrosing conditions associated with autoimmunity, cardiovascular disease and asthma. This Opinion article discusses the immunological mediators controlling fibrocyte differentiation and recruitment, describes the association of fibrocytes with chronic inflammatory diseases and compares the potential roles of fibrocytes in these disorders with those of macrophages and fibroblasts. It is hoped that this information prompts new opportunities for the study of these unique cells. PMID:21597472

  7. MAP4K Family Kinases in Immunity and Inflammation.

    PubMed

    Chuang, Huai-Chia; Wang, Xiaohong; Tan, Tse-Hua

    2016-01-01

    MAP kinase kinase kinase kinases (MAP4Ks) belong to the mammalian Ste20-like family of serine/threonine kinases. MAP4Ks including MAP4K1/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK have been reported to induce JNK activation through activating the MAP3K-MAP2K cascade. The physiological roles of MAP4Ks in immunity and inflammation are largely unknown until recent studies using biochemical approaches and knockout mice. Surprisingly, JNK is not the major target of MAP4Ks in immune cells; MAP4Ks regulate immune responses through novel targets. HPK1 inhibits T-cell receptor (TCR) signaling and B-cell receptor signaling via inducing phosphorylation/ubiquitination of SLP-76 and BLNK, respectively. GLK activates TCR signaling through phosphorylating/activating PKCθ. T-cell-mediated immune responses and Th17-mediated experimental autoimmune diseases are enhanced in HPK1 knockout mice but ameliorated in GLK knockout mice. Consistently, HPK1 levels are decreased in peripheral blood mononuclear cells and T cells from patients with psoriatic arthritis and systemic lupus erythematosus (SLE), respectively. Moreover, GLK levels are increased in T cells from patients with SLE, rheumatoid arthritis, or adult-onset Still's disease; the percentages of GLK-overexpression T cells are correlated with the disease activity. In addition, HGK phosphorylates and induces TRAF2 protein degradation, leading to negative regulation of IL-6 production in resting T cells. Loss of HGK in T cells results in spontaneous systemic inflammation and type 2 diabetes in mice. HGK is also involved in cancer cell migration. To date, the phenotypes of knockout mice for GCK, KHS, and MINK have not been reported; the roles of these three MAP4Ks in immune cell signaling are discussed in this review. Taken together, MAP4K family kinases play diverse roles in immune cell signaling, immune responses, and inflammation. PMID:26791862

  8. Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation

    PubMed Central

    Hermouet, Sylvie; Bigot-Corbel, Edith; Gardie, Betty

    2015-01-01

    Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal diseases characterized by the excessive and chronic production of mature cells from one or several of the myeloid lineages. Recent advances in the biology of MPNs have greatly facilitated their molecular diagnosis since most patients present with mutation(s) in the JAK2, MPL, or CALR genes. Yet the roles played by these mutations in the pathogenesis and main complications of the different subtypes of MPNs are not fully elucidated. Importantly, chronic inflammation has long been associated with MPN disease and some of the symptoms and complications can be linked to inflammation. Moreover, the JAK inhibitor clinical trials showed that the reduction of symptoms linked to inflammation was beneficial to patients even in the absence of significant decrease in the JAK2-V617F mutant load. These observations suggested that part of the inflammation observed in patients with JAK2-mutated MPNs may not be the consequence of JAK2 mutation. The aim of this paper is to review the different aspects of inflammation in MPNs, the molecular mechanisms involved, the role of specific genetic defects, and the evidence that increased production of certain cytokines depends or not on MPN-associated mutations, and to discuss possible nongenetic causes of inflammation. PMID:26538820

  9. Chronic immune thrombocytopenic purpura in hemophilia A.

    PubMed Central

    Reen, B. S.; Card, R. T.; McSheffrey, J. B.; Skinnider, L. F.

    1983-01-01

    Chronic immune thrombocytopenic purpura resistant to steroid therapy occurred in a 30-year-old patient with severe hemophilia A. This association has recently been reported in other patients, and a possible relation to the acquired immune deficiency syndrome (AIDS) has been suggested. Although this patient had been treated with factor VIII concentrate for 4 years, the proportions of helper and suppressor T cells were normal, and there was no evidence of AIDS. An uncomplicated splenectomy gave excellent results. All patients with hemophilia should have their platelet counts monitored closely and should report any unusual pattern of bleeding. PMID:6686949

  10. Gut microbiota and inflammation in chronic kidney disease patients

    PubMed Central

    Mafra, Denise; Fouque, Denis

    2015-01-01

    Inflammation is a multifactorial phenotype that in chronic kidney disease is associated with adverse patient outcomes. Recently, alterations in gut microbiota composition and intestinal barrier have been associated with inflammation and oxidative stress in CKD patients. Vanholder and Glorieux recently critically reviewed [Clin Kidney J (2015) 8 (2): 168-179] the current understanding of the role of gut microbiota in the production of uraemic toxins and the therapeutic implications. Where do we stand now? The basic mechanisms of the gut-kidney crosstalk must still be clarified. In addition, the efficacy and safety of therapeutic strategies to modulate the gut microbiota in order to decrease uraemic toxin production and inflammation in chronic kidney disease should be evaluated. Finally, an impact of such strategies on hard outcomes should be demonstrated before incorporation into routine clinical practice. PMID:26034597

  11. Innate Immunity and Inflammation in NAFLD/NASH.

    PubMed

    Arrese, Marco; Cabrera, Daniel; Kalergis, Alexis M; Feldstein, Ariel E

    2016-05-01

    Inflammation and hepatocyte injury and death are the hallmarks of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), which is a currently burgeoning public health problem. Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Thus, identification of the underlying mechanisms by which immune cells in the liver recognize cell damage signals or the presence of pathogens or pathogen-derived factors that activate them is relevant from a therapeutic perspective. In this review, we present new insights into the factors promoting the inflammatory response in NASH including sterile cell death processes resulting from lipotoxicity in hepatocytes as well as into the altered gut-liver axis function, which involves translocation of bacterial products into portal circulation as a result of gut leakiness. We further delineate the key immune cell types involved and how they recognize both damage-associated molecular patterns or pathogen-associated molecular patterns through binding of surface-expressed pattern recognition receptors, which initiate signaling cascades leading to injury amplification. The relevance of modulating these inflammatory signaling pathways as potential novel therapeutic strategies for the treatment of NASH is summarized. PMID:26841783

  12. Understanding innate immunity and inflammation in acne: implications for management.

    PubMed

    Dreno, B; Gollnick, H P M; Kang, S; Thiboutot, D; Bettoli, V; Torres, V; Leyden, J

    2015-06-01

    Acne has long been understood to have a complex physiological basis involving several main factors: hormonally-stimulated sebum production, abnormal keratinization of the pilosebaceous duct, and an inflammatory immune response to Propionibacterium acnes. Recent studies at the molecular and cellular level have begun clarifying how all of these factors interact, and the role of the innate immune system is better appreciated. Inflammation has been demonstrated in all acne lesions - the preclinical microcomedo, comedones, inflammatory lesions, 'post-inflammatory' erythema or hyperpigmentation, and scarring. Inflammation localized to the pilosebaceous unit can be considered the defining feature of acne and should be addressed via multiple therapeutic pathways. Clinicians tend to think oral antibiotics should be used to 'calm' inflammatory acne, but there is good evidence showing that topical retinoids also have anti-inflammatory properties as a class effect. For best therapeutic outcomes, most patients with acne should be treated first line with a topical retinoid plus an antimicrobial agent, as has been demonstrated in thousands of patients involved in clinical trials and recommended by the Global Alliance to Improve Outcomes in Acne for more than a decade. Moving away from reliance on antibiotic therapy for acne is particularly important in an era of worsening antimicrobial resistance and worldwide calls to reduce antibiotic use. Improved understanding about the role of P. acnes and the innate immune system in acne should help clinicians in designing efficacious treatment strategies. PMID:26059728

  13. The role of complement in inflammation and adaptive immunity.

    PubMed

    Barrington, R; Zhang, M; Fischer, M; Carroll, M C

    2001-04-01

    Major advances in our understanding of the immunobiology of complement were made within the past 5 years primarily due to the development of gene-targeting technology. New strains of mice bearing specific deficiencies in serum complement proteins or their receptors were developed using this approach. Characterization of these mice has provided new and exciting insights into the biology of the complement system. In this review, we discuss recent results on two important aspects of the complement system, i) host protection and inflammation, and ii) regulation of B lymphocytes of adaptive immunity. While these two roles appear distinct, they are linked. We discuss how natural antibody and classical pathway complement work together in host protection against bacterial infection on the one hand but, on the other, they co-operate to induce inflammation as observed in reperfusion injury. Significantly, the lymphocytes that produce natural antibody, the B-1 lymphocytes, are regulated in part by the complement system. PMID:11414363

  14. Link between chronic inflammation and human papillomavirus-induced carcinogenesis (Review)

    PubMed Central

    FERNANDES, JOSÉ VERÍSSIMO; DE MEDEIROS FERNANDES, THALES ALLYRIO ARAÚJO; DE AZEVEDO, JENNER CHRYSTIAN VERÍSSIMO; COBUCCI, RICARDO NEY OLIVEIRA; DE CARVALHO, MARIA GORETTI FREIRE; ANDRADE, VANIA SOUSA; DE ARAÚJO, JOSÉLIO MARIA GALVÃO

    2015-01-01

    Inflammation is a defense strategy against invading agents and harmful molecules that is activated immediately following a stimulus, and involves the release of cytokines and chemokines, which activate the innate immune response. These mediators act together to increase blood flow and vascular permeability, facilitating recruitment of effector cells to the site of injury. Following resolution of the injury and removal of the stimulus, inflammation is disabled, but if the stimulus persists, inflammation becomes chronic and is strongly associated with cancer. This is likely to be due to the fact that the inflammation leads to a wound that does not heal, requiring a constant renewal of cells, which increases the risk of neoplastic transformation. Debris from phagocytosis, including the reactive species of oxygen and nitrogen that cause damage to DNA already damaged by the leukotrienes and prostaglandins, has an impact on inflammation and various carcinogenic routes. There is an association between chronic inflammation, persistent infection and cancer, where oncogenic action is mediated by autocrine and paracrine signals, causing changes in somatic cells under the influence of the microbial genome or of epigenetic factors. Among the infectious agents associated with cancer, certain genotypes of human papillomavirus (HPV) stand out. HPV is responsible for virtually all cases of cervical cancer and a lower proportion of cancers of the vagina, vulva, anus, penis and a number of extragenital cancers. In the present review, recent advances in the mechanisms involved in the inflammatory response are presented with their participation in the process of carcinogenesis, emphasizing the role of chronic inflammation in the development of HPV-induced cervical cancer. PMID:25663851

  15. Inflammation on the Mind: Visualizing Immunity in the Central Nervous System

    PubMed Central

    Kang, Silvia S.

    2016-01-01

    The central nervous system (CNS) is a remarkably complex structure that utilizes electrochemical signaling to coordinate activities throughout the entire body. Because the nervous system contains nonreplicative cells, it is postulated that, through evolutionary pressures, this compartment has acquired specialized mechanisms to limit damage. One potential source of damage comes from our immune system, which has the capacity to survey the CNS and periphery for the presence of foreign material. The immune system is equipped with numerous effector mechanisms and can greatly alter the homeostasis and function of the CNS. Degeneration, autoimmunity, and pathogen infection can all result in acute, and sometimes chronic, inflammation within the CNS. Understanding the specialized functionality of innate and adaptive immune cells within the CNS is critical to the design of more efficacious treatments to mitigate CNS inflammatory conditions. Much of our knowledge of CNS-immune interactions stems from seminal studies that have used static and dynamic imaging approaches to visualize inflammatory cells responding to different CNS conditions. This review will focus on how imaging techniques have elevated our understanding of CNS inflammation as well as the exciting prospects that lie ahead as we begin to pursue investigation of the inflamed CNS in real time. PMID:19521688

  16. Designing Immune Therapy for Chronic Hepatitis B

    PubMed Central

    Fazle Akbar, Sheikh Mohammad; Al-Mahtab, Mamun; Hiasa, Yoichi

    2014-01-01

    Presently-available antiviral drugs may not be a satisfactory option for treatment of patients with chronic hepatitis B (CHB). In spite of presence of several antiviral drugs, sustained off-treatment clinical responses are not common in CHB patients treated with antiviral drugs. In addition, antiviral drug treatment may have limited effects on blocking the progression of HBV-related complications. However, substantial long-term risk of viral resistance and drug toxicity are related with maintenance antiviral therapy in CHB patients with presently-available antiviral agents. The infinite treatments with antiviral drugs for CHB patients are also costly and may be unbearable by most patients of developing and resource-constrained countries. In this situation, there is pressing need to develop new and innovative therapeutic approaches for patients with chronic hepatitis B virus (HBV) infection. Immune therapy has emerged as an alternate therapeutic approach for CHB patients because studies have shown that host immunity is either impaired or derailed or distorted or diminished in CHB patients compared to patients with acute resolved hepatitis B who contain the HBV replication and control liver damages. Both non antigen-specific immune modulators and HBV antigen-specific agents have been used in CHB patients during last three decades. However, similar to antiviral therapy, the ongoing regimens of immune therapeutic approaches have also been unable to show real promises for treating CHB patients. The concept of immune therapy for treating CHB patients seems to be rationale and scientific, however, concerns remain about suitable designs of immune therapy for CHB patients. PMID:25755566

  17. Long QT Syndrome: An Emerging Role for Inflammation and Immunity

    PubMed Central

    Lazzerini, Pietro Enea; Capecchi, Pier Leopoldo; Laghi-Pasini, Franco

    2015-01-01

    The long QT syndrome (LQTS), classified as congenital or acquired, is a multi-factorial disorder of myocardial repolarization predisposing to life-threatening ventricular arrhythmias, particularly torsades de pointes. In the latest years, inflammation and immunity have been increasingly recognized as novel factors crucially involved in modulating ventricular repolarization. In the present paper, we critically review the available information on this topic, also analyzing putative mechanisms and potential interplays with the other etiologic factors, either acquired or inherited. Accumulating data indicate inflammatory activation as a potential cause of acquired LQTS. The putative underlying mechanisms are complex but essentially cytokine-mediated, including both direct actions on cardiomyocyte ion channels expression and function, and indirect effects resulting from an increased central nervous system sympathetic drive on the heart. Autoimmunity represents another recently arising cause of acquired LQTS. Indeed, increasing evidence demonstrates that autoantibodies may affect myocardial electric properties by directly cross-reacting with the cardiomyocyte and interfering with specific ion currents as a result of molecular mimicry mechanisms. Intriguingly, recent data suggest that inflammation and immunity may be also involved in modulating the clinical expression of congenital forms of LQTS, possibly triggering or enhancing electrical instability in patients who already are genetically predisposed to arrhythmias. In this view, targeting immuno-inflammatory pathways may in the future represent an attractive therapeutic approach in a number of LQTS patients, thus opening new exciting avenues in antiarrhythmic therapy. PMID:26798623

  18. Lymphocytes in non-immune inflammation: a specific subclass of lymphoid cells?

    PubMed Central

    Leme, J. G.; Verissimo de Mello, S. B.; Falcao, R. P.; Rocha, J. R.

    1981-01-01

    Rats were subjected to various experimental procedures which affected lymphocyte numbers, in an attempt to investigate the participation of individual subpopulations of these cells in the development of acute, non-immune inflammation. Deficient T function, as evidenced in neonatally thymectomized animals, or in 6-week-old animals thymectomized and afterwards exposed to multiple total-body X-ray irradiations, did not interfere with the development of the acute inflammatory responses of the animals to carrageenin. In the former circumstance, the numbers of circulating B lymphocytes, identified by the presence of surface immunoglobulins, were increased. In thymectomized and irradiated rats, the B-lymphocyte subpopulation was reduced. Circumstances causing attenuated inflammatory reactions to carrageenin resulted, first, from lymphocyte depletion by chronic drainage from the thoracic duct and, second, from irradiation of the animals with a single large dose of X-ray, the animals being tested 24 h after irradiation. B lymphocytes in blood remained within the normal range after chronic lymphatic drainage, but a large dose of X-ray markedly reduced their number. In both cases the attenuation of the responses to carrageenin did not seem to be associated with nonspecific hyporeactivity, or with the effect of the treatments on the other blood cells, It is suggested that the development of acute, non-immune inflammation is influenced by lymphoid cells which might constitute a specific subclass of cells, distinct from fully differentiated T and B lymphocytes. PMID:7236499

  19. Local and remote immune-mediated inflammation after mild peripheral nerve compression in rats.

    PubMed

    Schmid, Annina B; Coppieters, Michel W; Ruitenberg, Marc J; McLachlan, Elspeth M

    2013-07-01

    After experimental nerve injuries that extensively disrupt axons, such as chronic constriction injury, immune cells invade the nerve, related dorsal root ganglia (DRGs), and spinal cord, leading to hyperexcitability, raised sensitivity, and pain. Entrapment neuropathies, such as carpal tunnel syndrome, involve minimal axon damage, but patients often report widespread symptoms. To understand the underlying pathology, a tube was placed around the sciatic nerve in 8-week-old rats, leading to progressive mild compression as the animals grew. Immunofluorescence was used to examine myelin and axonal integrity, glia, macrophages, and T lymphocytes in the nerve, L5 DRGs, and spinal cord after 12 weeks. Tubes that did not constrict the nerve when applied caused extensive and ongoing loss of myelin, together with compromise of small-, but not large-, diameter axons. Macrophages and T lymphocytes infiltrated the nerve and DRGs. Activated glia proliferated in DRGs but not in spinal cord. Histologic findings were supported by clinical hyperalgesia to blunt pressure and cold allodynia. Tubes that did not compress the nerve induced only minor local inflammation. Thus, progressive mild nerve compression resulted in chronic local and remote immune-mediated inflammation depending on the degree of compression. Such neuroinflammation may explain the widespread symptoms in patients with entrapment neuropathies. PMID:23771220

  20. Chronic Inflammation Links Cancer and Parkinson’s Disease

    PubMed Central

    Li, Zhiming; Zheng, Zaozao; Ruan, Jun; Li, Zhi; Tzeng, Chi-Meng

    2016-01-01

    An increasing number of genetic studies suggest that the pathogenesis of Parkinson’s disease (PD) and cancer share common genes, pathways, and mechanisms. Despite a disruption in a wide range of similar biological processes, the end result is very different: uncontrolled proliferation and early neurodegeneration. Thus, the links between the molecular mechanisms that cause PD and cancer remain to be elucidated. We propose that chronic inflammation in neurons and tumors contributes to a microenvironment that favors the accumulation of DNA mutations and facilitates disease formation. This article appraises the key role of microglia, establishes the genetic role of COX2 and CARD15 in PD and cancer, and discusses prevention and treatment with this new perspective in mind. We examine the evidence that chronic inflammation is an important link between cancer and PD. PMID:27375474

  1. Chronic Inflammation and Cytokines in the Tumor Microenvironment

    PubMed Central

    Landskron, Glauben; De la Fuente, Marjorie; Thuwajit, Peti; Thuwajit, Chanitra; Hermoso, Marcela A.

    2014-01-01

    Acute inflammation is a response to an alteration induced by a pathogen or a physical or chemical insult, which functions to eliminate the source of the damage and restore homeostasis to the affected tissue. However, chronic inflammation triggers cellular events that can promote malignant transformation of cells and carcinogenesis. Several inflammatory mediators, such as TNF-α, IL-6, TGF-β, and IL-10, have been shown to participate in both the initiation and progression of cancer. In this review, we explore the role of these cytokines in important events of carcinogenesis, such as their capacity to generate reactive oxygen and nitrogen species, their potential mutagenic effect, and their involvement in mechanisms for epithelial mesenchymal transition, angiogenesis, and metastasis. Finally, we will provide an in-depth analysis of the participation of these cytokines in two types of cancer attributable to chronic inflammatory disease: colitis-associated colorectal cancer and cholangiocarcinoma. PMID:24901008

  2. Cigarette Smoke, Bacteria, Mold, Microbial Toxins, and Chronic Lung Inflammation

    PubMed Central

    Pauly, John L.; Paszkiewicz, Geraldine

    2011-01-01

    Chronic inflammation associated with cigarette smoke fosters malignant transformation and tumor cell proliferation and promotes certain nonneoplastic pulmonary diseases. The question arises as to whether chronic inflammation and/or colonization of the airway can be attributed, at least in part, to tobacco-associated microbes (bacteria, fungi, and spores) and/or microbial toxins (endotoxins and mycotoxins) in tobacco. To address this question, a literature search of documents in various databases was performed. The databases included PubMed, Legacy Tobacco Documents Library, and US Patents. This investigation documents that tobacco companies have identified and quantified bacteria, fungi, and microbial toxins at harvest, throughout fermentation, and during storage. Also characterized was the microbial flora of diverse smoking and smokeless tobacco articles. Evidence-based health concerns expressed in investigations of microbes and microbial toxins in cigarettes, cigarette smoke, and smokeless tobacco products are reasonable; they warrant review by regulatory authorities and, if necessary, additional investigation to address scientific gaps. PMID:21772847

  3. Inflammation and nutrition in children with chronic kidney disease.

    PubMed

    Tu, Juan; Cheung, Wai W; Mak, Robert H

    2016-05-01

    Chronic inflammation and nutritional imbalance are important comorbid conditions that correlate with poor clinical outcomes in children with chronic kidney disease (CKD). Nutritional disorders such as cachexia/protein energy wasting, obesity and growth retardation negatively impact the quality of life and disease progression in children with CKD. Inadequate nutrition has been associated with growth disturbances in children with CKD. On the other hand, over-nutrition and obesity are associated with poor outcomes in children with CKD. The exact mechanisms leading to these unfavorable conditions are not fully elucidated and are most likely multifactorial. In this review, we focus on the pathophysiology of nutrition disorders and inflammation and their impact on clinical outcomes in children with CKD. PMID:27152263

  4. Inflammation and nutrition in children with chronic kidney disease

    PubMed Central

    Tu, Juan; Cheung, Wai W; Mak, Robert H

    2016-01-01

    Chronic inflammation and nutritional imbalance are important comorbid conditions that correlate with poor clinical outcomes in children with chronic kidney disease (CKD). Nutritional disorders such as cachexia/protein energy wasting, obesity and growth retardation negatively impact the quality of life and disease progression in children with CKD. Inadequate nutrition has been associated with growth disturbances in children with CKD. On the other hand, over-nutrition and obesity are associated with poor outcomes in children with CKD. The exact mechanisms leading to these unfavorable conditions are not fully elucidated and are most likely multifactorial. In this review, we focus on the pathophysiology of nutrition disorders and inflammation and their impact on clinical outcomes in children with CKD. PMID:27152263

  5. IRF5 controls both acute and chronic inflammation

    PubMed Central

    Weiss, Miriam; Byrne, Adam J.; Blazek, Katrina; Saliba, David G.; Pease, James E.; Perocheau, Dany; Feldmann, Marc; Udalova, Irina A.

    2015-01-01

    Whereas the importance of macrophages in chronic inflammatory diseases is well recognized, there is an increasing awareness that neutrophils may also play an important role. In addition to the well-documented heterogeneity of macrophage phenotypes and functions, neutrophils also show remarkable phenotypic diversity among tissues. Understanding the molecular pathways that control this heterogeneity should provide abundant scope for the generation of more specific and effective therapeutics. We have shown that the transcription factor IFN regulatory factor 5 (IRF5) polarizes macrophages toward an inflammatory phenotype. IRF5 is also expressed in other myeloid cells, including neutrophils, where it was linked to neutrophil function. In this study we explored the role of IRF5 in models of acute inflammation, including antigen-induced inflammatory arthritis and lung injury, both involving an extensive influx of neutrophils. Mice lacking IRF5 accumulate far fewer neutrophils at the site of inflammation due to the reduced levels of chemokines important for neutrophil recruitment, such as the chemokine (C-X-C motif) ligand 1. Furthermore we found that neutrophils express little IRF5 in the joints and that their migratory properties are not affected by the IRF5 deficiency. These studies extend prior ones suggesting that inhibiting IRF5 might be useful for chronic macrophage-induced inflammation and suggest that IRF5 blockade would ameliorate more acute forms of inflammation, including lung injury. PMID:26283380

  6. Insulin-like growth factor-1 endues monocytes with immune suppressive ability to inhibit inflammation in the intestine

    PubMed Central

    Ge, Rong-Ti; Mo, Li-Hua; Wu, Ruijin; Liu, Jiang-Qi; Zhang, Huan-Ping; Liu, Zhigang; Liu, Zhanju; Yang, Ping-Chang

    2015-01-01

    The pathogenesis of some chronic inflammation such as inflammatory bowel disease is unclear. Insulin-like growth factor-1 (IGF1) has active immune regulatory capability. This study aims to investigate into the mechanism by which IGF1 modulates the monocyte (Mo) properties to inhibit immune inflammation in the intestine. In this study, the production of IGF1 by intestinal epithelial cells was evaluated by real time RT-PCR and Western blotting. Mos were analyzed by flow cytometry. A mouse colitis model was created with trinitrobenzene sulfonic acid. The results showed that mouse IECs produced IGF1, which could be up regulated by exposure to CpG-ODN (CpG-oligodeoxynueleotides) in the culture. Culture the CpG-ODN-primed IEC cells and Mos or exposure of Mos to IGF1 in the culture induced the Mos to express IL-10. The IGF1-primed Mos showed the immune suppressive effect on inhibiting the immune inflammation in the mouse colon. In conclusion, the IGF1-primed Mos are capable of suppressing immune inflammation in the intestine. PMID:25588622

  7. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

    PubMed Central

    Jurk, Diana; Wilson, Caroline; Passos, João F.; Oakley, Fiona; Correia-Melo, Clara; Greaves, Laura; Saretzki, Gabriele; Fox, Chris; Lawless, Conor; Anderson, Rhys; Hewitt, Graeme; Pender, Sylvia LF; Fullard, Nicola; Nelson, Glyn; Mann, Jelena; van de Sluis, Bart; Mann, Derek A.; von Zglinicki, Thomas

    2014-01-01

    Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1−/− fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1−/− tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor. PMID:24960204

  8. Obesity and Obese-related Chronic Low-grade Inflammation in Promotion of Colorectal Cancer Development.

    PubMed

    Pietrzyk, Lukasz; Torres, Anna; Maciejewski, Ryszard; Torres, Kamil

    2015-01-01

    Colorectal cancer (CRC) is a worldwide health problem, being the third most commonly detected cancer in males and the second in females. Rising CRC incidence trends are mainly regarded as a part of the rapid 'Westernization' of life-style and are associated with calorically excessive high-fat/low-fibre diet, consumption of refined products, lack of physical activity, and obesity. Most recent epidemiological and clinical investigations have consistently evidenced a significant relationship between obesity-driven inflammation in particular steps of colorectal cancer development, including initiation, promotion, progression, and metastasis. Inflammation in obesity occurs by several mechanisms. Roles of imbalanced metabolism (MetS), distinct immune cells, cytokines, and other immune mediators have been suggested in the inflammatory processes. Critical mechanisms are accounted to proinflammatory cytokines (e.g. IL-1, IL-6, IL-8) and tumor necrosis factor-α (TNF-α). These molecules are secreted by macrophages and are considered as major agents in the transition between acute and chronic inflammation and inflammation-related CRC. The second factor promoting the CRC development in obese individuals is altered adipokine concentrations (leptin and adiponectin). The role of leptin and adiponectin in cancer cell proliferation, invasion, and metastasis is attributable to the activation of several signal transduction pathways (JAK/STAT, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase (PI3K), mTOR, and 5'AMPK signaling pathways) and multiple dysregulation (COX-2 downregulation, mRNA expression). PMID:26028066

  9. Intravenous immune globulin in chronic lymphocytic leukaemia.

    PubMed Central

    Gamm, H; Huber, C; Chapel, H; Lee, M; Ries, F; Dicato, M A

    1994-01-01

    The most common complication of chronic lymphocytic leukaemia (CLL) is infection, which occurs mainly in advanced stages of disease or in those patients with hypogammaglobulinaemia. Intravenous immune globulin (IVIG) has been shown to be a useful prophylactic therapy against infections in such patients. A randomized, double-blind study on 36 patients receiving either 500 mg/kg or 250 mg/kg IVIG every 4 weeks was undertaken to determine the dose regimen required. There was no significant difference in the two treatment groups and we found that CLL patients were equally protected with low-dose IVIG. PMID:8033428

  10. Natural killer cells regulate eosinophilic inflammation in chronic rhinosinusitis

    PubMed Central

    Kim, Ji Heui; Choi, Go Eun; Lee, Bong-Jae; Kwon, Seog Woon; Lee, Seung-Hyo; Kim, Hun Sik; Jang, Yong Ju

    2016-01-01

    Eosinophils play a major pathologic role in the pathogenesis of diverse inflammatory diseases including chronic rhinosinusitis (CRS). Dysregulated production of prostaglandin (PG), particularly PGD2, is considered to be an important contributing factor to eosinophilic inflammation in CRS primarily through proinflammatory and chemotactic effects on eosinophils. Here, we provide evidence that PGD2 can promote eosinophilic inflammation through a suppression of Natural killer (NK) cell effector function and NK cell-mediated eosinophil regulation. Eosinophil apoptosis mediated by NK cells was significantly decreased in CRS patients compared with healthy controls. This decrease was associated with NK cell dysfunction and eosinophilic inflammation. Tissue eosinophils were positively correlated with blood eosinophils in CRS patients. In a murine model of CRS, NK cell depletion caused an exacerbation of blood eosinophilia and eosinophilic inflammation in the sinonasal tissue. PGD2 and its metabolite, but not PGE2 and a panel of cytokines including TGF-β, were increased in CRS patients compared with controls. Effector functions of NK cells were potently suppressed by PGD2-dependent, rather than PGE2-dependent, pathway in controls and CRS patients. Thus, our results suggest decreased NK cell-mediated eosinophil regulation, possibly through an increased level of PGD2, as a previously unrecognized link between PG dysregulation and eosinophilic inflammation in CRS. PMID:27271931

  11. Natural killer cells regulate eosinophilic inflammation in chronic rhinosinusitis.

    PubMed

    Kim, Ji Heui; Choi, Go Eun; Lee, Bong-Jae; Kwon, Seog Woon; Lee, Seung-Hyo; Kim, Hun Sik; Jang, Yong Ju

    2016-01-01

    Eosinophils play a major pathologic role in the pathogenesis of diverse inflammatory diseases including chronic rhinosinusitis (CRS). Dysregulated production of prostaglandin (PG), particularly PGD2, is considered to be an important contributing factor to eosinophilic inflammation in CRS primarily through proinflammatory and chemotactic effects on eosinophils. Here, we provide evidence that PGD2 can promote eosinophilic inflammation through a suppression of Natural killer (NK) cell effector function and NK cell-mediated eosinophil regulation. Eosinophil apoptosis mediated by NK cells was significantly decreased in CRS patients compared with healthy controls. This decrease was associated with NK cell dysfunction and eosinophilic inflammation. Tissue eosinophils were positively correlated with blood eosinophils in CRS patients. In a murine model of CRS, NK cell depletion caused an exacerbation of blood eosinophilia and eosinophilic inflammation in the sinonasal tissue. PGD2 and its metabolite, but not PGE2 and a panel of cytokines including TGF-β, were increased in CRS patients compared with controls. Effector functions of NK cells were potently suppressed by PGD2-dependent, rather than PGE2-dependent, pathway in controls and CRS patients. Thus, our results suggest decreased NK cell-mediated eosinophil regulation, possibly through an increased level of PGD2, as a previously unrecognized link between PG dysregulation and eosinophilic inflammation in CRS. PMID:27271931

  12. Expression of Heat Shock Protein 27 in Benign Prostatic Hyperplasia with Chronic Inflammation

    PubMed Central

    Jiang, Yuqing; Wang, Xiuli; Guo, Yuexian; Li, Wenping; Yang, Shijie; Li, Wei; Cai, Wenqing

    2015-01-01

    Background Heat shock protein 27 (HSP 27) is known as a mediator in immune response and has been recently found to be expressed in prostate cancer. This study aimed to investigate the role of HSP27 in inflammatory BPH. Material/Methods Hospitalized BPH patients who received TURP were divided into 4 groups by the presence and degrees of chronic inflammation: non-inflammatory BPH (NI BPH), mild-inflammatory BPH (MI BPH), moderate-inflammatory BPH (MOI BPH), and severe-inflammatory BPH (SI BPH). Expressions of HSP 27, TNF-α, IL-6, and CD3 in prostate tissues and serum of patients were detected by immunohistochemistry and ELISA. Results Expression of HSP27 in BPH with histological inflammation was significantly higher than in non-inflammatory BPH. In inflammatory BPH groups, HSP27 expression gradually increased along with increasing inflammation. There was a significant correlation between the expression of TNF-α, IL-6, CD3 and HSP27 among different inflammatory BPH groups. Conclusions HSP27 expression level is associated with the degree of chronic inflammation in BPH and may participate in the pathological process in inflammatory BPH. PMID:26434601

  13. Serum Autoantibodies in Chronic Prostate Inflammation in Prostate Cancer Patients

    PubMed Central

    Schlick, Bettina; Massoner, Petra; Lueking, Angelika; Charoentong, Pornpimol; Blattner, Mirjam; Schaefer, Georg; Marquart, Klaus; Theek, Carmen; Amersdorfer, Peter; Zielinski, Dirk; Kirchner, Matthias; Trajanoski, Zlatko; Rubin, Mark A.; Müllner, Stefan; Schulz-Knappe, Peter; Klocker, Helmut

    2016-01-01

    Background Chronic inflammation is frequently observed on histological analysis of malignant and non-malignant prostate specimens. It is a suspected supporting factor for prostate diseases and their progression and a main cause of false positive PSA tests in cancer screening. We hypothesized that inflammation induces autoantibodies, which may be useful biomarkers. We aimed to identify and validate prostate inflammation associated serum autoantibodies in prostate cancer patients and evaluate the expression of corresponding autoantigens. Methods Radical prostatectomy specimens of prostate cancer patients (N = 70) were classified into high and low inflammation groups according to the amount of tissue infiltrating lymphocytes. The corresponding pre-surgery blood serum samples were scrutinized for autoantibodies using a low-density protein array. Selected autoantigens were identified in prostate tissue and their expression pattern analyzed by immunohistochemistry and qPCR. The identified autoantibody profile was cross-checked in an independent sample set (N = 63) using the Luminex-bead protein array technology. Results Protein array screening identified 165 autoantibodies differentially abundant in the serum of high compared to low inflammation patients. The expression pattern of three corresponding antigens were established in benign and cancer tissue by immunohistochemistry and qPCR: SPAST (Spastin), STX18 (Syntaxin 18) and SPOP (speckle-type POZ protein). Of these, SPAST was significantly increased in prostate tissue with high inflammation. All three autoantigens were differentially expressed in primary and/or castration resistant prostate tumors when analyzed in an inflammation-independent tissue microarray. Cross-validation of the inflammation autoantibody profile on an independent sample set using a Luminex-bead protein array, retrieved 51 of the significantly discriminating autoantibodies. Three autoantibodies were significantly upregulated in both screens, MUT

  14. miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation.

    PubMed

    Hu, Ruozhen; Kagele, Dominique A; Huffaker, Thomas B; Runtsch, Marah C; Alexander, Margaret; Liu, Jin; Bake, Erin; Su, Wei; Williams, Matthew A; Rao, Dinesh S; Möller, Thomas; Garden, Gwenn A; Round, June L; O'Connell, Ryan M

    2014-10-16

    Chronic inflammation is a contributing factor to most life-shortening human diseases. However, the molecular and cellular mechanisms that sustain chronic inflammatory responses remain poorly understood, making it difficult to treat this deleterious condition. Using a mouse model of age-dependent inflammation that results from a deficiency in miR-146a, we demonstrate that miR-155 contributed to the progressive inflammatory disease that emerged as Mir146a(-/-) mice grew older. Upon analyzing lymphocytes from inflamed versus healthy middle-aged mice, we found elevated numbers of T follicular helper (Tfh) cells, germinal center (GC) B cells, and autoantibodies, all occurring in a miR-155-dependent manner. Further, Cd4-cre Mir155(fl/fl) mice were generated and demonstrated that miR-155 functions in T cells, in addition to its established role in B cells, to promote humoral immunity in a variety of contexts. Taken together, our study discovers that miR-146a and miR-155 counterregulate Tfh cell development that drives aberrant GC reactions during chronic inflammation. PMID:25367574

  15. The Interplay between NLRs and Autophagy in Immunity and Inflammation

    PubMed Central

    Carneiro, Leticia A. M.; Travassos, Leonardo H.

    2013-01-01

    Since they were first described as cytosolic sensors of microbial molecules a decade ago, the Nod-like receptors (NLRs) have been shown to have many different and important roles in various aspects of immune and inflammatory responses, ranging from antimicrobial mechanisms to control of adaptive responses. In this review, we focus on the interplay between NLRs and autophagy, an evolutionarily conserved mechanism that is crucial for homeostasis and has recently been shown to be involved in the protective response against infections. Furthermore, the association between mutations of NLRs as well as proteins that form the autophagic machinery and inflammatory diseases such as Crohn’s disease highlight the importance of these proteins and their interactions in the regulation of inflammation. PMID:24273538

  16. Inhalation of Environmental Stressors & Chronic Inflammation: Autoimmunity and Neurodegeneration

    PubMed Central

    Gomez-Mejiba, Sandra E.; Zhai, Zili; Akram, Hammad; Pye, Quentin N.; Hensley, Kenneth; Kurien, Biji T.; Scofield, R. Hal; Ramirez, Dario C.

    2009-01-01

    Human life expectancy and welfare has decreased because of the increase in environmental stressors in the air. An environmental stressor is a natural or human-made component present in our environment that upon reaching an organic system produces a coordinated response. This response usually involves a modification of the metabolism and physiology of the system. Inhaled environmental stressors damage the airways and lung parenchyma, producing irritation, recruitment of inflammatory cells, and oxidative modification of biomolecules. Oxidatively modified biomolecules, their degradation products, and adducts with other biomolecules can reach the systemic circulation, and when found in higher concentrations than normal they are considered to be biomarkers of systemic oxidative stress and inflammation. We classify them as metabolic stressors because they are not inert compounds; indeed, they amplify the inflammatory response by inducing inflammation in the lung and other organs. Thus the lung is not only the target for environmental stressors, but it is also the source of a number of metabolic stressors that can induce and worsen pre-existing chronic inflammation. Metabolic stressors produced in the lung have a number of effects in tissues other than the lung, such as the brain, and they can also abrogate the mechanisms of immunotolerance. In this review, we discuss recent published evidence that suggests that inflammation in the lung is an important connection between air pollution and chronic inflammatory diseases such as autoimmunity and neurodegeneration, and we highlight the critical role of metabolic stressors produced in the lung. The understanding of this relationship between inhaled environmental pollutants and systemic inflammation will help us to: 1) understand the molecular mechanism of environment-associated diseases, and 2) find new biomarkers that will help us prevent the exposure of susceptible individuals and/or design novel therapies. PMID:18977456

  17. Chronic schistosome infection leads to modulation of granuloma formation and systemic immune suppression

    PubMed Central

    Lundy, Steven K.; Lukacs, Nicholas W.

    2012-01-01

    Schistosome worms have been infecting humans for millennia, but it is only in the last half century that we have begun to understand the complexities of this inter-relationship. As our sophistication about the inner workings of every aspect of the immune system has increased, it has also become obvious that schistosome infections have broad ranging effects on nearly all of the innate and adaptive immune response mechanisms. Selective pressures on both the worms and their hosts, has no doubt led to co-evolution of protective mechanisms, particularly those that favor granuloma formation around schistosome eggs and immune suppression during chronic infection. The immune modulatory effects that chronic schistosome infection and egg deposition elicit have been intensely studied, not only because of their major implications to public health issues, but also due to the emerging evidence that schistosome infection may protect humans from severe allergies and autoimmunity. Mouse models of schistosome infection have been extremely valuable for studying immune modulation and regulation, and in the discovery of novel aspects of immunity. A progression of immune reactions occurs during granuloma formation ranging from innate inflammation, to activation of each branch of adaptive immune response, and culminating in systemic immune suppression and granuloma fibrosis. Although molecular factors from schistosome eggs have been identified as mediators of immune modulation and suppressive functions of T and B cells, much work is still needed to define the mechanisms of the immune alteration and determine whether therapies for asthma or autoimmunity could be developed from these pathways. PMID:23429492

  18. Myeloid cell TRAF3 regulates immune responses and inhibits inflammation and tumor development in mice.

    PubMed

    Lalani, Almin I; Moore, Carissa R; Luo, Chang; Kreider, Benjamin Z; Liu, Yan; Morse, Herbert C; Xie, Ping

    2015-01-01

    Myeloid cells, including granulocytes, monocytes, macrophages, and dendritic cells, are crucial players in innate immunity and inflammation. These cells constitutively or inducibly express a number of receptors of the TNFR and TLR families, whose signals are transduced by TNFR-associated factor (TRAF) molecules. In vitro studies showed that TRAF3 is required for TLR-induced type I IFN production, but the in vivo function of TRAF3 in myeloid cells remains unknown. In this article, we report the generation and characterization of myeloid cell-specific TRAF3-deficient (M-TRAF3(-/-)) mice, which allowed us to gain insights into the in vivo functions of TRAF3 in myeloid cells. We found that TRAF3 ablation did not affect the maturation or homeostasis of myeloid cells in young adult mice, even though TRAF3-deficient macrophages and neutrophils exhibited constitutive NF-κB2 activation. However, in response to injections with LPS (a bacterial mimic) or polyinosinic-polycytidylic acid (a viral mimic), M-TRAF3(-/-) mice exhibited an altered profile of cytokine production. M-TRAF3(-/-) mice immunized with T cell-independent and -dependent Ags displayed elevated T cell-independent IgG3 and T cell-dependent IgG2b responses. Interestingly, 15- to 22-mo-old M-TRAF3(-/-) mice spontaneously developed chronic inflammation or tumors, often affecting multiple organs. Taken together, our findings indicate that TRAF3 expressed in myeloid cells regulates immune responses in myeloid cells and acts to inhibit inflammation and tumor development in mice. PMID:25422508

  19. Immune mediators of chronic pelvic pain syndrome

    PubMed Central

    Murphy, Stephen F.; Schaeffer, Anthony J.; Thumbikat, Praveen

    2016-01-01

    The cause of chronic pelvic pain syndrome (CPPS) has yet to be established. Since the late 1980s, cytokine, chemokine, and immunological classification studies using human samples have focused on identifying biomarkers for CPPS, but no diagnostically beneficial biomarkers have been identified, and these studies have done little to deepen our understanding of the mechanisms underlying chronic prostatic pain. Given the large number of men thought to be affected by this condition and the ineffective nature of current treatments, there is a pressing need to elucidate these mechanisms. Prostatitis types IIIa and IIIb are classified according to the presence of pain without concurrent presence of bacteria; however, it is becoming more evident that, although levels of bacteria are not directly associated with levels of pain, the presence of bacteria might act as the initiating factor that drives primary activation of mast-cell-mediated inflammation in the prostate. Mast cell activation is also known to suppress regulatory T cell (Treg) control of self-tolerance and also activate neural sensitization. This combination of established autoimmunity coupled with peripheral and central neural sensitization can result in the development of multiple symptoms, including pelvic pain and bladder irritation. Identifying these mechanisms as central mediators in CPPS offers new insight into the prospective treatment of the disease. PMID:24686526

  20. Immune mediators of chronic pelvic pain syndrome.

    PubMed

    Murphy, Stephen F; Schaeffer, Anthony J; Thumbikat, Praveen

    2014-05-01

    The cause of chronic pelvic pain syndrome (CPPS) has yet to be established. Since the late 1980s, cytokine, chemokine, and immunological classification studies using human samples have focused on identifying biomarkers for CPPS, but no diagnostically beneficial biomarkers have been identified, and these studies have done little to deepen our understanding of the mechanisms underlying chronic prostatic pain. Given the large number of men thought to be affected by this condition and the ineffective nature of current treatments, there is a pressing need to elucidate these mechanisms. Prostatitis types IIIa and IIIb are classified according to the presence of pain without concurrent presence of bacteria; however, it is becoming more evident that, although levels of bacteria are not directly associated with levels of pain, the presence of bacteria might act as the initiating factor that drives primary activation of mast-cell-mediated inflammation in the prostate. Mast cell activation is also known to suppress regulatory T cell (Treg) control of self-tolerance and also activate neural sensitization. This combination of established autoimmunity coupled with peripheral and central neural sensitization can result in the development of multiple symptoms, including pelvic pain and bladder irritation. Identifying these mechanisms as central mediators in CPPS offers new insight into the prospective treatment of the disease. PMID:24686526

  1. Systemic inflammation after inspiratory loading in chronic obstructive pulmonary disease

    PubMed Central

    Fuster, Antonia; Sauleda, Jaume; Sala, Ernest; Barceló, Bernardí; Pons, Jaume; Carrera, Miguel; Noguera, Aina; Togores, Bernat; Agustí, Alvar GN

    2008-01-01

    Objective Patients with chronic obstructive pulmonary disease (COPD) present systemic inflammation. Strenuous resistive breathing induces systemic inflammation in healthy subjects. We hypothesized that the increased respiratory load that characterizes COPD can contribute to systemic inflammation in these patients. Patients and methods To test this hypothesis, we compared leukocyte numbers and levels of circulating cytokines (tumor necrosis factor alpha [TNFα], interleukin-1β [IL-1β], IL-6, IL-8, and IL-10), before and 1 hour after maximal incremental inspiratory loading in 13 patients with stable COPD (forced expiratory volume in one second [FEV1] 29 ± 2.5% ref) and in 8 healthy sedentary subjects (FEV1 98 ± 5% ref). Results We found that: (1) at baseline, patients with COPD showed higher leukocyte counts and IL-8 levels than controls (p < 0.01); and, (2) one hour after maximal inspiratory loading these values were unchanged, except for IL-10, which increased in controls (p < 0.05) but not in patients with COPD. Conclusions This study confirms the presence of systemic inflammation in COPD, shows that maximal inspiratory loading does not increase the levels of pro-inflammatory cytokines (IL-1β, IL-8) in COPD patients or controls, but suggests that the former may be unable to mount an appropriate systemic anti-inflammatory response to exercise. PMID:18488438

  2. Toxic stress, inflammation and symptomatology of chronic complications in diabetes

    PubMed Central

    Downs, Charles A; Faulkner, Melissa Spezia

    2015-01-01

    Diabetes affects at least 382 million people worldwide and the incidence is expected to reach 592 million by 2035. The incidence of diabetes in youth is skyrocketing as evidenced by a 21% increase in type 1 diabetes and a 30.5% increase in type 2 diabetes in the United States between 2001 and 2009. The effects of toxic stress, the culmination of biological and environmental interactions, on the development of diabetes complications is gaining attention. Stress impacts the hypothalamus-pituitary-adrenal axis and contributes to inflammation, a key biological contributor to the pathogenesis of diabetes and its associated complications. This review provides an overview of common diabetic complications such as neuropathy, cognitive decline, depression, nephropathy and cardiovascular disease. The review also provides a discussion of the role of inflammation and stress in the development and progression of chronic complications of diabetes, associated symptomatology and importance of early identification of symptoms of depression, fatigue, exercise intolerance and pain. PMID:25987953

  3. The cutaneous vascular system in chronic skin inflammation

    PubMed Central

    Huggenberger, Reto; Detmar, Michael

    2011-01-01

    The blood and lymphatic vasculature play an important role in skin homeostasis. Angiogenesis and lymphangiogenesis – the growth of new vessels from existing ones - have received tremendous interest because of their role in promoting cancer spread. However, there is increasing evidence that both vessel types also play a major role in acute and chronic inflammatory disorders. Vessels change their phenotype in inflammation (vascular remodeling). In inflamed skin, vascular remodeling consists of a hyperpermeable, enlarged network of vessels with increased blood flow, and influx of inflammatory cells. During chronic inflammation, the activated endothelium expresses adhesion molecules, cytokines, and other molecules that lead to leukocyte rolling, attachment and migration into the skin. Recent studies reveal that inhibition of blood vessel activation exerts potent anti-inflammatory properties. Thus, anti-angiogenic drugs might be used to treat inflammatory conditions. In particular, topical application of anti-angiogenic drugs might be ideally suited to circumvent the adverse effects of systemic therapy with angiogenesis inhibitors. Our recent results indicate that stimulation of lymphatic vessel growth and function unexpectedly represents a novel approach for treating chronic inflammatory disorders. PMID:22076324

  4. Topical steroids for chronic wounds displaying abnormal inflammation

    PubMed Central

    Rangaraj, A; Richards, AJ; Riddell, A; Saravolac, VM; Harding, KG

    2013-01-01

    Introduction Chronic, non-healing wounds are often characterised by an excessive, and detrimental, inflammatory response. We review our experience of using a combined topical steroid, antibiotic and antifungal preparation in the treatment of chronic wounds displaying abnormal and excessive inflammation. Methods A retrospective review was undertaken of all patients being treated with a topical preparation containing a steroid (clobetasone butyrate 0.05%), antibiotic and antifungal at a tertiary wound healing centre over a ten-year period. Patients were selected as the primary treating physician felt the wounds were displaying excessive inflammation. Healing rates were calculated for before and during this treatment period for each patient. Changes in symptom burden (pain, odour and exudate levels) following topical application were also calculated. Results Overall, 34 ulcers were identified from 25 individual patients (mean age: 65 years, range: 37–97 years) and 331 clinic visits were analysed, spanning a total time of 14,670 days (7,721 days ‘before treatment’ time, 6,949 days ‘during treatment’ time). Following treatment, 24 ulcers demonstrated faster rates of healing, 3 ulcers showed no significant change in healing rates and 7 were healing more slowly (p=0.0006). Treatment generally reduced the burden of pain and exudate, without affecting odour. Conclusions In normal wound healing, inflammation represents a transient but essential phase of tissue repair. In selected cases, direct application of a steroid containing agent has been shown to improve healing rates, presumably by curtailing this phase. Further evaluation is required to establish the role of preparations containing topical steroids without antimicrobials in the management of chronic wounds. PMID:23676816

  5. Immunoglobulin E and Allergy: Antibodies in Immune Inflammation and Treatment.

    PubMed

    Karagiannis, Sophia N; Karagiannis, Panagiotis; Josephs, Debra H; Saul, Louise; Gilbert, Amy E; Upton, Nadine; Gould, Hannah J

    2013-10-01

    The pathogenic role of immunoglobulin E (IgE) antibodies in triggering and maintaining allergic inflammation in response to allergens is due to the binding of multivalent allergens to allergen-specific IgEs on sensitized effector cells. These interactions trigger effector cell activation, resulting in release of potent inflammatory mediators, recruitment of inflammatory cells, antigen presentation, and production of allergen-specific antibody responses. Since its discovery in the 1960s, the central role of IgE in allergic disease has been intensively studied, placing IgE and its functions at the heart of therapeutic efforts for the treatment of allergies. Here, we provide an overview of the nature, roles, and significance of IgE antibodies in allergic diseases, infections, and inflammation and the utility of antibodies as therapies. We place special emphasis on allergen-IgE-Fcε receptor complexes in the context of allergic and inflammatory diseases and describe strategies, including monoclonal antibodies, aimed at interrupting these complexes. Of clinical significance, one antibody, omalizumab, is presently in clinical use and works by preventing formation of IgE-Fcε receptor interactions. Active immunotherapy approaches with allergens and allergen derivatives have also demonstrated clinical benefits for patients with allergic diseases. These treatments are strongly associated with serum increases of IgE-neutralizing antibodies and feature a notable redirection of humoral responses towards production of antibodies of the IgG4 subclass in patients receiving immunotherapies. Lastly, we provide a new perspective on the rise of recombinant antibodies of the IgE class recognizing tumor-associated antigens, and we discuss the potential utility of tumor antigen-specific IgE antibodies to direct potent IgE-driven immune responses against tumors. PMID:26184813

  6. IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation.

    PubMed

    Mayo, Lior; Cunha, Andre Pires Da; Madi, Asaf; Beynon, Vanessa; Yang, Zhiping; Alvarez, Jorge I; Prat, Alexandre; Sobel, Raymond A; Kobzik, Lester; Lassmann, Hans; Quintana, Francisco J; Weiner, Howard L

    2016-07-01

    SEE WINGER AND ZAMVIL DOI101093/BRAIN/AWW121 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The innate immune system plays a central role in the chronic central nervous system inflammation that drives neurological disability in progressive forms of multiple sclerosis, for which there are no effective treatments. The mucosal immune system is a unique tolerogenic organ that provides a physiological approach for the induction of regulatory T cells. Here we report that nasal administration of CD3-specific antibody ameliorates disease in a progressive animal model of multiple sclerosis. This effect is IL-10-dependent and is mediated by the induction of regulatory T cells that share a similar transcriptional profile to Tr1 regulatory cells and that suppress the astrocyte inflammatory transcriptional program. Treatment results in an attenuated inflammatory milieu in the central nervous system, decreased microglia activation, reduced recruitment of peripheral monocytes, stabilization of the blood-brain barrier and less neurodegeneration. These findings suggest a new therapeutic approach for the treatment of progressive forms of multiple sclerosis and potentially other types of chronic central nervous system inflammation. PMID:27246324

  7. IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation

    PubMed Central

    Mayo, Lior; Cunha, Andre Pires Da; Madi, Asaf; Beynon, Vanessa; Yang, Zhiping; Alvarez, Jorge I.; Prat, Alexandre; Sobel, Raymond A.; Kobzik, Lester; Lassmann, Hans; Quintana, Francisco J.

    2016-01-01

    See Winger and Zamvil (doi:10.1093/brain/aww121) for a scientific commentary on this article. The innate immune system plays a central role in the chronic central nervous system inflammation that drives neurological disability in progressive forms of multiple sclerosis, for which there are no effective treatments. The mucosal immune system is a unique tolerogenic organ that provides a physiological approach for the induction of regulatory T cells. Here we report that nasal administration of CD3-specific antibody ameliorates disease in a progressive animal model of multiple sclerosis. This effect is IL-10-dependent and is mediated by the induction of regulatory T cells that share a similar transcriptional profile to Tr1 regulatory cells and that suppress the astrocyte inflammatory transcriptional program. Treatment results in an attenuated inflammatory milieu in the central nervous system, decreased microglia activation, reduced recruitment of peripheral monocytes, stabilization of the blood–brain barrier and less neurodegeneration. These findings suggest a new therapeutic approach for the treatment of progressive forms of multiple sclerosis and potentially other types of chronic central nervous system inflammation. PMID:27246324

  8. Predomination of IL-17-producing tryptase-positive/chymase-positive mast cells in azoospermic chronic testicular inflammation.

    PubMed

    Chen, S-J; Duan, Y-G; Haidl, G; Allam, J-P

    2016-08-01

    Chronic testicular inflammation and infection have been regarded as important factors in the pathogenesis of azoospermia. As key effector cells in innate and adaptive immune system, mast cells (MCs) were observed in inflammation and autoimmune disease. Furthermore, increased expression of tryptase-positive MCs has been reported in testicular disorders associated with male infertility/subfertility. However, little is known about the potential relationship between MCs and chronic testicular inflammation in azoospermic patients. Moreover, the preferential expression of MCs' subtypes in testis of these patients is still far from being understood. Thus, this study aimed to investigate characteristics of testicular MCs as well as their subtypes in azoospermic men with chronic testicular inflammation (AZI, n = 5) by immunohistochemical techniques. Our results showed significant increase of MCs in AZI, and more importantly, considerable numbers of tryptase-positive/chymase-positive MCs could also be demonstrated in AZI, when compared to control groups representing azoospermia without chronic testicular inflammation (AZW, n = 5) and normal spermatogenesis (NT, n = 5) respectively. Most interestingly, immunofluorescence staining revealed autoimmune-associated interleukin (IL)-17-producing MCs in AZI, whereas co-expression of MC markers with tumour necrosis factor (TNF)-α, IL-10 and IL-1β could not be detected. In conclusion, AZI is associated with significant increase of tryptase-positive/chymase-positive MCs expressing IL-17, and these MCs might contribute to the pathogenesis of AZI. PMID:26420243

  9. The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation.

    PubMed

    Grabiec, Aleksander M; Hussell, Tracy

    2016-07-01

    Acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by phagocytes in a process called 'efferocytosis'. Apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non-professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. Efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. Disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released 'damage associated molecular patterns' (DAMPS). To control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. However, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases Tyro3, Axl and MerTK (TAM), may delay or prevent inflammatory responses to subsequent infections. In this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections. PMID:26957481

  10. Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation.

    PubMed

    Garn, Holger; Bahn, Sabine; Baune, Bernhard T; Binder, Elisabeth B; Bisgaard, Hans; Chatila, Talal A; Chavakis, Triantafyllos; Culmsee, Carsten; Dannlowski, Udo; Gay, Steffen; Gern, James; Haahtela, Tari; Kircher, Tilo; Müller-Ladner, Ulf; Neurath, Markus F; Preissner, Klaus T; Reinhardt, Christoph; Rook, Graham; Russell, Shannon; Schmeck, Bernd; Stappenbeck, Thaddeus; Steinhoff, Ulrich; van Os, Jim; Weiss, Scott; Zemlin, Michael; Renz, Harald

    2016-07-01

    Recent research indicates that chronic inflammatory diseases, including allergies and autoimmune and neuropsychiatric diseases, share common pathways of cellular and molecular dysregulation. It was the aim of the International von-Behring-Röntgen Symposium (October 16-18, 2014, in Marburg, Germany) to discuss recent developments in this field. These include a concept of biodiversity; the contribution of urbanization, lifestyle factors, and nutrition (eg, vitamin D); and new mechanisms of metabolic and immune dysregulation, such as extracellular and intracellular RNAs and cellular and mitochondrial stress. Epigenetic mechanisms contribute further to altered gene expression and therefore to the development of chronic inflammation. These novel findings provide the foundation for further development of preventive and therapeutic strategies. PMID:27373325

  11. Effects of environmental pollutants on airways, allergic inflammation, and the immune response.

    PubMed

    Handzel, Z T

    2000-01-01

    Particulate and gaseous air pollutants are capable of damaging the airway epithelial lining and of shifting the local immune balance, thereby facilitating the induction of persistent inflammation. Epidemiological studies are inconclusive regarding whether air pollution increases the incidence of asthma and chronic bronchitis in the population. Clearly, environmental pollution can, however, precipitate attacks and emergency-room admissions in those already suffering from such conditions. The catastrophic potential of airborne pollution was demonstrated in the 1960s and 1970s, when inverted atmospheric pressure conditions trapped smog over cities on the Eastern coast of the United States and over Europe. This smog resulted in thousands of hospital admissions and dozens of deaths. With the general rise in the incidence of atopy and asthma in the Western population, it is of major public health interest to reduce, as much as possible, the exposure of such populations to anthropogenic and natural sources of pollution. PMID:11048334

  12. Diffuse large B cell lymphoma with chronic granulomatous inflammation.

    PubMed

    Nyunt, W W T; Wong, Y P; Wan Jamaludin, W F; Abdul Wahid, S F S

    2016-04-01

    Non-necrotic epithelioid granulomas have been reported in association with neoplasms including Hodgkin and non-Hodgkin lymphoma. We report a case of diffuse large B cell lymphoma with chronic granulomatous inflammation to highlight awareness of obscure tumour cells within the granuloma, to avoid delay in diagnosis and management of lymphoma. A 39-year-old Malay lady with no past medical history, presented with a 2-month history of progressive worsening of difficulty in breathing, cough, low-grade fever, loss of weight and loss of appetite. Chest X-ray showed an anterior mediastinal mass and computed tomography (CT)-guided biopsy was reported as chronic granulomatous inflammation suggestive of tuberculosis. After 2 months of anti-TB treatment, her symptoms were not relieved. The patient underwent another CT-guided biopsy of the anterior mediastinal mass in another hospital and the histopathology revealed diffuse large B cell lymphoma. The patient was referred for treatment. On histopathological review, the first sample showed noncaseating granulomas engulfing tumour cells and large abnormal lymphoid cells which were CD20 positive and with high Ki-67 proliferative index. The patient was diagnosed with diffuse large B cell lymphoma stage IV B IPSS score 3. She underwent chemotherapy (R-EPOCH) and responded well to treatment. PMID:27126666

  13. STATs in cancer inflammation and immunity: a leading role for STAT3

    PubMed Central

    Yu, Hua; Pardoll, Drew; Jove, Richard

    2016-01-01

    Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-κB (NF-κB) and interleukin-6 (IL-6)–GP130–Janus kinase (JAK) pathways, and by opposing STAT1- and NF-κB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy. PMID:19851315

  14. Olfactomedin 4 expression and functions in innate immunity, inflammation, and cancer.

    PubMed

    Liu, Wenli; Rodgers, Griffin P

    2016-06-01

    Olfactomedin 4 (OLFM4) is an olfactomedin domain-containing glycoprotein. Multiple signaling pathways and factors, including NF-κB, Wnt, Notch, PU.1, retinoic acids, estrogen receptor, and miR-486, regulate its expression. OLFM4 interacts with several other proteins, such as gene associated with retinoic-interferon-induced mortality 19 (GRIM-19), cadherins, lectins, nucleotide oligomerization domain-1 (NOD1) and nucleotide oligomerization domain-2 (NOD2), and cathepsins C and D, known to regulate important cellular functions. Recent investigations using Olfm4-deficient mouse models have provided important clues about its in vivo biological functions. Olfm4 inhibited Helicobacter pylori-induced NF-κB pathway activity and inflammation and facilitated H. pylori colonization in the mouse stomach. Olfm4-deficient mice exhibited enhanced immunity against Escherichia coli and Staphylococcus aureus infection. Olfm4 deletion in a chronic granulomatous disease mouse model rescued them from S. aureus infection. Olfm4 deletion in mice treated with azoxymethane/dextran sodium sulfate led to robust intestinal inflammation and intestinal crypt hyperplasia. Olfm4 deletion in Apc (Min/+) mice promoted intestinal polyp formation as well as adenocarcinoma development in the distal colon. Further, Olfm4-deficient mice spontaneously developed prostatic epithelial lesions as they age. OLFM4 expression is correlated with cancer differentiation, stage, metastasis, and prognosis in a variety of cancers, suggesting its potential clinical value as an early-stage cancer marker or a therapeutic target. Collectively, these data suggest that OLFM4 plays important roles in innate immunity against bacterial infection, gastrointestinal inflammation, and cancer. In this review, we have summarized OLFM4's initial characterization, expression, regulation, protein interactions, and biological functions. PMID:27178440

  15. Mast Cells as Cellular Sensors in Inflammation and Immunity

    PubMed Central

    Beghdadi, Walid; Madjene, Lydia Célia; Benhamou, Marc; Charles, Nicolas; Gautier, Gregory; Launay, Pierre; Blank, Ulrich

    2011-01-01

    Mast cells are localized in tissues. Intense research on these cells over the years has demonstrated their role as effector cells in the maintenance of tissue integrity following injury produced by infectious agents, toxins, metabolic states, etc. After stimulation they release a sophisticated array of inflammatory mediators, cytokines, and growth factors to orchestrate an inflammatory response. These mediators can directly initiate tissue responses on resident cells, but they have also been shown to regulate other infiltrating immune cell functions. Research in recent years has revealed that the outcome of mast cell actions is not always detrimental for the host but can also limit disease development. In addition, mast cell functions highly depend on the physiological context in the organism. Depending on the genetic background, strength of the injurious event, the particular microenvironment, mast cells direct responses ranging from pro- to anti-inflammatory. It appears that they have evolved as cellular sensors to discern their environment in order to initiate an appropriate physiological response either aimed to favor inflammation for repair or at the contrary limit the inflammatory process to prevent further damage. Like every sophisticated machinery, its dysregulation leads to pathology. Given the broad distribution of mast cells in tissues this also explains their implication in many inflammatory diseases. PMID:22566827

  16. Asbestos-Induced Cellular and Molecular Alteration of Immunocompetent Cells and Their Relationship with Chronic Inflammation and Carcinogenesis

    PubMed Central

    Matsuzaki, Hidenori; Maeda, Megumi; Lee, Suni; Nishimura, Yasumitsu; Kumagai-Takei, Naoko; Hayashi, Hiroaki; Yamamoto, Shoko; Hatayama, Tamayo; Kojima, Yoko; Tabata, Rika; Kishimoto, Takumi; Hiratsuka, Junichi; Otsuki, Takemi

    2012-01-01

    Asbestos causes lung fibrosis known as asbestosis as well as cancers such as malignant mesothelioma and lung cancer. Asbestos is a mineral silicate containing iron, magnesium, and calcium with a core of SiO2. The immunological effect of silica, SiO2, involves the dysregulation of autoimmunity because of the complications of autoimmune diseases found in silicosis. Asbestos can therefore cause alteration of immunocompetent cells to result in a decline of tumor immunity. Additionally, due to its physical characteristics, asbestos fibers remain in the lung, regional lymph nodes, and the pleural cavity, particularly at the opening sites of lymphatic vessels. Asbestos can induce chronic inflammation in these areas due to the production of reactive oxygen/nitrogen species. As a consequence, immunocompetent cells can have their cellular and molecular features altered by chronic and recurrent encounters with asbestos fibers, and there may be modification by the surrounding inflammation, all of which eventually lead to decreased tumor immunity. In this paper, the brief results of our investigation regarding reduction of tumor immunity of immunocompetent cells exposed to asbestos in vitro are discussed, as are our findings concerned with an investigation of chronic inflammation and analyses of peripheral blood samples derived from patients with pleural plaque and mesothelioma that have been exposed to asbestos. PMID:22500091

  17. The Role of the Transcriptional Regulation of Stromal Cells in Chronic Inflammation

    PubMed Central

    Valin, Alvaro; Pablos, José L.

    2015-01-01

    Chronic inflammation is a common process connecting pathologies that vary in their etiology and pathogenesis such as cancer, autoimmune diseases, and infections. The response of the immune system to tissue damage involves a carefully choreographed series of cellular interactions between immune and non-immune cells. In recent years, it has become clear that stromal resident cells have an essential role perpetuating the inflammatory environment and dictating in many cases the outcome of inflammatory based pathologies. Signal transduction pathways remain the main focus of study to understand how stimuli contribute to perpetuating the inflammatory response, mainly due to their potential role as therapeutic targets. However, molecular events orchestrated in the nucleus by transcription factors add additional levels of complexity and may be equally important for understanding the phenotypic differences of activated stromal components during the chronic inflammatory process. In this review, we focus on the contribution of transcription factors to the selective regulation of inducible proinflammatory genes, with special attention given to the regulation of the stromal fibroblastic cell function and response. PMID:26501341

  18. Interplay between Helicobacter pylori and immune cells in immune pathogenesis of gastric inflammation and mucosal pathology

    PubMed Central

    Tsai, Hwei-Fang; Hsu, Ping-Ning

    2010-01-01

    Helicobacter pylori infection is associated with an inflammatory response in the gastric mucosa, leading to chronic gastritis, peptic ulcers, gastric carcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. Recent studies have shown that apoptosis of gastric epithelial cells is increased during H. pylori infection. Apoptosis induced by microbial infections are factors implicated in the pathogenesis of H. pylori infection. The enhanced gastric epithelial cell apoptosis in H. pylori infection has been suggested to play an important role in the pathogenesis of chronic gastritis and gastric pathology. In addition to directly triggering apoptosis, H. pylori induces sensitivity to tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in gastric epithelial cells via modulation of TRAIL apoptosis signaling. Moreover, H. pylori infection induces infiltration of T lymphocytes and triggers inflammation to augment apoptosis. In H. pylori infection, there was significantly increased CCR6+CD3+ T-cell infiltration in the gastric mucosa, and the CCR6 ligand, CCL20 chemokine, was selectively expressed in inflamed gastric tissues. These results implicate that the interaction between CCL20 and CCR6 may play a role in recruiting T cells to the sites of inflammation in the gastric mucosa during Helicobacter infection. Through these mechanisms, chemokine-mediated T lymphocyte trafficking into inflamed epithelium is initiated and the mucosal injury in Helicobacter infection is induced. This article will review the recent novel findings on the interactions of H. pylori with diverse host epithelial signaling pathways and events involved in the initiation of gastric pathology, including gastric inflammation, mucosal damage and development of MALT lymphomas. PMID:20190789

  19. Bioactive Compounds Isolated from Microalgae in Chronic Inflammation and Cancer

    PubMed Central

    Talero, Elena; García-Mauriño, Sofía; Ávila-Román, Javier; Rodríguez-Luna, Azahara; Alcaide, Antonio; Motilva, Virginia

    2015-01-01

    The risk of onset of cancer is influenced by poorly controlled chronic inflammatory processes. Inflammatory diseases related to cancer development include inflammatory bowel disease, which can lead to colon cancer, or actinic keratosis, associated with chronic exposure to ultraviolet light, which can progress to squamous cell carcinoma. Chronic inflammatory states expose these patients to a number of signals with tumorigenic effects, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) activation, pro-inflammatory cytokines and prostaglandins release and ROS production. In addition, the participation of inflammasomes, autophagy and sirtuins has been demonstrated in pathological processes such as inflammation and cancer. Chemoprevention consists in the use of drugs, vitamins, or nutritional supplements to reduce the risk of developing or having a recurrence of cancer. Numerous in vitro and animal studies have established the potential colon and skin cancer chemopreventive properties of substances from marine environment, including microalgae species and their products (carotenoids, fatty acids, glycolipids, polysaccharides and proteins). This review summarizes the main mechanisms of actions of these compounds in the chemoprevention of these cancers. These actions include suppression of cell proliferation, induction of apoptosis, stimulation of antimetastatic and antiangiogenic responses and increased antioxidant and anti-inflammatory activity. PMID:26437418

  20. Effect of mesenchymal stem cells on inhibiting airway remodeling and airway inflammation in chronic asthma.

    PubMed

    Ge, Xiahui; Bai, Chong; Yang, Jianming; Lou, Guoliang; Li, Qiang; Chen, Ruohua

    2013-07-01

    Previous studies proved that bone marrow-derived mesenchymal stem cells (BMSCs) could improve a variety of immune-mediated disease by its immunomodulatory properties. In this study, we investigated the effect on airway remodeling and airway inflammation by administrating BMSCs in chronic asthmatic mice. Forty-eight female BALB/c mice were randomly distributed into PBS group, BMSCs treatment group, BMSCs control group, and asthmatic group. The levels of cytokine and immunoglobulin in serum and bronchoalveolar lavage fluid were detected by enzyme-linked immunosorbent assay. The number of CD4(+) CD25(+) regulatory T cells and morphometric analysis was determined by flow cytometry, hematoxylin-eosin, immunofluorescence staining, periodic-acid Schiff, and masson staining, respectively. We found that airway remodeling and airway inflammation were evident in asthmatic mice. Moreover, low level of IL-12 and high levels of IL-13, IL-4, OVA-specific IgG1, IgE, and IgG2a and the fewer number of CD4(+) CD25(+) regulatory T cells were present in asthmatic group. However, transplantation of BMSCs significantly decreased airway inflammation and airway remodeling and level of IL-4, OVA-specific IgE, and OVA-specific IgG1, but elevated level of IL-12 and the number of CD4 + CD25 + regulatory T cells in asthma (P < 0.05). However, BMSCs did not contribute to lung regeneration and had no significant effect on levels of IL-10, IFN-Y, and IL-13. In our study, BMSCs engraftment prohibited airway inflammation and airway remodeling in chronic asthmatic group. The beneficial effect of BMSCs might involved the modulation imbalance cytokine toward a new balance Th1-Th2 profiles and up-regulation of protective CD4 + CD25 + regulatory T cells in asthma, but not contribution to lung regeneration. PMID:23334934

  1. Chronic Inflammation and Pain in a TNFR (p55/p75-/-) Dual Deficient Murine Model

    PubMed Central

    Westlund, Karin N.; Zhang, Liping; Ma, Fei; Oz, Helieh S.

    2012-01-01

    Many aspects of tissue damage following acute or chronic inflammatory reactions can be directly attributed to the concomitant biosynthesis and release of inducible early pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Conversely, systemic inflammation is impacted by consequences of tissue damage. Dysregulated TNFα contributes to numerous pathophysiological conditions including inflammatory bowel disease (IBD) and arthritis. Inflammatory stimuli trigger proteolytic cleavage and shedding of extracellular domains of TNFα receptors giving rise to two soluble fragments (p55 sTNFR1 and p75 sTNFR2) that block further binding, activity and synthesis of TNFα. We hypothesized that absence of sTNFR inhibitory feedback control would result in accumulated high levels of TNFα and other inflammatory factors promoting the cardinal signs of chronic inflammation and pain. The present study reports a translational murine model of chronic arthritis precipitated by two consecutive inflammatory insults. The “double hit” procedures provoke a chronic inflammatory response and pain related behaviors in mice that are dually deficient in p55 (TNFR1) and p75 (TNFR2). The inflammation and pain related behaviors are transient in similarly treated wild type (WT) mice. The complete Freund's adjuvant (CFA) method was used initially to induce knee joint inflammation, tactile mechanical and heat hypersensitivity, and gait disturbance. After these transient effects of the insult were resolved, a recrudescence persisting at least through 23 weeks was promoted by gastrointestinal (GI) insult with dilute intra-colonic mustard oil (MO) only in the mutant mice and was reversed by a P2X7 antagonist. Serum Proteome Profiling analysis revealed high levels of serum inflammatory factors TNFα, RANTES, CXCL9 (MIG), CXCL10 (IP-10), and CCL2 (MCP-1). In conclusion, these data suggest that impaired signaling of TNFα due to deficit of the two protective soluble p55 and p75 sTNFR inhibitory

  2. Adhesive capsulitis: An age related symptom of metabolic syndrome and chronic low-grade inflammation?

    PubMed

    Pietrzak, Max

    2016-03-01

    Adhesive capsulitis (AC) is very poorly understood, particularly it's underlying etiology. Obesity and metabolic syndrome, which are strongly associated with chronic low grade inflammation, are becoming increasingly understood to underlie a raft of morbid states including upper limb pain syndromes, diabetes (DM), cardiovascular disease (CVD), cancer and central nervous system dysfunction and degeneration. Notwithstanding age, two of the strongest established risk factors for AC are DM and CVD. The hypothesis argues that similar to DM and CVD, the inflammation and capsular fibrosis seen in AC is precipitated by metabolic syndrome and chronic low grade inflammation. These pathophysiological mechanisms are highly likely to be perpetuated by upregulation of pro-inflammatory cytokine production, sympathetic dominance of autonomic balance, and neuro-immune activation. The hypothesis predicts and describes how these processes may etiologically underpin and induce each sub-classification of AC. An improved understanding of the etiology of AC may lead to more accurate diagnosis, improved management, treatment outcomes, and reduce or prevent pain, disability and suffering associated with the disease. The paper follows on with a discussion of similarities between the pathophysiology of AC to general systemic inflammatory control mechanisms whereby connective tissue (CT) fibrosis is induced as a storage depot for leukocytes and chronic inflammatory cells. The potential role of hyaluronic acid (HA), the primary component of the extracellular matrix (ECM) and CT, in the pathophysiology of AC is also discussed with potential treatment implications. Lastly, a biochemical link between physical and mental health through the ECM is described and the concept of a periventricular-limbic central driver of CT dysfunction is introduced. PMID:26880627

  3. Acne: a new model of immune-mediated chronic inflammatory skin disease.

    PubMed

    Antiga, E; Verdelli, A; Bonciani, D; Bonciolini, V; Caproni, M; Fabbri, P

    2015-04-01

    Acne is a chronic inflammatory disease of the sebaceous-pilosebaceous unit. Interestingly, inflammation can be detected by histopathological examination and immuohistochemical analysis even in the apparently non-inflammatory acneic lesions, such as comedones. In the last years, it has been clearly demonstrated that acne development is linked to the combination of predisposing genetic factors and environmental triggers, among which a prominent role is played by the follicular colonization by Propionibacterium acnes (P. acnes). P. acnes displays several activities able to promote the development of acne skin lesions, including the promotion of follicular hyperkeratinisation, the induction of sebogenesis, and the stimulation of an inflammatory response by the secretion of proinflammatory molecules and by the activation of innate immunity, that is followed by a P. acnes-specific adaptive immune response. In addition, P. acnes-independent inflammation mediated by androgens or by a neurogenic activation, followed by the secretion in the skin of pro-inflammatory neuropeptides, can occur in acne lesions. In conclusion, acne can be considered as a model of immune-mediated chronic inflammatory skin disease, characterized by an innate immune response that is not able to control P. acnes followed by a Th1-mediated adaptive immune response, that becomes self-maintaining independently from P. acnes itself. PMID:25876146

  4. Tinospora cordifolia inhibits autoimmune arthritis by regulating key immune mediators of inflammation and bone damage.

    PubMed

    Sannegowda, K M; Venkatesha, S H; Moudgil, K D

    2015-12-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints leading to tissue damage. Despite the availability of potent drugs including the biologics, many patients fail to respond to them, whereas others suffer adverse effects following long-term use of these drugs. Accordingly, the use of natural herbal products by RA patients has been increasing over the years. However, limited information about the mechanism of action of these natural products is a major shortcoming that prevents the widespread acceptance of herbal therapy by professionals and patients alike. In this study, we demonstrated the anti-arthritic activity of Tinospora cordifolia extract (TCE) using the rat adjuvant-induced arthritis model of human RA and elaborated the immune mechanisms underlying this effect. TCE treatment suppressed arthritic inflammation and bone and cartilage damage. The anti-inflammatory effect of TCE was mediated via reduction of the pro-inflammatory cytokines such as: IL-1β, TNF-α, IL-6, and IL-17; the frequency of IL-17-producing T cells; and the production of chemokines such as RANTES. Furthermore, TCE treatment limited bone damage by shifting the balance of mediators of bone remodeling (e.g., receptor activator of nuclear factor-kB ligand [RANKL] and MMP-9) in favor of anti-osteoclastic activity. Our results suggest that TCE and its bioactive components should be evaluated for their utility as therapeutic adjuncts to conventional drugs against RA. PMID:26467057

  5. Green tea polyphenols avert chronic inflammation-induced myocardial fibrosis of female rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: Green tea proposes anti-inflammatory properties which may attenuate chronic inflammation-induced fibrosis of vessels. This study evaluated whether green tea polyphenols (GTP) can avert fibrosis or vascular disruption along with mechanisms in rats with chronic inflammation. Treatments: Fo...

  6. Apolipoprotein E promotes subretinal mononuclear phagocyte survival and chronic inflammation in age-related macular degeneration

    PubMed Central

    Levy, Olivier; Calippe, Bertrand; Lavalette, Sophie; Hu, Shulong J; Raoul, William; Dominguez, Elisa; Housset, Michael; Paques, Michel; Sahel, José-Alain; Bemelmans, Alexis-Pierre; Combadiere, Christophe; Guillonneau, Xavier; Sennlaub, Florian

    2015-01-01

    Physiologically, the retinal pigment epithelium (RPE) expresses immunosuppressive signals such as FAS ligand (FASL), which prevents the accumulation of leukocytes in the subretinal space. Age-related macular degeneration (AMD) is associated with a breakdown of the subretinal immunosuppressive environment and chronic accumulation of mononuclear phagocytes (MPs). We show that subretinal MPs in AMD patients accumulate on the RPE and express high levels of APOE. MPs of Cx3cr1−/− mice that develop MP accumulation on the RPE, photoreceptor degeneration, and increased choroidal neovascularization similarly express high levels of APOE. ApoE deletion in Cx3cr1−/− mice prevents pathogenic age- and stress-induced subretinal MP accumulation. We demonstrate that increased APOE levels induce IL-6 in MPs via the activation of the TLR2-CD14-dependent innate immunity receptor cluster. IL-6 in turn represses RPE FasL expression and prolongs subretinal MP survival. This mechanism may account, in part, for the MP accumulation observed in Cx3cr1−/− mice. Our results underline the inflammatory role of APOE in sterile inflammation in the immunosuppressive subretinal space. They provide rationale for the implication of IL-6 in AMD and open avenues toward therapies inhibiting pathogenic chronic inflammation in late AMD. PMID:25604058

  7. Immunometabolism of obesity and diabetes: microbiota link compartmentalized immunity in the gut to metabolic tissue inflammation.

    PubMed

    McPhee, Joseph B; Schertzer, Jonathan D

    2015-12-01

    The bacteria that inhabit us have emerged as factors linking immunity and metabolism. Changes in our microbiota can modify obesity and the immune underpinnings of metabolic diseases such as Type 2 diabetes. Obesity coincides with a low-level systemic inflammation, which also manifests within metabolic tissues such as adipose tissue and liver. This metabolic inflammation can promote insulin resistance and dysglycaemia. However, the obesity and metabolic disease-related immune responses that are compartmentalized in the intestinal environment do not necessarily parallel the inflammatory status of metabolic tissues that control blood glucose. In fact, a permissive immune environment in the gut can exacerbate metabolic tissue inflammation. Unravelling these discordant immune responses in different parts of the body and establishing a connection between nutrients, immunity and the microbiota in the gut is a complex challenge. Recent evidence positions the relationship between host gut barrier function, intestinal T cell responses and specific microbes at the crossroads of obesity and inflammation in metabolic disease. A key problem to be addressed is understanding how metabolite, immune or bacterial signals from the gut are relayed and transferred into systemic or metabolic tissue inflammation that can impair insulin action preceding Type 2 diabetes. PMID:26464517

  8. Natural killer T cells are dispensable in the development of allergen-induced airway hyperresponsiveness, inflammation and remodelling in a mouse model of chronic asthma.

    PubMed

    Koh, Y-I; Shim, J-U; Lee, J-H; Chung, I-J; Min, J-J; Rhee, J H; Lee, H C; Chung, D H; Wi, J-O

    2010-07-01

    Natural killer T (NK T) cells have been shown to play an essential role in the development of allergen-induced airway hyperresponsiveness (AHR) and/or airway inflammation in mouse models of acute asthma. Recently, NK T cells have been reported to be required for the development of AHR in a virus induced chronic asthma model. We investigated whether NK T cells were required for the development of allergen-induced AHR, airway inflammation and airway remodelling in a mouse model of chronic asthma. CD1d-/- mice that lack NK T cells were used for the experiments. In the chronic model, AHR, eosinophilic inflammation, remodelling characteristics including mucus metaplasia, subepithelial fibrosis and increased mass of the airway smooth muscle, T helper type 2 (Th2) immune response and immunoglobulin (Ig)E production were equally increased in both CD1d-/- mice and wild-type mice. However, in the acute model, AHR, eosinophilic inflammation, Th2 immune response and IgE production were significantly decreased in the CD1d-/- mice compared to wild-type. CD1d-dependent NK T cells may not be required for the development of allergen-induced AHR, eosinophilic airway inflammation and airway remodelling in chronic asthma model, although they play a role in the development of AHR and eosinophilic inflammation in acute asthma model. PMID:20456411

  9. Blood Biomarkers of Chronic Inflammation in Gulf War Illness

    PubMed Central

    Johnson, Gerhard J.; Slater, Billie C. S.; Leis, Linda A.; Rector, Thomas S.; Bach, Ronald R.

    2016-01-01

    Background More than twenty years following the end of the 1990–1991 Gulf War it is estimated that approximately 300,000 veterans of this conflict suffer from an unexplained chronic, multi-system disorder known as Gulf War Illness (GWI). The etiology of GWI may be exposure to chemical toxins, but it remains only partially defined, and its case definition is based only on symptoms. Objective criteria for the diagnosis of GWI are urgently needed for diagnosis and therapeutic research. Objective This study was designed to determine if blood biomarkers could provide objective criteria to assist diagnosis of GWI. Design A surveillance study of 85 Gulf War Veteran volunteers identified from the Department of Veterans Affairs Minnesota Gulf War registry was performed. All subjects were deployed to the Gulf War. Fifty seven subjects had GWI defined by CDC criteria, and 28 did not have symptomatic criteria for a diagnosis of GWI. Statistical analyses were performed on peripheral blood counts and assays of 61 plasma proteins using the Mann-Whitney rank sum test to compare biomarker distributions and stepwise logistic regression to formulate a diagnostic model. Results Lymphocyte, monocyte, neutrophil, and platelet counts were higher in GWI subjects. Six serum proteins associated with inflammation were significantly different in GWI subjects. A diagnostic model of three biomarkers—lymphocytes, monocytes, and C reactive protein—had a predicted probability of 90% (CI 76–90%) for diagnosing GWI when the probability of having GWI was above 70%. Significance The results of the current study indicate that inflammation is a component of the pathobiology of GWI. Analysis of the data resulted in a model utilizing three readily measurable biomarkers that appears to significantly augment the symptom-based case definition of GWI. These new observations are highly relevant to the diagnosis of GWI, and to therapeutic trials. PMID:27352030

  10. Portal Chronic Inflammation in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Brunt, Elizabeth M.; Kleiner, David E.; Wilson, Laura A.; Unalp, Aynur; Behling, Cynthia E.; Lavine, Joel E.; Neuschwander-Tetri, Brent A.

    2009-01-01

    Untreated adult nonalcoholic fatty liver disease (NAFLD) is characterized by absent or mild portal chronic inflammation (CI); in the portal-based pediatric pattern of NAFLD, portal CI may be a predominant component. This study was undertaken to correlate clinical features with portal CI in the subjects enrolled in the NASH CRN. Methods Histology from central grading and clinical parameters temporally related to the biopsy were evaluated from 728 adults and 205 children. Results Sixty percent of adult biopsies had mild, 23% had more than mild, and 16% had no portal CI. In children, 76% had mild, 14% were more than mild, and 10% had no portal CI. In neither group were autoantibodies, elevated ALT, or generic use of “any” medications associated with the presence or degree of portal CI. Clinical features associated with “more than mild” in adults were older age (51 y v 44 y) (p<0.0001), female gender (p=0.001), higher BMI (p<0.0001), elevated insulin levels (median 20 v 14uU/ml) (p=0.001), higher HOMA-IR (median 5 v 3) (p<0.0001), and medications used for NAFLD (p=0.0004), diabetes (p<0.0001), and hypertension (p<0.0001). The same comparisons for “more than mild” v “none” in the pediatric biopsies showed only an association with younger age (12 y v 14 y) (p=0.01), but there was a trend favoring boys. There was no association with BMI, insulin or HOMA-IR. In both groups, lobular and portal inflammation scores had no association, but there was an association with a definite steatohepatitis diagnosis (p<0.0001 for both). Features in the adult biopsies associated with “more than mild” were steatosis amount (p=0.01and location (p<0.0001), presence of ballooning (p<0.0001), and advanced fibrosis (p<0.0001). In the pediatric biopsies, “more than mild” compared with “none” was associated with steatosis location (p=0.0008), and fibrosis score (p<0.0001), specifically, the pediatric (zone 1 accentuation) pattern (p<0.001) and portal

  11. Chronic inflammation imposes aberrant cell fate in regenerating epithelia through mechanotransduction.

    PubMed

    Nowell, Craig S; Odermatt, Pascal D; Azzolin, Luca; Hohnel, Sylke; Wagner, Erwin F; Fantner, Georg E; Lutolf, Matthias P; Barrandon, Yann; Piccolo, Stefano; Radtke, Freddy

    2016-02-01

    Chronic inflammation is associated with a variety of pathological conditions in epithelial tissues, including cancer, metaplasia and aberrant wound healing. In relation to this, a significant body of evidence suggests that aberration of epithelial stem and progenitor cell function is a contributing factor in inflammation-related disease, although the underlying cellular and molecular mechanisms remain to be fully elucidated. In this study, we have delineated the effect of chronic inflammation on epithelial stem/progenitor cells using the corneal epithelium as a model tissue. Using a combination of mouse genetics, pharmacological approaches and in vitro assays, we demonstrate that chronic inflammation elicits aberrant mechanotransduction in the regenerating corneal epithelium. As a consequence, a YAP-TAZ/β-catenin cascade is triggered, resulting in the induction of epidermal differentiation on the ocular surface. Collectively, the results of this study demonstrate that chronic inflammation and mechanotransduction are linked and act to elicit pathological responses in regenerating epithelia. PMID:26689676

  12. IL-33 and thymic stromal lymphopoietin mediate immune pathology in response to chronic airborne allergen exposure.

    PubMed

    Iijima, Koji; Kobayashi, Takao; Hara, Kenichiro; Kephart, Gail M; Ziegler, Steven F; McKenzie, Andrew N; Kita, Hirohito

    2014-08-15

    Humans are frequently exposed to various airborne allergens in the atmospheric environment. These allergens may trigger a complex network of immune responses in the airways, resulting in asthma and other chronic airway diseases. In this study, we investigated the immunological mechanisms involved in the pathological changes induced by chronic exposure to multiple airborne allergens. Naive mice were exposed intranasally to a combination of common airborne allergens, including the house dust mite, Alternaria, and Aspergillus, for up to 8 wk. These allergens acted synergistically and induced robust eosinophilic airway inflammation, specific IgE Ab production, type 2 cytokine response, and airway hyperresponsiveness in 4 wk, followed by airway remodeling in 8 wk. Increased lung infiltration of T cells, B cells, and type 2 innate lymphoid cells was observed. CD4(+) T cells and type 2 innate lymphoid cells contributed to the sources of IL-5 and IL-13, suggesting involvement of both innate and adaptive immunity in this model. The lung levels of IL-33 increased quickly within several hours after allergen exposure and continued to rise throughout the chronic phase of inflammation. Mice deficient in IL-33R (Il1rl1(-/-)) and thymic stromal lymphopoietin receptor (Tslpr(-/-)) showed significant reduction in airway inflammation, IgE Ab levels, and airway hyperresponsiveness. In contrast, mice deficient in IL-25R or IL-1R showed minimal differences as compared with wild-type animals. Thus, chronic exposure to natural airborne allergens triggers a network of innate and adaptive type 2 immune responses and airway pathology, and IL-33 and thymic stromal lymphopoietin most likely play key roles in this process. PMID:25015831

  13. Noncoding RNAs and chronic inflammation: Micro-managing the fire within.

    PubMed

    Alexander, Margaret; O'Connell, Ryan M

    2015-09-01

    Inflammatory responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled chronic inflammation can occur. Chronic inflammation is now recognized as a contributing factor to many age-associated diseases including metabolic disorders, arthritis, neurodegeneration, and cardiovascular disease. Due to the connection between chronic inflammation and these diseases, it is essential to understand underlying mechanisms behind this process. In this review, factors that contribute to chronic inflammation are discussed. Further, we emphasize the emerging roles of microRNAs (miRNAs) and other noncoding RNAs (ncRNA) in regulating chronic inflammatory states, making them important future diagnostic markers and therapeutic targets. PMID:26249326

  14. Innate and Adaptive Immune Regulation During Chronic Viral Infections

    PubMed Central

    Zuniga, Elina I.; Macal, Monica; Lewis, Gavin M.; Harker, James A.

    2015-01-01

    Chronic viral infections represent a unique challenge to the infected host. Persistently replicating viruses outcompete or subvert the initial antiviral response, allowing the establishment of chronic infections that result in continuous stimulation of both the innate and adaptive immune compartments. This causes a profound reprogramming of the host immune system, including attenuation and persistent low levels of type I interferons, progressive loss (or exhaustion) of CD8+ T cell functions, and specialization of CD4+ T cells to produce interleukin-21 and promote antibody-mediated immunity and immune regulation. Epigenetic, transcriptional, posttranscriptional, and metabolic changes underlie this adaptation or recalibration of immune cells to the emerging new environment in order to strike an often imperfect balance between the host and the infectious pathogen. In this review we discuss the common immunological hallmarks observed across a range of different persistently replicating viruses and host species, the underlying molecular mechanisms, and the biological and clinical implications. PMID:26958929

  15. Suppression of Adaptive Immune Cell Activation Does Not Alter Innate Immune Adipose Inflammation or Insulin Resistance in Obesity

    PubMed Central

    Subramanian, Manikandan; Ozcan, Lale; Ghorpade, Devram Sampat; Ferrante, Anthony W.; Tabas, Ira

    2015-01-01

    Obesity-induced inflammation in visceral adipose tissue (VAT) is a major contributor to insulin resistance and type 2 diabetes. Whereas innate immune cells, notably macrophages, contribute to visceral adipose tissue (VAT) inflammation and insulin resistance, the role of adaptive immunity is less well defined. To address this critical gap, we used a model in which endogenous activation of T cells was suppressed in obese mice by blocking MyD88-mediated maturation of CD11c+ antigen-presenting cells. VAT CD11c+ cells from Cd11cCre+Myd88fl/fl vs. control Myd88fl/fl mice were defective in activating T cells in vitro, and VAT T and B cell activation was markedly reduced in Cd11cCre+Myd88fl/fl obese mice. However, neither macrophage-mediated VAT inflammation nor systemic inflammation were altered in Cd11cCre+Myd88fl/fl mice, thereby enabling a focused analysis on adaptive immunity. Unexpectedly, fasting blood glucose, plasma insulin, and the glucose response to glucose and insulin were completely unaltered in Cd11cCre+Myd88fl/fl vs. control obese mice. Thus, CD11c+ cells activate VAT T and B cells in obese mice, but suppression of this process does not have a discernible effect on macrophage-mediated VAT inflammation or systemic glucose homeostasis. PMID:26317499

  16. Abnormal immune regulation and low-grade inflammation in IBS: does one size fit all?

    PubMed

    Schmulson, Max; Chey, William D

    2012-02-01

    Evidences suggest that there is low-grade inflammation in the colonic mucosa and/or a state of immune activation in patients with irritable bowel syndrome (IBS). Results from available studies are inconsistent mainly because of differences in measures, methodologies and study populations. In this issue, Chang et al. evaluated a comprehensive set of cytokines, immune markers and immune-related cells in patients with non post infectious IBS (non PI-IBS) and controls. The main finding was a lower expression of the mRNA of the anti-inflammatory IL-10 cytokine in the colonic mucosa of women with non PI-IBS without any differences in the cell counts. These results suggest that in non PI-IBS, there is altered immune regulation/activation without evidence of low-grade mucosal inflammation. Further, PI and non PI-IBS may be associated with different alterations in immune function/activation. PMID:22306945

  17. Common mechanisms involved in Alzheimer's disease and type 2 diabetes: a key role of chronic bacterial infection and inflammation

    PubMed Central

    Miklossy, Judith; McGeer, Patrick L.

    2016-01-01

    Strong epidemiologic evidence and common molecular mechanisms support an association between Alzheimer's disease (AD) and type 2-diabetes. Local inflammation and amyloidosis occur in both diseases and are associated with periodontitis and various infectious agents. This article reviews the evidence for the presence of local inflammation and bacteria in type 2 diabetes and discusses host pathogen interactions in chronic inflammatory disorders. Chlamydophyla pneumoniae, Helicobacter pylori and spirochetes are demonstrated in association with dementia and brain lesions in AD and islet lesions in type 2 diabetes. The presence of pathogens in host tissues activates immune responses through Toll-like receptor signaling pathways. Evasion of pathogens from complement-mediated attack results in persistent infection, inflammation and amyloidosis. Amyloid beta and the pancreatic amyloid called amylin bind to lipid bilayers and produce Ca(2+) influx and bacteriolysis. Similarly to AD, accumulation of amylin deposits in type 2 diabetes may result from an innate immune response to chronic bacterial infections, which are known to be associated with amyloidosis. Further research based on an infectious origin of both AD and type 2 diabetes may lead to novel treatment strategies. PMID:26961231

  18. Common mechanisms involved in Alzheimer's disease and type 2 diabetes: a key role of chronic bacterial infection and inflammation.

    PubMed

    Miklossy, Judith; McGeer, Patrick L

    2016-04-01

    Strong epidemiologic evidence and common molecular mechanisms support an association between Alzheimer's disease (AD) and type 2-diabetes. Local inflammation and amyloidosis occur in both diseases and are associated with periodontitis and various infectious agents. This article reviews the evidence for the presence of local inflammation and bacteria in type 2 diabetes and discusses host pathogen interactions in chronic inflammatory disorders. Chlamydophyla pneumoniae, Helicobacter pylori and spirochetes are demonstrated in association with dementia and brain lesions in AD and islet lesions in type 2 diabetes. The presence of pathogens in host tissues activates immune responses through Toll-like receptor signaling pathways. Evasion of pathogens from complement-mediated attack results in persistent infection, inflammation and amyloidosis. Amyloid beta and the pancreatic amyloid called amylin bind to lipid bilayers and produce Ca(2+) influx and bacteriolysis. Similarly to AD, accumulation of amylin deposits in type 2 diabetes may result from an innate immune response to chronic bacterial infections, which are known to be associated with amyloidosis. Further research based on an infectious origin of both AD and type 2 diabetes may lead to novel treatment strategies. PMID:26961231

  19. Tryptophan hydroxylase-1 regulates immune tolerance and inflammation.

    PubMed

    Nowak, Elizabeth C; de Vries, Victor C; Wasiuk, Anna; Ahonen, Cory; Bennett, Kathryn A; Le Mercier, Isabelle; Ha, Dae-Gon; Noelle, Randolph J

    2012-10-22

    Nutrient deprivation based on the loss of essential amino acids by catabolic enzymes in the microenvironment is a critical means to control inflammatory responses and immune tolerance. Here we report the novel finding that Tph-1 (tryptophan hydroxylase-1), a synthase which catalyses the conversion of tryptophan to serotonin and exhausts tryptophan, is a potent regulator of immunity. In models of skin allograft tolerance, tumor growth, and experimental autoimmune encephalomyelitis, Tph-1 deficiency breaks allograft tolerance, induces tumor remission, and intensifies neuroinflammation, respectively. All of these effects of Tph-1 deficiency are independent of its downstream product serotonin. Because mast cells (MCs) appear to be the major source of Tph-1 and restoration of Tph-1 in the MC compartment in vivo compensates for the defect, these experiments introduce a fundamentally new mechanism of MC-mediated immune suppression that broadly impacts multiple arms of immunity. PMID:23008335

  20. Role of the Microbiota in Immunity and inflammation

    PubMed Central

    Belkaid, Yasmine; Hand, Timothy

    2014-01-01

    The microbiota plays a fundamental role on the induction, training and function of the host immune system. In return, the immune system has largely evolved as a means to maintain the symbiotic relationship of the host with these highly diverse and evolving microbes. When operating optimally this immune system–microbiota alliance allows the induction of protective responses to pathogens and the maintenance of regulatory pathways involved in the maintenance of tolerance to innocuous antigens. However, in high-income countries overuse of antibiotics, changes in diet, and elimination of constitutive partners such as nematodes has selected for a microbiota that lack the resilience and diversity required to establish balanced immune responses. This phenomenon is proposed to account for some of the dramatic rise in autoimmune and inflammatory disorders in parts of the world where our symbiotic relationship with the microbiota has been the most affected. PMID:24679531

  1. Systemic biomarkers of inflammation and haemostasis in patients with chronic necrotizing pulmonary aspergillosis

    PubMed Central

    2012-01-01

    Background The purpose of this study was to investigate mediators of inflammation and haemostasis in patients with chronic necrotizing pulmonary aspergillosis (CNPA), a locally, destructive process of the lung due to invasion by Aspergillus species. Methods Measurements of selected biomarkers in 10 patients with CNPA and 19 healthy, matched controls were performed with enzyme-linked immunosorbent assay (ELISA) and multiplex methodology. The gene expressions of relevant biomarkers were analyzed with real-time quantitative RT-PCR. Results Increased concentrations of circulating mediators of inflammation interleukin (IL)-6, IL-8, RANTES, TNF-α, ICAM-1 and mediators involved in endothelial activation and thrombosis (vWF, TF and PAI-1) were observed in patients with CNPA. The concentration of the anti-inflammatory cytokine IL-10 was increased both in plasma and in PBMC in the patient population. The gene expression of CD40L was decreased in PBMC from the patient group, accompanied by decreased concentrations of soluble (s) CD40L in the circulation. Conclusions The proinflammatory response against Aspergillus may be counteracted by reduced CD40L and sCD40L, as well as increased IL-10, which may compromise the immune response against Aspergillus in patients with CNPA. PMID:22731696

  2. Role of DNA repair in host immune response and inflammation.

    PubMed

    Fontes, Fabrícia Lima; Pinheiro, Daniele Maria Lopes; Oliveira, Ana Helena Sales de; Oliveira, Rayssa Karla de Medeiros; Lajus, Tirzah Braz Petta; Agnez-Lima, Lucymara Fassarella

    2015-01-01

    In recent years, the understanding of how DNA repair contributes to the development of innate and acquired immunity has emerged. The DNA damage incurred during the inflammatory response triggers the activation of DNA repair pathways, which are required for host-cell survival. Here, we reviewed current understanding of the mechanism by which DNA repair contributes to protection against the oxidized DNA damage generated during infectious and inflammatory diseases and its involvement in innate and adaptive immunity. We discussed the functional role of DNA repair enzymes in the immune activation and the relevance of these processes to: transcriptional regulation of cytokines and other genes involved in the inflammatory response; V(D)J recombination; class-switch recombination (CSR); and somatic hypermutation (SHM). These three last processes of DNA damage repair are required for effective humoral adaptive immunity, creating genetic diversity in developing T and B cells. Furthermore, viral replication is also dependent on host DNA repair mechanisms. Therefore, the elucidation of the pathways of DNA damage and its repair that activate innate and adaptive immunity will be important for a better understanding of the immune and inflammatory disorders and developing new therapeutic interventions for treatment of these diseases and for improving their outcome. PMID:25795123

  3. [Atherogenesis as a reflection of immune inflammation in the vascular wall].

    PubMed

    Nagornev, V A; Iakovleva, O A; Mal'tseva, S V

    2000-01-01

    Despite numerous basic and applied studies into the pathogenesis and treatment of atherosclerosis, there is no theory which could explain the development of the whole complex of changes united under the term "atherosclerosis". Examining the causes of atherosclerosis disclosed a pathogenetic association of the immunoregulatory signal CD40-CD40L with the occurrence of arterial atherosclerotic lesions. Studies of the immune mechanisms responsible for the pathogenesis of atherosclerosis (autoimmune complexes containing oxidative modification of LDL, T and B lymphocytes, inflammation mediators, hemoadhesive molecules, and immunoregulatory molecules showed the leading role of autoimmune mechanisms in atherosclerosis. The conceptual result of the studies is that the authors have elucidated the leading role of immune inflammation in the appearance and development of arterial atherosclerotic lesions. The development of a new concept of assessing the pathogenesis of atherosclerosis in the context of immune inflammation in the vascular wall opens new vistas for the treatment of this disease. PMID:11247126

  4. Immunization in children with chronic renal failure.

    PubMed

    Laube, Guido F; Berger, Christoph; Goetschel, Philippe; Leumann, Ernst; Neuhaus, Thomas J

    2002-08-01

    Infections jeopardize children on immunosuppression after organ transplantation. Immunization is protective in healthy children. The aims of this study were to analyze the rate and efficacy of immunization in 62 children undergoing dialysis and renal transplantation (RTPL) between 1987 and 2000. The analysis was based on clinical findings, vaccination certificates, and measurement of specific serum antibodies. A member of the renal unit administered vaccinations. All 62 patients were immunized against diphtheria, tetanus, pertussis, poliomyelitis, measles, mumps, rubella, and hepatitis B. Since introduction in 1991 and 1995, 44 and 42 children were also vaccinated against influenza and Hemophilus influenzae type b, respectively. Of 16 patients with a negative history, 14 were given varicella vaccine; 16 children on peritoneal dialysis (PD) or with nephrotic syndrome were immunized against Streptococcus pneumoniae. All vaccinated patients had detectable serum antibodies against measles, mumps, rubella, varicella, hepatitis B, H. influenzae, and S. pneumoniae. There were 3 infections despite vaccination; 1 patient developed varicella after RTPL and 1 patient on PD had 2 episodes of peritonitis caused by H. influenzae and S. pneumoniae. In conclusion, monitoring and administration of the vaccines by the renal team enabled a high immunization rate. Whether vaccines, as documented by antibody titers, or by the low prevalence in the general population promoted the low prevalence of infections remains open, as there were at least a few vaccination failures. PMID:12185473

  5. The Role of Immune Cells in Chronic HBV Infection

    PubMed Central

    Li, Hai-Jun; Zhai, Nai-Cui; Song, Hong-Xiao; Yang, Yang; Cui, An; Li, Tian-Yang; Tu, Zheng-Kun

    2015-01-01

    Hepatitis B virus (HBV) infection is a major cause of chronic liver diseases that may progress to liver cirrhosis and hepatocellular carcinoma. Host immune responses are important factors that determine whether HBV infection is cleared or persists. After infection, viral replication occurs inside hepatocytes, and the secretion of infectious virions can take place at high rates for decades. Consequently, HBV DNA and viral proteins, like HBV early antigen (HBeAg) and HBV surface antigen (HBsAg), can be easily detected in serum. Chronic infection with HBV is the result of an ineffective antiviral immune response towards the virus. In this review, we discuss the role of immune cells in chronic HBV infection. PMID:26807384

  6. Angiotensin II in inflammation, immunity and rheumatoid arthritis

    PubMed Central

    Chang, Y; Wei, W

    2015-01-01

    Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that is characterized by increased cardiovascular morbidity and mortality, independent of the traditional risk factors for cardiovascular disease. Although classically known for its role in the regulation of circulatory homeostasis, angiotensin II (Ang II) is recognized to act as a powerful proinflammatory mediator. Some research has showed that Ang II plays important roles in autoimmune diseases, including RA, systemic lupus erythematosus and multiple sclerosis. Ang II blockers prove effective in reducing inflammation and autoimmunity in rheumatic diseases and their relative safety, together with their effects for reducing the cardiovascular disease risk, suggest that Ang II blockers may at least act as effective adjunctive therapy for disease control in patients with RA. The present review focuses systematically on the potential impact of Ang II and its receptors on inflammation and immunomodulation in patients with RA. PMID:25302847

  7. Therapeutics targeting inflammation in the immune reconstitution inflammatory syndrome.

    PubMed

    Shahani, Lokesh; Hamill, Richard J

    2016-01-01

    Immune reconstitution inflammatory syndrome (IRIS) is characterized by improvement in a previously incompetent human immune system manifesting as worsening of clinical symptoms secondary to the ability of the immune system to now mount a vigorous inflammatory response. IRIS was first recognized in the setting of human immunodeficiency virus, and this clinical setting continues to be where it is most frequently encountered. Hallmarks of the pathogenesis of IRIS, independent of the clinical presentation and the underlying pathogen, include excessive activation of the immune system, with increased circulating effector memory T cells, and elevated levels of serum cytokines and inflammatory markers. Patients with undiagnosed opportunistic infections remain at risk for unmasking IRIS at the time of active antiretroviral therapy (ART) initiation. Systematic screening for opportunistic infections before starting ART is a key element to prevent this phenomenon. Appropriate management of IRIS requires prompt recognition of the syndrome and exclusion of alternative diagnoses, particularly underlying infections and drug resistance. Controlled studies supporting the use of pharmacologic interventions in IRIS are scare, and recommendations are based on case series and expert opinions. The only controlled trial published to date, showed reduction in morbidity in patients with paradoxical tuberculosis-related IRIS with the use of oral corticosteroids. There are currently limited data to recommend other anti-inflammatory or immunomodulatory therapies that are discussed in this review, and further research is needed. Ongoing research regarding the immune pathogenesis of IRIS will likely direct future rational therapeutic approaches and clinical trials. PMID:26303886

  8. Inflammation in chronic periodontitis and significant systemic diseases.

    PubMed

    Rethman, Michael P

    2010-04-01

    Endogenous chemical mediators play seminal roles in the initiation, persistence, and resolution of inflammation. Recent studies have revealed parallels between inflammatory mediators and mechanisms common to oral and systemic diseases. These relationships imply that novel therapeutics that profoundly modulate inflammatory mediators may improve clinical outcomes. Key source for this article is a 2008 conference reported in a Journal of Periodontology supplement titled Proceedings of the 2008 Workshop on Inflammation; Inflammation and Periodontal Diseases: A Reappraisal. PMID:20509364

  9. Natural killer T cells: innate lymphocytes positioned as a bridge between acute and chronic inflammation?

    PubMed Central

    Fox, Lisa; Hegde, Subramanya

    2010-01-01

    Natural killer T cells are an innate population of T lymphocytes that recognize antigens derived from host lipids and glycolipids. In this review, we focus on how these unique T cells are positioned to influence both acute and chronic inflammatory processes through their early recruitment to sites of inflammation, interactions with myeloid antigen presenting cells, and recognition of lipids associated with inflammation. PMID:20850561

  10. NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi.

    PubMed

    Tupin, Emmanuel; Benhnia, Mohammed Rafii-El-Idrissi; Kinjo, Yuki; Patsey, Rebeca; Lena, Christopher J; Haller, Matthew C; Caimano, Melissa J; Imamura, Masakazu; Wong, Chi-Huey; Crotty, Shane; Radolf, Justin D; Sellati, Timothy J; Kronenberg, Mitchell

    2008-12-16

    Borrelia burgdorferi is the etiologic agent of Lyme disease, a multisystem inflammatory disorder that principally targets the skin, joints, heart, and nervous system. The role of T lymphocytes in the development of chronic inflammation resulting from B. burgdorferi infection has been controversial. We previously showed that natural killer T (NKT) cells with an invariant (i) TCR alpha chain (iNKT cells) recognize glycolipids from B. burgdorferi, but did not establish an in vivo role for iNKT cells in Lyme disease pathogenesis. Here, we evaluate the importance of iNKT cells for host defense against these pathogenic spirochetes by using Valpha14i NKT cell-deficient (Jalpha18(-/-)) BALB/c mice. On tick inoculation with B. burgdorferi, Jalpha18(-/-) mice exhibited more severe and prolonged arthritis as well as a reduced ability to clear spirochetes from infected tissues. Valpha14i NKT cell deficiency also resulted in increased production of antibodies directed against both B. burgdorferi protein antigens and borrelial diacylglycerols; the latter finding demonstrates that anti-glycolipid antibody production does not require cognate help from Valpha14i NKT cells. Valpha14i NKT cells in infected wild-type mice expressed surface activation markers and produced IFNgamma in vivo after infection, suggesting a participatory role for this unique population in cellular immunity. Our data are consistent with the hypothesis that the antigen-specific activation of Valpha14i NKT cells is important for the prevention of persistent joint inflammation and spirochete clearance, and they counter the long-standing notion that humoral rather than cellular immunity is sufficient to facilitate Lyme disease resolution. PMID:19060201

  11. NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi

    PubMed Central

    Tupin, Emmanuel; Benhnia, Mohammed Rafii-El-Idrissi; Kinjo, Yuki; Patsey, Rebeca; Lena, Christopher J.; Haller, Matthew C.; Caimano, Melissa J.; Imamura, Masakazu; Wong, Chi-Huey; Crotty, Shane; Radolf, Justin D.; Sellati, Timothy J.; Kronenberg, Mitchell

    2008-01-01

    Borrelia burgdorferi is the etiologic agent of Lyme disease, a multisystem inflammatory disorder that principally targets the skin, joints, heart, and nervous system. The role of T lymphocytes in the development of chronic inflammation resulting from B. burgdorferi infection has been controversial. We previously showed that natural killer T (NKT) cells with an invariant (i) TCR α chain (iNKT cells) recognize glycolipids from B. burgdorferi, but did not establish an in vivo role for iNKT cells in Lyme disease pathogenesis. Here, we evaluate the importance of iNKT cells for host defense against these pathogenic spirochetes by using Vα14i NKT cell-deficient (Jα18−/−) BALB/c mice. On tick inoculation with B. burgdorferi, Jα18−/− mice exhibited more severe and prolonged arthritis as well as a reduced ability to clear spirochetes from infected tissues. Vα14i NKT cell deficiency also resulted in increased production of antibodies directed against both B. burgdorferi protein antigens and borrelial diacylglycerols; the latter finding demonstrates that anti-glycolipid antibody production does not require cognate help from Vα14i NKT cells. Vα14i NKT cells in infected wild-type mice expressed surface activation markers and produced IFNγ in vivo after infection, suggesting a participatory role for this unique population in cellular immunity. Our data are consistent with the hypothesis that the antigen-specific activation of Vα14i NKT cells is important for the prevention of persistent joint inflammation and spirochete clearance, and they counter the long-standing notion that humoral rather than cellular immunity is sufficient to facilitate Lyme disease resolution. PMID:19060201

  12. Contribution of Defective PS Recognition and Efferocytosis to Chronic Inflammation and Autoimmunity

    PubMed Central

    Kimani, Stanley Gititu; Geng, Ke; Kasikara, Canan; Kumar, Sushil; Sriram, Ganapathy; Wu, Yi; Birge, Raymond B.

    2014-01-01

    The rapid and efficient clearance of apoptotic cells results in the elimination of auto-antigens and provides a strong anti-inflammatory and immunosuppressive signal to prevent autoimmunity. While professional and non-professional phagocytes utilize a wide array of surface receptors to recognize apoptotic cells, the recognition of phosphatidylserine (PS) on apoptotic cells by PS receptors on phagocytes is the emblematic signal for efferocytosis in metazoans. PS-dependent efferocytosis is associated with the production of anti-inflammatory factors such as IL-10 and TGF-β that function, in part, to maintain tolerance to auto-antigens. In contrast, when apoptotic cells fail to be recognized and processed for degradation, auto-antigens persist, such as self-nucleic acids, which can trigger immune activation leading to autoantibody production and autoimmunity. Despite the fact that genetic mouse models clearly demonstrate that loss of PS receptors can lead to age-dependent auto-immune diseases reminiscent of systemic lupus erythematosus (SLE), the link between PS and defective clearance in chronic inflammation and human autoimmunity is not well delineated. In this perspective, we review emerging questions developing in the field that may be of relevance to SLE and human autoimmunity. PMID:25426118

  13. Effects of chronic intermittent hypoxia on allergen-induced airway inflammation in rats.

    PubMed

    Broytman, Oleg; Braun, Rudolf K; Morgan, Barbara J; Pegelow, David F; Hsu, Pei-Ning; Mei, Linda S; Koya, Ajay K; Eldridge, Marlowe; Teodorescu, Mihaela

    2015-02-01

    Obstructive sleep apnea aggravates asthma, but its mechanisms are unknown. Chronic intermittent hypoxia is one hallmark feature of sleep apnea. In this study, we tested the effects of chronic intermittent hypoxia on allergen-induced inflammation in rats. Four groups (n = 9-11/group) of ovalbumin (OVA)-sensitized Brown-Norway rats underwent intermittent hypoxia (10% oxygen, 30 cycles/h, 10 h/d) or normoxia for 30 days concurrent with weekly OVA or vehicle challenges. Lung physiology, differential leukocyte counts from bronchoalveolar lavage, and histology (Picro Sirius Red staining for collagen content) were compared between groups 2 days after the last challenge. Gene expression in bronchoalveolar lavage cells was quantified by quantitative PCR. Compared with normoxia, chronic intermittent hypoxia reduced the FEV0.1/FVC ratio (P = 0.005), peak expiratory flow (P = 0.002), and mean midexpiratory flow (P = 0.004), predominantly in medium and large airways; decreased the baseline eosinophil number (P = 0.01) and amplified the effect of OVA on monocyte number (P = 0.02 for the interaction); in proximal airways, increased (P = 0.008), whereas in distal airways it decreased (P = 0.004), collagen density; induced qualitative emphysematous changes in lung periphery; and increased expression of the M2 macrophage marker YM-1 and augmented OVA-induced expression of plasminogen activator inhibitor-1. Chronic intermittent hypoxia alters immune response to allergen toward a more TH-1-predominant cellular phenotype with collagen deposition and matrix degradation, leading to airflow limitation. These findings highlight the potential of sleep apnea to aggravate airway dysfunction in patients with preexistent asthma. PMID:25004109

  14. Role of Inflammation and Immunity in Hypertension: Recent Epidemiological, Laboratory, and Clinical Evidence.

    PubMed

    Caillon, Antoine; Schiffrin, Ernesto L

    2016-03-01

    Inflammation has been shown to play an important role in the mechanisms involved in the pathogenesis of hypertension. Accordingly, innate and adaptive immune responses participate in blood pressure elevation. Here, we describe recent immunity studies focusing on novel inflammatory mechanisms during the hypertensive process. Different subpopulations of cells involved in innate and adaptive immune responses, such as monocyte/macrophages and dendritic cells on the one hand and B and T lymphocytes on the other hand, play roles leading to vascular injury in hypertension. Innate lymphoid cells, including natural killer cells and γ/δ T cells, have recently been demonstrated to participate in hypertensive mechanisms triggering vascular inflammation. In summary, we discuss the evidence of interaction of these different inflammatory and immune components in both experimental models and in humans during the development of hypertension. PMID:26846785

  15. Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model.

    PubMed

    Bonfield, Tracey L; Koloze, Mary; Lennon, Donald P; Zuchowski, Brandon; Yang, Sung Eun; Caplan, Arnold I

    2010-12-01

    Allogeneic human mesenchymal stem cells (hMSCs) introduced intravenously can have profound anti-inflammatory activity resulting in suppression of graft vs. host disease as well as regenerative events in the case of stroke, infarct, spinal cord injury, meniscus regeneration, tendinitis, acute renal failure, and heart disease in human and animal models of these diseases. hMSCs produce bioactive factors that provide molecular cuing for: 1) immunosuppression of T cells; 2) antiscarring; 3) angiogenesis; 4) antiapoptosis; and 5) regeneration (i.e., mitotic for host-derived progenitor cells). Studies have shown that hMSCs have profound effects on the immune system and are well-tolerated and therapeutically active in immunocompetent rodent models of multiple sclerosis and stroke. Furthermore, intravenous administration of MSCs results in pulmonary localization. Asthma is a major debilitating pulmonary disease that impacts in excess of 150 million people in the world with uncontrolled asthma potentially leading to death. In addition, the socioeconomic impact of asthma-associated illnesses at the pediatric and adult level are in the millions of dollars in healthcare costs and lost days of work. hMSCs may provide a viable multiaction therapeutic for this inflammatory lung disease by secreting bioactive factors or directing cellular activity. Our studies show the effectiveness and specificity of the hMSCs on decreasing chronic airway inflammation associated with the murine ovalbumin model of asthma. In addition, the results from these studies verify the in vivo immunoeffectiveness of hMSCs in rodents and support the potential therapeutic use of hMSCs for the treatment of airway inflammation associated with chronic asthma. PMID:20817776

  16. Estrogen receptors alpha mediates postischemic inflammation in chronically estrogen-deprived mice.

    PubMed

    Cordeau, Pierre; Lalancette-Hébert, Mélanie; Weng, Yuan Cheng; Kriz, Jasna

    2016-04-01

    Estrogens are known to exert neuroprotective and immuneomodulatory effects after stroke. However, at present, little is known about the role of estrogens and its receptors in postischemic inflammation after menopause. Here, we provide important in vivo evidence of a distinct shift in microglial phenotypes in the model of postmenopause brain. Using a model-system for live imaging of microglial activation in the context of chronic estrogen- and ERα-deficiency associated with aging, we observed a marked deregulation of the TLR2 signals and/or microglial activation in ovariectomized and/or ERα knockout mice. Further analysis revealed a 5.7-fold increase in IL-6, a 4.7-fold increase in phospho-Stat3 levels suggesting an overactivation of JAK/STAT3 pathway and significantly larger infarction in ERα knockouts chronically deprived of estrogen. Taken together, our results suggest that in the experimental model of menopause and/or aging, ERα mediates innate immune responses and/or microglial activation, and ischemia-induced production of IL-6. Based on our results, we propose that the loss of functional ERα may lead to deregulation of postischemic inflammatory responses and increased vulnerability to ischemic injury in aging female brains. PMID:26973103

  17. Compartmentalized intrathecal immunoglobulin synthesis during HIV infection - a model of chronic CNS inflammation?

    PubMed

    Bonnan, Mickael; Barroso, Bruno; Demasles, Stéphanie; Krim, Elsa; Marasescu, Raluca; Miquel, Marie

    2015-08-15

    HIV infects the central nervous system (CNS) during primary infection and persists in resident macrophages. CNS infection initiates a strong local immune response that fails to control the virus but is responsible for by-stander lesions involved in neurocognitive disorders. Although highly active anti-retroviral therapy now offers an almost complete control of CNS viral proliferation, low-grade CNS inflammation persists. This review focuses on HIV-induced intrathecal immunoglobulin (Ig) synthesis. Intrathecal Ig synthesis early occurs in more than three-quarters of patients in response to viral infection of the CNS and persists throughout the course of the disease. Viral antigens are targeted but this specific response accounts for <5% of the whole intrathecal synthesis. Although the nature and mechanisms leading to non-specific synthesis are unknown, this prominent proportion is comparable to that observed in various CNS viral infections. Cerebrospinal fluid-floating antibody-secreting cells account for a minority of the whole synthesis, which mainly takes place in perivascular inflammatory infiltrates of the CNS parenchyma. B-cell traffic and lineage across the blood-brain-barrier have not yet been described. We review common technical pitfalls and update the pending questions in the field. Moreover, since HIV infection is associated with an intrathecal chronic oligoclonal (and mostly non-specific) Ig synthesis and associates with low-grade axonal lesions, this could be an interesting model of the chronic intrathecal synthesis occurring during multiple sclerosis. PMID:26198917

  18. IFN-γ differentially regulates subsets of Gr-1(+)CD11b(+) myeloid cells in chronic inflammation.

    PubMed

    Zhan, Xiaoxia; Fang, Yimin; Hu, Shengfeng; Wu, Yongjian; Yang, Kun; Liao, Chunxin; Zhang, Yuanqing; Huang, Xi; Wu, Minhao

    2015-08-01

    During chronic inflammation, prolonged over-reactive immune response may lead to tissue destruction, while immune suppression hinders tissue repair and pathogen elimination. Therefore, precise regulation of the immune response is needed to avoid immuno-pathology. Interferon-gamma (IFN-γ) is widely used in clinical treatment of inflammatory diseases. However, the underlying mechanism remains unclear. Here, we evaluated the role of IFN-γ on CD11b(+)Gr-1(+) myeloid cell differentiation and function, using a heat-killed Mycobacterium bovis BCG-induced chronic inflammation model. After challenge with heat-killed BCG, two subpopulations of CD11b(+)Gr-1(+) myeloid cells were generated in the mouse spleen. Phenotypical, morphological and functional analysis indicated that the CD11b(+)Gr-1(high) Ly6G(high) Ly6C(low) subset was neutrophil-like myeloid-derived inducer cells (N-MDICs), which promoted T cell activation, while the other subset was CD11b(+)Gr-1(low) Ly6G(neg) Ly6C(high) monocyte-like myeloid-derived suppressor cells (M-MDSCs) that displayed extensive suppressor function. IFN-γ treatment dampened N-MDICs-mediated T cell activation through up-regulating T cell suppressive mediators, reactive oxygen species (ROS) and arginase I. While for M-MDSCs, IFN-γ reduced their suppressing activity by decreasing the arginase activity. Our study provides evidence that IFN-γ balances the over-reactive vs compromised immune response through different regulation of distinct myeloid subsets, and therefore displays significant therapeutic potential for effective immuno-therapy of chronic inflammatory diseases. PMID:26021804

  19. Exercise in Regulation of Inflammation-Immune Axis Function in Cancer Initiation and Progression

    PubMed Central

    Koelwyn, Graeme J.; Wennerberg, Erik; Demaria, Sandra; Jones, Lee W.

    2016-01-01

    Pharmacologic manipulation of the immune system is emerging as a viable and robust treatment for some cancer patients. Exercise-induced modulation of the immune system may be another adjunctive strategy for inhibiting tumor initiation and progression. In healthy individuals, exercise has been shown to modulate a number of cell subsets involved in innate and adaptive immunity. Here, we provide an overview of the current state of knowledge pertaining to exercise modulation of the inflammation-immune axis in cancer. The current evidence suggests that exercise may be a promising adjunctive strategy that can favorably alter numerous components of the immune system, which, in turn, may modulate tumorigenesis. However, many important knowledge gaps are evident. To this end, we propose a framework to guide future research efforts investigating the immune effects of exercise in cancer. PMID:26676894

  20. Innate and Adaptive Immunity Synergize to Trigger Inflammation in the Mammary Gland

    PubMed Central

    Rainard, Pascal; Cunha, Patricia; Gilbert, Florence B.

    2016-01-01

    The mammary gland is able to detect and react to bacterial intrusion through innate immunity mechanisms, but mammary inflammation can also result from antigen-specific adaptive immunity. We postulated that innate and adaptive immune responses could synergize to trigger inflammation in the mammary gland. To test this hypothesis, we immunized cows with the model antigen ovalbumin and challenged the sensitized animals with either Escherichia coli lipopolysaccharide (LPS) as innate immunity agonist, ovalbumin as adaptive immunity agonist, or both agonists in three different udder quarters of lactating cows. There was a significant amplification of the initial milk leukocytosis in the quarters challenged with the two agonists compared to leukocytosis in quarters challenged with LPS or ovalbumin alone. This synergistic response occurred only with the cows that developed the ovalbumin-specific inflammatory response, and there were significant correlations between milk leukocytosis and production of IL-17A and IFN-γ in a whole-blood ovalbumin stimulation assay. The antigen-specific response induced substantial concentrations of IL-17A and IFN-γ in milk contrary to the response to LPS. Such a synergy at the onset of the reaction of the mammary gland suggests that induction of antigen-specific immune response with bacterial antigens could improve the initial immune response to infection, hence reducing the bacterial load and contributing to protection. PMID:27100324

  1. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Balestro, Elisabetta; Calabrese, Fiorella; Turato, Graziella; Lunardi, Francesca; Bazzan, Erica; Marulli, Giuseppe; Biondini, Davide; Rossi, Emanuela; Sanduzzi, Alessandro; Rea, Federico; Rigobello, Chiara; Gregori, Dario; Baraldo, Simonetta; Spagnolo, Paolo

    2016-01-01

    The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define “slow” or “rapid” disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression. PMID:27159038

  2. Avian Influenza Viruses, Inflammation, and CD8(+) T Cell Immunity.

    PubMed

    Wang, Zhongfang; Loh, Liyen; Kedzierski, Lukasz; Kedzierska, Katherine

    2016-01-01

    Avian influenza viruses (AIVs) circulate naturally in wild aquatic birds, infect domestic poultry, and are capable of causing sporadic bird-to-human transmissions. AIVs capable of infecting humans include a highly pathogenic AIV H5N1, first detected in humans in 1997, and a low pathogenic AIV H7N9, reported in humans in 2013. Both H5N1 and H7N9 cause severe influenza disease in humans, manifested by acute respiratory distress syndrome, multi-organ failure, and high mortality rates of 60% and 35%, respectively. Ongoing circulation of H5N1 and H7N9 viruses in wild birds and poultry, and their ability to infect humans emphasizes their epidemic and pandemic potential and poses a public health threat. It is, thus, imperative to understand the host immune responses to the AIVs so we can control severe influenza disease caused by H5N1 or H7N9 and rationally design new immunotherapies and vaccines. This review summarizes our current knowledge on AIV epidemiology, disease symptoms, inflammatory processes underlying the AIV infection in humans, and recent studies on universal pre-existing CD8(+) T cell immunity to AIVs. Immune responses driving the host recovery from AIV infection in patients hospitalized with severe influenza disease are also discussed. PMID:26973644

  3. Targeting Rho-GTPases in immune cell migration and inflammation

    PubMed Central

    Biro, Maté; Munoz, Marcia A; Weninger, Wolfgang

    2014-01-01

    Leukocytes are unmatched migrators capable of traversing barriers and tissues of remarkably varied structural composition. An effective immune response relies on the ability of its constituent cells to infiltrate target sites. Yet, unwarranted mobilization of immune cells can lead to inflammatory diseases and tissue damage ranging in severity from mild to life-threatening. The efficacy and plasticity of leukocyte migration is driven by the precise spatiotemporal regulation of the actin cytoskeleton. The small GTPases of the Rho family (Rho-GTPases), and their immediate downstream effector kinases, are key regulators of cellular actomyosin dynamics and are therefore considered prime pharmacological targets for stemming leukocyte motility in inflammatory disorders. This review describes advances in the development of small-molecule inhibitors aimed at modulating the Rho-GTPase-centric regulatory pathways governing motility, many of which stem from studies of cancer invasiveness. These inhibitors promise the advent of novel treatment options with high selectivity and potency against immune-mediated pathologies. Linked Articles This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24 PMID:24571448

  4. Avian Influenza Viruses, Inflammation, and CD8+ T Cell Immunity

    PubMed Central

    Wang, Zhongfang; Loh, Liyen; Kedzierski, Lukasz; Kedzierska, Katherine

    2016-01-01

    Avian influenza viruses (AIVs) circulate naturally in wild aquatic birds, infect domestic poultry, and are capable of causing sporadic bird-to-human transmissions. AIVs capable of infecting humans include a highly pathogenic AIV H5N1, first detected in humans in 1997, and a low pathogenic AIV H7N9, reported in humans in 2013. Both H5N1 and H7N9 cause severe influenza disease in humans, manifested by acute respiratory distress syndrome, multi-organ failure, and high mortality rates of 60% and 35%, respectively. Ongoing circulation of H5N1 and H7N9 viruses in wild birds and poultry, and their ability to infect humans emphasizes their epidemic and pandemic potential and poses a public health threat. It is, thus, imperative to understand the host immune responses to the AIVs so we can control severe influenza disease caused by H5N1 or H7N9 and rationally design new immunotherapies and vaccines. This review summarizes our current knowledge on AIV epidemiology, disease symptoms, inflammatory processes underlying the AIV infection in humans, and recent studies on universal pre-existing CD8+ T cell immunity to AIVs. Immune responses driving the host recovery from AIV infection in patients hospitalized with severe influenza disease are also discussed. PMID:26973644

  5. Inflammation, Immunity, and Hypertensive End-Organ Damage

    PubMed Central

    McMaster, William G.; Kirabo, Annet; Madhur, Meena S.; Harrison, David G.

    2015-01-01

    For more than 50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, DOCA-salt and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including IL-17, IFN-γ, TNFα and IL-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption and increased renal fibrosis. Very recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension including myocardial infarction, heart failure, renal failure and stroke. PMID:25767287

  6. The role of stromal cells in the persistence of chronic inflammation

    PubMed Central

    Naylor, A J; Filer, A; Buckley, C D

    2013-01-01

    Inflammation is an unstable state; it either resolves or persists. Inflammatory reactions often have a propensity for specific anatomical sites. Why inflammation persists with specific tissue tropism remains obscure. Increasing evidence suggests that stromal cells which define tissue architecture are the key cells involved, and therefore make attractive therapeutic targets. Research on stromal cells in general and fibroblasts in particular has so far been hampered by a lack of fibroblast-specific cell markers. This review highlights our increasing understanding of the role of fibroblasts in inflammation, and suggests that these cells provide the cellular basis for site specific chronic inflammation. PMID:23199320

  7. Chronic Inflammation in an Anophthalmic Socket due to a Room Temperature Vulcanized Silicone Implant

    PubMed Central

    Galindo-Ferreiro, Alicia; AlGhafri, Laila; Elkhamary, Sahar M.; Maktabi, Azza; Gálvez-Ruiz, Alberto; Galindo-Alonso, Julio; Schellini Proff, Silvana

    2016-01-01

    Two case reports are used to illustrate the signs and symptoms, complications and treatments of chronic socket inflammation due to intraorbital implants. The ophthalmic examination, surgeries and treatments are documented. Two anophthalmic cases that underwent enucleation and multiple orbital surgeries to enhance the anophthalmic socket volume developed pain, intense discharge and contracted cavities with chronic inflammation in the socket which was nonresponsive to medical therapy. Computed tomography indicated a hypodense foreign body in both cases causing an intense inflammatory reaction. The implants were removed by excisional surgery and a room temperature vulcanized silicone implant was retrieved in both cases. Socket inflammation resolved in both cases after implant removal. An intraorbital inflammatory reaction against an intraorbital implant can cause chronic socket inflammation in patients with a history of multiple surgeries. Diagnosis requires imaging and the definitive treatment is implant removal. PMID:27462246

  8. Natural Products as Tools for Defining How Cellular Metabolism Influences Cellular Immune and Inflammatory Function during Chronic Infection

    PubMed Central

    Lovelace, Erica S.; Polyak, Stephen J.

    2015-01-01

    Chronic viral infections like those caused by hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause disease that establishes an ongoing state of chronic inflammation. While there have been tremendous improvements towards curing HCV with directly acting antiviral agents (DAA) and keeping HIV viral loads below detection with antiretroviral therapy (ART), there is still a need to control inflammation in these diseases. Recent studies indicate that many natural products like curcumin, resveratrol and silymarin alter cellular metabolism and signal transduction pathways via enzymes such as adenosine monophosphate kinase (AMPK) and mechanistic target of rapamycin (mTOR), and these pathways directly influence cellular inflammatory status (such as NF-κB) and immune function. Natural products represent a vast toolkit to dissect and define how cellular metabolism controls cellular immune and inflammatory function. PMID:26633463

  9. Substance P at the Nexus of Mind and Body in Chronic Inflammation and Affective Disorders

    ERIC Educational Resources Information Center

    Rosenkranz, Melissa A.

    2007-01-01

    For decades, research has demonstrated that chronic diseases characterized by dysregulation of inflammation are particularly susceptible to exacerbation by stress and emotion. Likewise, rates of depression and anxiety are overrepresented in individuals suffering from chronic inflammatory disease. In recent years, substance P has been implicated in…

  10. Role of IL-10-producing regulatory B cells in modulating T-helper cell immune responses during silica-induced lung inflammation and fibrosis.

    PubMed

    Liu, Fangwei; Dai, Wujing; Li, Chao; Lu, Xiaowei; Chen, Ying; Weng, Dong; Chen, Jie

    2016-01-01

    Silicosis is characterized by chronic lung inflammation and fibrosis, which are seriously harmful to human health. Previous research demonstrated that uncontrolled T-helper (Th) cell immune responses were involved in the pathogenesis of silicosis. Lymphocytes also are reported to have important roles. Existing studies on lymphocyte regulation of Th immune responses were limited to T cells, such as the regulatory T (Treg) cell, which could negatively regulate inflammation and promote the process of silicosis. However, other regulatory subsets in silicosis have not been investigated in detail, and the mechanism of immune homeostasis modulation needs further exploration. Another regulatory lymphocyte, the regulatory B cell, has recently drawn increasing attention. In this study, we comprehensively showed the role of IL-10-producing regulatory B cell (B10) in a silicosis model of mice. B10 was inducible by silica instillation. Insufficient B10 amplified inflammation and attenuated lung fibrosis by promoting the Th1 immune response. Insufficient B10 clearly inhibited Treg and decreased the level of IL-10. Our study indicated that B10 could control lung inflammation and exacerbate lung fibrosis by inhibiting Th1 response and modulating the Th balance. The regulatory function of B10 could be associated with Treg induction and IL-10 secretion. PMID:27354007

  11. Role of IL-10-producing regulatory B cells in modulating T-helper cell immune responses during silica-induced lung inflammation and fibrosis

    PubMed Central

    Liu, Fangwei; Dai, Wujing; Li, Chao; Lu, Xiaowei; Chen, Ying; Weng, Dong; Chen, Jie

    2016-01-01

    Silicosis is characterized by chronic lung inflammation and fibrosis, which are seriously harmful to human health. Previous research demonstrated that uncontrolled T-helper (Th) cell immune responses were involved in the pathogenesis of silicosis. Lymphocytes also are reported to have important roles. Existing studies on lymphocyte regulation of Th immune responses were limited to T cells, such as the regulatory T (Treg) cell, which could negatively regulate inflammation and promote the process of silicosis. However, other regulatory subsets in silicosis have not been investigated in detail, and the mechanism of immune homeostasis modulation needs further exploration. Another regulatory lymphocyte, the regulatory B cell, has recently drawn increasing attention. In this study, we comprehensively showed the role of IL-10-producing regulatory B cell (B10) in a silicosis model of mice. B10 was inducible by silica instillation. Insufficient B10 amplified inflammation and attenuated lung fibrosis by promoting the Th1 immune response. Insufficient B10 clearly inhibited Treg and decreased the level of IL-10. Our study indicated that B10 could control lung inflammation and exacerbate lung fibrosis by inhibiting Th1 response and modulating the Th balance. The regulatory function of B10 could be associated with Treg induction and IL-10 secretion. PMID:27354007

  12. Endothelial Dysfunction and Inflammation: Immunity in Rheumatoid Arthritis

    PubMed Central

    Yang, XueZhi; Chang, Yan; Wei, Wei

    2016-01-01

    Inflammation, as a feature of rheumatoid arthritis (RA), leads to the activation of endothelial cells (ECs). Activated ECs induce atherosclerosis through an increased expression of leukocyte adhesion molecules. Endothelial dysfunction (ED) is recognized as a failure of endothelial repair mechanisms. It is also an early preclinical marker of atherosclerosis and is commonly found in RA patients. RA is now established as an independent cardiovascular risk factor, while mechanistic determinants of ED in RA are still poorly understood. An expanding body of study has shown that EC at a site of RA is both active participant and regulator of inflammatory process. Over the last decade, a role for endothelial dysfunction in RA associated with cardiovascular disease (CVD) has been hypothesized. At the same time, several maintenance drugs targeting this phenomenon have been tested, which has promising results. Assessment of endothelial function may be a useful tool to identify and monitor RA patients. PMID:27122657

  13. Clinical Relevance of Kynurenine Pathway in HIV/AIDS: An Immune Checkpoint at the Crossroads of Metabolism and Inflammation.

    PubMed

    Routy, Jean-Pierre; Mehraj, Vikram; Vyboh, Kishanda; Cao, Wei; Kema, Ido; Jenabian, Mohammad-Ali

    2015-01-01

    Tryptophan degradation along the kynurenine pathway is associated with a wide variety of pathophysiological processes, of which tumor tolerance and immune dysfunction in several chronic viral infections including HIV are well known. The kynurenine pathway is at the crossroads of metabolism and immunity and plays an important role in inflammation while also playing an opposing role in the control of acute and chronic infections. In this review we have summarized findings from recent studies reporting modulation of tryptophan degrading the kynurenine pathway in the context of HIV infection. This immuno-metabolic pathway is modulated by three distinct inducible enzymes: indoleamine 2,3-dioxygenase 1 and 2 and tryptophan 2,3-dioxygenase. Increased expression of these enzymes by antigen-presenting cells leads to local or systemic tryptophan depletion, resulting in a mechanism of defense against certain microorganisms. Conversely, it can also lead to immunosuppression by antigen-specific T-cell exhaustion and recruitment of T regulatory cells. Recently, among these enzymes, indoleamine 2,3-dioxygenase 1 has been recognized to be an immune response checkpoint that plays an important role in HIV immune dysfunction, even in the context of antiretroviral therapy. In addition to the activation of the kynurenine pathway by HIV proteins Tat and Nef, the tryptophan-degrading bacteria present in the intestinal flora have been associated with dysfunction of gut mucosal CD4 Th17/Th22 cells, leading to microbial translocation and creating a systemic kynurenine pathway activation cycle. This self-sustaining feedback loop has deleterious effects on disease progression and on neurocognitive impairment in HIV-infected patients. Therapy designed to break the vicious cycle of induced tryptophan degradation is warranted to revert immune exhaustion in HIV-infected persons. PMID:26035167

  14. Implications of compromised zinc status on bone loss associated with chronic inflammation in C57BL/6 mice

    PubMed Central

    Chongwatpol, Pitipa; Rendina-Ruedy, Elizabeth; Stoecker, Barbara J; Clarke, Stephen L; Lucas, Edralin A; Smith, Brenda J

    2015-01-01

    Compromised zinc status and chronic inflammation are independent factors that can contribute to bone loss. However, zinc’s role in regulating lymphoid and myeloid cell populations, combined with the interplay between the immune and skeletal systems raises the question as to the extent to which a low-grade inflammatory challenge in the context of marginal zinc deficiency would exacerbate bone loss. To address this question, young adult C57BL/6 male mice (n=32) were used in a 2×2 factorial design with dietary zinc (adequate or 35 ppm vs inadequate or −Zn =5 ppm) and lipopolysaccharide (LPS, 0 or 0.1 mg/kg body weight). Mice were fed their respective diets for 10 weeks. On the 6th week, mice had a slow release pellet implanted to induce a low-grade inflammation for the final 4 weeks of the study. −Zn induced a decrease in total white cell counts and peripheral lymphocytes, whereas LPS increased blood monocytes. LPS significantly reduced spine bone mineral density and trabecular bone volume and number of the vertebral body compared with both zinc adequate and inadequate without LPS groups. Likewise, the most pronounced effects on bone strength occurred with LPS, however, −Zn also had negative effects on the bone von Mises stresses. LPS induced an increase in TNF-α and this response was further increased with −Zn. Although the marginal zinc deficiency altered immune function, bone loss was not exacerbated with low-grade chronic inflammation in marginally zinc-deficient young adult mice. These findings demonstrate that in young adult animals an immune challenge modestly increases the inflammatory response and worsens bone biomechanics in the context of a marginal zinc deficiency, but not to the extent that more severe adverse outcomes are observed on bone structural parameters. PMID:26203271

  15. Inflammation and Immunity in Diseases of the Arterial Tree: Players and Layers

    PubMed Central

    Libby, Peter; Hansson, Göran K.

    2014-01-01

    The hypothesis that immunity and inflammation participate in the pathogenesis of vascular diseases has now gained widespread recognition and stimulated work around the globe. Broadening knowledge has extended the recognition of the role of immune and inflammatory mechanisms to all of the layers of the artery, to all levels of the arterial tree, and implicated virtually all arms, cellular “players,” and effector molecules and pathways involved in these crucial host defenses, that turn against us in disease. We provide here a guide to a compendium series of papers that aimed to look forward, and broaden the traditional focus of immunopathogenesis of arterial disease, with the goal of integrating the “players” and the “layers” involved. While the field has advanced remarkably, much remains to be done, and this commentary also aims to highlight some of the gaps that future research should strive to close regarding the participation of inflammation and immunity in arterial diseases. PMID:25593275

  16. Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective

    PubMed Central

    Neumann, Silke; Shields, Nicholas J.; Balle, Thomas; Chebib, Mary; Clarkson, Andrew N.

    2015-01-01

    Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer’s disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR) ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells. PMID:26690125

  17. Effects of inhaled therapy on biomarkers of systemic inflammation in stable chronic obstructive pulmonary disease.

    PubMed

    Antoniu, Sabina A

    2010-03-01

    In chronic obstructive pulmonary disease (COPD) airways inflammation is associated in more advanced stages with systemic inflammation. COPD-associated systemic inflammation syndrome is defined currently with rather non-specific biomarkers such as C-reactive protein (CRP) but there are also other 'organ-specific' biomarkers such as surfactant protein-D which are still not well characterized but might represent more appropriate and reliable alternatives to the non-specific biomarkers. Inhaled therapies are the mainstay in stable COPD and they were demonstrated to reduce airway inflammation and more recently in the case of inhaled corticosteroids alone or combined with long-acting beta-2 agonists to reduce systemic inflammation as well. This paper focuses on current and potential biomarkers of systemic inflammation in COPD and on the systemic anti-inflammatory effects of inhaled therapies in stable COPD. PMID:19929747

  18. CD11c(+) monocyte/macrophages promote chronic Helicobacter hepaticus-induced intestinal inflammation through the production of IL-23.

    PubMed

    Arnold, I C; Mathisen, S; Schulthess, J; Danne, C; Hegazy, A N; Powrie, F

    2016-03-01

    In inflammatory bowel diseases, a breakdown in host microbial interactions accompanies sustained activation of immune cells in the gut. Functional studies suggest a key role for interleukin-23 (IL-23) in orchestrating intestinal inflammation. IL-23 can be produced by various mononuclear phagocytes (MNPs) following acute microbial stimulation, but little is known about the key cellular sources of IL-23 that drive chronic intestinal inflammation. Here we have addressed this question using a physiological model of bacteria-driven colitis. By combining conditional gene ablation and gene expression profiling, we found that IL-23 production by CD11c(+) MNPs was essential to trigger intestinal immunopathology and identified MHCII(+) monocytes and macrophages as the major source of IL-23. Expression of IL-23 by monocytes was acquired during their differentiation in the intestine and correlated with the expression of major histocompatibility complex class II (MHCII) and CD64. In contrast, Batf3-dependent CD103(+) CD11b(-) dendritic cells were dispensable for bacteria-induced colitis in this model. These studies reinforce the pathogenic role of monocytes in dysregulated responses to intestinal bacteria and identify production of IL-23 as a key component of this response. Further understanding of the functional sources of IL-23 in diverse forms of intestinal inflammation may lead to novel therapeutic strategies aimed at interrupting IL-23-driven immune pathology. PMID:26242598

  19. Macrophage TCF-4 co-activates p65 to potentiate chronic inflammation and insulin resistance in mice.

    PubMed

    Kang, Xia; Hou, Along; Wang, Rui; Liu, Da; Xiang, Wei; Xie, Qingyun; Zhang, Bo; Gan, Lixia; Zheng, Wei; Miao, Hongming

    2016-07-01

    Transcription factor 4 (TCF-4) was recently identified as a candidate gene for the cause of type 2 diabetes, although the mechanisms have not been fully elucidated. In the present study, we demonstrated that the TCF-4 transgene in macrophages aggravated high-fat diet (HFD)-induced insulin resistance and chronic inflammation, characterized by the elevation of proinflammatory cytokines in the blood, liver and white adipose tissue, as well as a proinflammatory profile of immune cells in visceral fats in mice. Mechanistically, TCF-4 functioned as a co-activator of p65 to amplify the saturated free fatty acid (FFA)-stimulated promoter activity, mRNA transcription and secretion of proinflammatory cytokines in primary macrophages. Blockage of p65 with a specific interfering RNA or inhibitor could prevent TCF-4-enhanced expression of proinflammatory cytokines in FFA/lipopolysaccharide-treated primary macrophages. The p65 inhibitor could abolish macrophage TCF-4 transgene-aggravated systemic inflammation, glucose intolerance and insulin resistance in HFD-treated mice. In addition, we demonstrated that the mRNA expression of TCF-4 in the peripheral blood monocytes from humans was positively correlated to the levels of interleukin (IL)-1β, tumour necrosis factor α, IL-6 and fasting plasma glucose. In summary, we identified TCF-4 as a co-activator of p65 in the potentiation of proinflammatory cytokine production in macrophages and aggravation of HFD-induced chronic inflammation and insulin resistance in mice. PMID:27129186

  20. Melatonin and its relation to the immune system and inflammation.

    PubMed

    Reiter, R J; Calvo, J R; Karbownik, M; Qi, W; Tan, D X

    2000-01-01

    Melatonin (N-acetyl-5-methoxytryptamine) was initially thought to be produced exclusively in the pineal gland. Subsequently its synthesis was demonstrated in other organs, for example, the retinas, and very high concentrations of melatonin are found at other sites, for example, bone marrow cells and bile. The origin of the high level of melatonin in these locations has not been definitively established, but it is likely not exclusively of pineal origin. Melatonin has been shown to possess anti-inflammatory effects, among a number of actions. Melatonin reduces tissue destruction during inflammatory reactions by a number of means. Thus melatonin, by virtue of its ability to directly scavenge toxic free radicals, reduces macromolecular damage in all organs. The free radicals and reactive oxygen and nitrogen species known to be scavenged by melatonin include the highly toxic hydroxyl radical (.OH), peroxynitrite anion (ONOO-), and hypochlorous acid (HOCl), among others. These agents all contribute to the inflammatory response and associated tissue destruction. Additionally, melatonin has other means to lower the damage resulting from inflammation. Thus, it prevents the translocation of nuclear factor-kappa B (NF-kappa B) to the nucleus and its binding to DNA, thereby reducing the upregulation of a variety of proinflammatory cytokines, for example, interleukins and tumor neurosis factor-alpha. Finally, there is indirect evidence that melatonin inhibits the production of adhesion molecules that promote the sticking of leukocytes to endothelial cells. By this means melatonin attenuates transendothelial cell migration and edema, which contribute to tissue damage. PMID:11268363

  1. CD39 and CD73 in immunity and inflammation

    PubMed Central

    Antonioli, Luca; Pacher, Pál; Vizi, E. Sylvester; Haskó, György

    2013-01-01

    The enzymatic activities of CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemical nature of purinergic signals delivered to immune cells through the conversion of ADP/ATP to AMP and AMP to adenosine, respectively. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39/CD73 pathway changes dynamically with the pathophysiological context in which it is embedded. It is becoming increasingly appreciated that altering this catabolic machinery can change the course or dictate the outcome of several pathophysiological events, such as AIDS, autoimmune diseases, infections, atherosclerosis, ischemia-reperfusion injury, and cancer, suggesting these ecto-enzymes are novel therapeutic targets for managing a variety of disorders. PMID:23601906

  2. Contribution of inflammation to vascular disease in chronic kidney disease patients.

    PubMed

    Suliman, Mohamed E; Stenvinkel, Peter

    2008-05-01

    Chronic kidney disease (CKD) is characterized by an exceptionally high mortality rate, much of which results from cardiovascular disease (CVD). Chronic low-grade inflammation, as evidenced by increased levels of pro-inflammatory cytokines and C-reactive protein (CRP), is a common feature of CKD and may cause atherosclerotic CVD through various pathogenetic mechanisms. Evidence suggests that persistent inflammation may also be a risk factor for progression of CKD, which may result in a vicious inflammation-driven circle. The causes of inflammation in CKD are multifactorial. The influence of various comorbidities may contribute to inflammation in the setting of progressive loss of renal function. Available data suggest that pro-inflammatory cytokines also play a central role in the genesis of the metabolic syndrome. There is a lack of epidemiological data on the prevalence and consequences of inflammation in relation to protein-energy wasting (PEW) and CVD in CKD patients from developing countries. The 'westernization' of nutritional intakes and changes of life style besides the high prevalence of chronic infections in developing countries are possible additive contributors to a high prevalence of inflammation, PEW and CVD among CKD patients. Also, genetic differences may affect inflammatory responses and nutritional status and, thus, the susceptibility to CVD in different regions. PMID:18445891

  3. Smoking Is Associated with Acute and Chronic Prostatic Inflammation: Results from the REDUCE Study.

    PubMed

    Moreira, Daniel M; Nickel, J Curtis; Gerber, Leah; Muller, Roberto L; Andriole, Gerald L; Castro-Santamaria, Ramiro; Freedland, Stephen J

    2015-04-01

    Both anti- and proinflammatory effects of cigarette smoking have been described. As prostate inflammation is common, we hypothesized smoking could contribute to prostate inflammation. Thus, we evaluated the association of smoking status with acute and chronic inflammation within the prostate of men undergoing prostate biopsy. We retrospectively analyzed 8,190 men ages 50 to 75 years with PSA levels between 2.5 and 10 ng/mL enrolled in the Reduction by Dutasteride of Prostate Cancer Events study. Smoking status was self-defined as never, former, or current. Prostate inflammation was assessed by systematic central review blinded to smoking status. The association of smoking with inflammation in the baseline, 2-year, and 4-year biopsies was evaluated with univariable and multivariable logistic regressions. At study enrollment, 1,233 (15%), 3,203 (39%), and 3,754 (46%) men were current, former, and never smokers, respectively. Current smokers were significantly younger and had smaller prostates than former and never smokers (all P < 0.05). Former smokers were significantly heavier than current and never smokers (P < 0.001). Acute and chronic prostate inflammations were identified in 1,261 (15%) and 6,352 (78%) baseline biopsies, respectively. In univariable analysis, current smokers were more likely to have acute inflammation than former (OR, 1.35; P, 0.001) and never smokers (OR, 1.36; P, 0.001). The results were unchanged at 2- and 4-year biopsies. In contrast, current smoking was linked with chronic inflammation in the baseline biopsy, but not at 2- and 4-year biopsies. In conclusion, among men undergoing prostate biopsy, current smoking was independently associated with acute and possibly chronic prostate inflammations. PMID:25644151

  4. A new hypothesis: some metastases are the result of inflammatory processes by adapted cells, especially adapted immune cells at sites of inflammation

    PubMed Central

    Shahriyari, Leili

    2016-01-01

    There is an old hypothesis that metastasis is the result of migration of tumor cells from the tumor to a distant site. In this article, we propose another mechanism for metastasis, for cancers that are initiated at the site of chronic inflammation. We suggest that cells at the site of chronic inflammation might become adapted to the inflammatory process, and these adaptations may lead to the initiation of an inflammatory tumor. For example, in an inflammatory tumor immune cells might be adapted to send signals of proliferation or angiogenesis, and epithelial cells might be adapted to proliferation (like inactivation of tumor suppressor genes). Therefore, we hypothesize that metastasis could be the result of an inflammatory process by adapted cells, especially adapted immune cells at the site of inflammation, as well as the migration of tumor cells with the help of activated platelets, which travel between sites of inflammation.  If this hypothesis is correct, then any treatment causing necrotic cell death may not be a good solution. Because necrotic cells in the tumor micro-environment or anywhere in the body activate the immune system to initiate the inflammatory process, and the involvement of adapted immune cells in the inflammatory processes leads to the formation and progression of tumors. Adapted activated immune cells send more signals of proliferation and/or angiogenesis than normal cells. Moreover, if there were adapted epithelial cells, they would divide at a much higher rate in response to the proliferation signals than normal cells. Thus, not only would the tumor come back after the treatment, but it would also grow more aggressively. PMID:27158448

  5. Pulmonary and Systemic Immune Response to Chronic Lunar Dust Inhalation

    NASA Technical Reports Server (NTRS)

    Crucian, Brian; Quiriarte, Heather; Nelman, Mayra; Lam, Chiu-wing; James, John T.; Sams, Clarence

    2014-01-01

    Background: Due to millennia of meteorite impact with virtually no erosive effects, the surface of the Moon is covered by a layer of ultra-fine, reactive Lunar dust. Very little is known regarding the toxicity of Lunar dust on human physiology. Given the size and electrostatic characteristics of Lunar dust, countermeasures to ensure non-exposure of astronauts will be difficult. To ensure astronaut safety during any future prolonged Lunar missions, it is necessary to establish the effect of chronic pulmonary Lunar dust exposure on all physiological systems. Methods: This study assessed the toxicity of airborne lunar dust exposure in rats on pulmonary and system immune system parameters. Rats were exposed to 0, 20.8, or 60.8 mg/m3 of lunar dust (6h/d; 5d/wk) for up to 13 weeks. Sacrifices occurred after exposure durations of 1day, 7 days, 4 weeks and 13 weeks post-exposure, when both blood and lung lavage fluid were collected for analysis. Lavage and blood assays included leukocyte distribution by flow cytometry, electron/fluorescent microscopy, and cytokine concentration. Cytokine production profiles following mitogenic stimulation were performed on whole blood only. Results: Untreated lavage fluid was comprised primarily of pulmonary macrophages. Lunar dust inhalation resulted in an influx of neutrophils and lymphocytes. Although the percentage of lymphocytes increased, the T cell CD4:CD8 ratio was unchanged. Cytokine analysis of the lavage fluid showed increased levels of IL-1b and TNFa. These alterations generally persisted through the 13 week sampling. Blood analysis showed few systemic effects from the lunar dust inhalation. By week 4, the peripheral granulocyte percentage was elevated in the treated rats. Plasma cytokine levels were unchanged in all treated rats compared to controls. Peripheral blood analysis showed an increased granulocyte percentage and altered cytokine production profiles consisting of increased in IL-1b and IL-6, and decreased IL-2

  6. Chronic liver inflammation modifies DNA methylation at the precancerous stage of murine hepatocarcinogenesis

    PubMed Central

    Stoyanov, Evgeniy; Ludwig, Guy; Mizrahi, Lina; Olam, Devorah; Schnitzer-Perlman, Temima; Tasika, Elena; Sass, Gabriele; Tiegs, Gisa; Jiang, Yong; Nie, Ting; Kohler, James; Schinazi, Raymond F.; Vertino, Paula M.; Cedar, Howard; Galun, Eithan; Goldenberg, Daniel

    2015-01-01

    Chronic liver inflammation precedes the majority of hepatocellular carcinomas (HCC). Here, we explore the connection between chronic inflammation and DNA methylation in the liver at the late precancerous stages of HCC development in Mdr2−/− (Mdr2/Abcb4-knockout) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation followed by hybridization with “CpG islands” (CGIs) microarrays, we found specific CGIs in 76 genes which were hypermethylated in the Mdr2−/− liver compared to age-matched healthy controls. The observed hypermethylation resulted mainly from an age-dependent decrease of methylation of the specific CGIs in control livers with no decrease in mutant mice. Chronic inflammation did not change global levels of DNA methylation in Mdr2−/− liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2−/− livers affected either hepatocyte, or non-hepatocyte, or both fractions without a correlation between changes of gene methylation and expression. Our findings demonstrate that chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and non-hepatocyte liver cells. These changes may serve as useful markers of an increased regenerative activity and of a late precancerous stage in the chronically inflamed liver. PMID:25918251

  7. Prostatic inflammation induces fibrosis in a mouse model of chronic bacterial infection.

    PubMed

    Wong, Letitia; Hutson, Paul R; Bushman, Wade

    2014-01-01

    Inflammation of the prostate is strongly correlated with development of lower urinary tract symptoms and several studies have implicated prostatic fibrosis in the pathogenesis of bladder outlet obstruction. It has been postulated that inflammation induces prostatic fibrosis but this relationship has never been tested. Here, we characterized the fibrotic response to inflammation in a mouse model of chronic bacterial-induced prostatic inflammation. Transurethral instillation of the uropathogenic E. coli into C3H/HeOuJ male mice induced persistent prostatic inflammation followed by a significant increase in collagen deposition and hydroxyproline content. This fibrotic response to inflammation was accompanied with an increase in collagen synthesis determined by the incorporation of 3H-hydroxyproline and mRNA expression of several collagen remodeling-associated genes, including Col1a1, Col1a2, Col3a1, Mmp2, Mmp9, and Lox. Correlation analysis revealed a positive correlation of inflammation severity with collagen deposition and immunohistochemical staining revealed that CD45+VIM+ fibrocytes were abundant in inflamed prostates at the time point coinciding with increased collagen synthesis. Furthermore, flow cytometric analysis demonstrated an increased percentage of these CD45+VIM+ fibrocytes among collagen type I expressing cells. These data show-for the first time-that chronic prostatic inflammation induces collagen deposition and implicates fibrocytes in the fibrotic process. PMID:24950301

  8. The Gut Epithelial Receptor LRRC19 Promotes the Recruitment of Immune Cells and Gut Inflammation.

    PubMed

    Cao, Shuisong; Su, Xiaomin; Zeng, Benhua; Yan, Hui; Huang, Yugang; Wang, Enlin; Yun, Huan; Zhang, Yuan; Liu, Feifei; Li, Wenxia; Wei, Hong; Che, Yongzhe; Yang, Rongcun

    2016-02-01

    Commensal microbes are necessary for a healthy gut immune system. However, the mechanism involving these microbes that establish and maintain gut immune responses is largely unknown. Here, we have found that the gut immune receptor leucine-rich repeat (LRR) C19 is involved in host-microbiota interactions. LRRC19 deficiency not only impairs the gut immune system but also reduces inflammatory responses in gut tissues. We demonstrate that the LRRC19-associated chemokines CCL6, CCL9, CXCL9, and CXCL10 play a critical role in immune cell recruitment and intestinal inflammation. The expression of these chemokines is associated with regenerating islet-derived (REG) protein-mediated microbiotas. We also found that the expression of REGs may be regulated by gut Lactobacillus through LRRC19-mediated activation of NF-κB. Therefore, our study establishes a regulatory axis of LRRC19, REGs, altered microbiotas, and chemokines for the recruitment of immune cells and the regulation of intestinal inflammation. PMID:26776522

  9. The Gut Epithelial Receptor LRRC19 Promotes the Recruitment of Immune Cells and Gut Inflammation

    PubMed Central

    Cao, Shuisong; Su, Xiaomin; Zeng, Benhua; Yan, Hui; Huang, Yugang; Wang, Enlin; Yun, Huan; Zhang, Yuan; Liu, Feifei; Li, Wenxia; Wei, Hong; Che, Yongzhe; Yang, Rongcun

    2016-01-01

    Summary Commensal microbes are necessary for a healthy gut immune system. However, the mechanism involving these microbes that establish and maintain gut immune responses is largely unknown. Here, we have found that the gut immune receptor leucine-rich repeat (LRR) C19 is involved in host-microbiota interactions. LRRC19 deficiency not only impairs the gut immune system but also reduces inflammatory responses in gut tissues. We demonstrate that the LRRC19-associated chemokines CCL6, CCL9, CXCL9, and CXCL10 play a critical role in immune cell recruitment and intestinal inflammation. The expression of these chemokines is associated with regenerating islet-derived (REG) protein-mediated microbiotas. We also found that the expression of REGs may be regulated by gut Lactobacillus through LRRC19-mediated activation of NF-κB. Therefore, our study establishes a regulatory axis of LRRC19, REGs, altered microbiotas, and chemokines for the recruitment of immune cells and the regulation of intestinal inflammation. PMID:26776522

  10. Type II NKT-TFH cells against Gaucher lipids regulate B-cell immunity and inflammation

    PubMed Central

    Nair, Shiny; Boddupalli, Chandra Sekhar; Verma, Rakesh; Liu, Jun; Yang, Ruhua; Pastores, Gregory M.; Mistry, Pramod K.

    2015-01-01

    Chronic inflammation including B-cell activation is commonly observed in both inherited (Gaucher disease [GD]) and acquired disorders of lipid metabolism. However, the cellular mechanisms underlying B-cell activation in these settings remain to be elucidated. Here, we report that β-glucosylceramide 22:0 (βGL1-22) and glucosylsphingosine (LGL1), 2 major sphingolipids accumulated in GD, can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Human βGL1-22– and LGL1-reactive CD1d tetramer–positive T cells have a distinct T-cell receptor usage and genomic and cytokine profiles compared with the classical type I NKT cells. In contrast to type I NKT cells, βGL1-22– and LGL1-specific NKT cells constitutively express T-follicular helper (TFH) phenotype. Injection of these lipids leads to an increase in respective lipid-specific type II NKT cells in vivo and downstream induction of germinal center B cells, hypergammaglobulinemia, and production of antilipid antibodies. Human βGL1-22– and LGL1-specific NKT cells can provide efficient cognate help to B cells in vitro. Frequency of LGL1-specific T cells in GD mouse models and patients correlates with disease activity and therapeutic response. Our studies identify a novel type II NKT-mediated pathway for glucosphingolipid-mediated dysregulation of humoral immunity and increased risk of B-cell malignancy observed in metabolic lipid disorders. PMID:25499455

  11. The Immune System in Tissue Environments Regaining Homeostasis after Injury: Is “Inflammation” Always Inflammation?

    PubMed Central

    2016-01-01

    Inflammation is a response to infections or tissue injuries. Inflammation was once defined by clinical signs, later by the presence of leukocytes, and nowadays by expression of “proinflammatory” cytokines and chemokines. But leukocytes and cytokines often have rather anti-inflammatory, proregenerative, and homeostatic effects. Is there a need to redefine “inflammation”? In this review, we discuss the functions of “inflammatory” mediators/regulators of the innate immune system that determine tissue environments to fulfill the need of the tissue while regaining homeostasis after injury. PMID:27597803

  12. Cell Walls of Saccharomyces cerevisiae Differentially Modulated Innate Immunity and Glucose Metabolism during Late Systemic Inflammation

    PubMed Central

    Baurhoo, Bushansingh; Ferket, Peter; Ashwell, Chris M.; de Oliviera, Jean; Zhao, Xin

    2012-01-01

    Background Salmonella causes acute systemic inflammation by using its virulence factors to invade the intestinal epithelium. But, prolonged inflammation may provoke severe body catabolism and immunological diseases. Salmonella has become more life-threatening due to emergence of multiple-antibiotic resistant strains. Mannose-rich oligosaccharides (MOS) from cells walls of Saccharomyces cerevisiae have shown to bind mannose-specific lectin of Gram-negative bacteria including Salmonella, and prevent their adherence to intestinal epithelial cells. However, whether MOS may potentially mitigate systemic inflammation is not investigated yet. Moreover, molecular events underlying innate immune responses and metabolic activities during late inflammation, in presence or absence of MOS, are unknown. Methods and Principal Findings Using a Salmonella LPS-induced systemic inflammation chicken model and microarray analysis, we investigated the effects of MOS and virginiamycin (VIRG, a sub-therapeutic antibiotic) on innate immunity and glucose metabolism during late inflammation. Here, we demonstrate that MOS and VIRG modulated innate immunity and metabolic genes differently. Innate immune responses were principally mediated by intestinal IL-3, but not TNF-α, IL-1 or IL-6, whereas glucose mobilization occurred through intestinal gluconeogenesis only. MOS inherently induced IL-3 expression in control hosts. Consequent to LPS challenge, IL-3 induction in VIRG hosts but not differentially expressed in MOS hosts revealed that MOS counteracted LPS's detrimental inflammatory effects. Metabolic pathways are built to elucidate the mechanisms by which VIRG host's higher energy requirements were met: including gene up-regulations for intestinal gluconeogenesis (PEPCK) and liver glycolysis (ENO2), and intriguingly liver fatty acid synthesis through ATP citrate synthase (CS) down-regulation and ATP citrate lyase (ACLY) and malic enzyme (ME) up-regulations. However, MOS host's lower energy

  13. Tumor Necrosis Factor Superfamily in Innate Immunity and Inflammation

    PubMed Central

    Šedý, John; Bekiaris, Vasileios; Ware, Carl F.

    2015-01-01

    The tumor necrosis factor superfamily (TNFSF) and its corresponding receptor superfamily (TNFRSF) form communication pathways required for developmental, homeostatic, and stimulus-responsive processes in vivo. Although this receptor–ligand system operates between many different cell types and organ systems, many of these proteins play specific roles in immune system function. The TNFSF and TNFRSF proteins lymphotoxins, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes), lymphotoxin-β receptor (LT-βR), and HVEM are used by embryonic and adult innate lymphocytes to promote the development and homeostasis of lymphoid organs. Lymphotoxin-expressing innate-acting B cells construct microenvironments in lymphoid organs that restrict pathogen spread and initiate interferon defenses. Recent results illustrate how the communication networks formed among these cytokines and the coreceptors B and T lymphocyte attenuator (BTLA) and CD160 both inhibit and activate innate lymphoid cells (ILCs), innate γδ T cells, and natural killer (NK) cells. Understanding the role of TNFSF/TNFRSF and interacting proteins in innate cells will likely reveal avenues for future therapeutics for human disease. PMID:25524549

  14. Tumor necrosis factor superfamily in innate immunity and inflammation.

    PubMed

    Šedý, John; Bekiaris, Vasileios; Ware, Carl F

    2015-04-01

    The tumor necrosis factor superfamily (TNFSF) and its corresponding receptor superfamily (TNFRSF) form communication pathways required for developmental, homeostatic, and stimulus-responsive processes in vivo. Although this receptor-ligand system operates between many different cell types and organ systems, many of these proteins play specific roles in immune system function. The TNFSF and TNFRSF proteins lymphotoxins, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes), lymphotoxin-β receptor (LT-βR), and HVEM are used by embryonic and adult innate lymphocytes to promote the development and homeostasis of lymphoid organs. Lymphotoxin-expressing innate-acting B cells construct microenvironments in lymphoid organs that restrict pathogen spread and initiate interferon defenses. Recent results illustrate how the communication networks formed among these cytokines and the coreceptors B and T lymphocyte attenuator (BTLA) and CD160 both inhibit and activate innate lymphoid cells (ILCs), innate γδ T cells, and natural killer (NK) cells. Understanding the role of TNFSF/TNFRSF and interacting proteins in innate cells will likely reveal avenues for future therapeutics for human disease. PMID:25524549

  15. A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis

    PubMed Central

    Fransén-Pettersson, Nina; Duarte, Nadia; Nilsson, Julia; Lundholm, Marie; Mayans, Sofia; Larefalk, Åsa; Hannibal, Tine D.; Hansen, Lisbeth; Schmidt-Christensen, Anja; Ivars, Fredrik; Cardell, Susanna; Palmqvist, Richard; Rozell, Björn

    2016-01-01

    Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders. PMID:27441847

  16. Microbiota alterations in acute and chronic gastrointestinal inflammation of cats and dogs

    PubMed Central

    Honneffer, Julia B; Minamoto, Yasushi; Suchodolski, Jan S

    2014-01-01

    The intestinal microbiota is the collection of the living microorganisms (bacteria, fungi, protozoa, and viruses) inhabiting the gastrointestinal tract. Novel bacterial identification approaches have revealed that the gastrointestinal microbiota of dogs and cats is, similarly to humans, a highly complex ecosystem. Studies in dogs and cats have demonstrated that acute and chronic gastrointestinal diseases, including inflammatory bowel disease (IBD), are associated with alterations in the small intestinal and fecal microbial communities. Of interest is that these alterations are generally similar to the dysbiosis observed in humans with IBD or animal models of intestinal inflammation, suggesting that microbial responses to inflammatory conditions of the gut are conserved across mammalian host types. Studies have also revealed possible underlying susceptibilities in the innate immune system of dogs and cats with IBD, which further demonstrate the intricate relationship between gut microbiota and host health. Commonly identified microbiome changes in IBD are decreases in bacterial groups within the phyla Firmicutes and Bacteroidetes, and increases within Proteobacteia. Furthermore, a reduction in the diversity of Clostridium clusters XIVa and IV (i.e., Lachnospiraceae and Clostridium coccoides subgroups) are associated with IBD, suggesting that these bacterial groups may play an important role in maintenance of gastrointestinal health. Future studies are warranted to evaluate the functional changes associated with intestinal dysbiosis in dogs and cats. PMID:25469017

  17. Microbiota alterations in acute and chronic gastrointestinal inflammation of cats and dogs.

    PubMed

    Honneffer, Julia B; Minamoto, Yasushi; Suchodolski, Jan S

    2014-11-28

    The intestinal microbiota is the collection of the living microorganisms (bacteria, fungi, protozoa, and viruses) inhabiting the gastrointestinal tract. Novel bacterial identification approaches have revealed that the gastrointestinal microbiota of dogs and cats is, similarly to humans, a highly complex ecosystem. Studies in dogs and cats have demonstrated that acute and chronic gastrointestinal diseases, including inflammatory bowel disease (IBD), are associated with alterations in the small intestinal and fecal microbial communities. Of interest is that these alterations are generally similar to the dysbiosis observed in humans with IBD or animal models of intestinal inflammation, suggesting that microbial responses to inflammatory conditions of the gut are conserved across mammalian host types. Studies have also revealed possible underlying susceptibilities in the innate immune system of dogs and cats with IBD, which further demonstrate the intricate relationship between gut microbiota and host health. Commonly identified microbiome changes in IBD are decreases in bacterial groups within the phyla Firmicutes and Bacteroidetes, and increases within Proteobacteia. Furthermore, a reduction in the diversity of Clostridium clusters XIVa and IV (i.e., Lachnospiraceae and Clostridium coccoides subgroups) are associated with IBD, suggesting that these bacterial groups may play an important role in maintenance of gastrointestinal health. Future studies are warranted to evaluate the functional changes associated with intestinal dysbiosis in dogs and cats. PMID:25469017

  18. Mammalian Antimicrobial Peptides: Promising Therapeutic Targets Against Infection and Chronic Inflammation.

    PubMed

    Dutta, Pujarini; Das, Santasabuj

    2016-01-01

    Antimicrobial peptides (AMPs) are integral components of the host innate immune system and functional throughout the plant and animal kingdoms. AMPs are short cationic molecules and lethal against a wide range of bacteria, viruses, fungi, yeast and protozoa due to their membranolytic effects on the negatively-charged microbial membranes. In addition, they exert multiple immunomodulatory roles like chemotaxis, modulation of cytokine and chemokine expression, leukocyte activation etc. Since AMPs suffer loss of microbicidal properties under serum and tissue environments, their capacity to modulate the immune system may predominates under the physiological conditions. Discovery of new antibiotics is lagging far behind the rapidly spreading drug resistance among the microorganisms. Both natural and synthetic AMPs have shown promise as 'next generation antibiotics' due to their unique mode of action, which minimises the chance of development of microbial resistance. In addition, they have therapeutic potential against non-infectious diseases like chronic inflammation and cancer. Many of the synthetic AMPs are currently undergoing clinical trials for the treatment of debilitating diseases, such as catheter-related infections, diabetic foot ulcers, chemotherapy-associated infections etc. Some of them have already entered the market as topical preparations. In this review, we synopsise the current literature of natural and synthetic AMPs in different infectious and inflammatory diseases of human microfloral habitats, especially the gastrointestinal, respiratory and genitourinary tracts and the skin. We also discuss the classification of AMPs, their mode action and antimicrobial spectrum, including the pathogen evasion mechanisms. In short, we tried to present the locus standi of AMPs in relation to human diseases and highlight the most promising synthetic peptides emerging from the clinical trials. Finally, we focused on the limitations and hurdles in terms of cost of

  19. TIR8/SIGIRR is an Interleukin-1 Receptor/Toll Like Receptor Family Member with Regulatory Functions in Inflammation and Immunity

    PubMed Central

    Riva, Federica; Bonavita, Eduardo; Barbati, Elisa; Muzio, Marta; Mantovani, Alberto; Garlanda, Cecilia

    2012-01-01

    Interleukin-1R like receptors (ILRs) and Toll Like Receptors (TLRs) are key receptors of innate immunity, inflammation, and orientation of the adaptive response. They belong to a superfamily characterized by the presence of a conserved intracellular domain, the Toll/IL-1R (TIR) domain, which is involved in the activation of a signaling cascade leading to activation of transcription factors associated to inflammation. The activation of inflammatory responses and immunity by ILRs or TLRs signaling is potentially detrimental for the host in acute and chronic conditions and is tightly regulated at different levels by receptor antagonists, decoy receptors or signaling molecules, and miRNAs. Recent evidence suggests that the ILRs family member TIR8 (also known as SIGIRR) is a regulatory protein acting intracellularly to inhibit ILRs and TLRs signaling. In particular, current evidence suggests that TIR8/SIGIRR dampens TLRs-mediated activation and inhibits signaling receptor complexes of IL-1 family members associated with Th1 (IL-18), Th2 (IL-33), and Th17 (IL-1) differentiation. Studies with Tir8/Sigirr-deficient mice showed that the ability to dampen signaling from ILRs and TLRs family members makes TIR8/SIGIRR a key regulator of inflammation. Here, we summarize our current understanding of the structure and function of TIR8/SIGIRR, focusing on its role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation. PMID:23112799

  20. Chronic beryllium disease: an updated model interaction between innate and acquired immunity.

    PubMed

    Sawyer, Richard T; Maier, Lisa A

    2011-02-01

    During the last decade, there have been concerted efforts to reduce beryllium (Be) exposure in the workplace and thereby reduce potential cases of this occupational lung disorder. Despite these efforts, it is estimated that there are at least one million Be-exposed individuals in the U.S. who are potentially at risk for developing chronic beryllium disease (CBD). Previously, we reviewed the current CBD literature and proposed that CBD represents a model interaction between innate and acquired immunity (Sawyer et al., Int Immunopharmacol 2:249-261, 2002). We closed this review with a section on "future directions" that identified key gaps in our understanding of the pathogenesis of CBD. In the intervening period, progress has been made to fill in some of these gaps, and the current review will provide an update on that progress. Based on recent findings, we provide a new hypothesis to explain how Be drives sustained chronic inflammation and granuloma formation in CBD leading to progressive compromised lung function in CBD patients. This paradigm has direct implications for our understanding of the development of an immune response to Be, but is also likely applicable to other immune-mediated lung diseases of known and unknown etiology. PMID:20981472

  1. Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases

    PubMed Central

    2014-01-01

    Insulin resistance (IR) is a general phenomenon of many physiological states, disease states, and diseases. IR has been described in diabetes mellitus, obesity, infection, sepsis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, chronic mental stress, and others. In arthritis, abnormalities of glucose homeostasis were described in 1920; and in 1950 combined glucose and insulin tests unmistakably demonstrated IR. The phenomenon is now described in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatica, and others. In chronic inflammatory diseases, cytokine-neutralizing strategies normalize insulin sensitivity. This paper delineates that IR is either based on inflammatory factors (activation of the immune/ repair system) or on the brain (mental activation via stress axes). Due to the selfishness of the immune system and the selfishness of the brain, both can induce IR independent of each other. Consequently, the immune system can block the brain (for example, by sickness behavior) and the brain can block the immune system (for example, stress-induced immune system alterations). Based on considerations of evolutionary medicine, it is discussed that obesity per se is not a disease. Obesity-related IR depends on provoking factors from either the immune system or the brain. Chronic inflammation and/or stress axis activation are thus needed for obesity-related IR. Due to redundant pathways in stimulating IR, a simple one factor-neutralizing strategy might help in chronic inflammatory diseases (inflammation is the key), but not in obesity-related IR. The new considerations towards IR are interrelated to the published theories of IR (thrifty genotype, thrifty phenotype, and others). PMID:25608958

  2. Coincident Helminth Infection Modulates Systemic Inflammation and Immune Activation in Active Pulmonary Tuberculosis

    PubMed Central

    George, Parakkal Jovvian; Kumar, Nathella Pavan; Sridhar, Rathinam; Hanna, Luke E.; Nair, Dina; Banurekha, Vaithilingam V.; Nutman, Thomas B.; Babu, Subash

    2014-01-01

    Background Helminth infections are known to modulate innate and adaptive immune responses in active and latent tuberculosis (TB). However, the role of helminth infections in modulating responses associated with inflammation and immune activation (reflecting disease activity and/or severity) in TB is not known. Methodology We measured markers of inflammation and immune activation in active pulmonary TB individuals (ATB) with co-incidental Strongyloides stercoralis (Ss) infection. These included systemic levels of acute phase proteins, matrix metalloproteinases and their endogenous inhibitors and immune activation markers. As a control, we measured the systemic levels of the same molecules in TB-uninfected individuals (NTB) with or without Ss infection. Principal Findings Our data confirm that ATB is associated with elevated levels of the various measured molecules when compared to those seen in NTB. Our data also reveal that co-incident Ss infection in ATB individuals is associated with significantly decreased circulating levels of acute phase proteins, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases as well as the systemic immune activation markers, sCD14 and sCD163. These changes are specific to ATB since they are absent in NTB individuals with Ss infection. Conclusions Our data therefore reveal a profound effect of Ss infection on the markers associated with TB disease activity and severity and indicate that co-incidental helminth infections might dampen the severity of TB disease. PMID:25375117

  3. Requirement for interleukin-1 to drive brain inflammation reveals tissue-specific mechanisms of innate immunity

    PubMed Central

    Giles, James A; Greenhalgh, Andrew D; Davies, Claire L; Denes, Adam; Shaw, Tovah; Coutts, Graham; Rothwell, Nancy J; McColl, Barry W; Allan, Stuart M

    2015-01-01

    The immune system is implicated in a wide range of disorders affecting the brain and is, therefore, an attractive target for therapy. Interleukin-1 (IL-1) is a potent regulator of the innate immune system important for host defense but is also associated with injury and disease in the brain. Here, we show that IL-1 is a key mediator driving an innate immune response to inflammatory challenge in the mouse brain but is dispensable in extracerebral tissues including the lung and peritoneum. We also demonstrate that IL-1α is an important ligand contributing to the CNS dependence on IL-1 and that IL-1 derived from the CNS compartment (most likely microglia) is the major source driving this effect. These data reveal previously unknown tissue-specific requirements for IL-1 in driving innate immunity and suggest that IL-1-mediated inflammation in the brain could be selectively targeted without compromising systemic innate immune responses that are important for resistance to infection. This property could be exploited to mitigate injury- and disease-associated inflammation in the brain without increasing susceptibility to systemic infection, an important complication in several neurological disorders. PMID:25367678

  4. Bile acids in regulation of inflammation and immunity: friend or foe?

    PubMed

    Zhu, Ci; Fuchs, Claudia D; Halilbasic, Emina; Trauner, Michael

    2016-01-01

    Apart from their pivotal role in dietary lipid absorption and cholesterol homeostasis, bile acids (BAs) are increasingly recognised as important signalling molecules in the regulation of systemic endocrine functions. As such BAs are natural ligands for several nuclear hormone receptors and G-protein-coupled receptors. Through activating various signalling pathways, BAs not only regulate their own synthesis, enterohepatic recirculation and metabolism, but also immune homeostasis. This makes BAs attractive therapeutic agents for managing metabolic and inflammatory liver disorders. Recent experimental and clinical evidence indicates that BAs exert beneficial effects in cholestatic and metabolically driven inflammatory diseases. This review elucidates how different BAs function as pathogenetic factors and potential therapeutic agents for inflammation-driven liver diseases, focusing on their role in regulation of inflammation and immunity. PMID:27586800

  5. Low-grade inflammation in chronic diseases: an integrative pathophysiology anticipated by homeopathy?

    PubMed

    Adler, Ubiratan Cardinalli

    2011-05-01

    Pro-inflammatory cytokines and their chronic effect - low-grade inflammation - have been associated with diverse chronic conditions. Nonsteroidal anti-inflammatory drugs (NSAIDs) were recently proposed as a treatment strategy. Samuel Hahnemann, the founder of homeopathy, had already hypothesized a systemic and progressive disorder as the cause of many chronic diseases - the Psora theory. He also advised of the consequences of palliative use for chronic diseases, as a contrary effect of the "of the life-preserving principle" could worsen the course of those diseases. The hypotheses presented here are that the main aspects of Hahnemann's Psora theory are supported by current data on the role of pro-inflammatory cytokines and that the use of NSAIDs to treat chronic low-grade inflammation can produce a contrary, rebound effect, as anticipated by Hahnemann. By diverting from the "palliative action-rebound effect" course, not only homeopathy but integrative medicine could provide different approaches to the treatment of low-grade chronic inflammation. Studies assessing inflammatory markers in chronic integrative treatments are recommended. PMID:21277692

  6. Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans

    PubMed Central

    Meydani, Simin N.; Das, Sai K.; Pieper, Carl F.; Lewis, Michael R.; Klein, Sam; Dixit, Vishwa D.; Gupta, Alok K.; Villareal, Dennis T.; Bhapkar, Manjushri; Huang, Megan; Fuss, Paul J.; Roberts, Susan B.; Holloszy, John O.; Fontana, Luigi

    2016-01-01

    Calorie restriction (CR) inhibits inflammation and slows aging in many animal species, but in rodents housed in pathogen-free facilities, CR impairs immunity against certain pathogens. However, little is known about the effects of long-term moderate CR on immune function in humans. In this multi-center, randomized clinical trial to determine CR's effect on inflammation and cell-mediated immunity, 218 healthy non-obese adults (20-50 y), were assigned 25% CR (n=143) or an ad-libitum (AL) diet (n=75), and outcomes tested at baseline, 12, and 24 months of CR. CR induced a 10.4% weight loss over the 2-y period. Relative to AL group, CR reduced circulating inflammatory markers, including total WBC and lymphocyte counts, ICAM-1 and leptin. Serum CRP and TNF-α concentrations were about 40% and 50% lower in CR group, respectively. CR had no effect on the delayed-type hypersensitivity skin response or antibody response to vaccines, nor did it cause difference in clinically significant infections. In conclusion, long-term moderate CR without malnutrition induces a significant and persistent inhibition of inflammation without impairing key in vivo indicators of cell-mediated immunity. Given the established role of these pro-inflammatory molecules in the pathogenesis of multiple chronic diseases, these CR-induced adaptations suggest a shift toward a healthy phenotype. PMID:27410480

  7. Immune enhancement during chronic ethanol feeding in mice - Autoimmune phenomena

    SciTech Connect

    Honchel, R.; Rhoads, C.A.; Fitzpatrick, E.A.; McClain, C.J.; Kaplan, A.M.; Cohen, D.A. )

    1991-03-11

    Chronic alcohol abuse in humans is often associated with diminished immune reactivity and enhanced susceptibility to infections. However, many alcohol-dependent individuals display signs of autoimmunity, which has been implicated in alcohol-associated liver damage. This study demonstrates that C57Bl/6 mice placed on the Lieber-DeCarli liquid ethanol diet for up to 9 weeks displayed augmented immune reactivity as compared to mice placed on an isocaloric control diet. Spleen cells were significantly more responsive to the mitogens, LPS and ConA, as early as 3 weeks after initiation of EtOH feeding and this hyperresponsiveness persisted throughout the 9 week feeding period. Similar enhancement of the mixed lymphocyte response was also seen in EtOH fed mice. The enhancement of immune responsiveness was not related to a change in the numbers or percentages of B cells, T cells, or in the CD4/CD8 T cell ratios as determined by flow cytometry. These studies indicate that under certain conditions of ethanol feeding in mice, enhancement rather than suppression of the immune system may occur. This system may be a model to evaluate possible induction of autoimmune responses during chronic ethanol abuse. Studies are underway to measure the presence of auto-antibodies in the sera of these ethanol fed mice.

  8. Innate immunity and inflammation of the bovine female reproductive tract in health and disease.

    PubMed

    Sheldon, I Martin; Cronin, James G; Healey, Gareth D; Gabler, Christoph; Heuwieser, Wolfgang; Streyl, Dominik; Bromfield, John J; Miyamoto, Akio; Fergani, Chrys; Dobson, Hilary

    2014-09-01

    Mammalian reproductive physiology and the development of viviparity co-evolved with inflammation and immunity over millennia. Many inflammatory mediators contribute to paracrine and endocrine signalling, and the maintenance of tissue homeostasis in the female reproductive tract. However, inflammation is also a feature of microbial infections of the reproductive tract. Bacteria and viruses commonly cause endometritis, perturb ovarian follicle development and suppress the endocrine activity of the hypothalamus and pituitary in cattle. Innate immunity is an evolutionary ancient system that orchestrates host cell inflammatory responses aimed at eliminating pathogens and repairing damaged tissue. Pattern recognition receptors on host cells bind pathogen-associated molecular patterns and damage-associated molecular patterns, leading to the activation of intracellular MAPK and NFκB signalling pathways and the release of inflammatory mediators. Inflammatory mediators typically include the interleukin cytokines IL1β and IL6, chemokines such as IL8, interferons and prostaglandins. This review outlines the mechanisms of inflammation and innate immunity in the bovine female reproductive tract during health and disease condition. PMID:24890752

  9. Liver Stiffness Measurement-Based Scoring System for Significant Inflammation Related to Chronic Hepatitis B

    PubMed Central

    Hong, Mei-Zhu; Zhang, Ru-Mian; Chen, Guo-Liang; Huang, Wen-Qi; Min, Feng; Chen, Tian; Xu, Jin-Chao; Pan, Jin-Shui

    2014-01-01

    Objectives Liver biopsy is indispensable because liver stiffness measurement alone cannot provide information on intrahepatic inflammation. However, the presence of fibrosis highly correlates with inflammation. We constructed a noninvasive model to determine significant inflammation in chronic hepatitis B patients by using liver stiffness measurement and serum markers. Methods The training set included chronic hepatitis B patients (n = 327), and the validation set included 106 patients; liver biopsies were performed, liver histology was scored, and serum markers were investigated. All patients underwent liver stiffness measurement. Results An inflammation activity scoring system for significant inflammation was constructed. In the training set, the area under the curve, sensitivity, and specificity of the fibrosis-based activity score were 0.964, 91.9%, and 90.8% in the HBeAg(+) patients and 0.978, 85.0%, and 94.0% in the HBeAg(−) patients, respectively. In the validation set, the area under the curve, sensitivity, and specificity of the fibrosis-based activity score were 0.971, 90.5%, and 92.5% in the HBeAg(+) patients and 0.977, 95.2%, and 95.8% in the HBeAg(−) patients. The liver stiffness measurement-based activity score was comparable to that of the fibrosis-based activity score in both HBeAg(+) and HBeAg(−) patients for recognizing significant inflammation (G ≥3). Conclusions Significant inflammation can be accurately predicted by this novel method. The liver stiffness measurement-based scoring system can be used without the aid of computers and provides a noninvasive alternative for the prediction of chronic hepatitis B-related significant inflammation. PMID:25360742

  10. Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

    PubMed Central

    Gellerup, Dane D.; Balgeman, Alexis J.; Nelson, Chase W.; Ericsen, Adam J.; Scarlotta, Matthew; Hughes, Austin L.

    2015-01-01

    ABSTRACT Anti-HIV CD8 T cells included in therapeutic treatments will need to target epitopes that do not accumulate escape mutations. Identifying the epitopes that do not accumulate variants but retain immunogenicity depends on both host major histocompatibility complex (MHC) genetics and the likelihood for an epitope to tolerate variation. We previously found that immune escape during acute SIV infection is conditional; the accumulation of mutations in T cell epitopes is limited, and the rate of accumulation depends on the number of epitopes being targeted. We have now tested the hypothesis that conditional immune escape extends into chronic SIV infection and that epitopes with a preserved wild-type sequence have the potential to elicit epitope-specific CD8 T cells. We deep sequenced simian immunodeficiency virus (SIV) from Mauritian cynomolgus macaques (MCMs) that were homozygous and heterozygous for the M3 MHC haplotype and had been infected with SIV for about 1 year. When interrogating variation within individual epitopes restricted by M3 MHC alleles, we found three categories of epitopes, which we called categories A, B, and C. Category B epitopes readily accumulated variants in M3-homozygous MCMs, but this was less common in M3-heterozygous MCMs. We then determined that chronic CD8 T cells specific for these epitopes were more likely preserved in the M3-heterozygous MCMs than M3-homozygous MCMs. We provide evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are homozygous for a set of MHC alleles are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. IMPORTANCE Anti-HIV CD8 T cells that are part of therapeutic treatments will need to target epitopes that do not accumulate escape mutations. Defining these epitope sequences is a necessary precursor to designing approaches that enhance the functionality of CD8 T cells with the potential to control virus replication during chronic

  11. Emerging roles for HMGB1 protein in immunity, inflammation, and cancer

    PubMed Central

    Martinotti, Simona; Patrone, Mauro; Ranzato, Elia

    2015-01-01

    High-mobility group box 1 (HMGB1) protein is a member of the highly conserved non-histone DNA binding protein family. First identified in 1973, as one of a group of chromatin-associated proteins with high acidic and basic amino acid content, it was so named for its characteristic rapid mobility in polyacrylamide gel electrophoresis. HMGB1 was later discovered to have another function. It is released from a variety of cells into the extracellular milieu to act on specific cell-surface receptors. In this latter role, HMGB1 is a proinflammatory cytokine that may contribute to many inflammatory diseases, including sepsis. Therefore, HMGB1 regulates intracellular cascades influencing immune cell functions, including chemotaxis and immune modulation. The bioactivity of the HMGB1 is determined by specific posttranslational modifications that regulate its role in inflammation and immunity. During tumor development, HMGB1 has been reported to play paradoxical roles in promoting both cell survival and death by regulating multiple signaling pathways. In this review, we focus on the role of HMGB1 in physiological and pathological responses, as well as the mechanisms by which it contributes to immunity, inflammation, and cancer progression.

  12. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis.

    PubMed

    Klose, Christoph S N; Artis, David

    2016-06-21

    Research over the last 7 years has led to the formal identification of innate lymphoid cells (ILCs), increased the understanding of their tissue distribution and has established essential functions of ILCs in diverse physiological processes. These include resistance to pathogens, the regulation of autoimmune inflammation, tissue remodeling, cancer and metabolic homeostasis. Notably, many ILC functions appear to be regulated by mechanisms distinct from those of other innate and adaptive immune cells. In this Review, we focus on how group 2 ILC (ILC2) and group 3 ILC (ILC3) responses are regulated and how these cells interact with other immune and non-immune cells to mediate their functions. We highlight experimental evidence from mouse models and patient-based studies that have elucidated the effects of ILCs on the maintenance of tissue homeostasis and the consequences for health and disease. PMID:27328006

  13. Osteoprotective Effect of Alfacalcidol in Female Rats with Systemic Chronic Inflammation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Studies have shown that alfacalcidol (a hydroxylated form of vitamin D) mitigates glucocorticoid-induced bone loss. This study was undertaken to explore the mechanism and bone microarchitecture of alfacalcidol in rats with systemic chronic inflammation. Thirty female rats (3-month-old) assigned to ...

  14. Antioxidant Effect of Spirulina (Arthrospira) maxima on Chronic Inflammation Induced by Freund's Complete Adjuvant in Rats

    PubMed Central

    Gutiérrez-Rebolledo, Gabriel Alfonso; Galar-Martínez, Marcela; García-Rodríguez, Rosa Virginia; Chamorro-Cevallos, Germán A.; Hernández-Reyes, Ana Gabriela

    2015-01-01

    Abstract One of the major mechanisms in the pathogenesis of chronic inflammation is the excessive production of reactive oxygen and reactive nitrogen species, and therefore, oxidative stress. Spirulina (Arthrospira) maxima has marked antioxidant activity in vivo and in vitro, as well as anti-inflammatory activity in certain experimental models, the latter activity being mediated probably by the antioxidant activity of this cyanobacterium. In the present study, chronic inflammation was induced through injection of Freund's complete adjuvant (CFA) in rats treated daily with Spirulina (Arthrospira) maxima for 2 weeks beginning on day 14. Joint diameter, body temperature, and motor capacity were assessed each week. On days 0 and 28, total and differential leukocyte counts and serum oxidative damage were determined, the latter by assessing lipid peroxidation and protein carbonyl content. At the end of the study, oxidative damage to joints was likewise evaluated. Results show that S. maxima favors increased mobility, as well as body temperature regulation, and a number of circulating leukocytes, lymphocytes, and monocytes in specimens with CFA-induced chronic inflammation and also protects against oxidative damage in joint tissue as well as serum. In conclusion, the protection afforded by S. maxima against development of chronic inflammation is due to its antioxidant activity. PMID:25599112

  15. Green tea polyphenols attenuate deterioration of bone microarchitecture in female rats with systemic chronic inflammation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Introduction: Our previous study demonstrated that green tea polyphenols (GTP) benefit bone health in female rats with chronic inflammation, because of GTP’s antioxidant capacity. The current study further evaluates whether GTP can restore bone microstructure along with related mechanism in rats wit...

  16. Plasma biomarkers of chronic inflammation are elevated in overweight Mexican-American children

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Excess body weight is associated with an accumulation of chronic, low-grade inflammation that has been implicated in the pathophysiology of various diseases. The obesity epidemic is more prevalent in certain ethnic groups. Despite this health disparity, few published studies have measured biomarke...

  17. Antioxidant Effect of Spirulina (Arthrospira) maxima on Chronic Inflammation Induced by Freund's Complete Adjuvant in Rats.

    PubMed

    Gutiérrez-Rebolledo, Gabriel Alfonso; Galar-Martínez, Marcela; García-Rodríguez, Rosa Virginia; Chamorro-Cevallos, Germán A; Hernández-Reyes, Ana Gabriela; Martínez-Galero, Elizdath

    2015-08-01

    One of the major mechanisms in the pathogenesis of chronic inflammation is the excessive production of reactive oxygen and reactive nitrogen species, and therefore, oxidative stress. Spirulina (Arthrospira) maxima has marked antioxidant activity in vivo and in vitro, as well as anti-inflammatory activity in certain experimental models, the latter activity being mediated probably by the antioxidant activity of this cyanobacterium. In the present study, chronic inflammation was induced through injection of Freund's complete adjuvant (CFA) in rats treated daily with Spirulina (Arthrospira) maxima for 2 weeks beginning on day 14. Joint diameter, body temperature, and motor capacity were assessed each week. On days 0 and 28, total and differential leukocyte counts and serum oxidative damage were determined, the latter by assessing lipid peroxidation and protein carbonyl content. At the end of the study, oxidative damage to joints was likewise evaluated. Results show that S. maxima favors increased mobility, as well as body temperature regulation, and a number of circulating leukocytes, lymphocytes, and monocytes in specimens with CFA-induced chronic inflammation and also protects against oxidative damage in joint tissue as well as serum. In conclusion, the protection afforded by S. maxima against development of chronic inflammation is due to its antioxidant activity. PMID:25599112

  18. Early-life enteric infections: relation between chronic systemic inflammation and poor cognition in children.

    PubMed

    Oriá, Reinaldo B; Murray-Kolb, Laura E; Scharf, Rebecca J; Pendergast, Laura L; Lang, Dennis R; Kolling, Glynis L; Guerrant, Richard L

    2016-06-01

    The intestinal microbiota undergoes active remodeling in the first 6 to 18 months of life, during which time the characteristics of the adult microbiota are developed. This process is strongly influenced by the early diet and enteric pathogens. Enteric infections and malnutrition early in life may favor microbiota dysbiosis and small intestinal bacterial overgrowth, resulting in intestinal barrier dysfunction and translocation of intestinal bacterial products, ultimately leading to low-grade, chronic, subclinical systemic inflammation. The leaky gut-derived low-grade systemic inflammation may have profound consequences on the gut-liver-brain axis, compromising normal growth, metabolism, and cognitive development. This review examines recent data suggesting that early-life enteric infections that lead to intestinal barrier disruption may shift the intestinal microbiota toward chronic systemic inflammation and subsequent impaired cognitive development. PMID:27142301

  19. Effect of P2Y12 inhibitors on inflammation and immunity.

    PubMed

    Thomas, Mark R; Storey, Robert F

    2015-08-31

    Platelet P2Y12 inhibitors form a major part of the treatment strategy for patients with acute coronary syndromes (ACS) due to the importance of the platelet P2Y12 receptor in mediating the pathophysiology of arterial thrombosis. It has been increasingly recognised that platelets also have a critical role in inflammation and immune responses. P2Y12 inhibitors reduce platelet release of pro-inflammatory α-granule contents and the formation of pro-inflammatory platelet-leukocyte aggregates. These are important mediators of inflammation in a variety of different contexts. Clinical evidence shows that P2Y12 inhibition by clopidogrel is associated with a reduction in platelet-related mediators of inflammation, such as soluble P-selectin and CD40L, following atherothrombosis. Clopidogrel in addition to aspirin, compared to aspirin alone, also reduces markers of systemic inflammation such as tumour necrosis factor (TNF) α and C-reactive protein (CRP) following ACS. The more potent thienopyridine P2Y12 inhibitor, prasugrel, has been shown to decrease platelet P-selectin expression and platelet-leukocyte aggregate formation compared to clopidogrel. The PLATO study suggested that the novel P2Y12 inhibitor ticagrelor might improve clinical outcomes from pulmonary infections and sepsis compared to clopidogrel in patients with ACS. Ticagrelor is a more potent P2Y12 inhibitor than clopidogrel and also inhibits cellular adenosine uptake via equilibrative nucleoside transporter (ENT) 1, whereas clopidogrel does not. Further examination of the involvement of these mechanisms in inflammation and immunity is therefore warranted. PMID:26156883

  20. Elevated lipopolysaccharide in the colon evokes intestinal inflammation, aggravated in immune modulator-impaired mice.

    PubMed

    Im, Eunok; Riegler, Franz Martin; Pothoulakis, Charalabos; Rhee, Sang Hoon

    2012-08-15

    Frequency of gram-negative bacteria is markedly enhanced in inflamed gut, leading to augmented LPS in the intestine. Although LPS in the intestine is considered harmless and, rather, provides protective effects against epithelial injury, it has been suggested that LPS causes intestinal inflammation, such as necrotizing enterocolitis. Therefore, direct effects of LPS in the intestine remain to be studied. In this study, we examine the effect of LPS in the colon of mice instilled with LPS by rectal enema. We found that augmented LPS on the luminal side of the colon elicited inflammation in the small intestine remotely, not in the colon; this inflammation was characterized by body weight loss, increased fluid secretion, enhanced inflammatory cytokine production, and epithelial damage. In contrast to the inflamed small intestine induced by colonic LPS, the colonic epithelium did not exhibit histological tissue damage or inflammatory lesions, although intracolonic LPS treatment elicited inflammatory cytokine gene expression in the colon tissues. Moreover, we found that intracolonic LPS treatment substantially decreased the frequency of immune-suppressive regulatory T cells (CD4(+)/CD25(+) and CD4(+)/Foxp3(+)). We were intrigued to find that LPS-promoted intestinal inflammation is exacerbated in immune modulator-impaired IL-10(-/-) and Rag-1(-/-) mice. In conclusion, our results provide evidence that elevated LPS in the colon is able to cause intestinal inflammation and, therefore, suggest a physiological explanation for the importance of maintaining the balance between gram-negative and gram-positive bacteria in the intestine to maintain homeostasis in the gut. PMID:22723263

  1. Polyphasic innate immune responses to acute and chronic LCMV infection

    PubMed Central

    Norris, Brian A.; Uebelhoer, Luke S.; Nakaya, Helder I.; Price, Aryn A.; Grakoui, Arash; Pulendran, Bali

    2013-01-01

    Summary Resolution of acute and chronic viral infections requires activation of innate cells to initiate and maintain adaptive immune responses. Here we report that infection with acute Armstrong (ARM) or chronic Clone 13 (C13) strains of lymphocytic choriomeningitis virus (LCMV) led to two distinct phases of innate immune response. During the first 72hr of infection, dendritic cells upregulated activation markers, and stimulated anti-viral CD8+ T cells, independent of viral strain. Seven days after infection, there was an increase in Ly6Chi monocytic and Gr-1hi neutrophilic cells in lymphoid organs and blood. This expansion in cell numbers was enhanced and sustained in C13 infection, whereas it occurred only transiently with ARM infection. These cells resembled myeloid-derived suppressor cells, and potently suppressed T cell proliferation. The reduction of monocytic cells in Ccr2−/− mice or after Gr-1 antibody depletion enhanced anti-viral T cell function. Thus, innate cells have an important immunomodulatory role throughout chronic infection. PMID:23438822

  2. The Gut as a Source of Inflammation in Chronic Kidney Disease.

    PubMed

    Lau, Wei Ling; Kalantar-Zadeh, Kamyar; Vaziri, Nosratola D

    2015-01-01

    Chronic inflammation is a non-traditional risk factor for cardiovascular mortality in the chronic kidney disease (CKD) population. In recent years, the gastrointestinal tract has emerged as a major instigator of systemic inflammation in CKD. Postmortem studies previously discovered gut wall inflammation throughout the digestive tract in chronic dialysis patients. In CKD animals, colon wall inflammation is associated with breakdown of the epithelial tight junction barrier ('leaky gut') and translocation of bacterial DNA and endotoxin into the bloodstream. Gut bacterial DNA and endotoxin have also been detected in the serum from CKD and dialysis patients, whereby endotoxin levels increase with the CKD stage and correlate with the severity of systemic inflammation in the dialysis population. The CKD diet that is low in plant fiber and symbiotic organisms (in adherence with low potassium, low phosphorus intake) can alter the normal gut microbiome, leading to overgrowth of bacteria that produce uremic toxins such as cresyl and indoxyl molecules. The translocation of these toxins from the 'leaky gut' into the bloodstream further promotes systemic inflammation, adverse cardiovascular outcomes and CKD progression. Data are lacking on optimal fiber and yogurt consumption in CKD that would favor growth of a more symbiotic microbiome while avoiding potassium and phosphorus overload. Prebiotic and probiotic formulations have shown promise in small clinical trials, in terms of lowering serum levels of uremic toxins and improving quality of life. The evidence points to a strong relationship between intestinal inflammation and adverse outcomes in CKD, and more trials investigating gut-targeted therapeutics are needed. PMID:25967288

  3. The gut as a source of inflammation in chronic kidney disease

    PubMed Central

    Lau, Wei Ling; Kalantar-Zadeh, Kamyar; Vaziri, Nosratola D.

    2015-01-01

    Chronic inflammation is a non-traditional risk factor for cardiovascular mortality in the chronic kidney disease (CKD) population. In recent years the gastrointestinal tract has emerged as a major instigator of systemic inflammation in CKD. Post-mortem studies previously discovered gut wall inflammation present throughout the digestive tract in chronic dialysis patients. In CKD animals, colon wall inflammation is associated with breakdown of the epithelial tight junction barrier (“leaky gut”) and translocation of bacterial DNA and endotoxin into the bloodstream. Gut bacterial DNA and endotoxin have also been detected in the serum from CKD and dialysis patients, whereby endotoxin levels increase with CKD stage and correlate with severity of systemic inflammation in the dialysis population. The CKD diet that is low in plant fiber and symbiotic organisms (in adherence with low potassium, low phosphorus intake) can alter the normal gut microbiome, leading to overgrowth of bacteria that produce uremic toxins such as cresyl and indoxyl molecules. The translocation of these toxins from the “leaky gut” into the bloodstream further promotes systemic inflammation, adverse cardiovascular outcomes and CKD progression. Data is lacking on optimal fiber and yogurt consumption in CKD that would favor growth of a more symbiotic microbiome while avoiding potassium and phosphorus overload. Prebiotic and probiotic formulations have shown promise in small clinical trials, in terms of lowering serum levels of uremic toxins and improving quality of life. The evidence points to a strong relationship between intestinal inflammation and adverse outcomes in CKD, and more trials investigating gut-targeted therapeutics are needed. PMID:25967288

  4. Studies of T-cell activation in chronic inflammation

    PubMed Central

    2002-01-01

    Chapter summary The strong association between specific alleles encoded within the MHC class II region and the development of rheumatoid arthritis (RA) has provided the best evidence to date that CD4+ T cells play a role in the pathogenesis of this chronic inflammatory disease. However, the unusual phenotype of synovial T cells, including their profound proliferative hyporesponsiveness to TCR ligation, has challenged the notion that T-cell effector responses are driven by cognate cartilage antigens in inflamed synovial joints. The hierarchy of T-cell dysfunction from peripheral blood to inflamed joint suggests that these defects are acquired through prolonged exposure to proinflammatory cytokines such as tumour necrosis factor (TNF)-α. Indeed, there are now compelling data to suggest that chronic cytokine activation may contribute substantially to the phenotype and effector function of synovial T cells. Studies reveal that chronic exposure of T cells to TNF uncouples TCR signal transduction pathways by impairing the assembly and stability of the TCR/CD3 complex at the cell surface. Despite this membrane-proximal effect, TNF selectively uncouples downstream signalling pathways, as is shown by the dramatic suppression of calcium signalling responses, while Ras/ERK activation is spared. On the basis of these data, it is proposed that T-cell survival and effector responses are driven by antigen-independent, cytokine-dependent mechanisms, and that therapeutic strategies that seek to restore T-cell homeostasis rather than further depress T-cell function should be explored in the future. PMID:12110140

  5. The Relations Between Immunity, Oxidative Stress and Inflammation Markers, in Childhood Obesity.

    PubMed

    Laura Anca, Popescu; Bogdana, Virgolici; Olivia, Timnea; Horia, Virgolici; Dumitru, Oraseanu; Leon, Zagrean

    2014-10-01

    Oxidative stress, inflammation and insulin resistance are the principal culprits in childhood obesity. Immune modifications are also important in the development of the obesity complications.The aim of this study is to find the relations for some immunity parameters with markers for oxidative stress and inflammation. Sixty obese children (10-16 years old) and thirty age and sex matched lean children were involved. The activities for erythrocyte superoxid dismutase (SOD), for erythrocyte glutathione peroxidase (GPx) and serum thioredoxin level were measured by ELISA, as oxidative stress markers. Circulating immune complexes (CIC), complement fractions C3, C4 and the self-antibodies, antismooth muscle antibodies (ASMA), antiliver-kidney microsome antibodies (LKM1) were measured by ELISA methods. Ceruloplasmin, haptoglobin and C reactive protein (CRP) were measured as inflammatory markers by immunoturbidimetric methods. ceruloplasmin (p<0.001), haptoglobin (p<0.001), CRP (p<0.05) and activity for SOD (p<0.001) were measured, while thioredoxin concentration (p<0.04) was reduced. The antibodies LKM1 and ASMA and GPx activity were not modified between groups. Positive correlations (for p<0.05) were calculated between SOD activity and LKM1 (r=0.37), GPx activity and ASMA (r=0.27), haptoglobin and C3 (r=0.33), ceruloplasmin and CIC (r=0.41), CRP and C3 (p<0.27) and negative correlations were calculated for C4 both with GPx activity (r= -0.28) and with thioredoxin level (r= -0.27). In the obese children versus the lean ones, higher levels for C3 (p<0.001), C4(p<0.001), CIC (p<0.05), In conclusion, this study demonstrates that immune modifications, inflammation and oxidative stress are related and they act in cluster in childhood obesity. PMID:26461379

  6. Effect of DHU001, a Polyherbal Formula on Formalin-induced Paw Chronic Inflammation of Mice

    PubMed Central

    Cho, Yoon-Hee; Chung, In-Kwon; Cheon, Woo-Hyun; Lee, Hyeung-Sik

    2011-01-01

    The effect of DHU001, a mixed herbal formula consisted of 7 types aqueous extracts for various respiratory disorders were evaluated on the formalin-induced paw chronic inflammation in mice after oral administration. Mice were subaponeurotically injected in the left hind paw with 0.02 ml of 3.75% formalin, then subjected to 500, 250 and 125 mg/kg of DHU001 oral administration, once a day for 10 days during which then the hind-paw thickness and volume were measured daily. The paw wet-weight, histological profiles, histomorphometrical analyses and paw tumor necrosis factor (TNF)-α contents were conducted at termination. After two formalin treatments, a marked increase in the paw thickness and volume was detected in the formalin-injected control as compared with that in the intact control, plus at the time of sacrifice the paw wet-weights, paw TNF-α contents were also dramatically increased with severe chronic inflammation signs at histopathological observations. However, these formalin-induced chronic inflammatory changes were dramatically decreased by treatment of dexamethasone and all three different dosages of DHU001. DHU001 has favorable effects on formalin-induced chronic inflammation mediated by TNF-α suppression, and DHU001 may represent an alternative approach for the treatment of chronic inflammatory diseases. PMID:24278557

  7. Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics.

    PubMed

    Pastorelli, Luca; De Salvo, Carlo; Mercado, Joseph R; Vecchi, Maurizio; Pizarro, Theresa T

    2013-01-01

    The gut mucosa is constantly challenged by a bombardment of foreign antigens and environmental microorganisms. As such, the precise regulation of the intestinal barrier allows the maintenance of mucosal immune homeostasis and prevents the onset of uncontrolled inflammation. In support of this concept, emerging evidence points to defects in components of the epithelial barrier as etiologic factors in the pathogenesis of inflammatory bowel diseases (IBDs). In fact, the integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, epithelial cell integrity, as well as the production of mucus. The purpose of this review is to systematically evaluate how alterations in the aforementioned epithelial components can lead to the disruption of intestinal immune homeostasis, and subsequent inflammation. In this regard, the wealth of data from mouse models of intestinal inflammation and human genetics are pivotal in understanding pathogenic pathways, for example, that are initiated from the specific loss of function of a single protein leading to the onset of intestinal disease. On the other hand, several recently proposed therapeutic approaches to treat human IBD are targeted at enhancing different elements of gut barrier function, further supporting a primary role of the epithelium in the pathogenesis of chronic intestinal inflammation and emphasizing the importance of maintaining a healthy and effective intestinal barrier. PMID:24062746

  8. Role of vitamins D, E and C in immunity and inflammation.

    PubMed

    Shaik-Dasthagirisaheb, Y B; Varvara, G; Murmura, G; Saggini, A; Caraffa, A; Antinolfi, P; Tete', S; Tripodi, D; Conti, F; Cianchetti, E; Toniato, E; Rosati, M; Speranza, L; Pantalone, A; Saggini, R; Tei, M; Speziali, A; Conti, P; Theoharides, T C; Pandolfi, F

    2013-01-01

    Inflammatory responses are operationally characterized by pain, redness, heat and swelling at the site of infection and trauma. Mast cells reside near small blood vessels and, when activated, release potent mediators involved in allergy and inflammation. Vitamin D modulates contraction, inflammation and remodeling tissue. Vitamin D deficiency has been linked to multiple diseases and several data have demonstrated a strong relationship between serum vitamin D levels and tissue function. Therapy targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions. Mast cells are activated by oxidized lipoproteins, resulting in increased expression of inflammatory cytokines and suggesting that the reduction of oxidation of low density lipoprotein by vitamin E may also reduce mast cell activation. Vitamin C is also an anti-oxidant well-known as an anti-scurvy agent in humans. Vitamin C inhibits peroxidation of membrane phospholipids and acts as a scavenger of free radicals and is also required for the synthesis of several hormones and neurotransmitters. In humans, vitamin C reduces the duration of common cold symptoms, even if its effect is not clear. Supplementation of vitamin C improves the function of the human immune system, such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis and delayed-type hypersensitivity. Vitamin C depletion has been correlated with histaminemia which has been shown to damage endothelial-dependent vasodilation. However, the impact of these vitamins on allergy and inflammation is still not well understood. PMID:23830380

  9. Human Primary Immune Cells Exhibit Distinct Mechanical Properties that Are Modified by Inflammation.

    PubMed

    Bufi, Nathalie; Saitakis, Michael; Dogniaux, Stéphanie; Buschinger, Oscar; Bohineust, Armelle; Richert, Alain; Maurin, Mathieu; Hivroz, Claire; Asnacios, Atef

    2015-05-01

    T lymphocytes are key modulators of the immune response. Their activation requires cell-cell interaction with different myeloid cell populations of the immune system called antigen-presenting cells (APCs). Although T lymphocytes have recently been shown to respond to mechanical cues, in particular to the stiffness of their environment, little is known about the rigidity of APCs. In this study, single-cell microplate assays were performed to measure the viscoelastic moduli of different human myeloid primary APCs, i.e., monocytes (Ms, storage modulus of 520 +90/-80 Pa), dendritic cells (DCs, 440 +110/-90 Pa), and macrophages (MPHs, 900 +110/-100 Pa). Inflammatory conditions modulated these properties, with storage moduli ranging from 190 Pa to 1450 Pa. The effect of inflammation on the mechanical properties was independent of the induction of expression of commonly used APC maturation markers, making myeloid APC rigidity an additional feature of inflammation. In addition, the rigidity of human T lymphocytes was lower than that of all myeloid cells tested and among the lowest reported (Young's modulus of 85 ± 5 Pa). Finally, the viscoelastic properties of myeloid cells were dependent on both their filamentous actin content and myosin IIA activity, although the relative contribution of these parameters varied within cell types. These results indicate that T lymphocytes face different cell rigidities when interacting with myeloid APCs in vivo and that this mechanical landscape changes under inflammation. PMID:25954876

  10. Human Primary Immune Cells Exhibit Distinct Mechanical Properties that Are Modified by Inflammation

    PubMed Central

    Bufi, Nathalie; Saitakis, Michael; Dogniaux, Stéphanie; Buschinger, Oscar; Bohineust, Armelle; Richert, Alain; Maurin, Mathieu; Hivroz, Claire; Asnacios, Atef

    2015-01-01

    T lymphocytes are key modulators of the immune response. Their activation requires cell-cell interaction with different myeloid cell populations of the immune system called antigen-presenting cells (APCs). Although T lymphocytes have recently been shown to respond to mechanical cues, in particular to the stiffness of their environment, little is known about the rigidity of APCs. In this study, single-cell microplate assays were performed to measure the viscoelastic moduli of different human myeloid primary APCs, i.e., monocytes (Ms, storage modulus of 520 +90/−80 Pa), dendritic cells (DCs, 440 +110/−90 Pa), and macrophages (MPHs, 900 +110/−100 Pa). Inflammatory conditions modulated these properties, with storage moduli ranging from 190 Pa to 1450 Pa. The effect of inflammation on the mechanical properties was independent of the induction of expression of commonly used APC maturation markers, making myeloid APC rigidity an additional feature of inflammation. In addition, the rigidity of human T lymphocytes was lower than that of all myeloid cells tested and among the lowest reported (Young’s modulus of 85 ± 5 Pa). Finally, the viscoelastic properties of myeloid cells were dependent on both their filamentous actin content and myosin IIA activity, although the relative contribution of these parameters varied within cell types. These results indicate that T lymphocytes face different cell rigidities when interacting with myeloid APCs in vivo and that this mechanical landscape changes under inflammation. PMID:25954876

  11. Immune and hemorheological changes in Chronic Fatigue Syndrome

    PubMed Central

    2010-01-01

    Background Chronic Fatigue Syndrome (CFS) is a multifactorial disorder that affects various physiological systems including immune and neurological systems. The immune system has been substantially examined in CFS with equivocal results, however, little is known about the role of neutrophils and natural killer (NK) phenotypes in the pathomechanism of this disorder. Additionally the role of erythrocyte rheological characteristics in CFS has not been fully expounded. The objective of this present study was to determine deficiencies in lymphocyte function and erythrocyte rheology in CFS patients. Methods Flow cytometric measurements were performed for neutrophil function, lymphocyte numbers, NK phenotypes (CD56dimCD16+ and CD56brightCD16-) and NK cytotoxic activity. Erythrocyte aggregation, deformability and fibrinogen levels were also assessed. Results CFS patients (n = 10) had significant decreases in neutrophil respiratory burst, NK cytotoxic activity and CD56brightCD16- NK phenotypes in comparison to healthy controls (n = 10). However, hemorheological characteristic, aggregation, deformability, fibrinogen, lymphocyte numbers and CD56dimCD16+ NK cells were similar between the two groups. Conclusion These results indicate immune dysfunction as potential contributors to the mechanism of CFS, as indicated by decreases in neutrophil respiratory burst, NK cell activity and NK phenotypes. Thus, immune cell function and phenotypes may be important diagnostic markers for CFS. The absence of rheological changes may indicate no abnormalities in erythrocytes of CFS patients. PMID:20064266

  12. Nitric oxide-induced cellular stress and p53 activation in chronic inflammation

    PubMed Central

    Hofseth, Lorne J.; Saito, Shin'ichi; Hussain, S. Perwez; Espey, Michael G.; Miranda, Katrina M.; Araki, Yuzuru; Jhappan, Chamelli; Higashimoto, Yuichiro; He, Peijun; Linke, Steven P.; Quezado, Martha M.; Zurer, Irit; Rotter, Varda; Wink, David A.; Appella, Ettore; Harris, Curtis C.

    2003-01-01

    Free radical-induced cellular stress contributes to cancer during chronic inflammation. Here, we investigated mechanisms of p53 activation by the free radical, NO. NO from donor drugs induced both ataxia-telangiectasia mutated (ATM)- and ataxia-telangiectasia mutated and Rad3-related-dependent p53 posttranslational modifications, leading to an increase in p53 transcriptional targets and a G2/M cell cycle checkpoint. Such modifications were also identified in cells cocultured with NO-releasing macrophages. In noncancerous colon tissues from patients with ulcerative colitis (a cancer-prone chronic inflammatory disease), inducible NO synthase protein levels were positively correlated with p53 serine 15 phosphorylation levels. Immunostaining of HDM-2 and p21WAF1 was consistent with transcriptionally active p53. Our study highlights a pivotal role of NO in the induction of cellular stress and the activation of a p53 response pathway during chronic inflammation. PMID:12518062

  13. The Role of Innate Immunity and Aeroallergens in Chronic Rhinosinusitis.

    PubMed

    London, Nyall R; Tharakan, Anuj; Ramanathan, Murugappan

    2016-01-01

    Allergy has been inferred to contribute to the pathophysiology of chronic rhinosinusitis (CRS) although this role is controversial and the mechanism is debated. Furthermore, the role of aeroallergens in CRS is poorly defined and has been postulated to contribute to CRS through direct penetration in the sinuses or downstream systemic consequences. Common aeroallergens implicated in chronic rhinosinusitis include air pollution/second hand smoke, dust mite and pollen [1,2,3]. One emerging potential mechanism whereby aeroallergens contribute to CRS is through sinonasal epithelial barrier disruption (fig. 1). Characterization of cytokine disruption of sinonasal epithelial cell barrier has been described including interleukin (IL)-4 and IL-13, as well as aeroallergens such as house dust mite and cigarette smoke. Recent results have demonstrated severe barrier disruption in response to direct application of either particulate matter (PM) or house dust mite (HDM) to sinonasal epithelial cells. Sinonasal epithelial barrier disruption may contribute to CRS by enabling the perpetual and chronic exposure of inflammatory allergens and stimuli. The sinonasal epithelial barrier plays a significant role in innate immune host defense. Mechanisms of innate immune defense include pattern recognition receptors (PRRs), secreted endogenous antimicrobials and inflammatory cytokines that aid in repair mechanisms including IL-33. Here we discuss recent evidence implicating aeroallergens and dysregulated host innate immune responses in the development of CRS.

    1Fig. 1. Aeroallergens and inflammatory stimuli disrupt sinonasal epithelial barrier function. These agents act to destabilize the barrier through stimulating endocytosis and destruction of cell junction proteins via oxidative stress and MyD88-dependent mechanisms. Furthermore

  14. Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology.

    PubMed

    Vernooy, Juanita H J; Dentener, Mieke A; van Suylen, Robert J; Buurman, Wim A; Wouters, Emiel F M

    2002-01-01

    Lipopolysaccharide (LPS), a major proinflammatory glycolipid component of the gram-negative bacterial cell wall, is one of the agents ubiquitously present as contaminant on airborne particles, including air pollution, organic dusts, and cigarette smoke. Chronic exposure to significant levels of LPS is reported to be associated with the development and/or progression of many types of lung diseases, including asthma, chronic bronchitis, and progressive irreversible airflow obstruction, that are all characterized by chronic inflammatory processes in the lung. In the present study, pathologic effects of long-term LPS exposure to the lung were investigated in detail. To this end, a murine model in which mice were exposed to repeated intratracheal instillation of Escherichia coli LPS was developed. We show that long-term LPS instillation in mice results in persistent chronic pulmonary inflammation, characterized by peribronchial and perivascular lymphocytic aggregates (CD4(+), CD8(+), and CD19(+)), parenchymal accumulation of macrophages and CD8(+) T cells, and altered cytokine expression. Furthermore, airway and alveolar alterations such as mucus cell metaplasia, airway wall thickening, and irreversible alveolar enlargement accompanied the chronic inflammatory response. Interestingly, the observed inflammatory and pathologic changes mimic changes observed in human subjects with chronic inflammatory lung diseases, especially chronic obstructive pulmonary disease (COPD), suggesting that this murine model could be applicable to dissect the role of inflammation in the pathogenesis of these disease conditions. PMID:11751215

  15. Microbiome, Inflammation and Cancer

    PubMed Central

    Francescone, Ralph; Hou, Vivianty; Grivennikov, Sergei I.

    2014-01-01

    Inflammation has long been suspected to play a major role in the pathogenesis of cancer. Only recently however, have some mechanisms of its tumor promoting effects come to light. Microbes, both commensal and pathogenic, are critical regulators of the host immune system, and ultimately, of inflammation. Consequently, microbes have the potential power to influence tumor progression as well, through a wide variety of routes, including chronic activation of inflammation, alteration of tumor microenvironment, induction of genotoxic responses, and metabolism. In this review, we will provide a general overview of commensal microbiota, inflammation and cancer, and how microbes fit into this emerging field. PMID:24855005

  16. Local and systemic neutrophilic inflammation in patients with lung cancer and chronic obstructive pulmonary disease

    PubMed Central

    2013-01-01

    Background Recent investigations suggest that neutrophils play an important role in the immune response to lung cancer as well as chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the amount of neutrophils and markers of their activity in lung cancer and COPD and in coexistence of these two diseases. Methods In total, 267 persons were included in the study: 139 patients with lung cancer, 55 patients with lung cancer and COPD, 40 patients with COPD, and 33 healthy subjects. Peripheral blood and BAL fluid samples were obtained for cell count analysis and determination of NE, MPO levels and ROS production. NE and MPO levels in the serum and BAL fluid were determined by ELISA. ROS production was analyzed by flow cytometer. Results The percentage, cell count of neutrophils and neutrophil to lymphocyte ratio in the peripheral blood were significantly higher in lung cancer patients with or without COPD compared to COPD patients or healthy individuals (P < 0.05). The percentage and cell count of neutrophils in BAL fluid were significantly lower in patients with lung cancer with or without COPD than in patients with COPD (P < 0.05). However, BAL fluid and serum levels of both NE and MPO were significantly higher in patients with lung cancer than COPD patients or healthy individuals (P < 0.05). Neutrophils produced higher amounts of ROS in patients with lung cancer with or without COPD compared with COPD patients or healthy individuals (P < 0.05). Conclusions The results from this study demonstrate higher degree of local and systemic neutrophilic inflammation in patients with lung cancer (with or without COPD) than in patients with COPD. PMID:23919722

  17. Immunoregulatory molecules are master regulators of inflammation during the immune response

    PubMed Central

    Sánchez-Madrid, Francisco

    2014-01-01

    The balance between pro- and anti-inflammatory signalling is critical to maintain the immune homeostasis under physiological conditions as well as for the control of inflammation in different pathological settings. Recent progress in the signalling pathways that control this balance has led to the development of novel therapeutic agents for diseases characterized by alterations in the activation/suppression of the immune response. Different molecules have a key role in the regulation of the immune system, including the receptors PD-1 (Programmed cell Death 1), CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) and galectins; or the intracellular enzyme IDO (indoleamine 2,3-dioxygenase). In addition, other molecules as CD69, AhR (Aryl hydrocarbon Receptor), and GADD45 (Growth Arrest and DNA Damage-inducible 45) family members, have emerged as potential targets for the regulation of the activation/suppression balance of immune cells. This review offers a perspective on well-characterized as well as emergent negative immune regulatory molecules in the context of autoimmune inflammatory diseases. PMID:22819828

  18. Occlusion of retinal capillaries caused by glial cell proliferation in chronic ocular inflammation.

    PubMed

    Bianchi, E; Ripandelli, G; Feher, J; Plateroti, A M; Plateroti, R; Kovacs, I; Plateroti, P; Taurone, S; Artico, M

    2015-01-01

    The inner blood-retinal barrier is a gliovascular unit in which glial cells surround capillary endothelial cells and regulate retinal capillaries by paracrine interactions. During chronic ocular inflammation, microvascular complications can give rise to vascular proliferative lesions, which compromise visual acuity. This pathologic remodelling caused by proliferating Müller cells determines occlusion of retinal capillaries. The aim of the present study was to identify qualitative and quantitative alterations in the retinal capillaries in patients with post-traumatic chronic ocular inflammation or post-thrombotic vascular glaucoma. Moreover, we investigated the potential role of vascular endothelial growth factor (VEGF) and pro-inflammatory cytokines in retinal inflammation. Our electron microscopy findings demonstrated that during chronic ocular inflammation, thickening of the basement membrane, loss of pericytes and endothelial cells and proliferation of Müller cells occur with irreversible occlusion of retinal capillaries. Angiogenesis takes place as part of a regenerative reaction that results in fibrosis. We believe that VEGF and pro-inflammatory cytokines may be potential therapeutic targets in the treatment of this disease although further studies are required to confirm these findings. PMID:25792393

  19. Relationship Between Chronic Inflammation and the Stage and Histopathological Size of Colorectal Carcinoma

    PubMed Central

    Rasic, Ismar; Radovic, Svjetlana; Aksamija, Goran

    2016-01-01

    Objectives: The association of inflammatory reactions with almost all types of cancer supports the concept that inflammation is a critical component of tumor progression. The present study aimed to evaluate the relationship of serum markers of chronic inflammation with the stage of and histopathological size of colorectal carcinoma (CRC). Methods: This cross-sectional study included 90 patients of both sexes, mean age 66.2 (range 47-78) years, with clinically and histologically confirmed CRC, who were admitted to the Clinic for abdominal surgery UCCS for surgical treatment of CRC. The patients according to the stage of disease were divided into three groups (stage II–IV). The control group consisted of 30 subjects with no signs of malignancy and acute inflammatory diseases. Staging of CRC was done according to the TNM classification. In each patient, the preoperative blood samples were taken for determination of the parameters of inflammation: the erythrocyte sedimentation rate, white blood cells, C-reactive protein (CRP), fibrinogen and alpha 2 globulins. Results: It was confirmed that increasing markers of inflammation followed increasing stages of colorectal cancer, depth of tumor invasion and the occurrence of metastatic disease. CRP is a biomarker that consistently and significantly increases from the second to the fourth stage of colorectal cancer (7.2 (2.3-14.6) mg/L vs. 21.85 (12.3-41) mg/L vs. 38.6 (21.5-79) mg/L; p<0.01) and significantly correlates positively with the stage of CRC (r= 0.783, p<0.001), and the tumor size (r=0.249, p<0.05). Conclusion: The study results point to an increase in the degree of chronic inflammation throughout the progression of colorectal cancer. The most consistent marker of chronic inflammation that accompanies the progression of colorectal carcinoma is CRP. PMID:27147782

  20. Sonoelastography – A Useful Adjunct for Parotid Gland Ultrasound Assessment in Patients Suffering from Chronic Inflammation

    PubMed Central

    Wierzbicka, Małgorzata; Kałużny, Jarosław; Ruchała, Marek; Stajgis, Marek; Kopeć, Tomasz; Szyfter, Witold

    2014-01-01

    Background Shear wave elastography (SWE) is widely used in breast, liver, prostate and thyroid evaluations. Elastography provides additional information if used to assess parotid gland pathology. We assessed parotid glands by means of SWE to compare the parenchyma properties in different types of inflammation. Material/Methods Prospective analysis included 78 consecutive patients with parotid gland pathology: sialolithiasis (33), Stensen’s duct stenosis (15), chronic inflammation (10), and primary Sjögren syndrome (pSS) (20) treated at the Department of Otolaryngology, Head and Neck Surgery of PUMS. The primary predictor variable was type of parotid pathology, and secondary predictor variables were patient age and the duration and intensity of complaints. Ultrasound pictures were compared with elastography values of parotid parenchyma. Results Mean elasticity values for pSS (111 Kilopascals (kPa), Stensen’s duct stenosis (63 kPa), sialolithiasis (82 kPa), and chronic inflammation (77 kPa) were significantly higher than the mean value for healthy patients (24 kPa). Elasticity increased proportionally to the intensity of complaints: mild (51 kPa), moderate (78 kPa), and strong (90 kPa). Increased elasticity did not correspond with ultrasonographic pictures. In pSS the parenchyma was almost twice as stiff as in chronic inflammation (p=0.02), although subjective complaints were mostly mild or moderate, and the ultrasonographic picture did not present features of fibrosis. Conclusions Sonoelastography, by improving routine ultrasonographic assessment, might be a useful tool for parotid evaluations during the course of chronic inflammation. An extraordinarily high degree of stiffness was revealed in pSS despite lack of fibrosis by ultrasonography and moderate subjective complaints, suggesting that sonoelastography could be a valuable diagnostic tool. PMID:25398237

  1. Animal models to study acute and chronic intestinal inflammation in mammals.

    PubMed

    Jiminez, Janelle A; Uwiera, Trina C; Douglas Inglis, G; Uwiera, Richard R E

    2015-01-01

    Acute and chronic inflammatory diseases of the intestine impart a significant and negative impact on the health and well-being of human and non-human mammalian animals. Understanding the underlying mechanisms of inflammatory disease is mandatory to develop effective treatment and prevention strategies. As inflammatory disease etiologies are multifactorial, the use of appropriate animal models and associated metrics of disease are essential. In this regard, animal models used alone or in combination to study acute and chronic inflammatory disease of the mammalian intestine paired with commonly used inflammation-inducing agents are reviewed. This includes both chemical and biological incitants of inflammation, and both non-mammalian (i.e. nematodes, insects, and fish) and mammalian (i.e. rodents, rabbits, pigs, ruminants, dogs, and non-human primates) models of intestinal inflammation including germ-free, gnotobiotic, as well as surgical, and genetically modified animals. Importantly, chemical and biological incitants induce inflammation via a multitude of mechanisms, and intestinal inflammation and injury can vary greatly according to the incitant and animal model used, allowing studies to ascertain both long-term and short-term effects of inflammation. Thus, researchers and clinicians should be aware of the relative strengths and limitations of the various animal models used to study acute and chronic inflammatory diseases of the mammalian intestine, and the scope and relevance of outcomes achievable based on this knowledge. The ability to induce inflammation to mimic common human diseases is an important factor of a successful animal model, however other mechanisms of disease such as the amount of infective agent to induce disease, invasion mechanisms, and the effect various physiologic changes can have on inducing damage are also important features. In many cases, the use of multiple animal models in combination with both chemical and biological incitants is

  2. Retinol binding protein 4 in relation to diet, inflammation, immunity, and cardiovascular diseases.

    PubMed

    Zabetian-Targhi, Fateme; Mahmoudi, Mohammad J; Rezaei, Nima; Mahmoudi, Maryam

    2015-11-01

    Retinol binding protein 4 (RBP4), previously called retinol binding protein (RBP), is considered a specific carrier of retinol in the blood. It is also an adipokine that has been implicated in the pathophysiology of insulin resistance. RBP4 seems to be correlated with cardiometabolic markers in inflammatory chronic diseases, including obesity, type 2 diabetes, metabolic syndrome, and cardiovascular diseases (CVDs). It has recently been suggested that inflammation produced by RBP4 induces insulin resistance and CVD. The clinical relevance of this hypothesis is discussed in this review. Knowledge concerning the association of RBP4 with inflammation markers, oxidative stress, and CVDs as well as concerning the role of diet and antioxidants in decreasing RBP4 concentrations are discussed. Special attention is given to methodologies used in previously published studies and covariates that should be controlled when planning new studies on this adipokine. PMID:26567199

  3. Chronic Low Dose Chlorine Exposure Aggravates Allergic Inflammation and Airway Hyperresponsiveness and Activates Inflammasome Pathway

    PubMed Central

    Kim, Sae-Hoon; Park, Da-Eun; Lee, Hyun-Seung; Kang, Hye-Ryun; Cho, Sang-Heon

    2014-01-01

    Background Epidemiologic clinical studies suggested that chronic exposure to chlorine products is associated with development of asthma and aggravation of asthmatic symptoms. However, its underlying mechanism was not clearly understood. Studies were undertaken to define the effects and mechanisms of chronic low-dose chlorine exposure in the pathogenesis of airway inflammation and airway hyperresponsiveness (AHR). Methods Six week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low dose chlorine exposure of naturally vaporized gas of 5% sodium hypochlorite solution. Airway inflammation and AHR were evaluated by bronchoalveolar lavage (BAL) cell recovery and non-invasive phlethysmography, respectively. Real-time qPCR, Western blot assay, and ELISA were used to evaluate the mRNA and protein expressions of cytokines and other inflammatory mediators. Human A549 and murine epithelial (A549 and MLE12) and macrophage (AMJ2-C11) cells were used to define the responses to low dose chlorine exposure in vitro. Results Chronic low dose chlorine exposure significantly augmented airway inflammation and AHR in OVA-sensitized and challenged mice. The expression of Th2 cytokines IL-4 and IL-5 and proinflammatory cytokine IL-1β and IL-33 were significantly increased in OVA/Cl group compared with OVA group. The chlorine exposure also activates the major molecules associated with inflammasome pathway in the macrophages with increased expression of epithelial alarmins IL-33 and TSLP in vitro. Conclusion Chronic low dose exposure of chlorine aggravates allergic Th2 inflammation and AHR potentially through activation of inflammasome danger signaling pathways. PMID:25202911

  4. Lung disease severity, chronic inflammation, iron deficiency, and erythropoietin response in adults with cystic fibrosis.

    PubMed

    Fischer, R; Simmerlein, R; Huber, R M; Schiffl, H; Lang, S M

    2007-12-01

    Chronic lung disorders are usually associated with a hypoxia driven increase in red cell mass. However, patients with cystic fibrosis (CF) often have normal or decreased haemoglobin levels. The present prospective observational study in cystic fibrosis patients was performed to determine which factors were involved in alterations in the hematopoetic response to corresponding arterial oxygen pressure. Sixty adult patients (age 21-51) with stable CF were included. They all had vitamin A, D, E, and K but no vitamin B12 supplementation. Twenty-five patients were on oral Fe(2+) (100 mg/day). Resting arterial blood gases, lung function, complete blood counts, parameters of iron status, CRP, sputum microbiology and serum erythropoietin were measured at recruitment and after 3 and 6 months. Patients had varying degrees of pulmonary functional impairment and 9% were hypoxemic (arterial oxygen pressure <60 mm Hg). Low-grade systemic inflammation (CRP > 0.5 mg/dl) was present in 40% of the patients, who all had bacterial colonization. None of the patient had erythrocytosis and 12 patients had anemia. There was no significant difference in iron status between patients with or without chronic iron supplementation and erythropoietin levels were normal. During the 6 months observation period no significant changes occurred. The patients exhibited an impaired erythropoietic response to hypoxemia with normal or low hematocrit in spite of chronic lung disease which might be caused by chronic inflammation associated with CF. Linear multivariate regression analysis revealed CRP levels but neither iron substitution, nor erythropoietin levels nor lung function parameters as independent determinant of haemoglobin levels. CF may be associated with anemia of variable severity as expression of the chronic inflammation present in these patients. The therapeutic consequences are to treat the underlying inflammation rather than to supplement iron. PMID:17948283

  5. Inflammation Enhances the Risks of Stroke and Death in Chronic Chagas Disease Patients

    PubMed Central

    Guedes, Paulo Marcos Matta; de Andrade, Cléber Mesquita; Nunes, Daniela Ferreira; de Sena Pereira, Nathalie; Queiroga, Tamyres Bernadete Dantas; Machado-Coelho, George Luiz Lins; Nascimento, Manuela Sales Lima; Do-Valle-Matta, Maria Adelaide; da Câmara, Antônia Cláudia Jácome; Chiari, Egler; Galvão, Lúcia Maria da Cunha

    2016-01-01

    Ischemic strokes have been implicated as a cause of death in Chagas disease patients. Inflammation has been recognized as a key component in all ischemic processes, including the intravascular events triggered by vessel interruption, brain damage and repair. In this study, we evaluated the association between inflammatory markers and the death risk (DR) and stroke risk (SR) of patients with different clinical forms of chronic Chagas disease. The mRNA expression levels of cytokines, transcription factors expressed in the adaptive immune response (Th1, Th2, Th9, Th17, Th22 and regulatory T cell), and iNOS were analyzed by real-time PCR in peripheral blood mononuclear cells of chagasic patients who exhibited the indeterminate, cardiac, digestive and cardiodigestive clinical forms of the disease, and the levels of these transcripts were correlated with the DR and SR. Cardiac patients exhibited lower mRNA expression levels of GATA-3, FoxP3, AHR, IL-4, IL-9, IL-10 and IL-22 but exhibited higher expression of IFN-γ and TNF-α compared with indeterminate patients. Digestive patients showed similar levels of GATA-3, IL-4 and IL-10 than indeterminate patients. Cardiodigestive patients exhibited higher levels of TNF-α compared with indeterminate and digestive patients. Furthermore, we demonstrated that patients with high DR and SR exhibited lower GATA-3, FoxP3, and IL-10 expression and higher IFN-γ, TNF-α and iNOS mRNA expression than patients with low DR and SR. A negative correlation was observed between Foxp3 and IL-10 mRNA expression and the DR and SR. Moreover, TNF-α and iNOS expression was positively correlated with DR and SR. Our data suggest that an inflammatory imbalance in chronic Chagas disease patients is associated with a high DR and SR. This study provides a better understanding of the stroke pathobiology in the general population and might aid the development of therapeutic strategies for controlling the morbidity and mortality of Chagas disease. PMID

  6. Inflammation Enhances the Risks of Stroke and Death in Chronic Chagas Disease Patients.

    PubMed

    Guedes, Paulo Marcos Matta; de Andrade, Cléber Mesquita; Nunes, Daniela Ferreira; de Sena Pereira, Nathalie; Queiroga, Tamyres Bernadete Dantas; Machado-Coelho, George Luiz Lins; Nascimento, Manuela Sales Lima; Do-Valle-Matta, Maria Adelaide; da Câmara, Antônia Cláudia Jácome; Chiari, Egler; Galvão, Lúcia Maria da Cunha

    2016-04-01

    Ischemic strokes have been implicated as a cause of death in Chagas disease patients. Inflammation has been recognized as a key component in all ischemic processes, including the intravascular events triggered by vessel interruption, brain damage and repair. In this study, we evaluated the association between inflammatory markers and the death risk (DR) and stroke risk (SR) of patients with different clinical forms of chronic Chagas disease. The mRNA expression levels of cytokines, transcription factors expressed in the adaptive immune response (Th1, Th2, Th9, Th17, Th22 and regulatory T cell), and iNOS were analyzed by real-time PCR in peripheral blood mononuclear cells of chagasic patients who exhibited the indeterminate, cardiac, digestive and cardiodigestive clinical forms of the disease, and the levels of these transcripts were correlated with the DR and SR. Cardiac patients exhibited lower mRNA expression levels of GATA-3, FoxP3, AHR, IL-4, IL-9, IL-10 and IL-22 but exhibited higher expression of IFN-γ and TNF-α compared with indeterminate patients. Digestive patients showed similar levels of GATA-3, IL-4 and IL-10 than indeterminate patients. Cardiodigestive patients exhibited higher levels of TNF-α compared with indeterminate and digestive patients. Furthermore, we demonstrated that patients with high DR and SR exhibited lower GATA-3, FoxP3, and IL-10 expression and higher IFN-γ, TNF-α and iNOS mRNA expression than patients with low DR and SR. A negative correlation was observed between Foxp3 and IL-10 mRNA expression and the DR and SR. Moreover, TNF-α and iNOS expression was positively correlated with DR and SR. Our data suggest that an inflammatory imbalance in chronic Chagas disease patients is associated with a high DR and SR. This study provides a better understanding of the stroke pathobiology in the general population and might aid the development of therapeutic strategies for controlling the morbidity and mortality of Chagas disease. PMID

  7. Neither Primary nor Memory Immunity to Mycobacterium tuberculosis Infection Is Compromised in Mice with Chronic Enteric Helminth Infection

    PubMed Central

    Rafi, Wasiulla; Bhatt, Kamlesh; Gause, William C.

    2015-01-01

    Previously we had reported that Nippostrongylus brasiliensis, a helminth with a lung migratory phase, affected host resistance against Mycobacterium tuberculosis infection through the induction of alternatively activated (M2) macrophages. Several helminth species do not have an obligatory lung migratory phase but establish chronic infections in the host that include potent immune downregulatory effects, in part mediated through induction of a FoxP3+ T regulatory cell (Treg) response. Treg cells exhibit duality in their functions in host defense against M. tuberculosis infection since their depletion leads to enhanced priming of T cells in the lymph nodes and attendant improved control of M. tuberculosis infection, while their presence in the lung granuloma protects against excessive inflammation. Heligmosomoides polygyrus is a strictly murine enteric nematode that induces a strong FoxP3 Treg response in the host. Therefore, in this study we investigated whether host immunity to M. tuberculosis infection would be modulated in mice with chronic H. polygyrus infection. We report that neither primary nor memory immunity conferred by Mycobacterium bovis BCG vaccination was affected in mice with chronic enteric helminth infection, despite a systemic increase in FoxP3+ T regulatory cells. The findings indicate that anti-M. tuberculosis immunity is not similarly affected by all helminth species and highlight the need to consider this inequality in human coinfection studies. PMID:25605766

  8. Acupuncture and Immune Function in Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Randomized, Controlled Study

    PubMed Central

    Lee, Shaun Wen Huey; Liong, Men Long; Yuen, Kah Hay; Krieger, John N

    2014-01-01

    Objective The immune system has been implicated as one mechanism underlying the benefits of acupuncture therapy. Evidence suggests that acupuncture can ameliorate symptoms of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), but the association between clinical response and the immune system has not been investigated. Design/Setting We investigated 12 CP/CPPS patients participating in a prospective randomized clinical trial comparing acupuncture versus sham acupuncture for effects on cellular immunity. Blood samples were taken before the first needling and after the last of 20 treatment sessions (week 10). Patients also completed questionnaires examining their CP/CPPS symptoms and mood status at the baseline and end of study visits. Results At the end of study 8 of 12 participants (67%) were classified as treatment responders, 4 participants each from the acupuncture and sham groups. The acupuncture group averaged a 5% increase in natural killer cell levels compared to corresponding sham (-13%; p=0.03). Similarly, patients randomized to acupuncture reported a reduction in other white blood cell parameters examined, supporting the possibility that immunity might be important in the pathophysiology of CP/CPPS. Conclusions The specific effect of acupuncture on CP/CPPS remains unclear. Further research is warranted to examine the mechanisms by which acupuncture therapy may improve clinical symptoms in patients with CP/CPPS. PMID:25453515

  9. Implanted neural electrodes cause chronic, local inflammation that is correlated with local neurodegeneration

    NASA Astrophysics Data System (ADS)

    McConnell, George C.; Rees, Howard D.; Levey, Allan I.; Gutekunst, Claire-Anne; Gross, Robert E.; Bellamkonda, Ravi V.

    2009-10-01

    Prosthetic devices that are controlled by intracortical electrodes recording one's 'thoughts' are a reality today, and no longer merely in the realm of science fiction. However, widespread clinical use of implanted electrodes is hampered by a lack of reliability in chronic recordings, independent of the type of electrodes used. One major hypothesis has been that astroglial scar electrically impedes the electrodes. However, there is a temporal discrepancy between stabilization of scar's electrical properties and recording failure with recording failure lagging by 1 month. In this study, we test a possible explanation for this discrepancy: the hypothesis that chronic inflammation, due to the persistent presence of the electrode, causes a local neurodegenerative state in the immediate vicinity of the electrode. Through modulation of chronic inflammation via stab wound, electrode geometry and age-matched control, we found that after 16 weeks, animals with an increased level of chronic inflammation were associated with increased neuronal and dendritic, but not axonal, loss. We observed increased neuronal and dendritic loss 16 weeks after implantation compared to 8 weeks after implantation, suggesting that the local neurodegenerative state is progressive. After 16 weeks, we observed axonal pathology in the form of hyperphosphorylation of the protein tau in the immediate vicinity of the microelectrodes (as observed in Alzheimer's disease and other tauopathies). The results of this study suggest that a local, late onset neurodegenerative disease-like state surrounds the chronic electrodes and is a potential cause for chronic recording failure. These results also inform strategies to enhance our capability to attain reliable long-term recordings from implantable electrodes in the CNS.

  10. Immune and neurotrophin stimulation by electroconvulsive therapy: is some inflammation needed after all?

    PubMed

    van Buel, E M; Patas, K; Peters, M; Bosker, F J; Eisel, U L M; Klein, H C

    2015-01-01

    A low-grade inflammatory response is commonly seen in the peripheral blood of major depressive disorder (MDD) patients, especially those with refractory and chronic disease courses. However, electroconvulsive therapy (ECT), the most drastic intervention reserved for these patients, is closely associated with an enhanced haematogenous as well as neuroinflammatory immune response, as evidenced by both human and animal studies. A related line of experimental evidence further shows that inflammatory stimulation reinforces neurotrophin expression and may even mediate dramatic neurogenic and antidepressant-like effects following exposure to chronic stress. The current review therefore attempts a synthesis of our knowledge on the neurotrophic and immunological aspects of ECT and other electrically based treatments in psychiatry. Perhaps contrary to contemporary views, we conclude that targeted potentiation, rather than suppression, of inflammatory responses may be of therapeutic relevance to chronically depressed patients or a subgroup thereof. PMID:26218851

  11. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.

    PubMed

    Franceschi, Claudio; Campisi, Judith

    2014-06-01

    Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as "inflammaging." Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Nevertheless, the precise etiology of inflammaging and its potential causal role in contributing to adverse health outcomes remain largely unknown. The identification of pathways that control age-related inflammation across multiple systems is therefore important in order to understand whether treatments that modulate inflammaging may be beneficial in old people. The session on inflammation of the Advances in Gerosciences meeting held at the National Institutes of Health/National Institute on Aging in Bethesda on October 30 and 31, 2013 was aimed at defining these important unanswered questions about inflammaging. This article reports the main outcomes of this session. PMID:24833586

  12. Quality of life is associated with chronic inflammation in schizophrenia: a cross-sectional study

    PubMed Central

    M., Faugere; J.A., Micoulaud-Franchi; M., Alessandrini; R., Richieri; C., Faget-Agius; P., Auquier; C., Lançon; L., Boyer

    2015-01-01

    Inflammation may play a crucial role in the pathogenesis of schizophrenia. However, the association between chronic inflammation and health outcomes in schizophrenia remains unclear, particularly for patient-reported outcomes. The aim of this study was to investigate the relationship between quality of life (QoL) and chronic inflammation assessed using C -Reactive Protein (CRP) in patients with schizophrenia. Two hundred and fifty six patients with schizophrenia were enrolled in this study. After adjusting for key socio-demographic and clinical confounding factors, patients with high levels of CRP (>3.0 mg/l) had a lower QoL than patients with normal CRP levels (OR = 0.97, 95% CI = 0.94–0.99). An investigation of the dimensions of QoL revealed that psychological well-being, physical well-being and sentimental life were the most salient features of QoL associated with CRP. Significant associations were found between lower educational level (OR = 4.15, 95% CI = 1.55–11.07), higher body mass index (OR = 1.16, 95% CI = 1.06–1.28), higher Fagerström score (OR = 1.22, 95% CI = 1.01–1.47) and high levels of CRP. After replications with longitudinal approaches, the association between QoL and chronic inflammation may offer interesting interventional prospects to act both on inflammation and QoL in patients with schizophrenia. PMID:26041435

  13. Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues

    PubMed Central

    He, Tianyu; Brocca-Cofano, Egidio; Gillespie, Delbert G.; Xu, Cuiling; Stock, Jennifer L.; Ma, Dongzhu; Policicchio, Benjamin B.; Raehtz, Kevin D.; Rinaldo, Charles R.; Apetrei, Cristian; Jackson, Edwin K.; Macatangay, Bernard J. C.

    2015-01-01

    ABSTRACT The role of the adenosine (ADO) pathway in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/SIV) infection remains unclear. We compared SIVsab-induced changes of markers related to ADO production (CD39 and CD73) and breakdown (CD26 and adenosine deaminase) on T cells from blood, lymph nodes, and intestine collected from pigtailed macaques (PTMs) and African green monkeys (AGMs) that experience different SIVsab infection outcomes. We also measured ADO and inosine (INO) levels in tissues by mass spectrometry. Finally, we assessed the suppressive effect of ADO on proinflammatory cytokine production after T cell receptor stimulation. The baseline level of both CD39 and CD73 coexpression on regulatory T cells and ADO levels were higher in AGMs than in PTMs. Conversely, high INO levels associated with dramatic increases in CD26 expression and adenosine deaminase activity were observed in PTMs during chronic SIV infection. Immune activation and inflammation markers in the gut and periphery inversely correlated with ADO and directly correlated with INO. Ex vivo administration of ADO significantly suppressed proinflammatory cytokine production by T cells in both species. In conclusion, the opposite dynamics of ADO pathway-related markers and contrasting ADO/INO levels in species with divergent proinflammatory responses to SIV infection support a key role of ADO in controlling immune activation/inflammation in nonprogressive SIV infections. Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved in sparing natural hosts of SIVs from developing SIV-related gut dysfunction. Focusing studies of the ADO pathway on mucosal sites of viral replication is warranted. IMPORTANCE The mechanisms responsible for the severe gut dysfunction characteristic of progressive HIV and SIV infection in humans and macaques are not completely elucidated. We report that ADO may play a key role in controlling immune

  14. Escherichia coli-induced immune paralysis is not exacerbated during chronic filarial infection

    PubMed Central

    Buerfent, Benedikt C; Gondorf, Fabian; Wohlleber, Dirk; Schumak, Beatrix; Hoerauf, Achim; Hübner, Marc P

    2015-01-01

    Sepsis initially starts with a systemic inflammatory response (SIRS phase) and is followed by a compensatory anti-inflammatory response syndrome (CARS) that causes impaired adaptive T-cell immunity, immune paralysis and an increased susceptibility to secondary infections. In contrast, parasitic filariae release thousands of microfilariae into the peripheral blood without triggering inflammation, as they induce regulatory, anti-inflammatory host responses. Hence, we investigated the impact of chronic filarial infection on adaptive T-cell responses during the SIRS and CARS phases of a systemic bacterial infection and analysed the development of T-cell paralysis following a subsequent adenovirus challenge in BALB/c mice. Chronic filarial infection impaired adenovirus-specific CD8+ T-cell cytotoxicity and interferon-γ responses in the absence of a bacterial challenge and led to higher numbers of splenic CTLA-4+ CD4+ T cells, whereas splenic T-cell expression of CD69 and CD62 ligand, serum cytokine levels and regulatory T-cell frequencies were comparable to naive controls. Irrespective of filarial infection, the SIRS phase dominated 6–24 hr after intravenous Escherichia coli challenge with increased T-cell activation and pro-inflammatory cytokine production, whereas the CARS phase occurred 6 days post E. coli challenge and correlated with high levels of transforming growth factor-β and increased CD62 ligand T-cell expression. Escherichia coli-induced impairment of adenovirus-specific CD8+ T-cell cytotoxicity and interferon-γ production was not additionally impaired by chronic filarial infection. This suggests that filarial immunoregulation does not exacerbate E. coli-induced T-cell paralysis. PMID:25521437

  15. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation.

    PubMed

    Izcue, Ana; Coombes, Janine L; Powrie, Fiona

    2006-08-01

    The gastrointestinal (GI) tract is the main interface where the body encounters exogenous antigens. It is crucial that the local response here is tightly regulated to avoid an immune reaction against dietary antigens and commensal flora while still mounting an efficient defense against pathogens. Faults in establishing intestinal tolerance can lead to disease, inducing local and often also systemic inflammation. Studies in human as well as in animal models suggest a role for regulatory T cells (Tregs) in maintaining intestinal homeostasis. Transfer of Tregs can not only prevent the development of colitis in animal models but also cure established disease, acting both systemically and at the site of inflammation. In this review, we discuss the major regulatory pathways, including transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), and their role in Treg-mediated control of systemic and mucosal responses. In addition, we give an overview of the known mechanisms of lymphocyte migration to the intestine and discuss how CD103 expression can influence the balance between regulatory and effector T cells. Further understanding of the factors that control the activity of Tregs in different immune compartments may facilitate the design of strategies to target regulation in a tissue-specific way. PMID:16903919

  16. Immune Modulatory Effects of IL-22 on Allergen-Induced Pulmonary Inflammation

    PubMed Central

    Fang, Ping; Zhou, Li; Zhou, Yuqi; Kolls, Jay K.; Zheng, Tao; Zhu, Zhou

    2014-01-01

    IL-22 is a Th17/Th22 cytokine that is increased in asthma. However, recent animal studies showed controversial findings in the effects of IL-22 in allergic asthma. To determine the role of IL-22 in ovalbumin-induced allergic inflammation we generated inducible lung-specific IL-22 transgenic mice. Transgenic IL-22 expression and signaling activity in the lung were determined. Ovalbumin (OVA)-induced pulmonary inflammation, immune responses, and airway hyperresponsiveness (AHR) were examined and compared between IL-22 transgenic mice and wild type controls. Following doxycycline (Dox) induction, IL-22 protein was readily detected in the large (CC10 promoter) and small (SPC promoter) airway epithelial cells. IL-22 signaling was evidenced by phosphorylated STAT3. After OVA sensitization and challenge, compared to wild type littermates, IL-22 transgenic mice showed decreased eosinophils in the bronchoalveolar lavage (BAL), and in lung tissue, decreased mucus metaplasia in the airways, and reduced AHR. Among the cytokines and chemokines examined, IL-13 levels were reduced in the BAL fluid as well as in lymphocytes from local draining lymph nodes of IL-22 transgenic mice. No effect was seen on the levels of serum total or OVA-specific IgE or IgG. These findings indicate that IL-22 has immune modulatory effects on pulmonary inflammatory responses in allergen-induced asthma. PMID:25254361

  17. The pentraxins PTX3 and SAP in innate immunity, regulation of inflammation and tissue remodelling.

    PubMed

    Bottazzi, Barbara; Inforzato, Antonio; Messa, Massimo; Barbagallo, Marialuisa; Magrini, Elena; Garlanda, Cecilia; Mantovani, Alberto

    2016-06-01

    Pentraxins are a superfamily of fluid phase pattern recognition molecules conserved in evolution and characterized by a cyclic multimeric structure. C-reactive protein (CRP) and serum amyloid P component (SAP) constitute the short pentraxin arm of the superfamily. CRP and SAP are produced in the liver in response to IL-6 and are acute phase reactants in humans and mice respectively. In addition SAP has been shown to affect tissue remodelling and fibrosis by stabilizing all types of amyloid fibrils and by regulating monocyte to fibrocyte differentiation. Pentraxin 3 (PTX3) is the prototype of the long pentraxin arm. Gene targeted mice and genetic and epigenetic studies in humans suggest that PTX3 plays essential non-redundant roles in innate immunity and inflammation as well as in tissue remodelling. Recent studies have revealed the role of PTX3 as extrinsic oncosuppressor, able to tune cancer-related inflammation. In addition, at acidic pH PTX3 can interact with provisional matrix components promoting inflammatory matrix remodelling. Thus acidification during tissue repair sets PTX3 in a tissue remodelling and repair mode, suggesting that matrix and microbial recognition are common, ancestral features of the humoral arm of innate immunity. PMID:26921689

  18. Potential mechanisms underlying the role of chronic inflammation in age-related muscle wasting.

    PubMed

    Jo, Edward; Lee, Sang-Rok; Park, Bong-Sup; Kim, Jeong-Su

    2012-10-01

    Sarcopenia, an age-related condition characterized by progressive skeletal muscle degeneration, might exist as one of the primary clinical conditions underlying severe functional impairment as well as increased risk of co-morbidities in the elderly. Although the etiology of sarcopenia remains multifaceted, age-related chronic inflammation has been strongly implicated in muscle wasting and related sequelae during advanced age. Recent evidence suggests that aberrant, unresolved alterations in regular inflammatory processes during advanced age might ultimately operate as the link that drives skeletal muscle to become more degenerative and dysfunctional in nature. Such negative atrophic muscular outcomes might result from inflammation-induced disruption of central mechanisms regulating skeletal muscle morphology and remodeling. In addition, recent findings demonstrate an adverse confluence between sarcopenia and excessive adiposity (i.e. sarcopenic obesity), as the co-existence of such adverse alterations in body composition may exacerbate systemic inflammation and muscle wasting in the elderly. The following evidence-based review serves to examine sarcopenia from a mechanistic perspective with emphasis on chronic inflammation. PMID:22717404

  19. Protective effect of Clerodendrum colebrookianum Walp., on acute and chronic inflammation in rats

    PubMed Central

    Deb, Lokesh; Dey, Amitabha; Sakthivel, G.; Bhattamishra, Subrat Kumar; Dutta, Amitsankar

    2013-01-01

    Aim: To evaluate antioxidant, anti-inflammatory potential of the aqueous extracts and its aqueous, n-butanol, ethyl-acetate, and chloroform fractions of Clerodendrum colebrookianum Walp. leaves. Materials and Methods: In this present study, all the test samples were evaluated on in-vivo inflammatory model such as carrageenan and histamine-induced acute-inflammation and cotton pellet induced granuloma formation in albino male rats. Test samples were also employed in in-vitro assays like DPPH* free radical scavenging activity and COX inhibition assay. Results: The test samples at the dose of 200mg/kg/p.o. were found to cause significant inhibition of carrageenan and histamine-induced inflammation and cotton pallet-induced granuloma formation on acute and chronic inflammation in rats. The test samples, except n-butanol fraction, exhibited inhibitory effect for both COX-1 and COX-2, in in-vitro assay but their percentage of inhibition values differs from each other. The test samples (aqueous extracts, aqueous, n-butanol, ethyl-acetate, and chloroform fractions) at 100 μg concentration exhibits 54.37%, 33.88%, 62.85%, 56.28%, and 57.48% DPPH* radical-scavenging effect respectively in in-vitro antioxidant study. Conclusion: These observations established the anti-inflammatory effect of C. colebrookianum leaves in acute and chronic stages of inflammation by free radical scavenging and inhibition of COX-1 and COX-2. PMID:24014914

  20. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease

    PubMed Central

    George, Leena; Brightling, Christopher E.

    2016-01-01

    The chronic lung diseases, asthma and chronic obstructive pulmonary disease (COPD), are common affecting over 500 million people worldwide and causing substantial morbidity and mortality. Asthma is typically associated with Th2-mediated eosinophilic airway inflammation, in contrast to neutrophilic inflammation observed commonly in COPD. However, there is increasing evidence that the eosinophil might play an important role in 10–40% of patients with COPD. Consistently in both asthma and COPD a sputum eosinophilia is associated with a good response to corticosteroid therapy and tailored strategies aimed to normalize sputum eosinophils reduce exacerbation frequency and severity. Advances in our understanding of the multistep paradigm of eosinophil recruitment to the airway, and the consequence of eosinophilic inflammation, has led to the development of new therapies to target these molecular pathways. In this article we discuss the mechanisms of eosinophilic trafficking, the tools to assess eosinophilic airway inflammation in asthma and COPD during stable disease and exacerbations and review current and novel anti-eosinophilic treatments. PMID:26770668

  1. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease.

    PubMed

    George, Leena; Brightling, Christopher E

    2016-01-01

    The chronic lung diseases, asthma and chronic obstructive pulmonary disease (COPD), are common affecting over 500 million people worldwide and causing substantial morbidity and mortality. Asthma is typically associated with Th2-mediated eosinophilic airway inflammation, in contrast to neutrophilic inflammation observed commonly in COPD. However, there is increasing evidence that the eosinophil might play an important role in 10-40% of patients with COPD. Consistently in both asthma and COPD a sputum eosinophilia is associated with a good response to corticosteroid therapy and tailored strategies aimed to normalize sputum eosinophils reduce exacerbation frequency and severity. Advances in our understanding of the multistep paradigm of eosinophil recruitment to the airway, and the consequence of eosinophilic inflammation, has led to the development of new therapies to target these molecular pathways. In this article we discuss the mechanisms of eosinophilic trafficking, the tools to assess eosinophilic airway inflammation in asthma and COPD during stable disease and exacerbations and review current and novel anti-eosinophilic treatments. PMID:26770668

  2. Fas-activated serine/threonine phosphoprotein promotes immune-mediated pulmonary inflammation

    PubMed Central

    Simarro, Maria; Giannattasio, Giorgio; De la Fuente, Miguel A; Benarafa, Charaf; Subramanian, Kulandayan K.; Ishizawar, Rumey; Balestrieri, Barbara; Andersson, Emma M; Luo, Hongbo R.; Orduña, Antonio; Boyce, Joshua; Anderson, Paul

    2010-01-01

    We have generated Fas activated serine threonine phosphoprotein-deficient mice (FAST−/−) to study the in vivo role of FAST in immune system function. In a model of house dust mite (HDM)-induced allergic pulmonary inflammation, wild type mice develop a mixed cellular infiltrate composed of eosinophils, lymphocytes and neutrophils. FAST−/− mice develop airway inflammation that is distinguished by the near absence of neutrophils. Similarly, LPS-induced alveolar neutrophil recruitment is markedly reduced in FAST−/− mice compared to wild type controls. This is accompanied by reduced concentrations of cytokines (TNF-α, IL-6 and IL-23) and chemoattractants (MIP-2 and KC) in bronchoalveolar lavage fluids. As FAST−/− neutrophils exhibit normal chemotaxis and survival, impaired neutrophil recruitment is likely to be due to reduced production of chemoattractants within the pulmonary parenchyma. Studies using bone marrow chimeras implicate lung resident hematopoietic cells (e.g. pulmonary dendritic cells and/or alveolar macrophages) in this process. In conclusion, our results introduce FAST as a pro-inflammatory factor that modulates the function of lung resident hematopoietic cells to promote neutrophil recruitment and pulmonary inflammation. PMID:20363972

  3. Fatty acids and chronic low grade inflammation associated with obesity and the metabolic syndrome.

    PubMed

    Cooke, Aoife A; Connaughton, Ruth M; Lyons, Claire L; McMorrow, Aoibheann M; Roche, Helen M

    2016-08-15

    The metabolic syndrome is a group of obesity associated metabolic conditions that result in increased risk of cardiovascular disease and type 2 diabetes. Global increases in obesity rates have led to an increase in metabolic syndrome resulting in a demand for increased understanding of the mechanisms involved. This review examines the relationship between adipose tissue biology, lipid metabolism and chronic low grade inflammation relating to obesity and insulin resistance. PMID:27083551

  4. Effect of intranasal rosiglitazone on airway inflammation and remodeling in a murine model of chronic asthma

    PubMed Central

    Lee, Hwa Young; Rhee, Chin Kook; Kang, Ji Young; Park, Chan Kwon; Lee, Sook Young; Kwon, Soon Suk; Kim, Young Kyoon; Yoon, Hyoung Kyu

    2016-01-01

    Background/Aims: Asthma is characterized by airway hyperresponsiveness, inflammation, and remodeling. Peroxisome proliferator-activated receptors have been reported to regulate inflammatory responses in many cells. In this study, we examined the effects of intranasal rosiglitazone on airway remodeling in a chronic asthma model. Methods: We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated intranasally with rosiglitazone with or without an antagonist during OVA challenge. We determined airway inflammation and the degree of airway remodeling by smooth muscle actin area and collagen deposition. Results: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, compared with control mice. Additionally, the mice developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of rosiglitazone intranasally inhibited the eosinophilic inflammation significantly, and, importantly, airway smooth muscle remodeling in mice chronically exposed to OVA. Expression of Toll-like receptor (TLR)-4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was increased in the OVA group and decreased in the rosiglitazone group. Co-treatment with GW9660 (a rosiglitazone antagonist) and rosiglitazone increased the expression of TLR-4 and NF-κB. Conclusions: These results suggest that intranasal administration of rosiglitazone can prevent not only air way inf lammation but also air way remodeling associated with chronic allergen challenge. This beneficial effect is mediated by inhibition of TLR-4 and NF-κB pathways. PMID:26767862

  5. The "sweet" side of a long pentraxin: how glycosylation affects PTX3 functions in innate immunity and inflammation.

    PubMed

    Inforzato, Antonio; Reading, Patrick C; Barbati, Elisa; Bottazzi, Barbara; Garlanda, Cecilia; Mantovani, Alberto

    2012-01-01

    Innate immunity represents the first line of defense against pathogens and plays key roles in activation and orientation of the adaptive immune response. The innate immune system comprises both a cellular and a humoral arm. Components of the humoral arm include soluble pattern recognition molecules (PRMs) that recognize pathogen-associated molecular patterns and initiate the immune response in coordination with the cellular arm, therefore acting as functional ancestors of antibodies. The long pentraxin PTX3 is a prototypic soluble PRM that is produced at sites of infection and inflammation by both somatic and immune cells. Gene targeting of this evolutionarily conserved protein has revealed a non-redundant role in resistance to selected pathogens. Moreover, PTX3 exerts important functions at the crossroad between innate immunity, inflammation, and female fertility. The human PTX3 protein contains a single N-glycosylation site that is fully occupied by complex type oligosaccharides, mainly fucosylated and sialylated biantennary glycans. Glycosylation has been implicated in a number of PTX3 activities, including neutralization of influenza viruses, modulation of the complement system, and attenuation of leukocyte recruitment. Therefore, this post translational modification might act as a fine tuner of PTX3 functions in native immunity and inflammation. Here we review the studies on PTX3, with emphasis on the glycan-dependent mechanisms underlying pathogen recognition and crosstalk with other components of the innate immune system. PMID:23316195

  6. Chrysin alleviates allergic inflammation and airway remodeling in a murine model of chronic asthma.

    PubMed

    Yao, Jing; Jiang, Mingzi; Zhang, Yunshi; Liu, Xing; Du, Qiang; Feng, Ganzhu

    2016-03-01

    Asthma is a chronic airway inflammatory disorder and progresses mainly due to airway remodeling. Chrysin, a natural flavonoid, has been reported to possess multiple biologic activities, including anti-inflammation, anti-oxidation and anti-proliferation. The present study aimed to investigate whether chrysin could relieve allergic airway inflammation and remodeling in a murine model of chronic asthma and the mechanism involved. The female BALB/c mice sensitized and challenged with ovalbumin (OVA) successfully developed airway hyperresponsiveness (AHR), inflammation and remodeling. The experimental data showed that chrysin could alleviate OVA-induced AHR. Chrysin could also reduce OVA-induced increases in the number of inflammatory cells, especially eosinophils, interleukin (IL) -4, and IL-13 in bronchoalveolar lavage fluid (BALF) and total IgE in serum. The decreased interferon-γ (IFN-γ) level in BALF was also upregulated by chrysin. In addition, inflammatory cell infiltration, goblet cell hyperplasia and the expression of α-smooth muscle actin (α-SMA) around bronchioles were suppressed by chrysin. Furthermore, the phosphorylation levels of Akt and extracellular signal-regulated kinase (ERK) could be decreased by chrysin, which are associated with airway smooth muscle cell (ASMC) proliferation. These results indicate the promising therapeutic effect of chrysin on chronic asthma, especially the progression of airway remodeling. PMID:26780233

  7. Neutrophils confer T cell resistance to myeloid-derived suppressor cell-mediated suppression to promote chronic inflammation.

    PubMed

    Ryan, Sean O; Johnson, Jenny L; Cobb, Brian A

    2013-05-15

    Low-grade chronic inflammation can persist in aging humans unnoticed for years or even decades, inflicting continuous damage that can culminate later in life as organ dysfunction, physical frailty, and some of the most prominent debilitating and deadly age-associated diseases, including rheumatoid arthritis, diabetes, heart disease, and cancer. Despite the near universal acceptance of these associations, the mechanisms underlying unresolved inflammation remain poorly understood. In this study, we describe a novel inducible method to examine systemic chronic inflammation using susceptible animal models. Induced inflammation results in unresolved innate cellular responses and persistence of the same serum proinflammatory molecules used as diagnostic biomarkers and therapeutic targets for chronic inflammation in humans. Surprisingly, we found long-term persistence of an inflammation-associated neutrophil cell population constitutively producing the proinflammatory IFN-γ cytokine, which until now has only been detected transiently in acute inflammatory responses. Interestingly, these cells appear to confer T cell resistance to the otherwise potent anti-inflammatory function of myeloid-derived suppressor cells, revealing a novel mechanism for the maintenance of chronic inflammatory responses over time. This discovery represents an attractive target to resolve inflammation and prevent the inflammation-induced pathologies that are of critical concern for the well-being of the aging population. PMID:23576679

  8. Synergistic Effect of Green Tea Polyphenols and Vitamin D on Chronic Inflammation-Induced Bone Loss in Female Rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our recent study demonstrated a bone-protective role of green tea polyphenols (GTPs), extracted from green tea, in chronic inflammation-induced bone loss of female rats through reduction of inflammation and oxidative stress. This study further examines effects of GTPs in conjunction with vitamin D (...

  9. Chronic Activation of Innate Immunity Correlates With Poor Prognosis in Cancer Patients Treated With Oncolytic Adenovirus.

    PubMed

    Taipale, Kristian; Liikanen, Ilkka; Juhila, Juuso; Turkki, Riku; Tähtinen, Siri; Kankainen, Matti; Vassilev, Lotta; Ristimäki, Ari; Koski, Anniina; Kanerva, Anna; Diaconu, Iulia; Cerullo, Vincenzo; Vähä-Koskela, Markus; Oksanen, Minna; Linder, Nina; Joensuu, Timo; Lundin, Johan; Hemminki, Akseli

    2016-02-01

    Despite many clinical trials conducted with oncolytic viruses, the exact tumor-level mechanisms affecting therapeutic efficacy have not been established. Currently there are no biomarkers available that would predict the clinical outcome to any oncolytic virus. To assess the baseline immunological phenotype and find potential prognostic biomarkers, we monitored mRNA expression levels in 31 tumor biopsy or fluid samples from 27 patients treated with oncolytic adenovirus. Additionally, protein expression was studied from 19 biopsies using immunohistochemical staining. We found highly significant changes in several signaling pathways and genes associated with immune responses, such as B-cell receptor signaling (P < 0.001), granulocyte macrophage colony-stimulating factor (GM-CSF) signaling (P < 0.001), and leukocyte extravasation signaling (P < 0.001), in patients surviving a shorter time than their controls. In immunohistochemical analysis, markers CD4 and CD163 were significantly elevated (P = 0.020 and P = 0.016 respectively), in patients with shorter than expected survival. Interestingly, T-cell exhaustion marker TIM-3 was also found to be significantly upregulated (P = 0.006) in patients with poor prognosis. Collectively, these data suggest that activation of several functions of the innate immunity before treatment is associated with inferior survival in patients treated with oncolytic adenovirus. Conversely, lack of chronic innate inflammation at baseline may predict improved treatment outcome, as suggested by good overall prognosis. PMID:26310629

  10. PPARγ and the Innate Immune System Mediate the Resolution of Inflammation

    PubMed Central

    Croasdell, Amanda; Duffney, Parker F.; Kim, Nina; Lacy, Shannon H.; Sime, Patricia J.; Phipps, Richard P.

    2015-01-01

    The resolution of inflammation is an active and dynamic process, mediated in large part by the innate immune system. Resolution represents not only an increase in anti-inflammatory actions, but also a paradigm shift in immune cell function to restore homeostasis. PPARγ, a ligand activated transcription factor, has long been studied for its anti-inflammatory actions, but an emerging body of literature is investigating the role of PPARγ and its ligands (including thiazolidinediones, prostaglandins, and oleanolic acids) in all phases of resolution. PPARγ can shift production from pro- to anti-inflammatory mediators by neutrophils, platelets, and macrophages. PPARγ and its ligands further modulate platelet and neutrophil function, decreasing trafficking, promoting neutrophil apoptosis, and preventing platelet-leukocyte interactions. PPARγ alters macrophage trafficking, increases efferocytosis and phagocytosis, and promotes alternative M2 macrophage activation. There are also roles for this receptor in the adaptive immune response, particularly regarding B cells. These effects contribute towards the attenuation of multiple disease states, including COPD, colitis, Alzheimer's disease, and obesity in animal models. Finally, novel specialized proresolving mediators—eicosanoids with critical roles in resolution—may act through PPARγ modulation to promote resolution, providing another exciting area of therapeutic potential for this receptor. PMID:26713087

  11. TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis

    PubMed Central

    Schwartz, Erica S.; La, Jun-Ho; Scheff, Nicole N.; Davis, Brian M.; Albers, Kathryn M.; Gebhart, G.F.

    2013-01-01

    Visceral afferents expressing transient receptor potential channels TRPV1 and TRPA1 are thought to be required for neurogenic inflammation and development of inflammatory hyperalgesia. In a mouse model of chronic pancreatitis (CP) produced by repeated episodes (twice/wk) of caerulein-induced acute pancreatitis (AP), we studied involvement of these TRP channels in pancreatic inflammation and pain-related behaviors. Antagonists of the two TRP channels were administered at different times to block the neurogenic component of AP. Six bouts of AP (over 3 wks) increased pancreatic inflammation and pain-related behaviors, produced fibrosis, sprouting of pancreatic nerve fibers and increased TRPA1 and TRPV1 gene transcripts and a nociceptive marker, pERK, in pancreas afferent somata. Treatment with TRP antagonists, when initiated prior to week 3, decreased pancreatic inflammation and pain-related behaviors and also blocked development of histopathological changes in the pancreas and upregulation of TRPV1, TRPA1 and pERK in pancreatic afferents. Continued treatment with TRP antagonists blocked development of CP and pain behaviors even when mice were challenged with seven more weeks of twice/wk caerulein. When started after week 3, however, treatment with TRP antagonists was ineffective in blocking the transition from AP to CP and the emergence of pain behaviors. These results suggest 1) an important role for neurogenic inflammation in pancreatitis and pain-related behaviors, 2) there is transition from AP to CP, after which TRP channel antagonism is ineffective, and thus 3) that early intervention with TRP channel antagonists may effectively attenuate the transition to and development of CP. PMID:23536075

  12. The monocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation

    PubMed Central

    Maffei, Rossana; Bulgarelli, Jenny; Fiorcari, Stefania; Bertoncelli, Linda; Martinelli, Silvia; Guarnotta, Carla; Castelli, Ilaria; Deaglio, Silvia; Debbia, Giulia; De Biasi, Sara; Bonacorsi, Goretta; Zucchini, Patrizia; Narni, Franco; Tripodo, Claudio; Luppi, Mario; Cossarizza, Andrea; Marasca, Roberto

    2013-01-01

    Macrophages reside in tissues infiltrated by chronic lymphocytic leukemia B cells and the extent of infiltration is associated with adverse prognostic factors. We studied blood monocyte population by flow cytometry and whole-genome microarrays. A mixed lymphocyte reaction was performed to evaluate proliferation of T cells in contact with monocytes from patients and normal donors. Migration and gene modulation in normal monocytes cultured with CLL cells were also evaluated. The absolute number of monocytes increased in chronic lymphocytic leukemia patients compared to the number in normal controls (792±86 cells/μL versus 485±46 cells/μL, P=0.003). Higher numbers of non-classical CD14+CD16++ and Tie-2-expressing monocytes were also detected in patients. Furthermore, we performed a gene expression analysis of monocytes in chronic lymphocytic leukemia patients, showing up-regulation of RAP1GAP and down-regulation of tubulins and CDC42EP3, which would be expected to result in impairment of phagocytosis. We also detected gene alterations such as down-regulation of PTGR2, a reductase able to inactivate prostaglandin E2, indicating immunosuppressive activity. Accordingly, the proliferation of T cells in contact with monocytes from patients was inhibited compared to that of cells in contact with monocytes from normal controls. Finally, normal monocytes in vitro increased migration and up-regulated CD16, RAP1GAP, IL-10, IL-8, MMP9 and down-regulated PTGR2 in response to leukemic cells or conditioned media. In conclusion, altered composition and deregulation of genes involved in phagocytosis and inflammation were found in blood monocytes obtained from chronic lymphocytic leukemia patients, suggesting that leukemia-mediated “education” of immune elements may also include the establishment of a skewed phenotype in the monocyte/macrophage population. PMID:23349302

  13. Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway.

    PubMed

    Lucas, Kurt; Maes, Michael

    2013-08-01

    Activation of the Toll-like receptor 4 (TLR4) complex, a receptor of the innate immune system, may underpin the pathophysiology of many human diseases, including asthma, cardiovascular disorder, diabetes, obesity, metabolic syndrome, autoimmune disorders, neuroinflammatory disorders, schizophrenia, bipolar disorder, autism, clinical depression, chronic fatigue syndrome, alcohol abuse, and toluene inhalation. TLRs are pattern recognition receptors that recognize damage-associated molecular patterns and pathogen-associated molecular patterns, including lipopolysaccharide (LPS) from gram-negative bacteria. Here we focus on the environmental factors, which are known to trigger TLR4, e.g., ozone, atmosphere particulate matter, long-lived reactive oxygen intermediate, pentachlorophenol, ionizing radiation, and toluene. Activation of the TLR4 pathways may cause chronic inflammation and increased production of reactive oxygen and nitrogen species (ROS/RNS) and oxidative and nitrosative stress and therefore TLR-related diseases. This implies that drugs or substances that modify these pathways may prevent or improve the abovementioned diseases. Here we review some of the most promising drugs and agents that have the potential to attenuate TLR-mediated inflammation, e.g., anti-LPS strategies that aim to neutralize LPS (synthetic anti-LPS peptides and recombinant factor C) and TLR4/MyD88 antagonists, including eritoran, CyP, EM-163, epigallocatechin-3-gallate, 6-shogaol, cinnamon extract, N-acetylcysteine, melatonin, and molecular hydrogen. The authors posit that activation of the TLR radical (ROS/RNS) cycle is a common pathway underpinning many "civilization" disorders and that targeting the TLR radical cycle may be an effective method to treat many inflammatory disorders. PMID:23436141

  14. Eltrombopag: A Review in Paediatric Chronic Immune Thrombocytopenia.

    PubMed

    Burness, Celeste B; Keating, Gillian M; Garnock-Jones, Karly P

    2016-05-01

    Eltrombopag (Promacta(®); Revolade(®)) is an orally active thrombopoietin receptor agonist recently approved in the USA and the EU for use in paediatric patients aged ≥1 year with chronic immune thrombocytopenia (ITP) who have had an insufficient response or are refractory to other ITP treatments (e.g. corticosteroids, immunoglobulins or splenectomy). The efficacy of 7 or 13 weeks' therapy with oral eltrombopag (up to 75 mg/day) was compared with that of placebo in patients aged 1-17 years with previously treated chronic ITP in randomized, double-blind, multicentre phase II and III trials (PETIT and PETIT-2). In these trials, the platelet response rate (primary endpoint of PETIT) and the sustained platelet response rate (primary endpoint of PETIT-2) were significantly higher with eltrombopag than with placebo. A clinical benefit was shown by a reduction in the need for rescue therapy with eltrombopag versus placebo in both trials and a reduction of clinically significant bleeding in PETIT. During longer-term therapy (open-label treatment period for ≥24 weeks), eltrombopag maintained platelet counts above 50 × 10(9)/L in the majority of patients and approximately one-half of patients were able to reduce or discontinue concurrent ITP drugs. Eltrombopag was generally well tolerated. Current evidence suggests that eltrombopag is a valuable addition to the limited treatment options available for the management of chronic ITP in paediatric patients with an inadequate response to first-line therapies. PMID:27151255

  15. Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease

    SciTech Connect

    Yao Hongwei; Rahman, Irfan

    2011-07-15

    Chronic obstructive pulmonary disease (COPD) is a global health problem. The current therapies for COPD are poorly effective and the mainstays of pharmacotherapy are bronchodilators. A better understanding of the pathobiology of COPD is critical for the development of novel therapies. In the present review, we have discussed the roles of oxidative/aldehyde stress, inflammation/immunity, and chromatin remodeling in the pathogenesis of COPD. An imbalance of oxidants/antioxidants caused by cigarette smoke and other pollutants/biomass fuels plays an important role in the pathogenesis of COPD by regulating redox-sensitive transcription factors (e.g., NF-{kappa}B), autophagy and unfolded protein response leading to chronic lung inflammatory response. Cigarette smoke also activates canonical/alternative NF-{kappa}B pathways and their upstream kinases leading to sustained inflammatory response in lungs. Recently, epigenetic regulation has been shown to be critical for the development of COPD because the expression/activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in airways of COPD patients. Hence, the significant advances made in understanding the pathophysiology of COPD as described herein will identify novel therapeutic targets for intervention in COPD.

  16. Pre-neoplastic epigenetic disruption of transcriptional enhancers in chronic inflammation

    PubMed Central

    Kron, Ken J.; Bailey, Swneke D.; Roulois, David; Lupien, Mathieu; Line, Sérgio R. Peres; de Souza, Ana Paula; De Carvalho, Daniel D.

    2016-01-01

    Chronic periodontitis (CP) is a chronic inflammatory disease independently associated with higher incidence of oral cavity squamous cell carcinoma (OSCC). However, the molecular mechanism responsible for this increased incidence is unknown. Here we profiled the DNA methylome of CP patients and healthy controls and compared to a large set of OSCC samples from TCGA. We observed a significant overlap between the altered DNA methylation patterns in CP and in OSCC, suggesting an emergence of a pre-neoplastic epigenome in CP. Remarkably, the hypermethylated CpGs in CP were significantly enriched for enhancer elements. This aberrant enhancer methylation is functional and able to disrupt enhancer activity by preventing the binding of chromatin looping factors. This study provides new insights on the molecular mechanisms linking chronic inflammation and tumor predisposition, highlighting the role of epigenetic disruption of transcriptional enhancers. PMID:26908456

  17. Chronic Kidney Disease Influences Multiple Systems: Describing the Relationship between Oxidative Stress, Inflammation, Kidney Damage, and Concomitant Disease

    PubMed Central

    Tucker, Patrick S.; Scanlan, Aaron T.; Dalbo, Vincent J.

    2015-01-01

    Chronic kidney disease (CKD) is characterized by increased levels of oxidative stress and inflammation. Oxidative stress and inflammation promote renal injury via damage to molecular components of the kidney. Unfortunately, relationships between inflammation and oxidative stress are cyclical in that the inflammatory processes that exist to repair radical-mediated damage may be a source of additional free radicals, resulting in further damage to renal tissue. Oxidative stress and inflammation also have the ability to become systemic, serving to injure tissues distal to the site of original insult. This review describes select mediators in the exacerbatory relationship between oxidative stress, inflammation, and CKD. This review also discusses oxidative stress, inflammation, and CKD as they pertain to the development and progression of common CKD-associated comorbidities. Lastly, the utility of several widely accessible and cost-effective lifestyle interventions and their ability to reduce oxidative stress and inflammation are discussed and recommendations for future research are provided. PMID:25861414

  18. Modulation of Immunity and Inflammation by the Mineralocorticoid Receptor and Aldosterone

    PubMed Central

    Muñoz-Durango, N.; Vecchiola, A.; Gonzalez-Gomez, L. M.; Simon, F.; Riedel, C. A.; Fardella, C. E.; Kalergis, A. M.

    2015-01-01

    The mineralocorticoid receptor (MR) is a ligand dependent transcription factor. MR has been traditionally associated with the control of water and electrolyte homeostasis in order to keep blood pressure through aldosterone activation. However, there is growing evidence indicating that MR expression is not restricted to vascular and renal tissues, as it can be also expressed by cells of the immune system, where it responds to stimulation or antagonism, controlling immune cell function. On the other hand, aldosterone also has been associated with proinflammatory immune effects, such as the release of proinflammatory cytokines, generating oxidative stress and inducing fibrosis. The inflammatory participation of MR and aldosterone in the cardiovascular disease suggests an association with alterations in the immune system. Hypertensive patients show higher levels of proinflammatory mediators that can be modulated by MR antagonism. Although these proinflammatory properties have been observed in other autoimmune and chronic inflammatory diseases, the cellular and molecular mechanisms that mediate these effects remain unknown. Here we review and discuss the scientific work aimed at determining the immunological role of MR and aldosterone in humans, as well as animal models. PMID:26448944

  19. Inflammation in Reproductive Disorders

    PubMed Central

    Weiss, Gerson; Goldsmith, Laura T.; Taylor, Robert N.; Bellet, Dominique; Taylor, Hugh S.

    2011-01-01

    Inflammatory disorders account for a significant percentage of gynecologic disease, particularly in reproductive age women. Inflammation is a basic method by which we respond to infection, irritation, or injury. Inflammation is now recognized as a type of nonspecific immune response, either acute or chronic. In gynecology, inflammation leads to anatomic disorders primarily as a result of infectious disease; however inflammation can affect ovulation and hormone production as well as be associated with endometriosis. Similarly, immune cell trafficking is an important component of cyclic endometrial development in each menstrual cycle. These immune cells are required for endometrial function, producing a vast array of inflammatory cytokines. Inflammation alters endometrial receptivity, however it may also play a role in tissue repair and remodeling. Finally, inflammation affects the trophoblast and trophoblast—endometrial interaction. Some components of the immune response are required for optimal fertility and normal tissue remodeling. A better understanding of the necessary role of inflammation in reproduction will allow more rational and targeted treatment of inflammatory disorders in reproductive medicine. PMID:19208790

  20. Impaired Resolution of Inflammation in the Endoglin Heterozygous Mouse Model of Chronic Colitis

    PubMed Central

    Peter, Madonna R.; Sotov, Valentin; Douda, David N.; Ardelean, Daniela S.; Khan, Meraj A.; Robertson, Susan J.; Philpott, Dana J.

    2014-01-01

    Endoglin is a coreceptor of the TGF-β superfamily predominantly expressed on the vascular endothelium and selective subsets of immune cells. We previously demonstrated that Endoglin heterozygous (Eng+/−) mice subjected to dextran sulfate sodium (DSS) developed persistent gut inflammation and pathological angiogenesis. We now report that colitic Eng+/− mice have low colonic levels of active TGF-β1, which was associated with reduced expression of thrombospondin-1, an angiostatic factor known to activate TGF-β1. We also demonstrate dysregulated expression of BMPER and follistatin, which are extracellular regulators of the TGF-β superfamily that modulate angiogenesis and inflammation. Heightened colonic levels of the neutrophil chemoattractant and proangiogenic factor, CXCL1, were also observed in DSS-treated Eng+/− mice. Interestingly, despite increased macrophage and neutrophil infiltration, a gut-specific reduction in expression of the key phagocytic respiratory burst enzymes, NADPH oxidase 2 (Nox-2) and myeloperoxidase, was seen in Eng+/− mice undergoing persistent inflammation. Taken together, these findings suggest that endoglin is required for TGF-β superfamily mediated resolution of inflammation and fully functional myeloid cells. PMID:25114380

  1. Minocycline attenuates HIV-1 infection and suppresses chronic immune activation in humanized NOD/LtsZ-scidIL-2Rγnull mice

    PubMed Central

    Singh, Maneesh; Singh, Pratibha; Vaira, Dolores; Amand, Mathieu; Rahmouni, Souad; Moutschen, Michel

    2014-01-01

    More than a quarter of a century of research has established chronic immune activation and dysfunctional T cells as central features of chronic HIV infection and subsequent immunodeficiency. Consequently, the search for a new immunomodulatory therapy that could reduce immune activation and improve T-cell function has been increased. However, the lack of small animal models for in vivo HIV study has hampered progress. In the current study, we have investigated a model of cord blood haematopoietic progenitor cells (CB-HPCs) -transplanted humanized NOD/LtsZ-scidIL-2Rγnull mice in which progression of HIV infection is associated with widespread chronic immune activation and inflammation. Indeed, HIV infection in humanized NSG mice caused up-regulation of several T-cell immune activation markers such as CD38, HLA-DR, CD69 and co-receptor CCR5. T-cell exhaustion markers PD-1 and CTLA-4 were found to be significantly up-regulated on T cells. Moreover, increased plasmatic levels of lipopolysaccharide, sCD14 and interleukin-10 were also observed in infected mice. Treatment with minocycline resulted in a significant decrease of expression of cellular and plasma immune activation markers, inhibition of HIV replication and improved T-cell counts in HIV-infected humanized NSG mice. The study demonstrates that minocycline could be an effective, low-cost adjunctive treatment to regulate chronic immune activation and replication of HIV. PMID:24409837

  2. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer.

    PubMed

    Prendergast, George C; Smith, Courtney; Thomas, Sunil; Mandik-Nayak, Laura; Laury-Kleintop, Lisa; Metz, Richard; Muller, Alexander J

    2014-07-01

    Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells and myeloid-derived suppressor cells, and the promotion of tumor angiogenesis. Mechanistic investigations have defined the aryl hydrocarbon receptor, the master metabolic regulator mTORC1 and the stress kinase Gcn2 as key effector signaling elements for IDO, which also exerts a non-catalytic role in TGF-β signaling. Small-molecule inhibitors of IDO exhibit anticancer activity and cooperate with immunotherapy, radiotherapy or chemotherapy to trigger rapid regression of aggressive tumors otherwise resistant to treatment. Notably, the dramatic antitumor activity of certain targeted therapeutics such as imatinib (Gleevec) in gastrointestinal stromal tumors has been traced in part to IDO downregulation. Further, antitumor responses to immune checkpoint inhibitors can be heightened safely by a clinical lead inhibitor of the IDO pathway that relieves IDO-mediated suppression of mTORC1 in T cells. In this personal perspective on IDO as a nodal mediator of pathogenic inflammation and immune escape in cancer, we provide a conceptual foundation for the clinical development of IDO inhibitors as a novel class of immunomodulators with broad application in the treatment of advanced human cancer. PMID:24711084

  3. Indoleamine 2,3-dioxygenase pathways of pathgenic inflammation and immune escape in cancer

    PubMed Central

    Prendergast, George C.; Smith, Courtney; Thomas, Sunil; Mandik-Nayak, Laura; Laury-Kleintop, Lisa; Metz, Richard; Muller, Alexander J.

    2014-01-01

    Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells (Treg) and myeloid-derived suppressor cells (MDSC), and the promotion of tumor angiogenesis. Mechanistic investigations have defined the aryl hydrocarbon receptor AhR, the master metabolic regulator mTORC1 and the stress kinase Gcn2 as key effector signaling elements for IDO, which also exerts a non-catalytic role in TGF-β signaling. Small molecule inhibitors of IDO exhibit anticancer activity and cooperate with immunotherapy, radiotherapy or chemotherapy to trigger rapid regression of aggressive tumors otherwise resistant to treatment. Notably, the dramatic antitumor activity of certain targeted therapeutics such as imatinib (Gleevec) in GIST has been traced in part to IDO downregulation. Further, antitumor responses to immune checkpoint inhibitors can be heightened safely by a clinical lead inhibitor of the IDO pathway that relieves IDO-mediated suppression of mTORC1 in T cells. In this personal perspective on IDO as a nodal mediator of pathogenic inflammation and immune escape in cancer, we provide a conceptual foundation for the clinical development of IDO inhibitors as a novel class of immunomodulators with broad application in the treatment of advanced human cancer. PMID:24711084

  4. A20 prevents chronic liver inflammation and cancer by protecting hepatocytes from death.

    PubMed

    Catrysse, L; Farhang Ghahremani, M; Vereecke, L; Youssef, S A; Mc Guire, C; Sze, M; Weber, A; Heikenwalder, M; de Bruin, A; Beyaert, R; van Loo, G

    2016-01-01

    An important regulator of inflammatory signalling is the ubiquitin-editing protein A20 that acts as a break on nuclear factor-κB (NF-κB) activation, but also exerts important cytoprotective functions. A20 knockout mice are cachectic and die prematurely due to excessive multi-organ inflammation. To establish the importance of A20 in liver homeostasis and pathology, we developed a novel mouse line lacking A20 specifically in liver parenchymal cells. These mice spontaneously develop chronic liver inflammation but no fibrosis or hepatocellular carcinomas, illustrating an important role for A20 in normal liver tissue homeostasis. Hepatocyte-specific A20 knockout mice show sustained NF-κB-dependent gene expression in the liver upon tumor necrosis factor (TNF) or lipopolysaccharide injection, as well as hepatocyte apoptosis and lethality upon challenge with sublethal doses of TNF, demonstrating an essential role for A20 in the protection of mice against acute liver failure. Finally, chronic liver inflammation and enhanced hepatocyte apoptosis in hepatocyte-specific A20 knockout mice was associated with increased susceptibility to chemically or high fat-diet-induced hepatocellular carcinoma development. Together, these studies establish A20 as a crucial hepatoprotective factor. PMID:27253414

  5. Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

    PubMed Central

    2014-01-01

    Activation of nuclear factor-kappa B (NF- κB) as a mechanism of host defense against infection and stress is the central mediator of inflammatory responses. A normal (acute) inflammatory response is activated on urgent basis and is auto-regulated. Chronic inflammation that results due to failure in the regulatory mechanism, however, is largely considered as a critical determinant in the initiation and progression of various forms of cancer. Mechanistically, NF- κB favors this process by inducing various genes responsible for cell survival, proliferation, migration, invasion while at the same time antagonizing growth regulators including tumor suppressor p53. It has been shown by various independent investigations that a down regulation of NF- κB activity directly, or indirectly through the activation of the p53 pathway reduces tumor growth substantially. Therefore, there is a huge effort driven by many laboratories to understand the NF- κB signaling pathways to intervene the function of this crucial player in inflammation and tumorigenesis in order to find an effective inhibitor directly, or through the p53 tumor suppressor. We discuss here on the role of NF- κB in chronic inflammation and cancer, highlighting mutual antagonism between NF- κB and p53 pathways in the process. We also discuss prospective pharmacological modulators of these two pathways, including those that were already tested to affect this mutual antagonism. PMID:25152696

  6. Inhibitory effect of atractylenolide I on angiogenesis in chronic inflammation in vivo and in vitro.

    PubMed

    Wang, Changhe; Duan, Haijie; He, Langchong

    2009-06-10

    Angiogenesis is involved in the pathology of chronic inflammatory diseases. Application of anti-angiogenic strategies is beneficial in the treatment of inflammatory disorders. Atractylenolide I is an anti-inflammation agent. To further investigate the anti-angiogenesis mechanism of atractylenolide I in cell and mice based on inflammation model, the vascular index and microvessel outgrowth were measured by using the Freunds complete adjuvant (FCA) induced mouse air pouch model as well as the mice aortic ring co-cultured with peritoneal macrophages model. The ID(50) values of atractylenolide I were 15.15 mg/kg and 3.89 microg/ml for inhibiting the vascular index in vivo and microvessel outgrowth in vitro, respectively. Atractylenolide I could dose-dependently inhibit the production of nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) activity in the flute of mouse air pouch and the peritoneal macrophages stimulated by lipopolysaccharide (LPS). Atractylenolide I displayed a potent inhibitory effect on angiogenesis by a set of down-regulatory actions of NO, TNF-alpha, IL-1beta, IL-6, VEGF and PlGF in chronic inflammation. PMID:19356732

  7. Effects of kramecyne on LPS induced chronic inflammation and gastric ulcers.

    PubMed

    Alonso-Castro, Angel Josabad; Pérez-Ramos, Julia; Sánchez-Mendoza, Ernesto; Pérez-González, Cuauhtemoc; Pérez-Gutiérrez, Salud

    2015-06-01

    Preclinical Research Krameria cytisoides is used for the treatment of inflammation, stomach pain, and gastric ulcers. The active ingredient from this plant is a peroxide, kramecyne (KACY) which has anti-inflammatory effects. The aim of the present study was to evaluate the anti-inflammatory activities of KACY in lipopolysaccharide (LPS)-induced systemic chronic inflammation in mice for 60 days, using dexamethasone (DEX) as the positive control, vehicle (the LPS group) as the negative control and the control group (mice without inflammation). KACY did not affect survival, body weight or relative organ weight in mice but it: decreased nitric oxide (NO) production by 68%; prostaglandin E2 (PGE2 ) by 67%; increased release of anti-inflammatory cytokine IL-10 (2.0-fold), and reduced production of the proinflammatory cytokines, IL-6 (2.0-fold), IL-1β (2.4-fold), and TNF-α (2.0-fold). Furthermore, the gastroprotective effects of KACY in mice were evaluated in an ethanol-induced gastric ulcer model. The results showed that KACY at 50 and 100 mg/kg exerted gastroprotective effects with similar activity to 50 mg/kg ranitidine. In gastric tissues, KACY decreased the level of malondialdehyde (MDA) but increased the catalase (CAT) activity. KACY have potential for the treatment of chronic inflammatory diseases due its similar activity to that of DEX. It also has gastroprotective effects. PMID:26109468

  8. Bacillus-produced surfactin attenuates chronic inflammation in atherosclerotic lesions of ApoE(-/-) mice.

    PubMed

    Gan, Ping; Jin, Dong; Zhao, Xiuyun; Gao, Zhenqiu; Wang, Shengying; Du, Peng; Qi, Gaofu

    2016-06-01

    Bacillus-produced surfactin can inhibit acute inflammation in vitro and in vivo. However, there is no report whether surfactin could inhibit chronic inflammation in the atherosclerotic lesions. Apoliprotein E deficient (ApoE(-/-)) mice (fed on atherogenic diet) were intragastrically administered with surfactin for 9 doses, then the athero-protective effect of surfactin was determined in vivo. The results showed surfactin could induce anti-inflammatory factors such as IgA, transforming growth factor (TGF)-β and interleukin (IL)-10 in the intestine. Further investigation discovered that surfactin also systemically induced CD4(+)CD25(+)FoxP3(+) Tregs in spleen, which could inhibit T cells to produce pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon (IFN)-γ. The IgG subclass pattern with high titer of IgG1 (Th2-type) but low titer of IgG2a (Th1-type) was also found in the surfactin-treated mice. As a result, the attenuation of chronic inflammation was observed in the surfactin-treated groups accompanying with less TNF-α but more IL-10 in the atherosclerotic lesions. Moreover, surfactin could reduce serum total cholesterol and cholesterol in low-density lipoprotein, and increase serum cholesterol in high-density lipoprotein in mice. Collectively, surfactin could significantly attenuate atherosclerotic lesions on the aorta by restoration of the delicate balance of Th1/Th2 response in mice. PMID:27082998

  9. Leptin, adipocytes and breast cancer: Focus on inflammation and anti-tumor immunity.

    PubMed

    Delort, Laetitia; Rossary, Adrien; Farges, Marie-Chantal; Vasson, Marie-Paule; Caldefie-Chézet, Florence

    2015-11-01

    More than one million new cases of breast cancer are diagnosed worldwide each year and more than 400,000 deaths are caused by the disease. The origin of this pathology is multifactorial and involved genetic, hormonal, environmental and nutritional factors including obesity in postmenopausal women. The role played by the adipose tissue and their secretions, ie adipokines, is beginning to be recognized. Plasma adipokine levels, which are modulated during obesity, could have “remote” effects on mammary carcinogenesis. Breast cancer cells are surrounded and locally influenced by an adipocyte microenvironment, which is probably more extensive in obese people. Hence, leptin appears to be strongly involved in mammary carcinogenesis and may contribute to the local pro-inflammatory mechanisms, especially in obese patients, who have increased metastatic potential and greater risk of mortality. This review presents the multifaceted role of leptin in breast cancer development and the different molecular pathways involved such as inflammation, oxidative stress and antitumor immunity. PMID:25957709

  10. Inhibitors of apoptosis (IAPs) regulate intestinal immunity and inflammatory bowel disease (IBD) inflammation.

    PubMed

    Pedersen, Jannie; LaCasse, Eric C; Seidelin, Jakob B; Coskun, Mehmet; Nielsen, Ole H

    2014-11-01

    The inhibitor of apoptosis (IAP) family members, notably cIAP1, cIAP2, and XIAP, are critical and universal regulators of tumor necrosis factor (TNF) mediated survival, inflammatory, and death signaling pathways. Furthermore, IAPs mediate the signaling of nucleotide-binding oligomerization domain (NOD)1/NOD2 and other intracellular NOD-like receptors in response to bacterial pathogens. These pathways are important to the pathogenesis and treatment of inflammatory bowel disease (IBD). Inactivating mutations in the X-chromosome-linked IAP (XIAP) gene causes an immunodeficiency syndrome, X-linked lymphoproliferative disease type 2 (XLP2), in which 20% of patients develop severe intestinal inflammation. In addition, 4% of males with early-onset IBD also have inactivating mutations in XIAP. Therefore, the IAPs play a greater role in gut homeostasis, immunity and IBD development than previously suspected, and may have therapeutic potential. PMID:25282548

  11. Androgen receptor and immune inflammation in benign prostatic hyperplasia and prostate cancer

    PubMed Central

    Izumi, Kouji; Li, Lei; Chang, Chawnshang

    2014-01-01

    Both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are frequent diseases in middle-aged to elderly men worldwide. While both diseases are linked to abnormal growth of the prostate, the epidemiological and pathological features of these two prostate diseases are different. BPH nodules typically arise from the transitional zone, and, in contrast, PCa arises from the peripheral zone. Androgen deprivation therapy alone may not be sufficient to cure these two prostatic diseases due to its undesirable side effects. The alteration of androgen receptor-mediated inflammatory signals from infiltrating immune cells and prostate stromal/epithelial cells may play key roles in those unwanted events. Herein, this review will focus on the roles of androgen/androgen receptor signals in the inflammation-induced progression of BPH and PCa. PMID:26594314

  12. Sexual Orientation and Gender Differences in Markers of Inflammation and Immune Functioning

    PubMed Central

    Everett, Bethany G.; Rosario, Margaret; McLaughlin, Katie A.; Austin, S. Bryn

    2014-01-01

    Background Sexual minorities have documented elevated risk factors that can lead to inflammation and poor immune functioning Purpose Investigate disparities in C-Reactive protein and Epstein Barr Virus by gender and sexual orientation. Methods We used the National Longitudinal Study of Adolescent Health to examine disparities in CRP (N=11,462) and EBV (N=11,812). Results Among heterosexuals, women had higher levels of CRP and EBV than men. However, sexual-minority men had higher levels of CRP and EBV than heterosexual men and sexual minority women. Lesbians had lower levels of CRP than heterosexual women. Conclusions Gender differences in CRP and EBV found between men and women who identify as 100% heterosexual were reversed among sexual minorities and not explained by known risk factors (e.g. victimization, alcohol and tobacco use, BMI). More nuanced approaches to addressing gender differences in sexual orientation health disparities that include measures of gender nonconformity and minority stress are needed. PMID:24347405

  13. Arginase inhibition prevents inflammation and remodeling in a guinea pig model of chronic obstructive pulmonary disease.

    PubMed

    Pera, T; Zuidhof, A B; Smit, M; Menzen, M H; Klein, T; Flik, G; Zaagsma, J; Meurs, H; Maarsingh, H

    2014-05-01

    Airway inflammation and remodeling are major features of chronic obstructive pulmonary disease (COPD), whereas pulmonary hypertension is a common comorbidity associated with a poor disease prognosis. Recent studies in animal models have indicated that increased arginase activity contributes to features of asthma, including allergen-induced airway eosinophilia and mucus hypersecretion. Although cigarette smoke and lipopolysaccharide (LPS), major risk factors for COPD, may increase arginase expression, the role of arginase in COPD is unknown. This study aimed to investigate the role of arginase in pulmonary inflammation and remodeling using an animal model of COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pretreated by inhalation of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) or vehicle. Repeated LPS exposure increased lung arginase activity, resulting in increased l-ornithine/l-arginine and l-ornithine/l-citrulline ratios. Both ratios were reversed by ABH. ABH inhibited the LPS-induced increases in pulmonary IL-8, neutrophils, and goblet cells as well as airway fibrosis. Remarkably, LPS-induced right ventricular hypertrophy, indicative of pulmonary hypertension, was prevented by ABH. Strong correlations were found between arginase activity and inflammation, airway remodeling, and right ventricular hypertrophy. Increased arginase activity contributes to pulmonary inflammation, airway remodeling, and right ventricular hypertrophy in a guinea pig model of COPD, indicating therapeutic potential for arginase inhibitors in this disease. PMID:24563530

  14. Mechanical Stress as the Common Denominator between Chronic Inflammation, Cancer, and Alzheimer’s Disease

    PubMed Central

    Levy Nogueira, Marcel; da Veiga Moreira, Jorgelindo; Baronzio, Gian Franco; Dubois, Bruno; Steyaert, Jean-Marc; Schwartz, Laurent

    2015-01-01

    The pathogenesis of common diseases, such as Alzheimer’s disease (AD) and cancer, are currently poorly understood. Inflammation is a common risk factor for cancer and AD. Recent data, provided by our group and from others, demonstrate that increased pressure and inflammation are synonymous. There is a continuous increase in pressure from inflammation to fibrosis and then cancer. This is in line with the numerous papers reporting high interstitial pressure in cancer. But most authors focus on the role of pressure in the lack of delivery of chemotherapy in the center of the tumor. Pressure may also be a key factor in carcinogenesis. Increased pressure is responsible for oncogene activation and cytokine secretion. Accumulation of mechanical stress plays a key role in the development of diseases of old age, such as cardiomyopathy, atherosclerosis, and osteoarthritis. Growing evidence suggest also a possible link between mechanical stress in the pathogenesis of AD. The aim of this review is to describe environmental and endogenous mechanical factors possibly playing a pivotal role in the mechanism of chronic inflammation, AD, and cancer. PMID:26442209

  15. Breast implant (PIP), chronic inflammation and cancer: is there a connection? Case report.

    PubMed

    Gubitosi, Adelmo; Docimo, Giovanni; Ruggiero, Roberto; Esposito, Alessandro; Esposito, Emanuela; Foroni, Fabrizio

    2012-01-01

    The "PIP problem", in the field of the breast augmentation, represents today a surgical epidemiological emergency. The massive media coverage produced a kind of mass fear and many women are asking for explantations. A 47 y.o. female, breasts implanted with PIP devices for breast augmentation in 1998, came to our clinic asking for explantation and excisional biopsy of a 2.5 cm nodule adjacent to the upper side of the breast implant capsule. The outcome of the pathologic examination of the excised nodule was: ductal infiltrating carcinoma of the breast, medium degree of differentiation. After 7 days from the first operation the patient underwent a skin-sparing mastectomy with axillary limphadenectomy and immediate reconstruction by a submuscular placement of implant. The surgical specimen sent for pathologic examination revealed: "granulomatous inflammation by giant cells around extraneous material, lymph nodes, negative for cancer, showed extensive accumulation of foamy macrofages containing extraneous material". The findings of foreign material in granulomas and macrophages that are the primary inflammation body defense, suggest that the chronic inflammation, coming from mammary implants subject to leakage or/and osmotic shift, increase the risk of breast cancer. We therefore suggest improving the explantation/replacement of old implants. KEY WORDS: Breast cancer, Extraneous material, Immediate breast reconstruction, Inflammation, Pip Implant. PMID:23075481

  16. Resolving the Conundrum of Islet Transplantation by Linking Metabolic Dysregulation, Inflammation, and Immune Regulation

    PubMed Central

    Huang, Xiaolun; Moore, Daniel J.; Ketchum, Robert J.; Nunemaker, Craig S.; Kovatchev, Boris; McCall, Anthony L.; Brayman, Kenneth L.

    2008-01-01

    Although type 1 diabetes cannot be prevented or reversed, replacement of insulin production by transplantation of the pancreas or pancreatic islets represents a definitive solution. At present, transplantation can restore euglycemia, but this restoration is short-lived, requires islets from multiple donors, and necessitates lifelong immunosuppression. An emerging paradigm in transplantation and autoimmunity indicates that systemic inflammation contributes to tissue injury while disrupting immune tolerance. We identify multiple barriers to successful islet transplantation, each of which either contributes to the inflammatory state or is augmented by it. To optimize islet transplantation for diabetes reversal, we suggest that targeting these interacting barriers and the accompanying inflammation may represent an improved approach to achieve successful clinical islet transplantation by enhancing islet survival, regeneration or neogenesis potential, and tolerance induction. Overall, we consider the proinflammatory effects of important technical, immunological, and metabolic barriers including: 1) islet isolation and transplantation, including selection of implantation site; 2) recurrent autoimmunity, alloimmune rejection, and unique features of the autoimmune-prone immune system; and 3) the deranged metabolism of the islet transplant recipient. Consideration of these themes reveals that each is interrelated to and exacerbated by the other and that this connection is mediated by a systemic inflammatory state. This inflammatory state may form the central barrier to successful islet transplantation. Overall, there remains substantial promise in islet transplantation with several avenues of ongoing promising research. This review focuses on interactions between the technical, immunological, and metabolic barriers that must be overcome to optimize the success of this important therapeutic approach. PMID:18664617

  17. Regulation of apoptosis and innate immune stimuli in inflammation-induced preterm labor.

    PubMed

    Jaiswal, Mukesh K; Agrawal, Varkha; Mallers, Timothy; Gilman-Sachs, Alice; Hirsch, Emmet; Beaman, Kenneth D

    2013-12-01

    An innate immune response is required for successful implantation and placentation. This is regulated, in part, by the a2 isoform of V-ATPase (a2V) and the concurrent infiltration of M1 (inflammatory) and M2 (anti-inflammatory) macrophages to the uterus and placenta. The objective of the present study was to identify the role of a2V during inflammation-induced preterm labor in mice and its relationship to the regulation of apoptosis and innate immune responses. Using a mouse model of infection-induced preterm delivery, gestational tissues were collected 8 h after intrauterine inoculation on day 14.5 of pregnancy with either saline or peptidoglycan (PGN; a TLR 2 agonist) and polyinosinic-polycytidylic acid [poly(I:C); a TLR3 agonist], modeling Gram-positive bacterial and viral infections, respectively. Expression of a2V decreased significantly in the placenta, uterus, and fetal membranes during PGN+poly(I:C)-induced preterm labor. Expression of inducible NO synthase was significantly upregulated in PGN+poly(I:C)-treated placenta and uterus. PGN+poly(I:C) treatment disturbed adherens junction proteins and increased apoptotic cell death via an extrinsic pathway of apoptosis among uterine decidual cells and spongiotrophoblasts. F4/80(+) macrophages were increased and polarization was skewed in PGN+poly(I:C)-treated uterus toward double-positive CD11c(+) (M1) and CD206(+) (M2) cells, which are critical for the clearance of dying cells and rapid resolution of inflammation. Expression of Nlrp3 and activation of caspase-1 were increased in PGN+poly(I:C)-treated uterus, which could induce pyroptosis. These results suggest that the double hit of PGN+poly(I:C) induces preterm labor via reduction of a2V expression and simultaneous activation of apoptosis and inflammatory processes. PMID:24163412

  18. Analysis of local chronic inflammatory cell infiltrate combined with systemic inflammation improves prognostication in stage II colon cancer independent of standard clinicopathologic criteria.

    PubMed

    Turner, Natalie; Wong, Hui-Li; Templeton, Arnoud; Tripathy, Sagarika; Whiti Rogers, Te; Croxford, Matthew; Jones, Ian; Sinnathamby, Mathuranthakan; Desai, Jayesh; Tie, Jeanne; Bae, Susie; Christie, Michael; Gibbs, Peter; Tran, Ben

    2016-02-01

    In Stage II colon cancer, multiple independent studies have shown that a dense intratumoural immune infiltrate (local inflammation) is associated with improved outcomes, while systemic inflammation, measured by various markers, has been associated with poorer outcomes. However, previous studies have not considered the interaction between local and systemic inflammation, nor have they assessed the type of inflammatory response compared with standard clinicopathologic criteria. In order to evaluate the potential clinical utility of inflammatory markers in Stage II colon cancer, we examined local and systemic inflammation in a consecutive series of patients with resected Stage II colon cancer between 2000 and 2010 who were identified from a prospective clinical database. Increased intratumoural chronic inflammatory cell (CIC) density, as assessed by pathologist review of hematoxylin and eosin stained slides, was used to represent local inflammation. Neutrophil-to-lymphocyte ratio (NLR) >5, as calculated from pre-operative full blood counts, was used to represent systemic inflammation. In 396 eligible patients identified, there was a non-significant inverse relationship between local and systemic inflammation. Increased CIC density was significantly associated with improved overall (HR 0.45, p = 0.001) and recurrence-free survival (HR 0.37, p = 0.003). High NLR was significantly associated with poorer overall survival (HR 2.56, p < 0.001). The combination of these markers further stratified prognosis independent of standard high-risk criteria, with a dominant systemic inflammatory response (low CIC/high NLR) associated with the worst outcome (5-year overall survival 55.8%). With further validation this simple, inexpensive combined inflammatory biomarker might assist in patient selection for adjuvant chemotherapy in Stage II colon cancer. PMID:26270488

  19. Frontline Science: Splenic progenitors aid in maintaining high neutrophil numbers at sites of sterile chronic inflammation.

    PubMed

    Jhunjhunwala, Siddharth; Alvarez, David; Aresta-DaSilva, Stephanie; Tang, Katherine; Tang, Benjamin C; Greiner, Dale L; Newburger, Peter E; von Andrian, Ulrich H; Langer, Robert; Anderson, Daniel G

    2016-08-01

    Neutrophils are constantly generated from hematopoietic stem and progenitor cells in the bone marrow to maintain high numbers in circulation. A considerable number of neutrophils and their progenitors have been shown to be present in the spleen too; however, their exact role in this organ remains unclear. Herein, we sought to study the function of splenic neutrophils and their progenitors using a mouse model for sterile, peritoneal inflammation. In this microcapsule device implantation model, we show chronic neutrophil presence at implant sites, with recruitment from circulation as the primary mechanism for their prevalence in the peritoneal exudate. Furthermore, we demonstrate that progenitor populations in the spleen play a key role in maintaining elevated neutrophil numbers. Our results provide new insight into the role for splenic neutrophils and their progenitors and establish a model to study neutrophil function during sterile inflammation. PMID:26965635

  20. Roles of Chronic Low-Grade Inflammation in the Development of Ectopic Fat Deposition

    PubMed Central

    Mei, Mei; Yang, Shumin; Li, Qifu

    2014-01-01

    Pattern of fat distribution is a major determinant for metabolic homeostasis. As a depot of energy, the storage of triglycerides in adipose tissue contributes to the normal fat distribution. Decreased capacity of fat storage in adipose tissue may result in ectopic fat deposition in nonadipose tissues such as liver, pancreas, and kidney. As a critical biomarker of metabolic complications, chronic low-grade inflammation may have the ability to affect the process of lipid accumulation and further lead to the disorder of fat distribution. In this review, we have collected the evidence linking inflammation with ectopic fat deposition to get a better understanding of the underlying mechanism, which may provide us with novel therapeutic strategies for metabolic disorders. PMID:25143667

  1. Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease.

    PubMed

    Mafra, Denise; Lobo, Julie C; Barros, Amanda F; Koppe, Laetitia; Vaziri, Nosratola D; Fouque, Denis

    2014-01-01

    The normal intestinal microbiota plays a major role in the maintenance of health and disease prevention. In fact, the alteration of the intestinal microbiota has been shown to contribute to the pathogenesis of several pathological conditions, including obesity and insulin resistance, among others. Recent studies have revealed profound alterations of the gut microbial flora in patients and animals with chronic kidney disease (CKD). Alterations in the composition of the microbiome in CKD may contribute to the systemic inflammation and accumulation of gut-derived uremic toxins, which play a central role in the pathogenesis of accelerated cardiovascular disease and numerous other CKD-associated complications. This review is intended to provide a concise description of the potential role of the CKD-associated changes in the gut microbiome and its potential role the pathogenesis of inflammation and uremic toxicity. In addition, the potential efficacy of pre- and pro-biotics in the restoration of the microbiome is briefly described. PMID:24762311

  2. Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels

    PubMed Central

    Li, Changfei; Deng, Mengmeng; Hu, Jun; Li, Xin; Chen, Lizhao; Ju, Ying; Hao, Junli; Meng, Songdong

    2016-01-01

    Persistent inflammation in chronic hepatitis plays a major role in the development of hepatocellular carcinoma (HCC). In this study, the major inflammatory cytokines expressed in chronic hepatitis, IL-6 and TNF-α, induced a marked decrease in microRNA-122 (miR-122) levels, and miR-122 expression was downregulated in the livers of chronic hepatitis B (CHB) patients. The decrease of miR-122 caused upregulation of the proinflammatory chemokine CCL2. IL-6 and TNF-α suppressed miR-122 both by directly downregulating the transcription factor C/EBPα and indirectly upregulating c-myc, which blocks C/EBPα-mediated miR-122 transcription. In addition, IL-6 and TNF-α levels were elevated and miR-122 levels were decreased in mouse and rat models of diethylnitrosamine (DEN)-induced HCC. Restoration of miR-122 levels through delivery of agomir-122 suppressed DEN-induced hepatocarcinogenesis in mice. Our results show that inflammation-induced miR-122 downregulation in hepatitis contributes to carcinogenesis and suggest that increasing miR-122 may be an effective strategy for preventing HCC development in CHB patients. PMID:26933995

  3. Helicobacter pylori chronic infection and mucosal inflammation switches the human gastric glycosylation pathways

    PubMed Central

    Magalhães, Ana; Marcos-Pinto, Ricardo; Nairn, Alison V.; Rosa, Mitche dela; Ferreira, Rui M.; Junqueira-Neto, Susana; Freitas, Daniela; Gomes, Joana; Oliveira, Patrícia; Santos, Marta R.; Marcos, Nuno T.; Xiaogang, Wen; Figueiredo, Céu; Oliveira, Carla; Dinis-Ribeiro, Mário; Carneiro, Fátima; Moremen, Kelley W.; David, Leonor; Reis, Celso A.

    2015-01-01

    Helicobacter pylori exploits host glycoconjugates to colonize the gastric niche. Infection can persist for decades promoting chronic inflammation, and in a subset of individuals lesions can silently progress to cancer. This study shows that H. pylori chronic infection and gastric tissue inflammation result in a remodeling of the gastric glycophenotype with increased expression of sialyl-Lewis a/x antigens due to transcriptional up-regulation of the B3GNT5, B3GALT5, and FUT3 genes. We observed that H. pylori infected individuals present a marked gastric local proinflammatory signature with significantly higher TNF-α levels and demonstrated that TNF-induced activation of the NF-kappaB pathway results in B3GNT5 transcriptional up-regulation. Furthermore, we show that this gastric glycosylation shift, characterized by increased sialylation patterns, favors SabA-mediated H. pylori attachment to human inflamed gastric mucosa. This study provides novel clinically relevant insights into the regulatory mechanisms underlying H. pylori modulation of host glycosylation machinery, and phenotypic alterations crucial for life-long infection. Moreover, the biosynthetic pathways here identified as responsible for gastric mucosa increased sialylation, in response to H. pylori infection, can be exploited as drug targets for hindering bacteria adhesion and counteract the infection chronicity. PMID:26144047

  4. Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

    PubMed Central

    Fedeles, Bogdan I.; Freudenthal, Bret D.; Yau, Emily; Singh, Vipender; Chang, Shiou-chi; Li, Deyu; Delaney, James C.; Wilson, Samuel H.; Essigmann, John M.

    2015-01-01

    During chronic inflammation, neutrophil-secreted hypochlorous acid can damage nearby cells inducing the genomic accumulation of 5-chlorocytosine (5ClC), a known inflammation biomarker. Although 5ClC has been shown to promote epigenetic changes, it has been unknown heretofore if 5ClC directly perpetrates a mutagenic outcome within the cell. The present work shows that 5ClC is intrinsically mutagenic, both in vitro and, at a level of a single molecule per cell, in vivo. Using biochemical and genetic approaches, we have quantified the mutagenic and toxic properties of 5ClC, showing that this lesion caused C→T transitions at frequencies ranging from 3–9% depending on the polymerase traversing the lesion. X-ray crystallographic studies provided a molecular basis for the mutagenicity of 5ClC; a snapshot of human polymerase β replicating across a primed 5ClC-containing template uncovered 5ClC engaged in a nascent base pair with an incoming dATP analog. Accommodation of the chlorine substituent in the template major groove enabled a unique interaction between 5ClC and the incoming dATP, which would facilitate mutagenic lesion bypass. The type of mutation induced by 5ClC, the C→T transition, has been previously shown to occur in substantial amounts both in tissues under inflammatory stress and in the genomes of many inflammation-associated cancers. In fact, many sequence-specific mutational signatures uncovered in sequenced cancer genomes feature C→T mutations. Therefore, the mutagenic ability of 5ClC documented in the present study may constitute a direct functional link between chronic inflammation and the genetic changes that enable and promote malignant transformation. PMID:26243878

  5. Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer.

    PubMed

    Fedeles, Bogdan I; Freudenthal, Bret D; Yau, Emily; Singh, Vipender; Chang, Shiou-chi; Li, Deyu; Delaney, James C; Wilson, Samuel H; Essigmann, John M

    2015-08-18

    During chronic inflammation, neutrophil-secreted hypochlorous acid can damage nearby cells inducing the genomic accumulation of 5-chlorocytosine (5ClC), a known inflammation biomarker. Although 5ClC has been shown to promote epigenetic changes, it has been unknown heretofore if 5ClC directly perpetrates a mutagenic outcome within the cell. The present work shows that 5ClC is intrinsically mutagenic, both in vitro and, at a level of a single molecule per cell, in vivo. Using biochemical and genetic approaches, we have quantified the mutagenic and toxic properties of 5ClC, showing that this lesion caused C→T transitions at frequencies ranging from 3-9% depending on the polymerase traversing the lesion. X-ray crystallographic studies provided a molecular basis for the mutagenicity of 5ClC; a snapshot of human polymerase β replicating across a primed 5ClC-containing template uncovered 5ClC engaged in a nascent base pair with an incoming dATP analog. Accommodation of the chlorine substituent in the template major groove enabled a unique interaction between 5ClC and the incoming dATP, which would facilitate mutagenic lesion bypass. The type of mutation induced by 5ClC, the C→T transition, has been previously shown to occur in substantial amounts both in tissues under inflammatory stress and in the genomes of many inflammation-associated cancers. In fact, many sequence-specific mutational signatures uncovered in sequenced cancer genomes feature C→T mutations. Therefore, the mutagenic ability of 5ClC documented in the present study may constitute a direct functional link between chronic inflammation and the genetic changes that enable and promote malignant transformation. PMID:26243878

  6. The role of airway epithelial cells and innate immune cells in chronic respiratory disease

    PubMed Central

    Holtzman, Michael J.; Byers, Derek E.; Alexander-Brett, Jennifer; Wang, Xinyu

    2016-01-01

    An abnormal immune response to environmental agents is generally thought to be responsible for causing chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Based on studies of experimental models and human subjects, there is increasing evidence that the response of the innate immune system is crucial for the development of this type of airway disease. Airway epithelial cells and innate immune cells represent key components of the pathogenesis of chronic airway disease and are emerging targets for new therapies. In this Review, we summarize the innate immune mechanisms by which airway epithelial cells and innate immune cells regulate the development of chronic respiratory diseases. We also explain how these pathways are being targeted in the clinic to treat patients with these diseases. PMID:25234144

  7. Chronic unpredictable mild stress generates oxidative stress and systemic inflammation in rats.

    PubMed

    López-López, Ana Laura; Jaime, Herlinda Bonilla; Escobar Villanueva, María Del Carmen; Padilla, Malinalli Brianza; Palacios, Gonzalo Vázquez; Aguilar, Francisco Javier Alarcón

    2016-07-01

    Stress is considered to be a causal agent of chronic degenerative diseases, such as cardiovascular disease, diabetes mellitus, arthritis and Alzheimer's. Chronic glucocorticoid and catecholamine release into the circulation during the stress response has been suggested to activate damage mechanisms, which in the long term produce metabolic alterations associated with oxidative stress and inflammation. However, the consequences of stress in animal models for periods longer than 40days have not been explored. The goal of this work was to determine whether chronic unpredictable mild stress (CUMS) produced alterations in the redox state and the inflammatory profile of rats after 20, 40, and 60days. CUMS consisted of random exposure of the animals to different stressors. The following activities were measured in the liver and pancreas: reduced glutathione (GSH), lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC), and protein oxidation. Similarly, serum cytokine levels (IL-6, TNF-α, IL-1β, and IL-10) were determined. CUMS activated the stress response from day 20 until day 60. In the liver and pancreas, GHS levels were decreased from day 40, whereas protein lipid peroxidation and protein oxidation were increased. This is the first work to report that the pancreas redox state is subject to chronic stress conditions. The TAC was constant in the liver and reduced in the pancreas. An increase in the TNF-α, IL-1β, and IL-6 inflammatory markers and a decrease in the IL-10 level due to CUMS was shown, thereby resulting in the generation of a systemic inflammation state after 60days of treatment. Together, the CUMS consequences on day 60 suggest that both processes can contribute to the development of chronic degenerative diseases, such as cardiovascular disease and diabetes mellitus. CUMS is an animal model that in addition to avoiding habituation activates damage mechanisms such as oxidative stress and low-grade chronic

  8. Regulation of NO Synthesis, Local Inflammation, and Innate Immunity to Pathogens by BET Family Proteins

    PubMed Central

    Wienerroither, Sebastian; Rauch, Isabella; Rosebrock, Felix; Jamieson, Amanda M.; Bradner, James; Muhar, Matthias; Zuber, Johannes; Müller, Mathias

    2014-01-01

    Transcriptional activation of the Nos2 gene, encoding inducible nitric oxide synthase (iNOS), during infection or inflammation requires coordinate assembly of an initiation complex by the transcription factors NF-κB and type I interferon-activated ISGF3. Here we show that infection of macrophages with the intracellular bacterial pathogen Listeria monocytogenes caused binding of the BET proteins Brd2, Brd3, and, most prominently, Brd4 to the Nos2 promoter and that a profound reduction of Nos2 expression occurred in the presence of the BET inhibitor JQ1. RNA polymerase activity at the Nos2 gene was regulated through Brd-mediated C-terminal domain (CTD) phosphorylation at serine 5. Underscoring the critical importance of Brd for the regulation of immune responses, application of JQ1 reduced NO production in mice infected with L. monocytogenes, as well as innate resistance to L. monocytogenes and influenza virus. In a murine model of inflammatory disease, JQ1 treatment increased the colitogenic activity of dextran sodium sulfate (DSS). The data presented in our study suggest that BET protein inhibition in a clinical setting poses the risk of altering the innate immune response to infectious or inflammatory challenge. PMID:24248598

  9. Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment

    PubMed Central

    Beck, Kevin D.; Nguyen, Hal X.; Galvan, Manuel D.; Salazar, Desirée L.; Woodruff, Trent M.

    2010-01-01

    Traumatic injury to the central nervous system results in the disruption of the blood brain/spinal barrier, followed by the invasion of cells and other components of the immune system that can aggravate injury and affect subsequent repair and regeneration. Although studies of chronic neuroinflammation in the injured spinal cord of animals are clinically relevant to most patients living with traumatic injury to the brain or spinal cord, very little is known about chronic neuroinflammation, though several studies have tested the role of neuroinflammation in the acute period after injury. The present study characterizes a novel cell preparation method that assesses, quickly and effectively, the changes in the principal immune cell types by flow cytometry in the injured spinal cord, daily for the first 10 days and periodically up to 180 days after spinal cord injury. These data quantitatively demonstrate a novel time-dependent multiphasic response of cellular inflammation in the spinal cord after spinal cord injury and are verified by quantitative stereology of immunolabelled spinal cord sections at selected time points. The early phase of cellular inflammation is comprised principally of neutrophils (peaking 1 day post-injury), macrophages/microglia (peaking 7 days post-injury) and T cells (peaking 9 days post-injury). The late phase of cellular inflammation was detected after 14 days post-injury, peaked after 60 days post-injury and remained detectable throughout 180 days post-injury for all three cell types. Furthermore, the late phase of cellular inflammation (14–180 days post-injury) did not coincide with either further improvements, or new decrements, in open-field locomotor function after spinal cord injury. However, blockade of chemoattractant C5a-mediated inflammation after 14 days post-injury reduced locomotor recovery and myelination in the injured spinal cord, suggesting that the late inflammatory response serves a reparative function. Together, these

  10. Immune Imbalance in Nasal Polyps of Caucasian Chronic Rhinosinusitis Patients Is Associated with a Downregulation of E-Selectin

    PubMed Central

    Böscke, Robert; Waldmann, Anja; Bruchhage, Karl-Ludwig; Pries, Ralph; Wollenberg, Barbara

    2014-01-01

    Chronic rhinosinusitis with nasal polyps (CRSwNP) in Caucasians is a chronic Th2 inflammatory disease of the nasal and paranasal mucosa and the recruitment of leukocytes to the site of inflammation is poorly understood. We studied mRNA and protein expression profiles of adhesion molecules in nasal polyp and associated inferior turbinate tissues using molecular, biochemical, and immunohistological methods. Analysis showed a strongly decreased E-selectin expression in nasal polyps with a significant difference between eosinophil and neutrophil counts in nasal polyps and balanced counts in inferior turbinates. E-selectin expression is known to be downregulated in a Th2 milieu and has an essential role in immunosurveillance by locally activating neutrophil arrest and migratory function. A downregulation of E-selectin may come along with an immune imbalance in Caucasian nasal polyps due to a significant inhibition of neutrophil recruitment. Therefore, we suggest that an upregulation of E-selectin and the associated influx of neutrophils may play a significant role in the resolution of inflammation as well as for the pathophysiology of nasal polyps of Caucasian chronic rhinosinusitis patients. PMID:24995349

  11. Immune imbalance in nasal polyps of Caucasian chronic rhinosinusitis patients is associated with a downregulation of E-selectin.

    PubMed

    Könnecke, Michael; Böscke, Robert; Waldmann, Anja; Bruchhage, Karl-Ludwig; Linke, Robert; Pries, Ralph; Wollenberg, Barbara

    2014-01-01

    Chronic rhinosinusitis with nasal polyps (CRSwNP) in Caucasians is a chronic Th2 inflammatory disease of the nasal and paranasal mucosa and the recruitment of leukocytes to the site of inflammation is poorly understood. We studied mRNA and protein expression profiles of adhesion molecules in nasal polyp and associated inferior turbinate tissues using molecular, biochemical, and immunohistological methods. Analysis showed a strongly decreased E-selectin expression in nasal polyps with a significant difference between eosinophil and neutrophil counts in nasal polyps and balanced counts in inferior turbinates. E-selectin expression is known to be downregulated in a Th2 milieu and has an essential role in immunosurveillance by locally activating neutrophil arrest and migratory function. A downregulation of E-selectin may come along with an immune imbalance in Caucasian nasal polyps due to a significant inhibition of neutrophil recruitment. Therefore, we suggest that an upregulation of E-selectin and the associated influx of neutrophils may play a significant role in the resolution of inflammation as well as for the pathophysiology of nasal polyps of Caucasian chronic rhinosinusitis patients. PMID:24995349

  12. An extended chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids phenotype

    PubMed Central

    Lane, Chris; Phadke, Rahul; Howard, Robin

    2014-01-01

    Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described central nervous system inflammatory condition. In this case report we describe a patient initially with features consistent with this syndrome, who represented with seizures (not previously reported in this syndrome) and corresponding prominent cortical involvement on imaging (also not previously noted). Owing to diagnostic uncertainty, cerebral biopsy was performed revealing histology consistent with CLIPPERS, excluding other differentials. Following a further brainstem relapse, this patient was treated with high-dose steroids, subsequently switched to a tapering oral regime and now, azathioprine, a steroid-sparing agent. She remains well on this. PMID:24966263

  13. Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings

    PubMed Central

    Wolkowitz, Owen M.; Mellon, Synthia H.; Epel, Elissa S.; Lin, Jue; Dhabhar, Firdaus S.; Su, Yali; Reus, Victor I.; Rosser, Rebecca; Burke, Heather M.; Kupferman, Eve; Compagnone, Mariana; Nelson, J. Craig; Blackburn, Elizabeth H.

    2011-01-01

    Background Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of “accelerated aging” in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation. Methodology Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex. Principal Findings The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of “accelerated cell aging.” Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05). Conclusions These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is

  14. Lactobacillus rhamnosus GG reduces hepatic TNFα production and inflammation in chronic alcohol-induced liver injury.

    PubMed

    Wang, Yuhua; Liu, Yanlong; Kirpich, Irina; Ma, Zhenhua; Wang, Cuiling; Zhang, Min; Suttles, Jill; McClain, Craig; Feng, Wenke

    2013-09-01

    The therapeutic effects of probiotic treatment in alcoholic liver disease (ALD) have been studied in both patients and experimental animal models. Although the precise mechanisms of the pathogenesis of ALD are not fully understood, gut-derived endotoxin has been postulated to play a crucial role in hepatic inflammation. Previous studies have demonstrated that probiotic therapy reduces circulating endotoxin derived from intestinal gram-negative bacteria in ALD. In this study, we investigated the effects of probiotics on hepatic tumor necrosis factor-α (TNFα) production and inflammation in response to chronic alcohol ingestion. Mice were fed Lieber DeCarli liquid diet containing 5% alcohol for 8weeks, and Lactobacillus rhamnosus GG (LGG) was supplemented in the last 2 weeks. Eight-week alcohol feeding caused a significant increase in hepatic inflammation as shown by histological assessment and hepatic tissue myeloperoxidase activity assay. Two weeks of LGG supplementation reduced hepatic inflammation and liver injury and markedly reduced TNFα expression. Alcohol feeding increased hepatic mRNA expression of Toll-like receptors (TLRs) and CYP2E1 and decreased nuclear factor erythroid 2-related factor 2 expression. LGG supplementation attenuated these changes. Using human peripheral blood monocytes-derived macrophages, we also demonstrated that incubation with ethanol primes both lipopolysaccharide- and flagellin-induced TNFα production, and LGG culture supernatant reduced this induction in a dose-dependent manner. In addition, LGG treatment also significantly decreased alcohol-induced phosphorylation of p38 MAP kinase. In conclusion, probiotic LGG treatment reduced alcohol-induced hepatic inflammation by attenuation of TNFα production via inhibition of TLR4- and TLR5-mediated endotoxin activation. PMID:23618528

  15. Deficiency of Schnurri-2, an MHC Enhancer Binding Protein, Induces Mild Chronic Inflammation in the Brain and Confers Molecular, Neuronal, and Behavioral Phenotypes Related to Schizophrenia

    PubMed Central

    Takao, Keizo; Kobayashi, Katsunori; Hagihara, Hideo; Ohira, Koji; Shoji, Hirotaka; Hattori, Satoko; Koshimizu, Hisatsugu; Umemori, Juzoh; Toyama, Keiko; Nakamura, Hironori K; Kuroiwa, Mahomi; Maeda, Jun; Atsuzawa, Kimie; Esaki, Kayoko; Yamaguchi, Shun; Furuya, Shigeki; Takagi, Tsuyoshi; Walton, Noah M; Hayashi, Nobuhiro; Suzuki, Hidenori; Higuchi, Makoto; Usuda, Nobuteru; Suhara, Tetsuya; Nishi, Akinori; Matsumoto, Mitsuyuki; Ishii, Shunsuke; Miyakawa, Tsuyoshi

    2013-01-01

    Schnurri-2 (Shn-2), an nuclear factor-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia. PMID:23389689

  16. Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia.

    PubMed

    Takao, Keizo; Kobayashi, Katsunori; Hagihara, Hideo; Ohira, Koji; Shoji, Hirotaka; Hattori, Satoko; Koshimizu, Hisatsugu; Umemori, Juzoh; Toyama, Keiko; Nakamura, Hironori K; Kuroiwa, Mahomi; Maeda, Jun; Atsuzawa, Kimie; Esaki, Kayoko; Yamaguchi, Shun; Furuya, Shigeki; Takagi, Tsuyoshi; Walton, Noah M; Hayashi, Nobuhiro; Suzuki, Hidenori; Higuchi, Makoto; Usuda, Nobuteru; Suhara, Tetsuya; Nishi, Akinori; Matsumoto, Mitsuyuki; Ishii, Shunsuke; Miyakawa, Tsuyoshi

    2013-07-01

    Schnurri-2 (Shn-2), an nuclear factor-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia. PMID:23389689

  17. Adaptive immunity against gut microbiota enhances apoE-mediated immune regulation and reduces atherosclerosis and western-diet-related inflammation.

    PubMed

    Saita, Diego; Ferrarese, Roberto; Foglieni, Chiara; Esposito, Antonio; Canu, Tamara; Perani, Laura; Ceresola, Elisa Rita; Visconti, Laura; Burioni, Roberto; Clementi, Massimo; Canducci, Filippo

    2016-01-01

    Common features of immune-metabolic and inflammatory diseases such as metabolic syndrome, diabetes, obesity and cardiovascular diseases are an altered gut microbiota composition and a systemic pro-inflammatory state. We demonstrate that active immunization against the outer membrane protein of bacteria present in the gut enhances local and systemic immune control via apoE-mediated immune-modulation. Reduction of western-diet-associated inflammation was obtained for more than eighteen weeks after immunization. Immunized mice had reduced serum cytokine levels, reduced insulin and fasting glucose concentrations; and gene expression in both liver and visceral adipose tissue confirmed a reduced inflammatory steady-state after immunization. Moreover, both gut and atherosclerotic plaques of immunized mice showed reduced inflammatory cells and an increased M2 macrophage fraction. These results suggest that adaptive responses directed against microbes present in our microbiota have systemic beneficial consequences and demonstrate the key role of apoE in this mechanism that could be exploited to treat immune-metabolic diseases. PMID:27383250

  18. Adaptive immunity against gut microbiota enhances apoE-mediated immune regulation and reduces atherosclerosis and western-diet-related inflammation

    PubMed Central

    Saita, Diego; Ferrarese, Roberto; Foglieni, Chiara; Esposito, Antonio; Canu, Tamara; Perani, Laura; Ceresola, Elisa Rita; Visconti, Laura; Burioni, Roberto; Clementi, Massimo; Canducci, Filippo

    2016-01-01

    Common features of immune-metabolic and inflammatory diseases such as metabolic syndrome, diabetes, obesity and cardiovascular diseases are an altered gut microbiota composition and a systemic pro-inflammatory state. We demonstrate that active immunization against the outer membrane protein of bacteria present in the gut enhances local and systemic immune control via apoE-mediated immune-modulation. Reduction of western-diet-associated inflammation was obtained for more than eighteen weeks after immunization. Immunized mice had reduced serum cytokine levels, reduced insulin and fasting glucose concentrations; and gene expression in both liver and visceral adipose tissue confirmed a reduced inflammatory steady-state after immunization. Moreover, both gut and atherosclerotic plaques of immunized mice showed reduced inflammatory cells and an increased M2 macrophage fraction. These results suggest that adaptive responses directed against microbes present in our microbiota have systemic beneficial consequences and demonstrate the key role of apoE in this mechanism that could be exploited to treat immune-metabolic diseases. PMID:27383250

  19. Distinct effects of Lactobacillus plantarum KL30B and Escherichia coli 3A1 on the induction and development of acute and chronic inflammation

    PubMed Central

    Strus, Magdalena; Okoń, Krzysztof; Nowak, Bernadeta; Pilarczyk-Zurek, Magdalena; Heczko, Piotr; Gawda, Anna; Ciszek-Lenda, Marta; Skowron, Beata; Baranowska, Agnieszka

    2016-01-01

    Objective Enteric bacteria are involved in the pathogenesis of ulcerative colitis. In experimental colitis, a breakdown of the intestinal epithelial barrier results in inflow of various gut bacteria, induction of acute inflammation and finally, progression to chronic colitis. Material and methods In the present study we compared pro-inflammatory properties of two bacterial strains isolated from human microbiome, Escherichia coli 3A1 and Lactobacillus plantarum KL30B. The study was performed using two experimental models of acute inflammation: peritonitis in mice and trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. Results Both bacterial strains induced massive neutrophil infiltration upon injection into sterile peritoneal cavity. However, peritoneal exudate cells stimulated in vitro with E. coli 3A1, produced far more nitric oxide, than those stimulated with L. plantarum KL30B. Interestingly, distinct effect on the development of TNBS-induced colitis was observed after oral administration of the tested bacteria. Lactobacillus plantarum KL30B evoked strong acute colitis. On the contrary, the administration of E. coli 3A1 resulted in a progression of colitis to chronicity. Conclusions Our results show that distinct effects of bacterial administration on the development of ongoing inflammation is strain specific and depends on the final effect of cross-talk between bacteria and cells of the innate immune system. PMID:26862305

  20. Antagonism of CRTH2 ameliorates chronic epicutaneous sensitization-induced inflammation by multiple mechanisms.

    PubMed

    Boehme, Stefen A; Chen, Edward P; Franz-Bacon, Karin; Sásik, Roman; Sprague, L James; Ly, Tai Wei; Hardiman, Gary; Bacon, Kevin B

    2009-01-01

    Prostaglandin D(2) (PGD(2)) and its receptor chemoattractant receptor homologous molecule expressed on T(h)2 cells (CRTH2) have been implicated in the pathogenesis of numerous allergic diseases. We investigated the role of PGD(2) and CRTH2 in allergic cutaneous inflammation by using a highly potent and specific antagonist of CRTH2. Administration of this antagonist ameliorated cutaneous inflammation caused by either repeated epicutaneous ovalbumin or FITC sensitization. Gene expression and ELISA analysis revealed that there was reduced pro-inflammatory cytokine mRNA or protein produced. Importantly, the CRTH2 antagonist reduced total IgE, as well as antigen-specific IgE, IgG1 and IgG2a antibody levels. This reduction in antibody production correlated to reduced cytokines produced by splenocytes following in vitro antigen challenge. An examination of skin CD11c(+) dendritic cells (DC) showed that in mice treated with the CRTH2 antagonist, there was a decrease in the number of these cells that migrated to the draining lymph nodes in response to FITC application to the skin. Additionally, naive CD4(+) T lymphocytes co-cultured with skin-derived DC from CRTH2 antagonist-treated mice showed a reduced ability to produce a number of cytokines compared with DC from vehicle-treated mice. Collectively, these findings suggest that CRTH2 has a pivotal role in mediating the inflammation and the underlying immune response following epicutaneous sensitization. PMID:19066315

  1. Polymorphism in THBS1 Gene Is Associated with Post-Refractive Surgery Chronic Ocular Surface Inflammation

    PubMed Central

    Contreras-Ruiz, Laura; Ryan, Denise S.; Sia, Rose K.; Bower, Kraig S.; Dartt, Darlene A.; Masli, Sharmila

    2014-01-01

    Purpose To determine the association of single nucleotide polymorphisms (SNPs) of the thrombospondin 1 (THBS1) gene with development of chronic ocular surface inflammation (keratoconjunctivitis) after refractive surgery. Design Retrospective cohort study. Participants Active duty U.S. Army soldiers (n = 143) who opted for refractive surgery. Methods Conjunctival impression cytology samples collected from participants before the surgery were used to harvest DNA for genotyping 5 THBS1 SNPs (rs1478604, rs2228262, rs2292305, rs2228262, and rs3743125) using the Sequenom iPLEX Gold platform (Sequenom, San Diego, CA). Samples collected after surgery were used to harvest RNA for gene expression analysis by real-time polymerase chain reaction (PCR). Participants were followed for 1 year after surgery to monitor the status of keratoconjunctivitis. Main Outcome Measures Genetic basis of the development of chronic keratoconjunctivitis after refractive surgery. Results Carriers of minor alleles of 3 SNPs each were found to be more susceptible to developing chronic keratoconjunctivitis (rs1478604: odds ratio [OR], 2.5; 95% confidence interval [CI], 1.41–4.47; P = 2.5×10−3; rs2228262 and rs2292305: OR, 1.9; 95% CI, 1.05–3.51; P = 4.8×10−2). Carriers of the rs1478604 minor allele expressed significantly reduced levels of thrombospondin 1 (TSP1) (P = 0.042) and increased levels of an inflammatory cytokine associated with keratoconjunctivitis, interleukin-1 β (P = 0.025), in their ocular surface epithelial cells compared with homozygous major allele controls. Conclusions Genetic variation in the THBS1 gene that results in decreased expression of the encoded glycoprotein TSP1 in ocular surface epithelial cells significantly increases the susceptibility to develop chronic ocular surface inflammation after refractive surgery. Further investigation of THBS1 SNPs in a larger sample size is warranted. PMID:24679443

  2. Topical administration of hyaluronic acid in children with recurrent or chronic middle ear inflammations.

    PubMed

    Torretta, Sara; Marchisio, Paola; Rinaldi, Vittorio; Gaffuri, Michele; Pascariello, Carla; Drago, Lorenzo; Baggi, Elena; Pignataro, Lorenzo

    2016-09-01

    Hyaluronic acid (HA) treatment has been successfully performed in patients with recurrent upper airway infections or rhinitis. The aim of this study was to assess the efficacy and safety of the topical nasal administration of an HA-based compound by investigating its effects in children with recurrent or chronic middle ear inflammations and chronic adenoiditis. A prospective, single-blind, 1:1 randomised controlled study was performed to compare otoscopy, tympanometry and pure-tone audiometry in children which received the daily topical administration of normal 0.9% sodium chloride saline solution (control group) or 9 mg of sodium hyaluronate in 3 mL of a 0.9% sodium saline solution. The final analysis was based on 116 children (49.1% boys; mean age, 62.9 ± 17.9 months): 58 in the control group and 58 in the study group. At the end of follow-up, the prevalence of patients with impaired otoscopy was significantly lower in the study group (P value = 0.024) compared to baseline but not in the control group. In comparison with baseline, the prevalence of patients with impaired tympanometry at the end of the follow-up period was significantly lower in the study group (P value = 0.047) but not in the control group. The reduction in the prevalence of patients with conductive hearing loss (CHL) (P value = 0.008) and those with moderate CHL (P value = 0.048) was significant in the study group, but not in the control group. The mean auditory threshold had also significantly improved by the end of treatment in the study group (P value = 0.004) but not in the control group. Our findings confirm the safety of intermittent treatment with a topical nasal sodium hyaluronate solution and are the first to document its beneficial effect on clinical and audiological outcomes in children with recurrent or chronic middle ear inflammations associated with chronic adenoiditis. PMID:27481884

  3. Immune therapy including dendritic cell based therapy in chronic hepatitis B virus infection.

    PubMed

    Akbar, Sk Md Fazle; Horiike, Norio; Onji, Morikazu

    2006-05-14

    Hepatitis B virus (HBV) infection is a global public health problem. Of the approximately 2 billion people who have been infected worldwide, more than 400 million are chronic carriers of HBV. Considerable numbers of chronic HBV carriers suffer from progressive liver diseases. In addition, all HBV carriers are permanent source of this virus. There is no curative therapy for chronic HBV carriers. Antiviral drugs are recommended for about 10% patients, however, these drugs are costly, have limited efficacy, and possess considerable side effects. Recent studies have shown that immune responses of the host to the HBV are critically involved at every stage of chronic HBV infection: (1) These influence acquisition of chronic HBV carrier state, (2) They are important in the context of liver damages, (3) Recovery from chronic HBV-related liver diseases is dependent on nature and extent of HBV-specific immune responses. However, induction of adequate levels of HBV-specific immune responses in chronic HBV carriers is difficult. During the last one decade, hepatitis B vaccine has been administered to chronic HBV carriers as a therapeutic approach (vaccine therapy). The present regimen of vaccine therapy is safe and cheap, but not so effective. A dendritic cell-based therapeutic vaccine has recently been developed for treating chronic HBV infection. In this review, we will discuss about the concept, scientific logics, strategies and techniques of development of HBV-specific immune therapies including vaccine therapy and dendritic cell-based vaccine therapy for treating chronic HBV infection. PMID:16718812

  4. Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling.

    PubMed

    Johnson, Jill R; Wiley, Ryan E; Fattouh, Ramzi; Swirski, Filip K; Gajewska, Beata U; Coyle, Anthony J; Gutierrez-Ramos, José-Carlos; Ellis, Russ; Inman, Mark D; Jordana, Manel

    2004-02-01

    It is now fully appreciated that asthma is a disease of a chronic nature resulting from intermittent or continued aeroallergen exposure leading to airway inflammation. To investigate responses to continuous antigen exposure, mice were exposed to either house dust mite extract (HDM) or ovalbumin intranasally for five consecutive days, followed by 2 days of rest, for up to seven consecutive weeks. Continuous exposure to HDM, unlike ovalbumin, elicited severe and persistent eosinophilic airway inflammation. Flow cytometric analysis demonstrated an accumulation of CD4+ lymphocytes in the lung with elevated expression of inducible costimulator a marker of T cell activation, and of T1/ST2, a marker of helper T Type 2 effector cells. We also detected increased and sustained production of helper T cell Type 2-associated cytokines by splenocytes of HDM-exposed mice on in vitro HDM recall. Histologic analysis of the lung showed evidence of airway remodeling in mice exposed to HDM, with goblet cell hyperplasia, collagen deposition, and peribronchial accumulation of contractile tissue. In addition, HDM-exposed mice demonstrated severe airway hyperreactivity to methacholine. Finally, these responses were studied for up to 9 weeks after cessation of HDM exposure. We observed that whereas airway inflammation resolved fully, the remodeling changes did not resolve and airway hyperreactivity resolved only partly. PMID:14597485

  5. Chronic stress enhances microglia activation and exacerbates death of nigral dopaminergic neurons under conditions of inflammation

    PubMed Central

    2014-01-01

    Background Parkinson’s disease is an irreversible neurodegenerative disease linked to progressive movement disorders and is accompanied by an inflammatory reaction that is believed to contribute to its pathogenesis. Since sensitivity to inflammation is not the same in all brain structures, the aim of this work was to test whether physiological conditions as stress could enhance susceptibility to inflammation in the substantia nigra, where death of dopaminergic neurons takes place in Parkinson’s disease. Methods To achieve our aim, we induced an inflammatory process in nonstressed and stressed rats (subject to a chronic variate stress) by a single intranigral injection of lipopolysaccharide, a potent proinflammogen. The effect of this treatment was evaluated on inflammatory markers as well as on neuronal and glial populations. Results Data showed a synergistic effect between inflammation and stress, thus resulting in higher microglial activation and expression of proinflammatory markers. More important, the higher inflammatory response seen in stressed animals was associated with a higher rate of death of dopaminergic neurons in the substantia nigra, the most characteristic feature seen in Parkinson’s disease. This effect was dependent on glucocorticoids. Conclusions Our data demonstrate that stress sensitises midbrain microglia to further inflammatory stimulus. This suggests that stress may be an important risk factor in the degenerative processes and symptoms of Parkinson’s disease. PMID:24565378

  6. [Characteristics of bronchial inflammation in children with chronic non-productive cough].

    PubMed

    Bunu, Carmen; Vancea, Dorin; Păunescu, Virgil

    2003-01-01

    The aim of study was to correlate the bronchoalveolar lavage (BAL) cell subpopulations in light microscopy and clinical-functional parameters in 20 children with chronic nonproductive cough (potentially evolving to asthma) in comparison with 20 children with mild and moderate stable asthma. The results revealed a different BAL cell profile of chronic coughing children, characterized by a lower percent of total cells (0.279 +/- 0.055 x 10(6)/ml), eosinophils (0.97 +/- 0.80%), lymphocytes (6.02 +/- 0.85%) and epithelial cells (28.52 +/- 5.15%) and higher percent of macrophages (46.05 +/- 7.94%) and neutrophils (18.27 +/- 4.93%). Eosinophilic inflammation in BAL and bronchial hyper-responsiveness (PC20 methacholine = 1.73 +/- 0.15 mg/ml) were revealed in three cases with chronic cough. Based on these reasons, they were included in "cough variant asthma". In conclusion, children with nonproductive chronic cough represent a heterogenous group, with different underlying causes. Only a minority of these patients has "cough variant asthma", with a favorable response to inhaled corticotherapy. PMID:14702696

  7. Association of Mucosal Organisms with Patterns of Inflammation in Chronic Rhinosinusitis

    PubMed Central

    Chalermwatanachai, Thanit; Zhang, Nan; Holtappels, Gabriele; Bachert, Claus

    2015-01-01

    Background Chronic rhinosinusitis is a multifactorial process disease in which bacterial infection or colonization may play an important role in the initiation or persistence of inflammatory response. The association between mucosal bacteria presence and inflammatory patterns has only been partially explored. Objective To demonstrate specific mucosal microorganisms possible association with inflammatory patterns. Methods We collected nasal polyps or sinus tissues from a clinical selection of six patient groups with defined sinus disease using tissue biomarkers. In the tissues, we detected bacteria using peptide nucleic acid fluorescence in situ hybridization (PNA-FISH). Results After reviewing a total of 115 samples (15–20 samples per group), the mucosal presence of Staphylococcus aureus was correlated with IL-5 and SE-IgE positive chronic rhinosinusitis with nasal polyps and nasal polyps from cystic fibrosis patients. Chronic rhinosinusitis without nasal polyps with TNFα >20 pg/ml was associated with the mucosal presence of Pseudomonas aeruginosa. Conclusion This study identifies the relationship between intramucosal microbes and inflammatory patterns, suggesting that bacteria may affect the type of inflammation in chronic rhinosinusitis. Additional investigation is needed to further identify the nature of the relationship. PMID:26275068

  8. Diet and Inflammation in Alzheimer's Disease and Related Chronic Diseases: A Review.

    PubMed

    Gardener, Samantha L; Rainey-Smith, Stephanie R; Martins, Ralph N

    2015-12-01

    Inflammation is one of the pathological features of the neurodegenerative disease, Alzheimer's disease (AD). A number of additional disorders are likewise associated with a state of chronic inflammation, including obesity, cardiovascular disease, and type-2 diabetes, which are themselves risk factors for AD. Dietary components have been shown to modify the inflammatory process at several steps of the inflammatory pathway. This review aims to evaluate the published literature on the effect of consumption of pro- or anti-inflammatory dietary constituents on the severity of both AD pathology and related chronic diseases, concentrating on the dietary constituents of flavonoids, spices, and fats. Diet-based anti-inflammatory components could lead to the development of potent novel anti-inflammatory compounds for a range of diseases. However, further work is required to fully characterize the therapeutic potential of such compounds, including gaining an understanding of dose-dependent relationships and limiting factors to effectiveness. Nutritional interventions utilizing anti-inflammatory foods may prove to be a valuable asset in not only delaying or preventing the development of age-related neurodegenerative diseases such as AD, but also treating pre-existing conditions including type-2 diabetes, cardiovascular disease, and obesity. PMID:26682690

  9. Chronic inflammation in biomaterial induced periprosthetic osteolysis: NF-κB as a therapeutic target

    PubMed Central

    Lin, Tzu-hua; Tamaki, Yasunobu; Pajarinen, Jukka; Waters, Heather A.; Woo, Deanna K.; Yao, Zhenyu; Goodman, Stuart B.

    2013-01-01

    Biomaterial-induced tissue responses in patients with total joint replacement are associated with the generation of wear particles, which may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Inflammatory reactions associated with wear particles are mediated by several important signaling pathways, the most important of which involves the transcription factor NF-κB. NF-κB activation is essential for macrophage recruitment and maturation, as well as the production of pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β, IL-6, MCP1, etc. In addition, NF-κB activation contributes to osteoclast differentiation and maturation via RANK/RANKL signaling, which increases bone destruction and reduces bone formation. Targeting individual downstream cytokines directly (such as TNF-α or IL-1β) may not effectively prevent wear particle induced osteolysis. A more logical upstream therapeutic approach may be provided by direct modulation of the core IκB/IKKα/β/NF-κB signaling pathway in the local environment, however, the timing, dose, and strategy for administration should be considered. Suppression of chronic inflammation via inhibition of NF-κB activity in patients with malfunctioning joint replacements may be an effective strategy to mitigate wear particle induced periprosthetic osteolysis. PMID:24090989

  10. The adaptive imbalance in base excision–repair enzymes generates microsatellite instability in chronic inflammation

    PubMed Central

    Hofseth, Lorne J.; Khan, Mohammed A.; Ambrose, Mark; Nikolayeva, Olga; Xu-Welliver, Meng; Kartalou, Maria; Hussain, S. Perwez; Roth, Richard B.; Zhou, Xiaoling; Mechanic, Leah E.; Zurer, Irit; Rotter, Varda; Samson, Leona D.; Harris, Curtis C.

    2003-01-01

    Chronic infection and associated inflammation are key contributors to human carcinogenesis. Ulcerative colitis (UC) is an oxyradical overload disease and is characterized by free radical stress and colon cancer proneness. Here we examined tissues from noncancerous colons of ulcerative colitis patients to determine (a) the activity of two base excision–repair enzymes , AAG, the major 3-methyladenine DNA glycosylase, and APE1, the major apurinic site endonuclease; and (b) the prevalence of microsatellite instability (MSI). AAG and APE1 were significantly increased in UC colon epithelium undergoing elevated inflammation and MSI was positively correlated with their imbalanced enzymatic activities. These latter results were supported by mechanistic studies using yeast and human cell models in which overexpression of AAG and/or APE1 was associated with frameshift mutations and MSI. Our results are consistent with the hypothesis that the adaptive and imbalanced increase in AAG and APE1 is a novel mechanism contributing to MSI in patients with UC and may extend to chronic inflammatory or other diseases with MSI of unknown etiology. PMID:14679184

  11. Low-grade chronic inflammation perpetuated by modern diet as a promoter of obesity and osteoporosis.

    PubMed

    Ilich, Jasminka Z; Kelly, Owen J; Kim, Youjin; Spicer, Maria T

    2014-06-01

    Some of the universal characteristics of pre-agricultural hominin diets are strikingly different from the modern human diet. Hominin dietary choices were limited to wild plant and wild animal foods, while the modern diet includes more than 70 % of energy consumed from refined sugars, refined vegetable oils, and highly processed cereals and dairy products. The modern diet, with higher intake of fat has also resulted in a higher ratio of omega-6 (n-6) to omega-3 (n-3) polyunsaturated fatty acids (PUFA), contributing to low-grade chronic inflammation (LGCI) and thus promoting the development of many chronic diseases, including obesity and osteoporosis. In this review, we describe the changes in modern diet, focusing on the kind and amount of consumed fat; explain the shortcomings of the modern diet with regard to inflammatory processes; and delineate the reciprocity between adiposity and inflammatory processes, with inflammation being a common link between obesity and osteoporosis. We present the evidence that overconsumption of n-6 PUFA coupled with under-consumption of n-3 PUFA results in LGCI and, along with the increased presence of reactive oxygen species, leads to a shift in mesenchymal stem cells (precursors for both osteoblasts and adipocytes) lineage commitment toward increased adipogenesis and suppressed osteoblastogenesis. In turn, high n-6 to n-3 PUFA ratios in the modern diet, coupled with increased synthesis of pro-inflammatory cytokines due to adiposity, propagate obesity and osteoporosis by increasing or maintaining LGCI. PMID:24945416

  12. Impact of daily cooling treatment on skin inflammation in patients with chronic venous disease

    PubMed Central

    Mueller, Martina; King, Dana E.; Madisetti, Mohan; Prentice, Margie

    2015-01-01

    People with chronic venous disease are at high risk for developing venous leg ulcers. Inflammation is posited as a pathological factor for this chronic condition as evidenced by persistently elevated skin temperature. As part of a larger trial to test the effects of a cooling regimen on leg ulcer prevention, the objective of this preliminary study was to evaluate the first 30 days of intense daily cooling. Compared to a placebo control cuff, a gel cuff applied to the most severely affected lower leg skin for 30 minutes daily showed no statistically significant differences between temperatures taken in the home at baseline compared to those measured at the 1 month follow up visit. There were also no differences in temperatures noted between the two groups, although the temperatures in the treatment group were lower 30 minutes after treatment, an indication of adherence. There was no discernable decrease or increase in temperature at a given time point during the 30 day treatment period compared to the control group. It may be better to have patients monitor skin temperature on a daily basis and then apply the cuff as necessary, rather than requiring daily cooling based on baseline measurement. This “prn” approach may provide a sufficient cooling milieu to prevent escalation of inflammation and thwart ulcer occurrence or recurrence. Clinical trials registration #NCT01509599 PMID:25703058

  13. IL-32: A Novel Pluripotent Inflammatory Interleukin, towards Gastric Inflammation, Gastric Cancer, and Chronic Rhino Sinusitis

    PubMed Central

    2016-01-01

    A vast variety of nonstructural proteins have been studied for their key roles and involvement in a number of biological phenomenona. Interleukin-32 is a novel cytokine whose presence has been confirmed in most of the mammals except rodents. The IL-32 gene was identified on human chromosome 16 p13.3. The gene has eight exons and nine splice variants, namely, IL-32α, IL-32β, IL-32γ, IL-32δ, IL-32ε, IL-32ζ, IL-32η, IL-32θ, and IL-32s. It was found to induce the expression of various inflammatory cytokines including TNF-α, IL-6, and IL-1β as well as macrophage inflammatory protein-2 (MIP-2) and has been reported previously to be involved in the pathogenesis and progression of a number of inflammatory disorders, namely, inflammatory bowel disease (IBD), gastric inflammation and cancer, rheumatoid arthritis, and chronic obstructive pulmonary disease (COPD). In the current review, we have highlighted the involvement of IL-32 in gastric cancer, gastric inflammation, and chronic rhinosinusitis. We have also tried to explore various mechanisms suspected to induce the expression of this extraordinary cytokine as well as various mechanisms of action employed by IL-32 during the mediation and progression of the above said problems. PMID:27143819

  14. Diethylcarbamazine Reduces Chronic Inflammation and Fibrosis in Carbon Tetrachloride- (CCl4-) Induced Liver Injury in Mice

    PubMed Central

    Rocha, Sura Wanessa Santos; de França, Maria Eduarda Rocha; Rodrigues, Gabriel Barros; Barbosa, Karla Patrícia Sousa; Nunes, Ana Karolina Santana; Pastor, André Filipe; Oliveira, Anne Gabrielle Vasconcelos; Oliveira, Wilma Helena; Luna, Rayana Leal Almeida; Peixoto, Christina Alves

    2014-01-01

    This study investigated the anti-inflammatory effects of DEC on the CCl4-induced hepatotoxicity in C57BL/6 mice. Chronic inflammation was induced by i.p. administration of CCl4 0.5 μL/g of body weight through two injections a week for 6 weeks. DEC (50 mg/kg) was administered by gavage for 12 days before finishing the CCl4 induction. Histological analyses of the DEC-treated group exhibited reduced inflammatory process and prevented liver necrosis and fibrosis. Immunohistochemical and immunofluorescence analyses of the DEC-treated group showed reduced COX-2, IL1β, MDA, TGF-β, and αSMA immunopositivity, besides exhibiting decreased IL1β, COX-2, NFκB, IFNγ, and TGFβ expressions in the western blot analysis. The DEC group enhanced significantly the IL-10 expression. The reduction of hepatic injury in the DEC-treated group was confirmed by the COX-2 and iNOS mRNA expression levels. Based on the results of the present study, DEC can be used as a potential anti-inflammatory drug for chronic hepatic inflammation. PMID:25374445

  15. Circulating Mediators of Inflammation and Immune Activation in AIDS-Related Non-Hodgkin Lymphoma

    PubMed Central

    Nolen, Brian M.; Breen, Elizabeth Crabb; Bream, Jay H.; Jenkins, Frank J.; Kingsley, Lawrence A.; Rinaldo, Charles R.; Lokshin, Anna E.

    2014-01-01

    Background Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation. Methods This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed bead-based immunoassays. Results A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers. Conclusions These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease. PMID:24922518

  16. MODEL OF COLONIC INFLAMMATION: IMMUNE MODULATORY MECHANISMS IN INFLAMMATORY BOWEL DISEASE

    PubMed Central

    Wendelsdorf, Katherine; Bassaganya-Riera, Josep; Hontecillas, Raquel; Eubank, Stephen

    2010-01-01

    Inflammatory Bowel Disease (IBD) is an immunoinflammatory illness of the gut initiated by an immune response to bacteria in the microflora. The resulting immunopathogenesis leads to lesions in epithelial lining of the colon through which bacteria may infiltrate the tissue causing recurring bouts of diarrhea, rectal bleeding, and mal-nutrition. In healthy individuals such immunopathogenesis is avoided by the presence of regulatory cells that inhibit the inflammatory pathway. Highly relevant to the search for treatment strategies is the identification of components of the inflammatory pathway that allow regulatory mechanisms to be overridden and immunopathogenesis to proceed. In vitro techniques have identified cellular interactions involved in inflammation-regulation crosstalk. However, tracing immunological mechanisms discovered at the cellular level confidently back to an in vivo context of multiple, simultaneous interactions has met limited success. To explore the impact of specific interactions, we have constructed a system of 29 ordinary differential equations representing different phenotypes of T-cells, macrophages, dendritic cells, and epithelial cells as they move and interact with bacteria in the lumen, lamina propria, and lymphoid tissue of the colon. Simulations revealed the positive inflammatory feedback loop formed by inflammatory M1 macrophage activation of T-cells as a driving force underlying the immunopathology of IBD. Furthermore, strategies that remove M1 from the site of infection, by either i) increasing its potential to switch to a regulatory M2 phenotype or ii) increasing the rate of reversion (for M1 and M2 alike) to a resting state, cease immunopathogenesis even as bacteria are eliminated by other inflammatory cells. Based on these results, we identify macrophages and their mechanisms of plasticity as key targets for mucosal inflammation intervention strategies. In addition, we propose that the primary mechanism behind the association of

  17. The Environment-Immune Route to Chronic Disease

    EPA Science Inventory

    Specific environmental factors including chemicals, drugs, microbes and both physical and psychological factors can affect the immune system producing dysfunction and, ultimately, an increased risk ofchronic disease. Several different types of immune alterations can result from e...

  18. Inflammation as a Risk of Developing Chronic Kidney Disease in Rheumatoid Arthritis

    PubMed Central

    Kochi, Masako; Kohagura, Kentaro; Shiohira, Yoshiki; Iseki, Kunitoshi; Ohya, Yusuke

    2016-01-01

    Objective The relationship between chronic inflammation and the incidence of chronic kidney disease (CKD) remained not-clear in patients with rheumatoid arthritis (RA). This study aims to examine the relationship between persistently high C-reactive protein (CRP), a marker of inflammation, and the incidence of CKD in RA. Methods We retrospectively examined the relationship between the levels of CRP and incidence of CKD in 345 RA patients. The outcome of interest was incidence of CKD, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and/or positive dipstick testing for proteinuria for ≥3 months. We defined high CRP, as >3.0 mg/L. On the basis of three measurements of CRP for 6-months period, patients were divided into three groups: group 1, including patients with no high CRP values; group 2, patients with transient high CRP values (once or twice) and group 3, patients with persistently high CRP values. Results During a median follow-up period of 89 months, 14% of all patients developed CKD. The cumulative incidence of CKD was 7% in group 1, 14% in group 2 and 22% in group 3 (P = 0.008, log-rank test). In a multivariate analysis, including classical risk factors for CKD, persistently high CRP was an independent predictor of the incidence of CKD (hazard ratio, 3.00; 95% confidence interval, 1.23–8.53; P = 0.01). Conclusions Persistently high CRP was a significant risk factor for the incidence of CKD. Results suggest that persistent inflammation is a marker for the high risk of CKD in RA. PMID:27537204

  19. THE EFFECTS OF CHRONIC IMMUNE STIMULATION ON MUSCLE GROWTH IN RAINBOW TROUT

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Successful production of aquaculture species depends on efficient growth with low susceptibility to disease. Therefore, selection programs have focused on rapid growth combined with disease resistance. However, chronic immune stimulation diminishes muscle growth (a syndrome referred to as cachexia),...

  20. The Changes of Energy Interactions between Nucleus Function and Mitochondria Functions Causing Transmutation of Chronic Inflammation into Cancer Metabolism.

    PubMed

    Ponizovskiy, Michail R

    2016-01-01

    Interactions between nucleus and mitochondria functions induce the mechanism of maintenance stability of cellular internal energy according to the first law of thermodynamics in able-bodied cells and changes the mechanisms of maintenance stability of cellular internal energy creating a transition stationary state of ablebodied cells into quasi-stationary pathologic states of acute inflammation transiting then into chronic inflammation and then transmuting into cancer metabolism. The mechanisms' influences of intruding etiologic pathologic agents (microbe, virus, etc.) lead to these changes of energy interactions between nucleus and mitochondria functions causing general acute inflammation, then passing into local chronic inflammation, and reversing into cancer metabolism transmutation. Interactions between biochemical processes and biophysical processes of cellular capacitors' operations create a supplementary mechanism of maintenance stability of cellular internal energy in the norm and in pathology. Discussion of some scientific works eliminates doubts of the authors of these works. PMID:27480780

  1. Distinct immune signatures in the colon of Crohn's disease and ankylosing spondylitis patients in the absence of inflammation.

    PubMed

    Dunn, Elliott T J; Taylor, Edward S; Stebbings, Simon; Schultz, Michael; Butt, A Grant; Kemp, Roslyn A

    2016-05-01

    Crohn's disease (CD) is an inflammatory bowel disease characterized by patchy inflammation of the gastrointestinal tract. Ankylosing spondylitis (AS) is primarily characterized by inflammation of the lower vertebral column, and many patients with AS present with inflammatory gut symptoms. Genome-wide association studies have highlighted significant overlap in short nucleotide polymorphisms for both diseases. We hypothesized that patients with CD and AS have a common intestinal immune signature, characterized by inflammatory T cells, compared with healthy people. We designed a pilot study to determine both the feasibility of defining complex immune signatures from primary tissue, and differences in the local immune signature of people with inflammatory diseases compared with healthy people. Intestinal biopsies were obtained by colonoscopy from healthy patients, non-inflamed regions of CD patients and AS patients with inflammatory gut symptoms. A flow cytometry platform was developed measuring polyfunctional T-cell populations based on cytokines, surface molecules and transcription factors. There was overlap in the immune signature of people with CD or AS, characterized by changes in the frequency of regulatory T cells, compared with healthy people. There were significant differences in frequencies of other polyfunctional T-cell populations-CD patients had an increased frequency of T cells producing interleukin-22 (IL-22) and interferon-γ, whereas AS patients had an increased frequency of T cells producing IL-2; compared with healthy people. These data indicate that the local immune signature could be described in these patients and that distinct immune mechanisms may underlie disease progression. PMID:26647966

  2. Contributions of neutrophils to the adaptive immune response in autoimmune disease

    PubMed Central

    Pietrosimone, Kathryn M; Liu, Peng

    2016-01-01

    Neutrophils are granulocytic cytotoxic leukocytes of the innate immune system that activate during acute inflammation. Neutrophils can also persist beyond the acute phase of inflammation to impact the adaptive immune response during chronic inflammation. In the context of the autoimmune disease, neutrophils modulating T and B cell functions by producing cytokines and chemokines, forming neutrophil extracellular traps, and acting as or priming antigen presentation cells. Thus, neutrophils are actively involved in chronic inflammation and tissue damage in autoimmune disease. Using rheumatoid arthritis as an example, this review focuses on functions of neutrophils in adaptive immunity and the therapeutic potential of these cells in the treatment of autoimmune disease and chronic inflammation. PMID:27042404

  3. Impaired function of CTLA-4 in the lungs of patients with chronic beryllium disease contributes to persistent inflammation.

    PubMed

    Chain, Jennifer L; Martin, Allison K; Mack, Douglas G; Maier, Lisa A; Palmer, Brent E; Fontenot, Andrew P

    2013-08-15

    Chronic beryllium disease (CBD) is an occupational lung disorder characterized by granulomatous inflammation and the accumulation of beryllium-responsive CD4(+) T cells in the lung. These differentiated effector memory T cells secrete IL-2, IFN-γ, and TNF-α upon in vitro activation. Beryllium-responsive CD4(+) T cells in the lung are CD28 independent and have increased expression of the coinhibitory receptor, programmed death 1, resulting in Ag-specific T cells that proliferate poorly yet retain the ability to express Th1-type cytokines. To further investigate the role of coinhibitory receptors in the beryllium-induced immune response, we examined the expression of CTLA-4 in blood and bronchoalveolar lavage cells from subjects with CBD. CTLA-4 expression was elevated on CD4(+) T cells from the lungs of study subjects compared with blood. Furthermore, CTLA-4 expression was greatest in the beryllium-responsive subset of CD4(+) T cells that retained the ability to proliferate and express IL-2. Functional assays show that the induction of CTLA-4 signaling in blood cells inhibited beryllium-induced T cell proliferation while having no effect on the proliferative capacity of beryllium-responsive CD4(+) T cells in the lung. Collectively, our findings suggest a dysfunctional CTLA-4 pathway in the lung and its potential contribution to the persistent inflammatory response that characterizes CBD. PMID:23851684

  4. Coronary heart disease, chronic inflammation, and pathogenic social hierarchy: a biological limit to possible reductions in morbidity and mortality.

    PubMed

    Wallace, Rodrick; Wallace, Deborah; Wallace, Robert G

    2004-05-01

    We suggest that a particular form of social hierarchy, which we characterize as "pathogenic", can, from the earliest stages of life, exert a formal analog to evolutionary selection pressure, literally writing a permanent developmental image of itself upon immune function as chronic vascular inflammation and its consequences. The staged nature of resulting disease emerges "naturally" as a rough analog to punctuated equilibrium in evolutionary theory, although selection pressure is a passive filter rather than an active agent, like structured psychosocial stress. Exposure differs according to the social constructs of race, class, and ethnicity, accounting in large measure for observed population-level differences in rates of coronary heart disease across industrialized societies. American Apartheid, which enmeshes both majority and minority communities in a social construct of pathogenic hierarchy, appears to present a severe biological limit to continuing declines in coronary heart disease for powerful as well as subordinate subgroups: "Culture"--to use the words of the evolutionary anthropologist Robert Boyd--"is as much a part of human biology as the enamel on our teeth". PMID:15160975

  5. Coronary heart disease, chronic inflammation, and pathogenic social hierarchy: a biological limit to possible reductions in morbidity and mortality.

    PubMed Central

    Wallace, Rodrick; Wallace, Deborah; Wallace, Robert G.

    2004-01-01

    We suggest that a particular form of social hierarchy, which we characterize as "pathogenic", can, from the earliest stages of life, exert a formal analog to evolutionary selection pressure, literally writing a permanent developmental image of itself upon immune function as chronic vascular inflammation and its consequences. The staged nature of resulting disease emerges "naturally" as a rough analog to punctuated equilibrium in evolutionary theory, although selection pressure is a passive filter rather than an active agent, like structured psychosocial stress. Exposure differs according to the social constructs of race, class, and ethnicity, accounting in large measure for observed population-level differences in rates of coronary heart disease across industrialized societies. American Apartheid, which enmeshes both majority and minority communities in a social construct of pathogenic hierarchy, appears to present a severe biological limit to continuing declines in coronary heart disease for powerful as well as subordinate subgroups: "Culture"--to use the words of the evolutionary anthropologist Robert Boyd--"is as much a part of human biology as the enamel on our teeth". PMID:15160975

  6. Helicobacter pylori eradication in patients with chronic immune thrombocytopenic purpura

    PubMed Central

    Noonavath, Ravinder Naik; Lakshmi, Chandrasekharan Padma; Dutta, Tarun Kumar; Kate, Vikram

    2014-01-01

    AIM: To assess the effect of Helicobacter pylori (H. pylori) eradication on platelet counts in patients with chronic immune thrombocytopenic purpura (cITP). METHODS: A total of 36 cITP patients were included in the study. The diagnosis of H. pylori was done by rapid urease test and Giemsa staining of the gastric biopsy specimen. All H. pylori positive patients received standard triple therapy for 14 d and were subjected for repeat endoscopy at 6 wk. Patients who continued to be positive for H. pylori on second endoscopy received second line salvage therapy. All the patients were assessed for platelet response at 6 wk, 3rd and 6th months. RESULTS: Of the 36 patients, 17 were positive for H. pylori infection and eradication was achieved in 16 patients. The mean baseline platelet count in the eradicated patients was 88615.38 ± 30117.93/mm3 and platelet count after eradication at 6 wk, 3 mo and 6 mo was 143230.77 ± 52437.51/mm3 (P = 0.003), 152562.50 ± 52892.3/mm3 (P = 0.0001), 150187.50 ± 41796.68/mm3 (P = 0.0001) respectively and in the negative patients, the mean baseline count was 71000.00 ± 33216.46/mm3 and at 6 wk, 3rd and 6th month follow up was 137631.58 ± 74364.13/mm3 (P = 0.001), 125578.95 ± 71472.1/mm3 (P = 0.005), 77210.53 ± 56892.28/mm3 (P = 0.684) respectively. CONCLUSION: Eradication of H. pylori leads to increase in platelet counts in patients with cITP and can be recommended as a complementary treatment with conventional therapy. PMID:24944483

  7. Hyperoxia promotes polarization of the immune response in ovalbumin-induced airway inflammation, leading to a TH17 cell phenotype

    PubMed Central

    Nagato, Akinori C; Bezerra, Frank S; Talvani, André; Aarestrup, Beatriz J; Aarestrup, Fernando M

    2015-01-01

    Previous studies have demonstrated that hyperoxia-induced stress and oxidative damage to the lungs of mice lead to an increase in IL-6, TNF-α, and TGF-β expression. Together, IL-6 and TGF-β have been known to direct T cell differentiation toward the TH17 phenotype. In the current study, we tested the hypothesis that hyperoxia promotes the polarization of T cells to the TH17 cell phenotype in response to ovalbumin-induced acute airway inflammation. Airway inflammation was induced in female BALB/c mice by intraperitoneal sensitization and intranasal introduction of ovalbumin, followed by challenge methacholine. After the methacholine challenge, animals were exposed to hyperoxic conditions in an inhalation chamber for 24 h. The controls were subjected to normoxia or aluminum hydroxide dissolved in phosphate buffered saline. After 24 h of hyperoxia, the number of macrophages and lymphocytes decreased in animals with ovalbumin-induced airway inflammation, whereas the number of neutrophils increased after ovalbumin-induced airway inflammation. The results showed that expression of Nrf2, iNOS, T-bet and IL-17 increased after 24 of hyperoxia in both alveolar macrophages and in lung epithelial cells, compared with both animals that remained in room air, and animals with ovalbumin-induced airway inflammation. Hyperoxia alone without the induction of airway inflammation lead to increased levels of TNF-α and CCL5, whereas hyperoxia after inflammation lead to decreased CCL2 levels. Histological evidence of extravasation of inflammatory cells into the perivascular and peribronchial regions of the lungs was observed after pulmonary inflammation and hyperoxia. Hyperoxia promotes polarization of the immune response toward the TH17 phenotype, resulting in tissue damage associated with oxidative stress, and the migration of neutrophils to the lung and airways. Elucidating the effect of hyperoxia on ovalbumin-induced acute airway inflammation is relevant to preventing or

  8. Influenza immunization of chronically ill children in pediatric tertiary care hospitals.

    PubMed

    Dubé, Eve; Gagnon, Dominique; Huot, Caroline; Paré, Renée; Jacques, Solange; Kossowski, Alexandra; Quach, Caroline; Landry, Monique

    2014-01-01

    Despite a publicly funded immunization program and continuous promotional efforts, vaccine uptake for seasonal influenza in Quebec (Canada) remains under its goal of 80%. Missed opportunities can explain the low influenza vaccine rates among chronically ill children. To address that, demonstration projects using the live attenuated influenza vaccine (LAIV) were implemented in 3 pediatric tertiary care hospitals to evaluate the feasibility and acceptability of implementing influenza immunization of chronically ill children in hospitals' outpatient clinics. A diary was used to document barriers and enabling factors regarding the implementation, and a questionnaire was distributed to healthcare professionals involved in the project in each hospital. Parent's knowledge, attitudes and behaviors (KAB) about influenza immunization and acceptability of immunization in outpatient clinics were also measured with a questionnaire. As part of the project, 2,478 children were immunized. Enabling factors included the financial support received from Quebec ministry of Health, the nasal mode of administration of the LAIV and the presence of a leader specifically dedicated to influenza immunization. Barriers to influenza immunization in outpatient clinics included difficulties of hiring extra staff to work in immunization clinics and additional tasks added to regular activities of the clinics. Results from both questionnaires illustrated a high level of acceptability of seasonal influenza immunization in hospitals' outpatient clinics by parents and healthcare professionals. Influenza immunization in pediatric tertiary care hospital is an effective way to reach chronically ill children and does not involve major feasibility or acceptability issues. PMID:25483460

  9. Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I

    PubMed Central

    Gordts, Philip L.; Ellinwood, N. Matthew; Schwartz, Philip H.; Dickson, Patricia I.; Esko, Jeffrey D.; Wang, Raymond Y.

    2016-01-01

    Background Cardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease. Methods Gene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry. Results Gene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice. Conclusions Overexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for

  10. Down modulation of MHC surface molecules on B cells by suppressive immune complexes obtained from chronic intestinal schistosomiasis patients.

    PubMed

    Rezende, S A; Gollob, K J; Correa-Oliveira, R; Goes, A M

    1998-06-01

    Granulomatous inflammation around parasite eggs is the prominent lesion in human schistosomiasis. Studies have suggested the involvement of a series of suppressive mechanisms in the control of this reaction, such as macrophages, cytokines, idiotypic interactions and immune complexes (IC). The studies examine the role of IC obtained from chronic intestinal schistosomiasis patients (ISP) in the reactivity of peripheral blood mononuclear cells (PBMC). The results have shown that these immune complexes are able to suppress cell reactivity by inducing an increase in the production of soluble mediators such as prostaglandins and IL-10. To gain a better understanding of how this suppression occurs the present study examines the phenotypic pattern of PBMC after immune complex treatment in cell proliferation assays. These data show that cultures including immune complex present a higher percentage of B lymphocytes in which a lower expression of a MHC-class II gene product, HLA-DR was detected. This altered expression of the HLA-DR molecule on B lymphocytes after IC treatment suggests a novel mechanism for the suppression observed, that is, IC might decrease the antigen-presenting function of B lymphocytes. PMID:9698100

  11. High dietary fiber intake is associated with decreased inflammation and all-cause mortality in patients with chronic kidney disease

    PubMed Central

    Raj Krishnamurthy, Vidya M.; Wei, Guo; Baird, Bradley C.; Murtaugh, Maureen; Chonchol, Michel B.; Raphael, Kalani L.; Greene, Tom; Beddhu, Srinivasan

    2016-01-01

    Chronic kidney disease is considered an inflammatory state and a high fiber intake is associated with decreased inflammation in the general population. Here, we determined whether fiber intake is associated with decreased inflammation and mortality in chronic kidney disease, and whether kidney disease modifies the associations of fiber intake with inflammation and mortality. To do this, we analyzed data from 14,543 participants in the National Health and Nutrition Examination Survey III. The prevalence of chronic kidney disease (estimated glomerular filtration rate less than 60 ml/min per 1.73 m2) was 5.8%. For each 10-g/day increase in total fiber intake, the odds of elevated serum C-reactive protein levels were decreased by 11% and 38% in those without and with kidney disease, respectively. Dietary total fiber intake was not significantly associated with mortality in those without but was inversely related to mortality in those with kidney disease. The relationship of total fiber with inflammation and mortality differed significantly in those with and without kidney disease. Thus, high dietary total fiber intake is associated with lower risk of inflammation and mortality in kidney disease and these associations are stronger in magnitude in those with kidney disease. Interventional trials are needed to establish the effects of fiber intake on inflammation and mortality in kidney disease. PMID:22012132

  12. The immune protective effect of the Mediterranean diet against chronic low-grade inflammatory diseases.

    PubMed

    Casas, Rosa; Sacanella, Emilio; Estruch, Ramon

    2014-01-01

    Dietary patterns high in refined starches, sugar, and saturated and trans-fatty acids, poor in natural antioxidants and fiber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines. The Mediterranean Diet (MedDiet) is a nutritional model inspired by the traditional dietary pattern of some of the countries of the Mediterranean basin. This dietary pattern is characterized by the abundant consumption of olive oil, high consumption of plant foods (fruits, vegetables, pulses, cereals, nuts and seeds); frequent and moderate intake of wine (mainly with meals); moderate consumption of fish, seafood, yogurt, cheese, poultry and eggs; and low consumption of red meat, processed meat products and seeds. Several epidemiological studies have evaluated the effects of a Mediterranean pattern as protective against several diseases associated with chronic low-grade inflammation such as cancer, diabetes, obesity, atherosclerosis, metabolic syndrome and cognition disorders. The adoption of this dietary pattern could counter the effects of several inflammatory markers, decreasing, for example, the secretion of circulating and cellular biomarkers involved in the atherosclerotic process. Thus, the aim of this review was to consider the current evidence about the effectiveness of the MedDiet in these chronic inflammatory diseases due to its antioxidant and anti-inflammatory properties, which may not only act on classical risk factors but also on inflammatory biomarkers such as adhesion molecules, cytokines or molecules related to the stability of atheromatic plaque. PMID:25244229

  13. The Immune Protective Effect of the Mediterranean Diet against Chronic Low-grade Inflammatory Diseases

    PubMed Central

    Casas, Rosa; Sacanella, Emilio; Estruch, Ramon

    2014-01-01

    Dietary patterns high in refined starches, sugar, and saturated and trans-fatty acids, poor in natural antioxidants and fiber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines. The Mediterranean Diet (MedDiet) is a nutritional model inspired by the traditional dietary pattern of some of the countries of the Mediterranean basin. This dietary pattern is characterized by the abundant consumption of olive oil, high consumption of plant foods (fruits, vegetables, pulses, cereals, nuts and seeds); frequent and moderate intake of wine (mainly with meals); moderate consumption of fish, seafood, yogurt, cheese, poultry and eggs; and low consumption of red meat, processed meat products and seeds. Several epidemiological studies have evaluated the effects of a Mediterranean pattern as protective against several diseases associated with chronic low-grade inflammation such as cancer, diabetes, obesity, atherosclerosis, metabolic syndrome and cognition disorders. The adoption of this dietary pattern could counter the effects of several inflammatory markers, decreasing, for example, the secretion of circulating and cellular biomarkers involved in the atherosclerotic process. Thus, the aim of this review was to consider the current evidence about the effectiveness of the MedDiet in these chronic inflammatory diseases due to its antioxidant and anti-inflammatory properties, which may not only act on classical risk factors but also on inflammatory biomarkers such as adhesion molecules, cytokines or molecules related to the stability of atheromatic plaque. PMID:25244229

  14. Circulating Biomarkers of Immune Activation, Oxidative Stress and Inflammation Characterize Severe Canine Visceral Leishmaniasis.

    PubMed

    Solcà, Manuela S; Andrade, Bruno B; Abbehusen, Melissa Moura Costa; Teixeira, Clarissa R; Khouri, Ricardo; Valenzuela, Jesus G; Kamhawi, Shaden; Bozza, Patrícia Torres; Fraga, Deborah Bittencourt Mothé; Borges, Valeria Matos; Veras, Patrícia Sampaio Tavares; Brodskyn, Claudia Ida

    2016-01-01

    Clinical manifestations in canine visceral leishmaniasis (CVL) have not been clearly associated with immunological status or disease progression. We simultaneously assessed biomarkers of inflammation, immune activation, oxidative stress, and anti-sand fly saliva IgG concentrations in dog sera with different clinical manifestations to characterize a biosignature associated with CVL severity. In a cross-sectional exploratory study, a random population of 70 dogs from an endemic area in Brazil was classified according to CVL clinical severity and parasitological evaluation. A panel of biomarkers and anti-sand fly saliva IgG were measured in canine sera. Assessment of protein expression of profile biomarkers identified a distinct biosignature that could cluster separately animal groups with different clinical scores. Increasing severity scores were associated with a gradual decrease of LTB4 and PGE2, and a gradual increase in CXCL1 and CCL2. Discriminant analyses revealed that combined assessment of LTB4, PGE2 and CXCL1 was able to distinguish dogs with different clinical scores. Dogs with the highest clinical score values also exhibited high parasite loads and higher concentrations of anti-saliva antibodies. Our findings suggest CVL clinical severity is tightly associated with a distinct inflammatory profile hallmarked by a differential expression of circulating eicosanoids and chemokines. PMID:27595802

  15. Circulating Biomarkers of Immune Activation, Oxidative Stress and Inflammation Characterize Severe Canine Visceral Leishmaniasis

    PubMed Central

    Solcà, Manuela S.; Andrade, Bruno B.; Abbehusen, Melissa Moura Costa; Teixeira, Clarissa R.; Khouri, Ricardo; Valenzuela, Jesus G.; Kamhawi, Shaden; Bozza, Patrícia Torres; Fraga, Deborah Bittencourt Mothé; Borges, Valeria Matos; Veras, Patrícia Sampaio Tavares; Brodskyn, Claudia Ida

    2016-01-01

    Clinical manifestations in canine visceral leishmaniasis (CVL) have not been clearly associated with immunological status or disease progression. We simultaneously assessed biomarkers of inflammation, immune activation, oxidative stress, and anti-sand fly saliva IgG concentrations in dog sera with different clinical manifestations to characterize a biosignature associated with CVL severity. In a cross-sectional exploratory study, a random population of 70 dogs from an endemic area in Brazil was classified according to CVL clinical severity and parasitological evaluation. A panel of biomarkers and anti–sand fly saliva IgG were measured in canine sera. Assessment of protein expression of profile biomarkers identified a distinct biosignature that could cluster separately animal groups with different clinical scores. Increasing severity scores were associated with a gradual decrease of LTB4 and PGE2, and a gradual increase in CXCL1 and CCL2. Discriminant analyses revealed that combined assessment of LTB4, PGE2 and CXCL1 was able to distinguish dogs with different clinical scores. Dogs with the highest clinical score values also exhibited high parasite loads and higher concentrations of anti-saliva antibodies. Our findings suggest CVL clinical severity is tightly associated with a distinct inflammatory profile hallmarked by a differential expression of circulating eicosanoids and chemokines. PMID:27595802

  16. Immunology and Homeopathy. 2. Cells of the Immune System and Inflammation

    PubMed Central

    Bellavite, Paolo; Conforti, Anita; Pontarollo, Francesco; Ortolani, Riccardo

    2006-01-01

    Here we describe the results of some experimental laboratory studies aimed at verifying the efficacy of high dilutions of substances and of homeopathic medicines in models of inflammation and immunity. Studies carried out on basophils, lymphocytes, granulocytes and fibroblasts are reviewed. This approach may help to test under controlled conditions the main principles of homeopathy such as ‘similarity’ of drug action at the cellular level and the effects of dilution/dynamization on the drug activity. The current situation is that few and rather small groups are working on laboratory models for homeopathy. Regarding the interpretation of data in view of the simile principle, we observe that there are different levels of similarity and that the laboratory data give support to this principle, but have not yet yielded the ultimate answer to the action mechanism of homeopathy. Evidence of the biological activity in vitro of highly diluted-dynamized solutions is slowly accumulating, with some conflicting reports. It is our hope that this review of literature unknown to most people will give an original and useful insight into the ‘state-of-the-art’ of homeopathy, without final conclusions ‘for’ or ‘against’ this modality. This kind of uncertainty may be difficult to accept, but is conceivably the most open-minded position now. PMID:16550219

  17. Neutrophils Self-Regulate Immune Complex-Mediated Cutaneous Inflammation through CXCL2.

    PubMed

    Li, Jackson LiangYao; Lim, Chun Hwee; Tay, Fen Wei; Goh, Chi Ching; Devi, Sapna; Malleret, Benoit; Lee, Bernett; Bakocevic, Nadja; Chong, Shu Zhen; Evrard, Maximilien; Tanizaki, Hideaki; Lim, Hwee Ying; Russell, Bruce; Renia, Laurent; Zolezzi, Francesca; Poidinger, Michael; Angeli, Veronique; St John, Ashley L; Harris, John E; Tey, Hong Liang; Tan, Suet Mien; Kabashima, Kenji; Weninger, Wolfgang; Larbi, Anis; Ng, Lai Guan

    2016-02-01

    Deposition of immune complexes (ICs) in tissues triggers acute inflammatory pathology characterized by massive neutrophil influx leading to edema and hemorrhage, and is especially associated with vasculitis of the skin, but the mechanisms that regulate this type III hypersensitivity process remain poorly understood. Here, using a combination of multiphoton intravital microscopy and genomic approaches, we re-examined the cutaneous reverse passive Arthus reaction and observed that IC-activated neutrophils underwent transmigration, triggered further IC formation, and transported these ICs into the interstitium, whereas neutrophil depletion drastically reduced IC formation and ameliorated vascular leakage in vivo. Thereafter, we show that these neutrophils expressed high levels of CXCL2, which further amplified neutrophil recruitment and activation in an autocrine and/or paracrine manner. Notably, CXCL1 expression was restricted to tissue-resident cell types, but IC-activated neutrophils may also indirectly, via soluble factors, modulate macrophage CXCL1 expression. Consistent with their distinct cellular origins and localization, only neutralization of CXCL2 but not CXCL1 in the interstitium effectively reduced neutrophil recruitment. In summary, our study establishes that neutrophils are able to self-regulate their own recruitment and responses during IC-mediated inflammation through a CXCL2-driven feed forward loop. PMID:26802238

  18. An Immune-Inflammation Gene Expression Signature in Prostate Tumors of Smokers.

    PubMed

    Prueitt, Robyn L; Wallace, Tiffany A; Glynn, Sharon A; Yi, Ming; Tang, Wei; Luo, Jun; Dorsey, Tiffany H; Stagliano, Katherine E; Gillespie, John W; Hudson, Robert S; Terunuma, Atsushi; Shoe, Jennifer L; Haines, Diana C; Yfantis, Harris G; Han, Misop; Martin, Damali N; Jordan, Symone V; Borin, James F; Naslund, Michael J; Alexander, Richard B; Stephens, Robert M; Loffredo, Christopher A; Lee, Dong H; Putluri, Nagireddy; Sreekumar, Arun; Hurwitz, Arthur A; Ambs, Stefan

    2016-03-01

    Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer-prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers. Cancer Res; 76(5); 1055-65. ©2015 AACR. PMID:26719530

  19. Influence of Hepatic Inflammation on FibroScan Findings in Diagnosing Fibrosis in Patients with Chronic Hepatitis B.

    PubMed

    Zeng, Xianghua; Xu, Cheng; He, Dengming; Zhang, Huiyan; Xia, Jie; Shi, Dairong; Kong, Lingjun; He, Xiaoqin; Wang, Yuming

    2015-06-01

    Hepatic inflammation may affect the performance of FibroScan. This prospective study investigated the influence of hepatic inflammation on liver stiffness measurement (LSM) values by assessing FibroScan and liver biopsy findings in 325 patients with chronic hepatitis B. Liver fibrosis and inflammation were classified into five stages (S0-S4) and grades (G0-G4) according to the Scheuer scoring system. LSM values were correlated with fibrosis stage and inflammation grade (r = 0.479, p < 0.001, and r = 0.522, p < 0.001, respectively). Although LSM values increased in parallel with inflammation grade, no significant differences were found between patients with significant fibrosis (S2-S4) (p > 0.05). For inflammation grades G0, G1, G2 and G3, areas under receiver operating characteristic curves of FibroScan for significant fibrosis were 0.8267 (p < 0.001), 0.6956 (p < 0.001), 0.709 (p = 0.0012) and 0.6947 (p = 0.137), respectively. Inflammation has a significant influence on LSM values in patients with chronic hepatitis B with mild fibrosis, but not in those with significant fibrosis. PMID:25724309

  20. Liver Fibrosis and Mechanisms of the Protective Action of Medicinal Plants Targeting Inflammation and the Immune Response

    PubMed Central

    Moreno-Cuevas, Jorge E.; González-Garza, María Teresa; Maldonado-Bernal, Carmen; Cruz-Vega, Delia Elva

    2015-01-01

    Inflammation is a central feature of liver fibrosis as suggested by its role in the activation of hepatic stellate cells leading to extracellular matrix deposition. During liver injury, inflammatory cells are recruited in the injurious site through chemokines attraction. Thus, inflammation could be a target to reduce liver fibrosis. The pandemic trend of obesity, combined with the high incidence of alcohol intake and viral hepatitis infections, highlights the urgent need to find accessible antifibrotic therapies. Medicinal plants are achieving popularity as antifibrotic agents, supported by their safety, cost-effectiveness, and versatility. The aim of this review is to describe the role of inflammation and the immune response in the pathogenesis of liver fibrosis and detail the mechanisms of inhibition of both events by medicinal plants in order to reduce liver fibrosis. PMID:25954568

  1. A role of NF-E2 in chronic inflammation and clonal evolution in essential thrombocythemia, polycythemia vera and myelofibrosis?

    PubMed

    Hasselbalch, Hans C

    2014-02-01

    A novel murine model for myeloproliferative neoplasms (MPNs) generated by overexpression of the transcription factor NF-E2 has recently been described. Sustained overexpression of NF-E2 in this model induced myeloid expansion with anemia, leukocytosis and thrombocytosis. Herein, it is debated if NF-E2 overexpression also might have induced a sustained state of in vivo leukocyte and platelet activation with chronic and self-perpetuating production of inflammatory products from activated leukocytes and platelets. If so, this novel murine model also may excellently describe the deleterious impact of sustained chronic NF-E2 overexpression during uncontrolled chronic inflammation upon the hematopoietic system--the development of clonal myeloproliferation. Accordingly, this novel murine model may also have delivered the proof of concept of chronic inflammation as a trigger and driver of clonal evolution in MPNs. PMID:23932394

  2. Assessment of Inflammation in an Acute on Chronic Model of Inflammatory Bowel Disease with Ultrasound Molecular Imaging

    PubMed Central

    Machtaler, Steven; Knieling, Ferdinand; Luong, Richard; Tian, Lu; Willmann, Jürgen K.

    2015-01-01

    Background: Ultrasound (US) molecular imaging has shown promise in assessing inflammation in preclinical, murine models of inflammatory bowel disease. These models, however, initiated acute inflammation on previously normal colons, in contrast to patients where acute exacerbations are often in chronically inflamed regions. In this study, we explored the potential of dual P- and E-selectin targeted US imaging for assessing acute inflammation on a murine quiescent chronic inflammatory background. Methods: Chronic colitis was induced using three cycles of 4% DSS in male FVB mice. Acute inflammation was initiated 2 weeks after the final DSS cycle through rectal administration of 1% TNBS. Mice at different stages of inflammation were imaged using a small animal ultrasound system following i.v. injection of microbubbles targeted to P- and E-selectin. In vivo imaging results were correlated with ex vivo immunofluorescence and histology. Results: Induction of acute inflammation resulted in an increase in the targeted US signal from 5.5 ± 5.1 arbitrary units (a.u.) at day 0 to 61.0 ± 45.2 a.u. (P < 0.0001) at day 1, 36.3 ± 33.1 a.u. at day 3, returning to levels similar to control at day 5. Immunofluorescence showed significant increase in the percentage of P- and E-selectin positive vessels at day 1 (P-selectin: 21.0 ± 7.1% of vessels; P < 0.05; E-selectin: 16.4 ±3.7%; P < 0.05) compared to day 0 (P-selectin: 10.3 ± 5.7%; E-selectin: 7.3 ± 7.0%). Conclusions: Acute inflammation can be accurately measured in a clinically relevant murine model of chronic IBD using ultrasound molecular imaging with a dual P- and E- selectin-targeted contrast agent. PMID:26379784

  3. Sirtuins Link Inflammation and Metabolism

    PubMed Central

    Vachharajani, Vidula T.; Liu, Tiefu; Wang, Xianfeng; Hoth, Jason J.; Yoza, Barbara K.; McCall, Charles E.

    2016-01-01

    Sirtuins (SIRT), first discovered in yeast as NAD+ dependent epigenetic and metabolic regulators, have comparable activities in human physiology and disease. Mounting evidence supports that the seven-member mammalian sirtuin family (SIRT1–7) guard homeostasis by sensing bioenergy needs and responding by making alterations in the cell nutrients. Sirtuins play a critical role in restoring homeostasis during stress responses. Inflammation is designed to “defend and mend” against the invading organisms. Emerging evidence supports that metabolism and bioenergy reprogramming direct the sequential course of inflammation; failure of homeostasis retrieval results in many chronic and acute inflammatory diseases. Anabolic glycolysis quickly induced (compared to oxidative phosphorylation) for ROS and ATP generation is needed for immune activation to “defend” against invading microorganisms. Lipolysis/fatty acid oxidation, essential for cellular protection/hibernation and cell survival in order to “mend,” leads to immune repression. Acute/chronic inflammations are linked to altered glycolysis and fatty acid oxidation, at least in part, by NAD+ dependent function of sirtuins. Therapeutically targeting sirtuins may provide a new class of inflammation and immune regulators. This review discusses how sirtuins integrate metabolism, bioenergetics, and immunity during inflammation and how sirtuin-directed treatment improves outcome in chronic inflammatory diseases and in the extreme stress response of sepsis. PMID:26904696

  4. Sirtuins Link Inflammation and Metabolism.

    PubMed

    Vachharajani, Vidula T; Liu, Tiefu; Wang, Xianfeng; Hoth, Jason J; Yoza, Barbara K; McCall, Charles E

    2016-01-01

    Sirtuins (SIRT), first discovered in yeast as NAD+ dependent epigenetic and metabolic regulators, have comparable activities in human physiology and disease. Mounting evidence supports that the seven-member mammalian sirtuin family (SIRT1-7) guard homeostasis by sensing bioenergy needs and responding by making alterations in the cell nutrients. Sirtuins play a critical role in restoring homeostasis during stress responses. Inflammation is designed to "defend and mend" against the invading organisms. Emerging evidence supports that metabolism and bioenergy reprogramming direct the sequential course of inflammation; failure of homeostasis retrieval results in many chronic and acute inflammatory diseases. Anabolic glycolysis quickly induced (compared to oxidative phosphorylation) for ROS and ATP generation is needed for immune activation to "defend" against invading microorganisms. Lipolysis/fatty acid oxidation, essential for cellular protection/hibernation and cell survival in order to "mend," leads to immune repression. Acute/chronic inflammations are linked to altered glycolysis and fatty acid oxidation, at least in part, by NAD+ dependent function of sirtuins. Therapeutically targeting sirtuins may provide a new class of inflammation and immune regulators. This review discusses how sirtuins integrate metabolism, bioenergetics, and immunity during inflammation and how sirtuin-directed treatment improves outcome in chronic inflammatory diseases and in the extreme stress response of sepsis. PMID:26904696

  5. Basophils as a primary inducer of the T helper type 2 immunity in ovalbumin-induced allergic airway inflammation

    PubMed Central

    Zhong, Wenwei; Su, Wen; Zhang, Yanjie; Liu, Qi; Wu, Jinhong; Di, Caixia; Zhang, Zili; Xia, Zhenwei

    2014-01-01

    Antigen-induced allergic airway inflammation is mediated by T helper type 2 (Th2) cells and their cytokines, but the mechanism that initiates the Th2 immunity is not fully understood. Recent studies show that basophils play important roles in initiating Th2 immunity in some inflammatory models. Here we explored the role of basophils in ovalbumin (OVA) -induced airway allergic inflammation in BALB/c mice. We found that OVA sensitization and challenge resulted in a significant increase in the amount of basophils in blood and lung, along with the up-regulation of activation marker of CD200R. However, depletion of basophils with MAR-1 or Ba103 antibody attenuated airway inflammation, represented by the significantly decreased amount of the Th2 subset in spleen and draining lymph nodes, interlukin-4 level in lung and OVA-special immunoglobulin E (sIgE) levels in serum. On the other hand, adoptive transfer of basophils from OVA-challenged lung tissue to naive BALB/c mice provoked the Th2 immune response. In addition, pulmonary basophils from OVA-challenged mice were able to uptake DQ-OVA and express MHC class II molecules and CD40 in vivo, as well as to release interleukin-4 following stimulation by IgE–antigen complexes and promote Th2 polarization in vitro. These findings demonstrate that basophils may participate in Th2 immune responses in antigen-induced allergic airway inflammation and that they do so through facilitating antigen presentation and providing interleukin-4. PMID:24383680

  6. Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer's disease models.

    PubMed

    Lonskaya, I; Hebron, M L; Selby, S T; Turner, R S; Moussa, C E-H

    2015-09-24

    Alzheimer's disease (AD) brains exhibit plaques and tangles in association with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro-inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish APP mutations (TgAPP) and display progressive Aβ plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to determine pre-plaque effects on systemic and CNS inflammation using milliplex® ELISA. Plaque Aβ was detected at 4months in TgAPP and pre-plaque intracellular Aβ accumulation (2.5months) was associated with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α, IL-1β) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-γ. An inverse relationship of chemokines was observed as CCL2 and CCL5 were lower than WT mice at 2months and significantly increased after plaque appearance, while soluble CX3CL1 decreased. A change in glial profile was only robustly detected at 6months in Tg-APP mice and TKIs reduced astrocyte and dendritic cell number with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased CX3CL1. Bosutinib increased brain and blood IL-10 and CX3CL1, suggesting a protective role for soluble CX3CL1. Taken together these data suggest that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation. PMID:26235435

  7. Effects of N2-laser radiation on the immune system cells of patients with chronic bronchitis

    NASA Astrophysics Data System (ADS)

    Provorov, Alexander S.; Kozhevnikova, T. A.; Salmin, Vladimir V.

    2001-05-01

    In spite of various investigations devoted to a problem of chronic bronchitis, many problems concerning both the reasons of the origin of this disease, and the essence of the processes, explicating in the bronchial tubes, especially on early stages of the disease, remain insufficiently studied. It makes it difficult to use an integrated approach to chronic bronchitis, that would reflect the peculiarities of its etiology, pathogenesis, its clinical course and efficiency of the therapy. During the last years the data of the clinical laboratory analysis of chronic bronchitis in connection with its immune therapy have been accumulated. In the literature there is a lot of information about the violation of immune reactions in the organism of patients, methods of the immune therapy, the data of the successful application of the intravenous laser therapy in the treatment of obstructive chronic bronchitis and bronchial asthma. However, there is no research explaining the mechanisms of the laser radiation impact on the immune status of patients suffering from chronic bronchitis. According to this it has become extremely urgent to research the mechanisms of the laser radiation impact on immune competent cells of patients suffering from chronic bronchitis.

  8. Antiviral Efficacy and Host Innate Immunity Associated with SB 9200 Treatment in the Woodchuck Model of Chronic Hepatitis B.

    PubMed

    Korolowicz, Kyle E; Iyer, Radhakrishnan P; Czerwinski, Stefanie; Suresh, Manasa; Yang, Junming; Padmanabhan, Seetharamaiyer; Sheri, Anjaneyulu; Pandey, Rajendra K; Skell, Jeffrey; Marquis, Judith K; Kallakury, Bhaskar V; Tucker, Robin D; Menne, Stephan

    2016-01-01

    SB 9200, an oral prodrug of the dinucleotide SB 9000, is being developed for the treatment of chronic hepatitis B virus (HBV) infection and represents a novel class of antivirals. SB 9200 is thought to activate the viral sensor proteins, retinoic acid-inducible gene 1 (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) resulting in interferon (IFN) mediated antiviral immune responses in virus-infected cells. Additionally, the binding of SB 9200 to these sensor proteins could also sterically block the ability of the viral polymerase to access pre-genomic RNA for nucleic acid synthesis. The immune stimulating and direct antiviral properties of SB 9200 were evaluated in woodchucks chronically infected with woodchuck hepatitis virus (WHV) by daily, oral dosing at 15 and 30 mg/kg for 12 weeks. Prolonged treatment resulted in 2.2 and 3.7 log10 reductions in serum WHV DNA and in 0.5 and 1.6 log10 declines in serum WHV surface antigen from pretreatment level with the lower or higher dose of SB 9200, respectively. SB 9200 treatment also resulted in lower hepatic levels of WHV nucleic acids and antigen and reduced liver inflammation. Following treatment cessation, recrudescence of viral replication was observed but with dose-dependent delays in viral relapse. The antiviral effects were associated with dose-dependent and long-lasting induction of IFN-α, IFN-β and IFN-stimulated genes in blood and liver, which correlated with the prolonged activation of the RIG-I/NOD2 pathway and hepatic presence of elevated RIG-I protein levels. These results suggest that in addition to a direct antiviral activity, SB 9200 induces antiviral immunity during chronic hepadnaviral infection via activation of the viral sensor pathway. PMID:27552102

  9. Antiviral Efficacy and Host Innate Immunity Associated with SB 9200 Treatment in the Woodchuck Model of Chronic Hepatitis B

    PubMed Central

    Korolowicz, Kyle E.; Iyer, Radhakrishnan P.; Czerwinski, Stefanie; Suresh, Manasa; Yang, Junming; Padmanabhan, Seetharamaiyer; Sheri, Anjaneyulu; Pandey, Rajendra K.; Skell, Jeffrey; Marquis, Judith K.; Kallakury, Bhaskar V.; Tucker, Robin D.; Menne, Stephan

    2016-01-01

    SB 9200, an oral prodrug of the dinucleotide SB 9000, is being developed for the treatment of chronic hepatitis B virus (HBV) infection and represents a novel class of antivirals. SB 9200 is thought to activate the viral sensor proteins, retinoic acid-inducible gene 1 (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) resulting in interferon (IFN) mediated antiviral immune responses in virus-infected cells. Additionally, the binding of SB 9200 to these sensor proteins could also sterically block the ability of the viral polymerase to access pre-genomic RNA for nucleic acid synthesis. The immune stimulating and direct antiviral properties of SB 9200 were evaluated in woodchucks chronically infected with woodchuck hepatitis virus (WHV) by daily, oral dosing at 15 and 30 mg/kg for 12 weeks. Prolonged treatment resulted in 2.2 and 3.7 log10 reductions in serum WHV DNA and in 0.5 and 1.6 log10 declines in serum WHV surface antigen from pretreatment level with the lower or higher dose of SB 9200, respectively. SB 9200 treatment also resulted in lower hepatic levels of WHV nucleic acids and antigen and reduced liver inflammation. Following treatment cessation, recrudescence of viral replication was observed but with dose-dependent delays in viral relapse. The antiviral effects were associated with dose-dependent and long-lasting induction of IFN-α, IFN-β and IFN-stimulated genes in blood and liver, which correlated with the prolonged activation of the RIG-I/NOD2 pathway and hepatic presence of elevated RIG-I protein levels. These results suggest that in addition to a direct antiviral activity, SB 9200 induces antiviral immunity during chronic hepadnaviral infection via activation of the viral sensor pathway. PMID:27552102

  10. [Understanding and treatment strategy of the pathogenesis of periodontal disease based on chronic inflammation].

    PubMed

    Murakami, Tomohiko

    2016-05-01

    Prolonged inflammation continuously promotes the infiltration of macrophages in the organization and chronically induces the production of pro-inflammatory cytokines such as TNF and IL-1. In periodontal tissues, these inflammatory cytokines enhance the differentiation and activity of osteoclasts, which cause destruction of the alveolar bone. Therefore, inhibition of inflammatory cytokine production leads to the prevention or treatment of periodontal disease. IL-1 is a pro-inflammatory cytokine that strongly enhances the bone-resorbing activity of osteoclasts. Elucidation of mechanisms for the production of IL-1 is critical for understanding the pathogenesis of periodontal disease. This paper reviews recent findings of the molecular mechanisms regulating IL-1 production and focuses on inflammasome. PMID:27117624

  11. Toll-like receptors and chronic inflammation in rheumatic diseases: new developments.

    PubMed

    Joosten, Leo A B; Abdollahi-Roodsaz, Shahla; Dinarello, Charles A; O'Neill, Luke; Netea, Mihai G

    2016-06-01

    In the past few years, new developments have been reported on the role of Toll-like receptors (TLRs) in chronic inflammation in rheumatic diseases. The inhibitory function of TLR10 has been demonstrated. Receptors that enhance the function of TLRs, and several TLR inhibitors, have been identified. In addition, the role of the microbiome and TLRs in the onset of rheumatic diseases has been reported. We review novel insights on the role of TLRs in several inflammatory joint diseases, including rheumatoid arthritis, systemic lupus erythematosus, gout and Lyme arthritis, with a focus on the signalling mechanisms mediated by the Toll-IL-1 receptor (TIR) domain, the exogenous and endogenous ligands of TLRs, and the current and future therapeutic strategies to target TLR signalling in rheumatic diseases. PMID:27170508

  12. Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

    SciTech Connect

    Olivas-Calderón, Edgar; Recio-Vega, Rogelio; Gandolfi, A. Jay; Lantz, R. Clark; González-Cortes, Tania; Gonzalez-De Alba, Cesar; Froines, John R.; Espinosa-Fematt, Jorge A.

    2015-09-01

    Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero has been associated with an increase in respiratory symptoms or diseases in the adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that the exposure to arsenic during early childhood or in utero in children was associated with impairment in the lung function and suggested that this adverse effect could be due to a chronic inflammation response to the metalloid. Therefore, we designed this cross-sectional study in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their arsenic urinary levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the soluble receptor for advanced glycation end products' (sRAGE) sputum level was significantly lower and matrix metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsonic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/tissue inhibitor of metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. Arsenic-induced alterations in inflammatory biomarkers may contribute to the development of restrictive lung diseases. - Highlights: • First study in children evaluating lung inflammatory biomarkers and As levels

  13. Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance

    PubMed Central

    Nishimoto, Sachiko; Fukuda, Daiju; Higashikuni, Yasutomi; Tanaka, Kimie; Hirata, Yoichiro; Murata, Chie; Kim-Kaneyama, Joo-ri; Sato, Fukiko; Bando, Masahiro; Yagi, Shusuke; Soeki, Takeshi; Hayashi, Tetsuya; Imoto, Issei; Sakaue, Hiroshi; Shimabukuro, Michio; Sata, Masataka

    2016-01-01

    Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9−/−) macrophages. Fat-fed Tlr9−/− mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9−/− mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography–determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance. PMID:27051864

  14. Chronic PM2.5 Exposure and Inflammation: Determining Sensitive Subgroups in Mid-life Women

    PubMed Central

    Ostro, Bart; Malig, Brian; Broadwin, Rachel; Basu, Rupa; Gold, Ellen B.; Bromberger, Joyce T.; Derby, Carol; Feinstein, Steven; Greendale, Gail A.; Jackson, Elizabeth A.; Kravitz, Howard M.; Matthews, Karen A.; Sternfeld, Barbara; Tomey, Kristin; Green, Robin R.; Green, Rochelle

    2015-01-01

    Background Several cohort studies report associations between chronic exposure to ambient fine particles (PM2.5) and cardiovascular mortality. Uncertainty exists about biological mechanisms responsible for this observation, but systemic inflammation has been postulated. In addition, the subgroups susceptible to inflammation have not been fully elucidated. Methods We investigated whether certain subgroups are susceptible to the effects of long-term exposure to PM2.5 on C-reactive protein (CRP), a marker of inflammation directly linked to subsequent cardiovascular disease. We used data from the SWAN cohort of 1,923 mid-life women with up to five annual repeated measures of CRP. Linear mixed and GEE models accounting for repeated measurements within an individual were used to estimate the effects of prior-year PM2.5 exposure on CRP. We examined CRP as a continuous and as binary outcome for CRP greater than 3 mg/l, a level of clinical significance. Results We found strong associations between PM2.5 and CRP among several subgroups. For example a 10 µg/m3 increase in annual PM2.5 more than doubled the risk of CRP greater than 3 mg/l in older diabetics, smokers and the unmarried. Larger effects were also observed among those with low income, high blood pressure, or who were using hormone therapy, with indications of a protective effects for those using statins or consuming moderate amounts of alcohol. Conclusions In this study, we observed significant associations between long-term exposure to PM2.5 and CRP in several susceptible subgroups. This suggests a plausible pathway by which exposure to particulate matter may be associated with increased risk of cardiovascular disease. PMID:24792413

  15. Effect of paricalcitol on endothelial function and inflammation in type 2 diabetes and chronic kidney disease

    PubMed Central

    Thethi, Tina K.; Bajwa, Muhammad A.; Ghanim, Husam; Jo, Chanhee; Weir, Monica; Goldfine, Allison B.; Umpierrez, Guillermo; Desouza, Cyrus; Dandona, Paresh; Fang-Hollingsworth, Ying; Raghavan, Vasudevan; Fonseca, Vivian A.

    2015-01-01

    Aims Patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD) have impaired endothelial function. Vitamin D and its analogs may play a role in regulation of endothelial function and inflammation. We studied effects of paricalcitol compared to placebo on endothelial function and markers of inflammation and oxidative stress in patients with T2DM and CKD. Methods A double blind, randomized, placebo-controlled trial was conducted in 60 patients with T2DM and stage 3 or 4 CKD. Paricalcitol 1 mcg or placebo was administered orally once daily for three months. Brachial artery flow mediated dilatation (FMD), nitroglycerine mediated dilation (NMD), and plasma concentrations of inflammatory cytokines, tumor necrosis factor –α and interleukin-6, highly-sensitive C-reactive protein; endothelial surface proteins, intercellular adhesion molecule –1 and monocyte chemo attractant protein-1, and plasma glucose, insulin, free fatty acids, and urinary isoprostane were measured at baseline and end of three months. Results 27 patients in the paricalcitol group and 28 patients in the control group completed the study, though analysis of FMD at both time points was possible in 23 patients in each group. There was no significant difference in the change in FMD, NMD or the biomarkers examined after paricalcitol or placebo treatment. Conclusions Treatment with paricalcitol at this dose and duration did not affect brachial artery FMD or biomarkers of inflammation and oxidative stress. The lack of significance may be due to the fact that the study patients had advanced CKD and that effects of paricalcitol are not additive to the effects of glycemic, lipid and anti-hypertensive therapies. PMID:25633573

  16. Characterisation of cochlear inflammation in mice following acute and chronic noise exposure.

    PubMed

    Tan, Winston J T; Thorne, Peter R; Vlajkovic, Srdjan M

    2016-08-01

    Oxidative stress has been established as the key mechanism of the cochlear damage underlying noise-induced hearing loss, however, emerging evidence suggests that cochlear inflammation may also be a major contributor. This study aimed to improve our understanding of the cochlear inflammatory response associated with acute and chronic noise exposure. C57BL/6 mice were exposed to acute traumatic noise (100 dBSPL, 8-16 kHz for 24 h) and their cochleae collected at various intervals thereafter, up to 7 days. Using quantitative RT-PCR and immunohistochemistry, changes in expression levels of proinflammatory cytokines (TNF-α, IL-1β), chemokines (CCL2) and cell adhesion molecules (ICAM-1) were studied. All gene transcripts displayed similar dynamics of expression, with an early upregulation at 6 h post-exposure, followed by a second peak at 7 days. ICAM-1 immunoexpression increased significantly in the inferior region of the spiral ligament, peaking 24 h post-exposure. The early expression of proinflammatory mediators likely mediates the recruitment and extravasation of inflammatory cells into the noise-exposed cochlea. The occurrence of the latter expression peak is not clear, but it may be associated with reparative processes initiated in response to cochlear damage. Chronic exposure to moderate noise (90 dBSPL, 8-16 kHz, 2 h/day, up to 4 weeks) also elicited an inflammatory response, reaching a maximum after 2 weeks, suggesting that cochlear damage and hearing loss associated with chronic environmental noise exposure may be linked to inflammatory processes in the cochlea. This study thus provides further insight into the dynamics of the cochlear inflammatory response induced by exposure to acute and chronic noise. PMID:27109494

  17. A gut microbiota-targeted dietary intervention for amelioration of chronic inflammation underlying metabolic syndrome

    PubMed Central

    Xiao, Shuiming; Fei, Na; Pang, Xiaoyan; Shen, Jian; Wang, Linghua; Zhang, Baorang; Zhang, Menghui; Zhang, Xiaojun; Zhang, Chenhong; Li, Min; Sun, Lifeng; Xue, Zhengsheng; Wang, Jingjing; Feng, Jie; Yan, Feiyan; Zhao, Naisi; Liu, Jiaqi; Long, Wenmin; Zhao, Liping

    2014-01-01

    Chronic inflammation induced by endotoxin from a dysbiotic gut microbiota contributes to the development of obesity-related metabolic disorders. Modification of gut microbiota by a diet to balance its composition becomes a promising strategy to help manage obesity. A dietary scheme based on whole grains, traditional Chinese medicinal foods, and prebiotics (WTP diet) was designed to meet human nutritional needs as well as balance the gut microbiota. Ninety-three of 123 central obese volunteers (BMI ≥ 28 kg m−2) completed a self-controlled clinical trial consisting of 9-week intervention on WTP diet followed by a 14-week maintenance period. The average weight loss reached 5.79 ± 4.64 kg (6.62 ± 4.94%), in addition to improvement in insulin sensitivity, lipid profiles, and blood pressure. Pyrosequencing of fecal samples showed that phylotypes related to endotoxin-producing opportunistic pathogens of Enterobacteriaceae and Desulfovibrionaceae were reduced significantly, while those related to gut barrier-protecting bacteria of Bifidobacteriaceae increased. Gut permeability, measured as lactulose/mannitol ratio, was decreased compared with the baseline. Plasma endotoxin load as lipopolysaccharide-binding protein was also significantly reduced, with concomitant decrease in tumor necrosis factor-α, interleukin-6, and an increase in adiponectin. These results suggest that modulation of the gut microbiota via dietary intervention may enhance the intestinal barrier integrity, reduce circulating antigen load, and ultimately ameliorate the inflammation and metabolic phenotypes. PMID:24117923

  18. Antileukotriene Reverts the Early Effects of Inflammatory Response of Distal Parenchyma in Experimental Chronic Allergic Inflammation

    PubMed Central

    Gobbato, Nathália Brandão; de Souza, Flávia Castro Ribas; Fumagalli, Stella Bruna Napolitano; Lopes, Fernanda Degobbi Tenório Quirino dos Santos; Prado, Carla Máximo; Martins, Milton Arruda; Tibério, Iolanda de Fátima Lopes Calvo; Leick, Edna Aparecida

    2013-01-01

    Aims. Compare the effects of montelukast or dexamethasone in distal lung parenchyma and airway walls of guinea pigs (GP) with chronic allergic inflammation. Methods. GP have inhaled ovalbumin (OVA group-2x/week/4weeks). After the 4th inhalation, GP were treated with montelukast or dexamethasone. After 72 hours of the 7th inhalation, GP were anesthetised, and lungs were removed and submitted to histopathological evaluation. Results. Montelukast and dexamethasone treatments reduced the number of eosinophils in airway wall and distal lung parenchyma compared to OVA group (P < 0.05). On distal parenchyma, both treatments were effective in reducing RANTES, NF-κB, and fibronectin positive cells compared to OVA group (P < 0.001). Montelukast was more effective in reducing eotaxin positive cells on distal parenchyma compared to dexamethasone treatment (P < 0.001), while there was a more expressive reduction of IGF-I positive cells in OVA-D group (P < 0.001). On airway walls, montelukast and dexamethasone were effective in reducing IGF-I, RANTES, and fibronectin positive cells compared to OVA group (P < 0.05). Dexamethasone was more effective in reducing the number of eotaxin and NF-κB positive cells than Montelukast (P < 0.05). Conclusions. In this animal model, both treatments were effective in modulating allergic inflammation and remodeling distal lung parenchyma and airway wall, contributing to a better control of the inflammatory response. PMID:24151607

  19. Chronic Inflammation and Neutrophil Activation as Possible Causes of Joint Diseases in Ballet Dancers

    PubMed Central

    Borges, Leandro da Silva; Santos, Vinicius Coneglian; de Moura, Nivaldo Ribeiro; Dermargos, Alexandre; Cury-Boaventura, Maria Fernanda; Gorjão, Renata; Pithon-Curi, Tania Cristina; Hatanaka, Elaine

    2014-01-01

    Herein, we investigated the effects of a ballet class on the kinetic profiles of creatine kinase (CK) and lactate dehydrogenase (LDH) activities, cytokines, complement component 3 (C3), and the concentrations of immunoglobulin (Ig), IgA and IgM, in ballerinas. We also verified neutrophil death and ROS release. Blood samples were taken from 13 dancers before, immediately after, and 18 hours after a ballet class. The ballet class increased the plasma activities of CK-total (2.0-fold) immediately after class, while the activities of CK-cardiac muscle (1.0-fold) and LDH (3.0-fold) were observed to increase 18 hours after the class. Levels of the TNF-α, IL-1β, IgG, and IgA were not affected under the study conditions. The exercise was found to induce neutrophil apoptosis (6.0-fold) 18 hours after the ballet class. Additionally, immediately after the ballet class, the neutrophils from the ballerinas were found to be less responsive to PMA stimulus. Conclusion. Ballet class was found to result in inflammation in dancers. The inflammation caused by the ballet class remained for 18 hours after the exercise. These findings are important in preventing the development of chronic lesions that are commonly observed in dancers, such as those with arthritis and synovitis. PMID:24701035

  20. Elevated [11C]-D-Deprenyl Uptake in Chronic Whiplash Associated Disorder Suggests Persistent Musculoskeletal Inflammation

    PubMed Central

    Linnman, Clas; Appel, Lieuwe; Fredrikson, Mats; Gordh, Torsten; Söderlund, Anne; Långström, Bengt; Engler, Henry

    2011-01-01

    There are few diagnostic tools for chronic musculoskeletal pain as structural imaging methods seldom reveal pathological alterations. This is especially true for Whiplash Associated Disorder, for which physical signs of persistent injuries to the neck have yet to be established. Here, we sought to visualize inflammatory processes in the neck region by means Positron Emission Tomography using the tracer 11C-D-deprenyl, a potential marker for inflammation. Twenty-two patients with enduring pain after a rear impact car accident (Whiplash Associated Disorder grade II) and 14 healthy controls were investigated. Patients displayed significantly elevated tracer uptake in the neck, particularly in regions around the spineous process of the second cervical vertebra. This suggests that whiplash patients have signs of local persistent peripheral tissue inflammation, which may potentially serve as a diagnostic biomarker. The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that 11C-D-deprenyl is a promising tracer for these purposes. PMID:21541010

  1. Elevated [11C]-D-deprenyl uptake in chronic Whiplash Associated Disorder suggests persistent musculoskeletal inflammation.

    PubMed

    Linnman, Clas; Appel, Lieuwe; Fredrikson, Mats; Gordh, Torsten; Söderlund, Anne; Långström, Bengt; Engler, Henry

    2011-01-01

    There are few diagnostic tools for chronic musculoskeletal pain as structural imaging methods seldom reveal pathological alterations. This is especially true for Whiplash Associated Disorder, for which physical signs of persistent injuries to the neck have yet to be established. Here, we sought to visualize inflammatory processes in the neck region by means Positron Emission Tomography using the tracer (11)C-D-deprenyl, a potential marker for inflammation. Twenty-two patients with enduring pain after a rear impact car accident (Whiplash Associated Disorder grade II) and 14 healthy controls were investigated. Patients displayed significantly elevated tracer uptake in the neck, particularly in regions around the spineous process of the second cervical vertebra. This suggests that whiplash patients have signs of local persistent peripheral tissue inflammation, which may potentially serve as a diagnostic biomarker. The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that (11)C-D-deprenyl is a promising tracer for these purposes. PMID:21541010

  2. Intravenous Bone Marrow Stem Cell Grafts Preferentially Migrate to Spleen and Abrogate Chronic Inflammation in Stroke

    PubMed Central

    Acosta, Sandra A.; Tajiri, Naoki; Hoover, Jaclyn; Kaneko, Yuji

    2015-01-01

    Background and Purpose— Adult stem cell therapy is an experimental stroke treatment. Here, we assessed homing and anti-inflammatory effects of bone marrow stromal cells (hBMSCs) in chronic stroke. Methods— At 60 days post stroke, adult Sprague–Dawley rats received intravenous hBMSCs (4×106 labeled or nonlabeled cells) or vehicle (saline). A sham surgery group served as additional control. In vivo imaging was conducted between 1 hour and 11 days post transplantation, followed by histological examination. Results— Labeled hBMSCs migrated to spleen which emitted significantly higher fluorescent signal across all time points, especially during the first hour, and were modestly detected in the head region at the 12 hours and 11 days, compared with nonlabeled hBMSCs and vehicle-infused stroke animals, or sham (P<0.05). At 11 days post transplantation, ex vivo imaging confirmed preferential hBMSC migration to the spleen over the brain. Hematoxylin and eosin staining revealed significant 15% and 30% reductions in striatal infarct and peri-infarct area, and a trend of rescue against neuronal loss in the hippocampus. Unbiased stereology showed significant 75% and 60% decrements in major histocompatibility complex II–activated inflammatory cells in gray and white matter, and a 43% diminution in tumor necrosis factor-α cell density in the spleen of transplanted stroke animals compared with vehicle-infused stroke animals (P<0.05). Human antigen immunostaining revealed 0.03% hBMSCs survived in spleen and only 0.0007% in brain. MSC migration to spleen, but not brain, inversely correlated with reduced infarct, peri-infarct, and inflammation. Conclusions— hBMSC transplantation is therapeutic in chronic stroke possibly by abrogating the inflammation-plagued secondary cell death. PMID:26219646

  3. Chronic Pelvic Inflammation Diminished Ovarian Reserve as Indicated by Serum Anti Mülerrian Hormone

    PubMed Central

    Cui, Linlin; Sheng, Yan; Sun, Mei; Hu, Jingmei; Qin, Yingying; Chen, Zi-Jiang

    2016-01-01

    Objective To explore the potential damaging effect of chronic pelvic inflammation on ovarian reserve. Design Case-control study. Patients A total of 122 women with bilateral tubal occlusion, diagnosed by hysterosalipingography (HSG) and 217 women with normal fallopians were recruited. Measurements Serum anti-Mullerian hormone (AMH), basic follicle-stimulating hormone (FSH), luteining hormone (LH), estradiol (E2), and testosterone (T) were measured; and antral follicle counts (AFCs) were recorded. Results Significantly lower level of AMH was observed in women with bilateral tubal occlusion compared to control group [2.62 (2.95) ng/ml vs. 3.37 (3.11) ng/ml, P = 0.03], and the difference remained after adjustment of BMI (Padjust = 0.04). However, no statistical difference was found in the levels of FSH [7.00 (2.16) IU/L vs. 6.74 (2.30) IU/L], LH [4.18 (1.52) IU/L vs. 4.63 (2.52) IU/L], E2 [35.95 (20.40) pg/ml vs. 34.90 (17.85) pg/ml], T [25.07±11.46 ng/dl vs. 24.84±12.75 ng/dl], and AFC [6.00 (4.00) vs. 7.00 (4.00)] between two groups (p>0.05). Conclusions Women with bilateral tubal occlusion showed decreased AMH level, suggesting that chronic pelvic inflammation may diminish ovarian reserve. More caution should be paid when evaluating the detriment of PID on female fertility. PMID:27272680

  4. Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance.

    PubMed

    Kim, Chong Jai; Romero, Roberto; Chaemsaithong, Piya; Kim, Jung-Sun

    2015-10-01

    Chronic inflammatory lesions of the placenta are characterized by the infiltration of the organ by lymphocytes, plasma cells, and/or macrophages and may result from infections (viral, bacterial, parasitic) or be of immune origin (maternal anti-fetal rejection). The 3 major lesions are villitis (when the inflammatory process affects the villous tree), chronic chorioamnionitis (which affects the chorioamniotic membranes), and chronic deciduitis (which involves the decidua basalis). Maternal cellular infiltration is a common feature of the lesions. Villitis of unknown etiology (VUE) is a destructive villous inflammatory lesion that is characterized by the infiltration of maternal T cells (CD8+ cytotoxic T cells) into chorionic villi. Migration of maternal T cells into the villi is driven by the production of T-cell chemokines in the affected villi. Activation of macrophages in the villi has been implicated in the destruction of the villous architecture. VUE has been reported in association with preterm and term fetal growth restriction, preeclampsia, fetal death, and preterm labor. Infants whose placentas have VUE are at risk for death and abnormal neurodevelopmental outcome at the age of 2 years. Chronic chorioamnionitis is the most common lesion in late spontaneous preterm birth and is characterized by the infiltration of maternal CD8+ T cells into the chorioamniotic membranes. These cytotoxic T cells can induce trophoblast apoptosis and damage the fetal membranes. The lesion frequently is accompanied by VUE. Chronic deciduitis consists of the presence of lymphocytes or plasma cells in the basal plate of the placenta. This lesion is more common in pregnancies that result from egg donation and has been reported in a subset of patients with premature labor. Chronic placental inflammatory lesions can be due to maternal anti-fetal rejection, a process associated with the development of a novel form of fetal systemic inflammatory response. The syndrome is characterized

  5. Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology

    PubMed Central

    Larsen, Jeppe M; Musavian, Hanieh S; Butt, Tariq M; Ingvorsen, Camilla; Thysen, Anna H; Brix, Susanne

    2015-01-01

    Recent studies of healthy human airways have revealed colonization by a distinct commensal bacterial microbiota containing Gram-negative Prevotella spp. However, the immunological properties of these bacteria in the respiratory system remain unknown. Here we compare the innate respiratory immune response to three Gram-negative commensal Prevotella strains (Prevotella melaninogenica, Prevotella nanceiensis and Prevotella salivae) and three Gram-negative pathogenic Proteobacteria known to colonize lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma (Haemophilus influenzae B, non-typeable Haemophilus influenzae and Moraxella catarrhalis). The commensal Prevotella spp. and pathogenic Proteobacteria were found to exhibit intrinsic differences in innate inflammatory capacities on murine lung cells in vitro. In vivo in mice, non-typeable H. influenzae induced severe Toll-like receptor 2 (TLR2)-independent COPD-like inflammation characterized by predominant airway neutrophilia, expression of a neutrophilic cytokine/chemokine profile in lung tissue, and lung immunopathology. In comparison, P. nanceiensis induced a diminished neutrophilic airway inflammation and no detectable lung pathology. Interestingly, the inflammatory airway response to the Gram-negative bacteria P. nanceiensis was completely TLR2-dependent. These findings demonstrate weak inflammatory properties of Gram-negative airway commensal Prevotella spp. that may make colonization by these bacteria tolerable by the respiratory immune system. PMID:25179236

  6. Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune-deficient mice.

    PubMed

    Hurez, Vincent; Dao, Vinh; Liu, Aijie; Pandeswara, Srilakshmi; Gelfond, Jonathan; Sun, Lishi; Bergman, Molly; Orihuela, Carlos J; Galvan, Veronica; Padrón, Álvaro; Drerup, Justin; Liu, Yang; Hasty, Paul; Sharp, Zelton Dave; Curiel, Tyler J

    2015-12-01

    The mammalian (mechanistic) target of rapamycin (mTOR) regulates critical immune processes that remain incompletely defined. Interest in mTOR inhibitor drugs is heightened by recent demonstrations that the mTOR inhibitor rapamycin extends lifespan and healthspan in mice. Rapamycin or related analogues (rapalogues) also mitigate age-related debilities including increasing antigen-specific immunity, improving vaccine responses in elderly humans, and treating cancers and autoimmunity, suggesting important new clinical applications. Nonetheless, immune toxicity concerns for long-term mTOR inhibition, particularly immunosuppression, persist. Although mTOR is pivotal to fundamental, important immune pathways, little is reported on immune effects of mTOR inhibition in lifespan or healthspan extension, or with chronic mTOR inhibitor use. We comprehensively analyzed immune effects of rapamycin as used in lifespan extension studies. Gene expression profiling found many and novel changes in genes affecting differentiation, function, homeostasis, exhaustion, cell death, and inflammation in distinct T- and B-lymphocyte and myeloid cell subpopulations. Immune functions relevant to aging and inflammation, and to cancer and infections, and innate lymphoid cell effects were validated in vitro and in vivo. Rapamycin markedly prolonged lifespan and healthspan in cancer- and infection-prone mice supporting disease mitigation as a mechanism for mTOR suppression-mediated longevity extension. It modestly altered gut metagenomes, and some metagenomic effects were linked to immune outcomes. Our data show novel mTOR inhibitor immune effects meriting further studies in relation to longevity and healthspan extension. PMID:26315673

  7. NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-κB-Dependent and -Independent Functions

    PubMed Central

    Vlantis, Katerina; Wullaert, Andy; Polykratis, Apostolos; Kondylis, Vangelis; Dannappel, Marius; Schwarzer, Robin; Welz, Patrick; Corona, Teresa; Walczak, Henning; Weih, Falk; Klein, Ulf; Kelliher, Michelle; Pasparakis, Manolis

    2016-01-01

    Summary Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor κB (NF-κB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-κB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD. PMID:26982364

  8. Single platelets seal neutrophil-induced vascular breaches via GPVI during immune-complex-mediated inflammation in mice.

    PubMed

    Gros, Angèle; Syvannarath, Varouna; Lamrani, Lamia; Ollivier, Véronique; Loyau, Stéphane; Goerge, Tobias; Nieswandt, Bernhard; Jandrot-Perrus, Martine; Ho-Tin-Noé, Benoît

    2015-08-20

    Platelets protect vascular integrity during inflammation. Recent evidence suggests that this action is independent of thrombus formation and requires the engagement of glycoprotein VI (GPVI), but it remains unclear how platelets prevent inflammatory bleeding. We investigated whether platelets and GPVI act primarily by preventing detrimental effects of neutrophils using models of immune complex (IC)-mediated inflammation in mice immunodepleted in platelets and/or neutrophils or deficient in GPVI. Depletion of neutrophils prevented bleeding in thrombocytopenic and GPVI(-/-) mice during IC-mediated dermatitis. GPVI deficiency did not modify neutrophil recruitment, which was reduced by thrombocytopenia. Neutrophil cytotoxic activities were reduced in thrombocytopenic and GPVI(-/-) mice during IC-mediated inflammation. Intravital microscopy revealed that in this setting, intravascular binding sites for platelets were exposed by neutrophils, and GPVI supported the recruitment of individual platelets to these spots. Furthermore, the platelet secretory response accompanying IC-mediated inflammation was partly mediated by GPVI, and blocking of GPVI signaling impaired the vasculoprotective action of platelets. Together, our results show that GPVI plays a dual role in inflammation by enhancing neutrophil-damaging activities while supporting the activation and hemostatic adhesion of single platelets to neutrophil-induced vascular breaches. PMID:26036804

  9. Cell death and inflammation: the case for IL-1 family cytokines as the canonical DAMPs of the immune system.

    PubMed

    Martin, Seamus J

    2016-07-01

    It is well known that necrotic cells are capable of promoting inflammation through releasing so-called endogenous 'danger signals' that can promote activation of macrophages, dendritic cells, and other sentinel cells of the innate immune system. However, the identity of these endogenous proinflammatory molecules, also called damage-associated molecular patterns (DAMPs), has been debated since the 'danger model' was first advanced 20 years ago. While a relatively large number of molecules have been proposed to act as DAMPs, little consensus has emerged concerning which of these represent the key activators of sterile inflammation. Here I argue that the canonical DAMPs have long been hiding in plain sight, in the form of members of the extended IL-1 cytokine family (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ). The latter cytokines possess all of the characteristics expected of endogenous DAMPs and initiate inflammation in a manner strikingly similar to that utilized by the other major category of inflammatory triggers, pathogen-associated molecular patterns (PAMPs). Furthermore, many PAMPs upregulate the expression of IL-1 family DAMPs, enabling robust synergy between these distinct classes of inflammatory triggers. Thus, multiple lines of evidence now suggest that IL-1 family cytokines represent the key initiators of necrosis-initiated sterile inflammation, as well as amplifiers of inflammation in response to infection-associated tissue injury. PMID:27273805

  10. The combination of high-fat diet-induced obesity and chronic ulcerative colitis reciprocally exacerbates adipose tissue and colon inflammation

    PubMed Central

    2011-01-01

    Background This study evaluated the relationship between ulcerative colitis and obesity, which are both chronic diseases characterized by inflammation and increases in immune cells and pro-inflammatory cytokines. Methods Mice with chronic ulcerative colitis induced by 2 cycles of dextran sodium sulfate (DSS) in the first and fourth week of the experiment were fed a high-fat diet (HFD) to induce obesity by 8 weeks. The animals were divided into 4 \\ groups (control, colitis, HFD and colitis + HFD). Results Obesity alone did not raise histopathology scores, but the combination of obesity and colitis worsened the scores in the colon compared to colitis group. Despite the reduction in weight gain, there was increased inflammatory infiltrate in both the colon and visceral adipose tissue of colitis + HFD mice due to increased infiltration of macrophages, neutrophils and lymphocytes. Intravital microscopy of VAT microvasculature showed an increase in leukocyte adhesion and rolling and overexpression of adhesion molecules compared to other groups. Moreover, circulating lymphocytes, monocytes and neutrophils in the spleen and cecal lymph nodes were increased in the colitis + HFD group. Conclusion Our results demonstrated the relationship between ulcerative colitis and obesity as aggravating factors for each disease, with increased inflammation in the colon and adipose tissue and systemic alterations observed in the spleen, lymph nodes and bloodstream. PMID:22073943

  11. Green tea polyphenols mitigate bone loss of female rats in a chronic inflammation-induced bone loss model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of this study was to explore bioavailability, efficacy, and molecular mechanisms of green tea polyphenols (GTP) related to preventing bone loss in rats with chronic inflammation. A 2 (placebo vs. lipopolysaccharide, LPS) × 2 (no GTP vs. 0.5% GTP in drinking water) factorial design using ...

  12. Protective actions of green tea polyphenols and alfacalcidol on bone microstructure in female rats with chronic inflammation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study investigated the effects of green tea polyphenols (GTP) and alfacalcidol on bone microstructure and strength along with possible mechanisms in rats with chronic inflammation. A 12-week study using a 2 (no GTP vs. 0.5%, w/v GTP in drinking water) × 2 (no alfacalcidol vs. 0.05 ug/kg alfacal...

  13. Behavioral and monoamine perturbations in adult male mice with chronic inflammation induced by repeated peripheral lipopolysaccharide administration.

    PubMed

    Krishna, Saritha; Dodd, Celia A; Filipov, Nikolay M

    2016-04-01

    Considering the limited information on the ability of chronic peripheral inflammation to induce behavioral alterations, including on their persistence after inflammatory stimuli termination and on associated neurochemical perturbations, this study assessed the effects of chronic (0.25 mg/kg; i.p.; twice weekly) lipopolysaccharide (LPS) treatment on selected behavioral, neurochemical and molecular measures at different time points in adult male C57BL/6 mice. Behaviorally, LPS-treated mice were hypoactive after 6 weeks, whereas significant hyperactivity was observed after 12 weeks of LPS and 11 weeks after 13 week LPS treatment termination. Similar biphasic responses, i.e., early decrease followed by a delayed increase were observed in the open field test center time, suggestive of, respectively, increased and decreased anxiety. In a forced swim test, mice exhibited increased immobility (depressive behavior) at all times they were tested. Chronic LPS also produced persistent increase in splenic serotonin (5-HT) and time-dependent, brain region-specific alterations in striatal and prefrontocortical dopamine and 5-HT homeostasis. Microglia, but not astrocytes, were activated by LPS early and late, but their activation did not persist after LPS treatment termination. Above findings demonstrate that chronic peripheral inflammation initially causes hypoactivity and increased anxiety, followed by persistent hyperactivity and decreased anxiety. Notably, chronic LPS-induced depressive behavior appears early, persists long after LPS termination, and is associated with increased splenic 5-HT. Collectively, our data highlight the need for a greater focus on the peripheral/central monoamine alterations and lasting behavioral deficits induced by chronic peripheral inflammation as there are many pathological conditions where inflammation of a chronic nature is a hallmark feature. PMID:26802725

  14. Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment.

    PubMed

    Modiano, Jaime F; Lindborg, Beth A; McElmurry, Ron T; Lewellen, Mitzi; Forster, Colleen L; Zamora, Edward A; Schaack, Jerome; Bellgrau, Donald; O'Brien, Timothy D; Tolar, Jakub

    2015-11-01

    The potential of mesenchymal stromal cells (MSCs) to inhibit anti-tumor immunity is becoming increasingly well recognized, but the precise steps affected by these cells during the development of an anti-tumor immune response remain incompletely understood. Here, we examined how MSCs affect the steps required to mount an effective anti-tumor immune response following administration of adenovirus Fas ligand (Ad-FasL) in the Lewis lung carcinoma (LL3) model. Administration of bone marrow-derived MSCs with LL3 cells accelerated tumor growth significantly. MSCs inhibited the inflammation induced by Ad-FasL in the primary tumors, precluding their rejection; MSCs also reduced the consequent expansion of tumor-specific T cells in the treated hosts. When immune T cells were transferred to adoptive recipients, MSCs impaired, but did not completely abrogate the ability of these T cells to promote elimination of secondary tumors. This impairment was associated with a modest reduction in tumor-infiltrating T cells, with a significant reduction in tumor-infiltrating macrophages, and with a reorganization of the stromal environment. Our data indicate that MSCs in the tumor environment reduce the efficacy of immunotherapy by creating a functional and anatomic barrier that impairs inflammation, T cell priming and expansion, and T cell function-including recruitment of effector cells. PMID:26250807

  15. Immune-mediated Skin Inflammation is Similar in Severe Atopic Dermatitis Patients With or Without Filaggrin Mutation.

    PubMed

    Dajnoki, Zsolt; Béke, Gabriella; Mócsai, Gábor; Kapitány, Anikó; Gáspár, Krisztián; Hajdu, Krisztina; Emri, Gabriella; Nagy, Bence; Kovács, Ilona; Beke, Lívia; Dezső, Balázs; Szegedi, Andrea

    2016-06-15

    Inflammatory cytokines can impair the skin barrier, but the question as to whether barrier alterations affect keratinocyte immune responses remains unanswered. The aim of this study was to investigate whether immune-mediated skin inflammation differs between severe atopic dermatitis patients with or without filaggrin mutation. The levels of filaggrin, inflammatory T helper 2 polarizing cytokines (thymic stromal lymphopoietin (TSLP) and interleukin 33 (IL-33)) and chemokine (C-C motif) ligand 27 (CCL27), histological severity markers, T and dendritic cell counts in biopsies from lesional skin of severe atopic dermatitis patients with and without filaggrin mutation and healthy skin were quantified by immunohistochemistry. The results were confirmed by quantitative PCR analyses. No significant differences were found between the 2 patient groups. Expression of atopic dermatitis-specific cytokines showed significant correlation with histological severity. These findings suggest that the immune-mediated skin inflammation (represented by keratinocyte-derived factors, T cell and dendritic cell counts) is similar in the 2 patient groups with severe atopic dermatitis, and that immune activation is connected to the severity of the disease rather than to the origin of barrier alterations. PMID:26536977

  16. Airways inflammation in subjects with chronic bronchitis who have never smoked.

    PubMed Central

    Lusuardi, M.; Capelli, A.; Cerutti, C. G.; Spada, E. L.; Donner, C. F.

    1994-01-01

    ). The release of O2- both at baseline and after opsonised zymosan phagocytosis did not show any differences. Correlation analysis between FEV1 and BAL fluid data showed a negative correlation only with neutrophils/ml. CONCLUSIONS--Clinically stable non-smokers with chronic bronchitis show no alterations of local immune components, oxidant burden, and free elastase-like activity in BAL fluids, while the content of elastase-like activity in phagocytic cells is increased. As in smokers, bronchial neutrophilia is the most significant cellular modification which correlates with the degree of airflow obstruction. PMID:7878554

  17. Correlation of alkaline phosphatase activity to clinical parameters of inflammation in smokers suffering from chronic periodontitis

    PubMed Central

    Grover, Vishakha; Malhotra, Ranjan; Kapoor, Anoop; Bither, Rupika; Sachdeva, Sonia

    2016-01-01

    Context: Current clinical periodontal diagnostic techniques emphasize the assessment of clinical and radiographic signs of periodontal diseases which can provide a measure of history of disease. Hence, new methodologies for early identification and determination of periodontal disease activity need to be explored which will eventually result in expedited treatment. Aim: To evaluate the correlation of alkaline phosphatase (ALP) activity in gingival crevicular fluid (GCF) to clinical parameters of periodontal inflammation in smokers with chronic periodontitis. Materials and Methods: Study population included 15 smoker male patients in the age group of 35–55 years suffering from moderate generalized chronic periodontitis with history of smoking present. Following parameters were evaluated at baseline, 1 month and 3 months after scaling and root planing: plaque index, bleeding index, probing pocket depth (PD), relative attachment level (RAL), and GCF ALP activity. Statistical Analysis Used: Independent variables for measurements over time were analyzed by using Wilcoxon signed rank test. Results: A statistically significant reduction in all the clinical parameters and GCF ALP activity was observed from baseline to 1 month and 3 months. A correlation was observed between change in GCF ALP activity and PD reduction as well as gain in RAL at 3 months. Conclusion: The present study emphasizes that total ALP activity could be used as a marker for periodontal disease activity in smokers. Estimation of changes in the levels of this enzyme has a potential to aid in the detection of progression of periodontal disease and monitoring the response to periodontal therapy. PMID:27563197

  18. Collagenase-3 (matrix metalloproteinase-13) expression is induced in oral mucosal epithelium during chronic inflammation.

    PubMed Central

    Uitto, V. J.; Airola, K.; Vaalamo, M.; Johansson, N.; Putnins, E. E.; Firth, J. D.; Salonen, J.; López-Otín, C.; Saarialho-Kere, U.; Kähäri, V. M.

    1998-01-01

    Increased proliferation of mucosal epithelium during inflammation is associated with degradation of subepithelial connective tissue matrix and local invasion of the epithelial cells. Here we have studied, whether collagenase-3 (MMP-13), a collagenolytic matrix metalloproteinase with an exceptionally wide substrate specificity, is expressed in the epithelium of chronically inflamed mucosa. Examination of human gingival tissue sections from subjects with chronic adult periodontitis with in situ hybridization revealed marked expression of MMP-13 in basal cells of some epithelial rete ridges expanding into connective tissue. Immunohistochemical staining demonstrated that these cells also expressed strongly laminin-5, suggesting that they are actively migrating cells. A strong signal for MMP-13 mRNA was occasionally also noted in the suprabasal epithelial cells facing the gingival pocket, whereas no collagenase-1 (MMP-1) mRNA was detected in any areas of the epithelium. MMP-13 expression was also detected in fibroblast-like cells associated with collagen fibers of the inflamed subepithelial connective tissue. In organ culture of human oral mucosa, MMP-13 mRNA expression was observed in epithelial cells growing into connective tissue of the specimens. Regulation of MMP-13 expression was examined in cultured normal nonkeratinizing epithelial cells isolated from porcine periodontal ligament. In these cells, MMP-13 expression at the mRNA and protein level was potently enhanced (up to sixfold) by tumor necrosis factor-alpha, transforming growth factor-beta(1), and transforming growth factor-alpha and by keratinocyte growth factor in the presence of heparin. In addition, plating periodontal ligament epithelial cells on type I collagen stimulated MMP-13 expression (sevenfold) as compared with cells grown on tissue culture plastic. The results of this study show, that expression of MMP-13 is specifically induced in undifferentiated epithelial cells during chronic inflammation

  19. Natural Health Products, Modulation of Immune Function and Prevention of Chronic Diseases

    PubMed Central

    2005-01-01

    The immune system is increasingly found to be involved in the development of several chronic illnesses, for which allopathic medicine has provided limited tools for treatment and especially prevention. In that context, it appears worthwhile to target the immune system in order to modulate the risk of certain chronic illnesses. Meanwhile, natural health products (NHPs) are generating renewed interest, particularly in the prevention and treatment of several chronic diseases. Over 20 scientists from fields related to immune function and NHPs were thus convened to establish the state of knowledge on these subjects and to explore future research directions. This review summarizes the result of discussions held during the symposium. It thus seeks to be thought provoking rather than to comprehensively cover such broad areas of research. Notably, a brief overview of the immune system is presented, including potentially useful targets and strategies to keep it in an equilibrated state, in order to prevent certain disorders. The pertinence and limitations of targeting the immune system to prevent chronic diseases is also discussed. The paper then discusses the usefulness and limitations of current experimental tools available to study the immune modulating effects of NHPs. Finally, a concise review of some of the most studied NHPs showing promising immunomodulatory activity is given, and avenues for future research are described. PMID:16322809

  20. Montelukast versus Dexamethasone Treatment in a Guinea Pig Model of Chronic Pulmonary Neutrophilic Inflammation.

    PubMed

    Abdel Kawy, Hala S

    2016-08-01

    Airway inflammation in chronic obstructive pulmonary disease (COPD) is refractory to corticosteroids and hence COPD treatment is hindered and insufficient. This study assessed the effects of oral treatment with Montelukast (10 and 30 mg/kg) or dexamethasone (20 mg/kg) for 20 days on COPD model induced by chronic exposure to lipopolysaccharide (LPS). Six groups of male guinea pigs were studied. Group 1: naïve group, group 2: exposed to saline nebulization. Groups 3, 4, 5, and 6: exposed to 9 nebulizations of LPS (30 μg/ml) for 1 hour, 48 hours apart with or without treatment with Montelukast or dexamethasone. Airway hyperreactivity (AHR) to methacholine (MCh), histopathological study and bronchoalveolar lavage fluid (BALF) as well as lung tissue analyses were performed 48 hours after the final exposure to LPS (day 20). LPS-induced pulmonary dysfunction was associated with increased neutrophil count, leukotriene (LT) B4, and tumor necrosis factor (TNF)-α in BALF. Moreover, there was an increase in malondialdehyde (MDA) level and a decrease in histone deacetylases(HDAC) activity in the lung tissue. Both Montelukast (10 or 30 mg /kg) and dexamethasone significantly reduced neutrophil count in BALF and inflammatory cells in lung parenchyma as well as TNF-α, and MDA levels. However, dexamethasone was more effective (p < 0.05). Montelukast, at a dose of 30 mg /kg, significantly reduced specific airway resistance after the 9th LPS exposure, attenuated AHR to MCh, decreased LTB4 and increased HDAC activity in comparison to dexamethasone. These results suggest that treatment with Montelukast can be useful in chronic airway inflammatory diseases including COPD poorly responsive to glucocorticoids. PMID:26751767

  1. Chronic Inflammation and Angiogenic Signaling Axis Impairs Differentiation of Dental-Pulp Stem Cells

    PubMed Central

    Boyle, Michael; Chun, Crystal; Strojny, Chelsee; Narayanan, Raghuvaran; Bartholomew, Amelia; Sundivakkam, Premanand; Alapati, Satish

    2014-01-01

    Dental-pulp tissue is often exposed to inflammatory injury. Sequested growth factors or angiogenic signaling proteins that are released following inflammatory injury play a pivotal role in the formation of reparative dentin. While limited or moderate angiogenesis may be helpful for dental pulp maintenance, the induction of significant level of angiogenesis is probably highly detrimental. Hitherto, several studies have addressed the effects of proinflammatory stimuli on the survival and differentiation of dental-pulp stem cells (DPSC), in vitro. However, the mechanisms communal to the inflammatory and angiogenic signaling involved in DPSC survival and differentiation remain unknown. Our studies observed that short-term exposure to TNF-α (6 and 12 hours [hrs]) induced apoptosis with an upregulation of VEGF expression and NF-κB signaling. However, long-term (chronic) exposure (14 days) to TNF-α resulted in an increased proliferation with a concomitant shortening of the telomere length. Interestingly, DPSC pretreated with Nemo binding domain (NBD) peptide (a cell permeable NF-κB inhibitor) significantly ameliorated TNF-α- and/or VEGF-induced proliferation and the shortening of telomere length. NBD peptide pretreatment significantly improved TNF-α-induced downregulation of proteins essential for differentiation, such as bone morphogenic proteins (BMP)-1 & 2, BMP receptor isoforms-1&2, trasnforming growth factor (TGF), osteoactivin and osteocalcin. Additionally, inhibition of NF-κB signaling markedly increased the mineralization potential, a process abrogated by chronic exposure to TNF-α. Thus, our studies demonstrated that chronic inflammation mediates telomere shortening via NF-κB signaling in human DPSC. Resultant chromosomal instability leads to an emergence of increased proliferation of DPSC, while negatively regulating the differentiation of DPSC, in vitro. PMID:25427002

  2. Fc Gamma Receptor Signaling in Mast Cells Links Microbial Stimulation to Mucosal Immune Inflammation in the Intestine

    PubMed Central

    Chen, Xiao; Feng, Bai-Sui; Zheng, Peng-Yuan; Liao, Xue-Qing; Chong, Jasmine; Tang, Shang-Guo; Yang, Ping-Chang

    2008-01-01

    Microbes and microbial products are closely associated with the pathogenesis of inflammatory bowel disease (IBD); however, the mechanisms behind this connection remain unclear. It has been previously reported that flagellin-specific antibodies are increased in IBD patient sera. As mastocytosis is one of the pathological features of IBD, we hypothesized that flagellin-specific immune responses might activate mast cells that then contribute to the initiation and maintenance of intestinal inflammation. Thirty-two colonic biopsy samples were collected from IBD patients. A flagellin/flagellin-specific IgG/Fc gamma receptor I complex was identified on biopsied mast cells using both immunohistochemistry and co-immunoprecipitation experiments; this complex was shown to co-localize on the surfaces of mast cells in the colonic mucosa of patients with IBD. In addition, an ex vivo study showed flagellin-IgG was able to bind to human mast cells. These cells were found to be sensitized to flagellin-specific IgG; re-exposure to flagellin induced the mast cells to release inflammatory mediators. An animal model of IBD was then used to examine flagellin-specific immune responses in the intestine. Mice could be sensitized to flagellin, and repeated challenges with flagellin induced an IBD-like T helper 1 pattern of intestinal inflammation that could be inhibited by pretreatment with anti-Fc gamma receptor I antibodies. Therefore, flagellin-specific immune responses activate mast cells in the intestine and play important roles in the pathogenesis of intestinal immune inflammation. PMID:18974296

  3. The Innate Immune System in Acute and Chronic Wounds

    PubMed Central

    MacLeod, Amanda S.; Mansbridge, Jonathan N.

    2016-01-01

    Significance: This review article provides an overview of the critical roles of the innate immune system to wound healing. It explores aspects of dysregulation of individual innate immune elements known to compromise wound repair and promote nonhealing wounds. Understanding the key mechanisms whereby wound healing fails will provide seed concepts for the development of new therapeutic approaches. Recent Advances: Our understanding of the complex interactions of the innate immune system in wound healing has significantly improved, particularly in our understanding of the role of antimicrobials and peptides and the nature of the switch from inflammatory to reparative processes. This takes place against an emerging understanding of the relationship between human cells and commensal bacteria in the skin. Critical Issues: It is well established and accepted that early local inflammatory mediators in the wound bed function as an immunological vehicle to facilitate immune cell infiltration and microbial clearance upon injury to the skin barrier. Both impaired and excessive innate immune responses can promote nonhealing wounds. It appears that the switch from the inflammatory to the proliferative phase is tightly regulated and mediated, at least in part, by a change in macrophages. Defining the factors that initiate the switch in such macrophage phenotypes and functions is the subject of multiple investigations. Future Directions: The review highlights processes that may be useful targets for further investigation, particularly the switch from M1 to M2 macrophages that appears to be critical as dysregulation of this switch occurs during defective wound healing. PMID:26862464

  4. CXCL10-Mediates Macrophage, but not Other Innate Immune Cells-Associated Inflammation in Murine Nonalcoholic Steatohepatitis

    PubMed Central

    Tomita, Kyoko; Freeman, Brittany L.; Bronk, Steven F.; LeBrasseur, Nathan K.; White, Thomas A.; Hirsova, Petra; Ibrahim, Samar H.

    2016-01-01

    Nonalcoholic steatohepatitis (NASH) is an inflammatory lipotoxic disorder, but how inflammatory cells are recruited and activated within the liver is still unclear. We previously reported that lipotoxic hepatocytes release CXCL10-enriched extracellular vesicles, which are potently chemotactic for cells of the innate immune system. In the present study, we sought to determine the innate immune cell involved in the inflammatory response in murine NASH and the extent to which inhibition of the chemotactic ligand CXCL10 and its cognate receptor CXCR3 could attenuate liver inflammation, injury and fibrosis. C57BL/6J CXCL10−/−, CXCR3−/− and wild type (WT) mice were fed chow or high saturated fat, fructose, and cholesterol (FFC) diet. FFC-fed CXCL10−/− and WT mice displayed similar weight gain, metabolic profile, insulin resistance, and hepatic steatosis. In contrast, compared to the WT mice, FFC-fed CXCL10−/− mice had significantly attenuated liver inflammation, injury and fibrosis. Genetic deletion of CXCL10 reduced FFC-induced proinflammatory hepatic macrophage infiltration, while natural killer cells, natural killer T cells, neutrophils and dendritic cells hepatic infiltration were not significantly affected. Our results suggest that CXCL10−/− mice are protected against diet-induced NASH, in an obesity-independent manner. Macrophage-associated inflammation appears to be the key player in the CXCL10-mediated sterile inflammatory response in murine NASH. PMID:27349927

  5. Regulation of chronic inflammatory and immune processes by extracellular vesicles.

    PubMed

    Robbins, Paul D; Dorronsoro, Akaitz; Booker, Cori N

    2016-04-01

    Almost all cell types release extracellular vesicles (EVs), which are derived either from multivesicular bodies or from the plasma membrane. EVs contain a subset of proteins, lipids, and nucleic acids from the cell from which they are derived. EV factors, particularly small RNAs such as miRNAs, likely play important roles in cell-to-cell communication both locally and systemically. Most of the functions associated with EVs are in the regulation of immune responses to pathogens and cancer, as well as in regulating autoimmunity. This Review will focus on the different modes of immune regulation, both direct and indirect, by EVs. The therapeutic utility of EVs for the regulation of immune responses will also be discussed. PMID:27035808

  6. Metal-Based Nanoparticles and the Immune System: Activation, Inflammation, and Potential Applications

    PubMed Central

    Luo, Yueh-Hsia; Chang, Louis W.; Lin, Pinpin

    2015-01-01

    Nanomaterials, including metal-based nanoparticles, are used for various biological and medical applications. However, metals affect immune functions in many animal species including humans. Different physical and chemical properties induce different cellular responses, such as cellular uptake and intracellular biodistribution, leading to the different immune responses. The goals of this review are to summarize and discuss the innate and adaptive immune responses triggered by metal-based nanoparticles in a variety of immune system models. PMID:26125021

  7. Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity.

    PubMed

    Lang, Philipp A; Lang, Karl S; Xu, Haifeng C; Grusdat, Melanie; Parish, Ian A; Recher, Mike; Elford, Alisha R; Dhanji, Salim; Shaabani, Namir; Tran, Charles W; Dissanayake, Dilan; Rahbar, Ramtin; Ghazarian, Magar; Brüstle, Anne; Fine, Jason; Chen, Peter; Weaver, Casey T; Klose, Christoph; Diefenbach, Andreas; Häussinger, Dieter; Carlyle, James R; Kaech, Susan M; Mak, Tak W; Ohashi, Pamela S

    2012-01-24

    Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease. Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus. NK cell-deficient (Nfil3(-/-), E4BP4(-/-)) mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILE-infected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore, we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection. PMID:22167808

  8. Chronic lung inflammation in victims of toxic gas leak at Bhopal.

    PubMed

    Vijayan, V K; Sankaran, K; Sharma, S K; Misra, N P

    1995-02-01

    Bronchoalveolar lavage (BAL) studies in 20 patients at Bhopal, 1.3 +/- 0.4 yr and 2.7 +/- 0.6 yr after toxic gas exposure had revealed that the lower respiratory tract inflammation had progressed from initial macrophage alveolitis to macrophage-neutrophilic alveolitis. The interval between the two lavages was 1.4 +/- 0.6 yr. BAL studies in a new group of 24 patients 5.1 +/- 1.0 yr after exposure had confirmed chronic inflammation of the lower respiratory tract as evidenced by macrophage-neutrophilic alveolitis in these subjects as well. Clinical, radiographic and pulmonary function abnormalities were persistent in a proportion of subjects in both groups. Fibronectin (FN) levels were estimated in BAL fluid in 41 patients. Elevated FN levels were seen in 12 (29.3%) subjects and nine of these 12 had radiographic abnormalities. Severely exposed subjects (n = 30) had significantly higher BAL fibronectin levels compared to normal subjects and mild/moderately exposed subjects. Repeat FN estimations in BAL samples from 10 patients had revealed that five had abnormally high FN including three who had high FN on both occasions. The number of patients showing abnormal decline in pulmonary function was higher in patients with elevated FN than in patients with normal FN. Thus, persisting clinical, roentgenographic and ventilatory abnormalities, as well as macrophage-neutrophilic alveolitis along with abnormally elevated FN levels in a proportion of subjects, suggest the possibility that lung fibrosis can occur in subjects exposed to toxic gas at Bhopal. PMID:7708994

  9. Key mechanisms governing resolution of lung inflammation.

    PubMed

    Robb, C T; Regan, K H; Dorward, D A; Rossi, A G

    2016-07-01

    Innate immunity normally provides excellent defence against invading microorganisms. Acute inflammation is a form of innate immune defence and represents one of the primary responses to injury, infection and irritation, largely mediated by granulocyte effector cells such as neutrophils and eosinophils. Failure to remove an inflammatory stimulus (often resulting in failed resolution of inflammation) can lead to chronic inflammation resulting in tissue injury caused by high numbers of infiltrating activated granulocytes. Successful resolution of inflammation is dependent upon the removal of these cells. Under normal physiological conditions, apoptosis (programmed cell death) precedes phagocytic recognition and clearance of these cells by, for example, macrophages, dendritic and epithelial cells (a process known as efferocytosis). Inflammation contributes to immune defence within the respiratory mucosa (responsible for gas exchange) because lung epithelia are continuously exposed to a multiplicity of airborne pathogens, allergens and foreign particles. Failure to resolve inflammation within the respiratory mucosa is a major contributor of numerous lung diseases. This review will summarise the major mechanisms regulating lung inflammation, including key cellular interplays such as apoptotic cell clearance by alveolar macrophages and macrophage/neutrophil/epithelial cell interactions. The different acute and chronic inflammatory disease states caused by dysregulated/impaired resolution of lung inflammation will be discussed. Furthermore, the resolution of lung inflammation during neutrophil/eosinophil-dominant lung injury or enhanced resolution driven via pharmacological manipulation will also be considered. PMID:27116944

  10. Isoliquiritigenin Attenuates Adipose Tissue Inflammation in vitro and Adipose Tissue Fibrosis through Inhibition of Innate Immune Responses in Mice

    PubMed Central

    Watanabe, Yasuharu; Nagai, Yoshinori; Honda, Hiroe; Okamoto, Naoki; Yamamoto, Seiji; Hamashima, Takeru; Ishii, Yoko; Tanaka, Miyako; Suganami, Takayoshi; Sasahara, Masakiyo; Miyake, Kensuke; Takatsu, Kiyoshi

    2016-01-01

    Isoliquiritigenin (ILG) is a flavonoid derived from Glycyrrhiza uralensis and potently suppresses NLRP3 inflammasome activation resulting in the improvement of diet-induced adipose tissue inflammation. However, whether ILG affects other pathways besides the inflammasome in adipose tissue inflammation is unknown. We here show that ILG suppresses adipose tissue inflammation by affecting the paracrine loop containing saturated fatty acids and TNF-α by using a co-culture composed of adipocytes and macrophages. ILG suppressed inflammatory changes induced by the co-culture through inhibition of NF-κB activation. This effect was independent of either inhibition of inflammasome activation or activation of peroxisome proliferator-activated receptor-γ. Moreover, ILG suppressed TNF-α-induced activation of adipocytes, coincident with inhibition of IκBα phosphorylation. Additionally, TNF-α-mediated inhibition of Akt phosphorylation under insulin signaling was alleviated by ILG in adipocytes. ILG suppressed palmitic acid-induced activation of macrophages, with decreasing the level of phosphorylated Jnk expression. Intriguingly, ILG improved high fat diet-induced fibrosis in adipose tissue in vivo. Finally, ILG inhibited TLR4- or Mincle-stimulated expression of fibrosis-related genes in stromal vascular fraction from obese adipose tissue and macrophages in vitro. Thus, ILG can suppress adipose tissue inflammation by both inflammasome-dependent and -independent manners and attenuate adipose tissue fibrosis by targeting innate immune sensors. PMID:26975571

  11. Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction.

    PubMed

    Hu, Xia; Adebiyi, Morayo G; Luo, Jialie; Sun, Kaiqi; Le, Thanh-Thuy T; Zhang, Yujin; Wu, Hongyu; Zhao, Shushan; Karmouty-Quintana, Harry; Liu, Hong; Huang, Aji; Wen, Yuan Edward; Zaika, Oleg L; Mamenko, Mykola; Pochynyuk, Oleh M; Kellems, Rodney E; Eltzschig, Holger K; Blackburn, Michael R; Walters, Edgar T; Huang, Dong; Hu, Hongzhen; Xia, Yang

    2016-06-28

    The molecular mechanisms of chronic pain are poorly understood and effective mechanism-based treatments are lacking. Here, we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected chronic mechanical and thermal hypersensitivity due to sustained elevated circulating adenosine. Extending from Ada(-/-) mice, we further discovered that prolonged elevated adenosine contributed to chronic pain behaviors in two additional independent animal models: sickle cell disease mice, a model of severe pain with limited treatment, and complete Freund's adjuvant paw-injected mice, a well-accepted inflammatory model of chronic pain. Mechanistically, we revealed that activation of adenosine A2B receptors on myeloid cells caused nociceptor hyperexcitability and promoted chronic pain via soluble IL-6 receptor trans-signaling, and our findings determined that prolonged accumulated circulating adenosine contributes to chronic pain by promoting immune-neuronal interaction and revealed multiple therapeutic targets. PMID:27320922

  12. Nonresolving Inflammation in gp91phox-/- Mice, a Model of Human Chronic Granulomatous Disease, Has Lower Adenosine and Cyclic Adenosine 5′-Monophoshate

    PubMed Central

    Rajakariar, Ravindra; Newson, Justine; Jackson, Edwin K.; Sawmynaden, Precilla; Smith, Andrew; Rahman, Farooq; Yaqoob, Muhammad M; Gilroy, Derek W

    2009-01-01

    In chronic granulomatous disease (CGD) there is failure to generate reactive oxygen metabolites resulting in recurrent infections and persistent inflammatory events. As responses to sterile stimuli in murine models of CGD also result in non-resolving inflammation, we investigated whether defects in endogenous counter-regulatory mechanisms and/or pro-resolution pathways contribute to the aetiology of CGD. To this end we carried out a series of experiments finding, in the first instance that adenosine and cAMP, which dampen innate immune-mediated responses, show a biphasic profile in resolving peritonitis; peaking at onset, waning as inflammation progresses and rising again at resolution. We also found elevations in adenosine and cAMP in resolving human peritonitis. In gp91phox-/- mice, an experimental model of CGD, levels of adenosine and cAMP were significantly lower at onset and again at resolution. Corroborating the finding of others, we show that adenosine, signalling through its A2A receptor and therefore elevating cAMP is not only anti-inflammatory but, importantly, it does not impair pro-resolution pathways, properties typical of nonsteroidal anti-inflammatory drugs. Conversely, antagonising the A2A receptor worsens acute inflammation and prolongs resolution. Taking this further, activating the A2A receptor in gp91phox-/- mice was dramatically anti-inflammatory regardless of the phase of the inflammatory response A2A agonists were administered i.e. onset or resolution demonstrating wide and robust pharmacological flexibility that is unlikely to subvert pro-resolution pathways. Therefore, we describe the biphasic profile of adenosine and cAMP throughout the time course of acute inflammation that is dysregulated in CGD. PMID:19234224

  13. Possible role of Escherichia coli in propagation and perpetuation of chronic inflammation in ulcerative colitis

    PubMed Central

    2013-01-01

    Background This study investigated a possible role of Escherichia coli in propagation and perpetuation of the chronic inflammation in ulcerative colitis (UC). The lesions of UC are located superficially on the rectal and/or colonic mucosa. It is suggested that the commensal bacteria of the digestive tract may play a role in the pathogenesis of UC. Several studies have demonstrated proliferation of E. coli in the gut of UC patients. An increase in the number of E. coli in the inflamed tissue is most probably related to the abundance of iron ions produced by the bacteria. Methods Colon mucosal biopsies were collected from 30 patients with acute-phase UC, both from tissues with inflammatory changes (n = 30) and unchanged tissue with no inflammatory changes (n = 30) from the same patient. Biopsies were also taken from 16 patients with irritable bowel syndrome diarrhea who comprised the control group. Quantitative and qualitative analysis of the biopsy specimens was performed using culture methods and real-time polymerase chain reaction (PCR). Genotyping of the E. coli isolates was done using pulsed-field gel electrophoresis. Multiplex PCR was used to compare the E. coli strains for the presence of genes responsible for synthesis of iron acquisition proteins: iroN, iutA, iha, ireA, chuA, and hlyA. Results We demonstrated that there was a significant increase in the number of E. coli at the sites of inflammation in patients with UC compared to the control group (P = 0.031). Comparative analysis of the restriction patterns of E. coli isolated from inflammatory and unchanged tissues showed that the local inflammatory changes did not promote specific E. coli strains. There was a significant difference in the frequency of the iroN gene in E. coli isolated from patients with UC as compared to the control group. Conclusions The increase in the numbers of E. coli in the inflammatory tissues is related to the presence of chuA and iutA genes, which facilitate iron acquisition

  14. Caloric Restriction reduces inflammation and improves T cell-mediated immune response in obese mice but concomitant consumption of curcumin/piperine adds no further benefit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is associated with low-grade inflammation and impaired immune response. Caloric restriction (CR) has been shown to inhibit inflammatory response and enhance cell-mediated immune function. Curcumin, the bioactive phenolic component of turmeric spice, is proposed to have anti-obesity and anti-...

  15. Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non obese humans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Calorie restriction (CR) inhibits inflammation and slows aging in many animal species, but in rodents housed in pathogen-free facilities, CR impairs immunity against certain pathogens. However, little is known about the effects of long-term moderate CR on immune function in humans. In this multi-cen...

  16. Clec4A4 is a regulatory receptor for dendritic cells that impairs inflammation and T-cell immunity

    PubMed Central

    Uto, Tomofumi; Fukaya, Tomohiro; Takagi, Hideaki; Arimura, Keiichi; Nakamura, Takeshi; Kojima, Naoya; Malissen, Bernard; Sato, Katsuaki

    2016-01-01

    Dendritic cells (DCs) comprise several subsets that are critically involved in the initiation and regulation of immunity. Clec4A4/DC immunoreceptor 2 (DCIR2) is a C-type lectin receptor (CLR) exclusively expressed on CD8α− conventional DCs (cDCs). However, how Clec4A4 controls immune responses through regulation of the function of CD8α− cDCs remains unclear. Here we show that Clec4A4 is a regulatory receptor for the activation of CD8α− cDCs that impairs inflammation and T-cell immunity. Clec4a4−/−CD8α− cDCs show enhanced cytokine production and T-cell priming following Toll-like receptor (TLR)-mediated activation. Furthermore, Clec4a4−/− mice exhibit TLR-mediated hyperinflammation. On antigenic immunization, Clec4a4−/− mice show not only augmented T-cell responses but also progressive autoimmune pathogenesis. Conversely, Clec4a4−/− mice exhibit resistance to microbial infection, accompanied by enhanced T-cell responses against microbes. Thus, our findings highlight roles of Clec4A4 in regulation of the function of CD8α− cDCs for control of the magnitude and quality of immune response. PMID:27068492

  17. BCR-ABL transcript variations in chronic phase chronic myelogenous leukemia patients on imatinib first-line: Possible role of the autologous immune system.

    PubMed

    Clapp, Geoffrey D; Lepoutre, Thomas; Nicolini, Franck E; Levy, Doron

    2016-05-01

    Many chronic myelogenous leukemia (CML) patients in chronic phase who respond well to imatinib therapy show fluctuations in their leukemic loads in the long-term. We developed a mathematical model of CML that incorporates the intervention of an autologous immune response. Our results suggest that the patient's immune system plays a crucial role in imatinib therapy in maintaining disease control over time. The observed BCR-ABL/ABL oscillations in such patients provide a signature of the autologous immune response. PMID:27467931

  18. Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

    PubMed Central

    Olivas-Calderón, Edgar; Recio-Vega, Rogelio; Gandolfi, A. Jay; Lantz, R. Clark; González-Cortes, Tania; Alba, Cesar Gonzalez-De; Froines, John R.; Espinosa-Fematt, Jorge A.

    2016-01-01

    Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero is associated with an increase in respiratory symptoms and diseases in adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that exposure to arsenic during early childhood or in utero was associated with impairment in the lung function in children and suggested that this adverse effect could be due to a chronic inflammatory response to the metalloid. Therefore, a cross-sectional study was designed in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their As levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the Soluble Receptor for Advanced Glycation Endproducts (sRAGE) sputum level was significantly lower and Matrix Metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsenic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/Tissue Inhibitor of Metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. PMID:26048584

  19. Comparison of Watermelon and Carbohydrate Beverage on Exercise-Induced Alterations in Systemic Inflammation, Immune Dysfunction, and Plasma Antioxidant Capacity

    PubMed Central

    Shanely, R. Andrew; Nieman, David C.; Perkins-Veazie, Penelope; Henson, Dru A.; Meaney, Mary P.; Knab, Amy M.; Cialdell-Kam, Lynn

    2016-01-01

    Consuming carbohydrate- and antioxidant-rich fruits during exercise as a means of supporting and enhancing both performance and health is of interest to endurance athletes. Watermelon (WM) contains carbohydrate, lycopene, l-citrulline, and l-arginine. WM may support exercise performance, augment antioxidant capacity, and act as a countermeasure to exercise-induced inflammation and innate immune changes. Trained cyclists (n = 20, 48 ± 2 years) participated in a randomized, placebo controlled, crossover study. Subjects completed two 75 km cycling time trials after either 2 weeks ingestion of 980 mL/day WM puree or no treatment. Subjects drank either WM puree containing 0.2 gm/kg carbohydrate or a 6% carbohydrate beverage every 15 min during the time trials. Blood samples were taken pre-study and pre-, post-, 1 h post-exercise. WM ingestion versus no treatment for 2-weeks increased plasma l-citrulline and l-arginine concentrations (p < 0.0125). Exercise performance did not differ between WM puree or carbohydrate beverage trials (p > 0.05), however, the rating of perceived exertion was greater during the WM trial (p > 0.05). WM puree versus carbohydrate beverage resulted in a similar pattern of increase in blood glucose, and greater increases in post-exercise plasma antioxidant capacity, l-citrulline, l-arginine, and total nitrate (all p < 0.05), but without differences in systemic markers of inflammation or innate immune function. Daily WM puree consumption fully supported the energy demands of exercise, and increased post-exercise blood levels of WM nutritional components (l-citrulline and l-arginine), antioxidant capacity, and total nitrate, but without an influence on post-exercise inflammation and changes in innate immune function. PMID:27556488

  20. Comparison of Watermelon and Carbohydrate Beverage on Exercise-Induced Alterations in Systemic Inflammation, Immune Dysfunction, and Plasma Antioxidant Capacity.

    PubMed

    Shanely, R Andrew; Nieman, David C; Perkins-Veazie, Penelope; Henson, Dru A; Meaney, Mary P; Knab, Amy M; Cialdell-Kam, Lynn

    2016-01-01

    Consuming carbohydrate- and antioxidant-rich fruits during exercise as a means of supporting and enhancing both performance and health is of interest to endurance athletes. Watermelon (WM) contains carbohydrate, lycopene, l-citrulline, and l-arginine. WM may support exercise performance, augment antioxidant capacity, and act as a countermeasure to exercise-induced inflammation and innate immune changes. Trained cyclists (n = 20, 48 ± 2 years) participated in a randomized, placebo controlled, crossover study. Subjects completed two 75 km cycling time trials after either 2 weeks ingestion of 980 mL/day WM puree or no treatment. Subjects drank either WM puree containing 0.2 gm/kg carbohydrate or a 6% carbohydrate beverage every 15 min during the time trials. Blood samples were taken pre-study and pre-, post-, 1 h post-exercise. WM ingestion versus no treatment for 2-weeks increased plasma l-citrulline and l-arginine concentrations (p < 0.0125). Exercise performance did not differ between WM puree or carbohydrate beverage trials (p > 0.05), however, the rating of perceived exertion was greater during the WM trial (p > 0.05). WM puree versus carbohydrate beverage resulted in a similar pattern of increase in blood glucose, and greater increases in post-exercise plasma antioxidant capacity, l-citrulline, l-arginine, and total nitrate (all p < 0.05), but without differences in systemic markers of inflammation or innate immune function. Daily WM puree consumption fully supported the energy demands of exercise, and increased post-exercise blood levels of WM nutritional components (l-citrulline and l-arginine), antioxidant capacity, and total nitrate, but without an influence on post-exercise inflammation and changes in innate immune function. PMID:27556488

  1. Development and Validation of an Animal Model of Prostate Inflammation-Induced Chronic Pelvic Pain: Evaluating from Inflammation of the Prostate to Pain Behavioral Modifications

    PubMed Central

    Zeng, Feng; Chen, Hequn; Yang, Jinrui; Wang, Long; Cui, Yu; Guan, Xiao; Wang, Zhao; Niu, Jiping; Zu, Xiongbing; Qi, Lin; Zhang, Xiangyang; Tang, Zhengyan; Liu, Longfei

    2014-01-01

    Background Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) is the most common type of prostatitis. Due to the lack of a suitable animal model partly, the pathogenesis for this condition is obscure. In the current study we developed and validated an animal model for nonbacterial prostatitis and prostate inflammation-induced chronic pelvic pain in rats with the use of intraprostatic injection of λ-carrageenan. Methods Male Sprague-Dawley rats weighing 250–350 g were used for the experiments. After intraprostatic injection of 3% λ-carrageenan, at different time points(after 24 h, 7d, 14d and 30d of injection), radiant heat and von Frey filaments were applied to the scrotum of rats to measure the heat and mechanical thresholds respectively. Then the prostate was removed for histology, and cyclooxygenase (COX) 2 protein expression was determined by Western-blot. Evans blue(50 mg/kg) was also injected intravenously to assess for plasma protein extravasation at different time points after injection of λ-carrageenan. Results Compared to control group, inflamed animals showed a significant reduction in mechanical threshold (mechanical allodynia) at 24 h and 7d(p = 0.022,0.046, respectively), and a significant reduction in heat threshold (thermal hyperalgesia) at 24 h, 7d and 14d(p = 0.014, 0.018, 0.002, respectively) in the scrotal skin. Significant increase of inflammatory cell accumulation,COX2 expression and Evans blue extravasation were observed at 24 h, 7d and 14d after injection. Conclusions Intraprostatic λ-carrageenan injection induced neurogenic prostatitis and prostate inflammation pain, which lasted at least 2 weeks. The current model is expected to be a valuable preclinical tool to study the neurobiological mechanisms of male chronic pelvic pain. PMID:24823660

  2. Systemic Inflammation, Nutritional Status and Tumor Immune Microenvironment Determine Outcome of Resected Non-Small Cell Lung Cancer

    PubMed Central

    Alifano, Marco; Mansuet-Lupo, Audrey; Lococo, Filippo; Roche, Nicolas; Bobbio, Antonio; Canny, Emelyne; Schussler, Olivier; Dermine, Hervé; Régnard, Jean-François; Burroni, Barbara; Goc, Jérémy; Biton, Jérôme; Ouakrim, Hanane; Cremer, Isabelle; Dieu-Nosjean, Marie-Caroline; Damotte, Diane

    2014-01-01

    Background Hypothesizing that nutritional status, systemic inflammation and tumoral immune microenvironment play a role as determinants of lung cancer evolution, the purpose of this study was to assess their respective impact on long-term survival in resected non-small cell lung cancers (NSCLC). Methods and Findings Clinical, pathological and laboratory data of 303 patients surgically treated for NSCLC were retrospectively analyzed. C-reactive protein (CRP) and prealbumin levels were recorded, and tumoral infiltration by CD8+ lymphocytes and mature dendritic cells was assessed. We observed that factors related to nutritional status, systemic inflammation and tumoral immune microenvironment were correlated; significant correlations were also found between these factors and other relevant clinical-pathological parameters. With respect to outcome, at univariate analysis we found statistically significant associations between survival and the following variables: Karnofsky index, American Society of Anesthesiologists (ASA) class, CRP levels, prealbumin concentrations, extent of resection, pathologic stage, pT and pN parameters, presence of vascular emboli, and tumoral infiltration by either CD8+ lymphocytes or mature dendritic cells and, among adenocarcinoma type, tumor grade (all p<0.05). In multivariate analysis, prealbumin levels (Relative Risk (RR): 0.34 [0.16–0.73], p = 0.0056), CD8+ cell count in tumor tissue (RR = 0.37 [0.16–0.83], p = 0.0162), and disease stage (RR 1.73 [1.03–2.89]; 2.99[1.07–8.37], p = 0.0374- stage I vs II vs III-IV) were independent prognostic markers. When taken together, parameters related to systemic inflammation, nutrition and tumoral immune microenvironment allowed robust prognostic discrimination; indeed patients with undetectable CRP, high (>285 mg/L) prealbumin levels and high (>96/mm2) CD8+ cell count had a 5-year survival rate of 80% [60.9–91.1] as compared to 18% [7.9–35.6] in patients with an opposite

  3. Dietary supplementation of an ellagic acid-enriched pomegranate extract attenuates chronic colonic inflammation in rats.

    PubMed

    Rosillo, Maria Angeles; Sánchez-Hidalgo, Marina; Cárdeno, Ana; Aparicio-Soto, Marina; Sánchez-Fidalgo, Susana; Villegas, Isabel; de la Lastra, Catalina Alarcón

    2012-09-01

    Dietary polyphenols present in Punica granatum (pomegranate), such as ellagitannins and ellagic acid (EA) have shown to exert anti-inflammatory and antioxidant properties. This study was designed to evaluate the effects of a dietary EA-enriched pomegranate extract (PE) in a murine chronic model of Cronh's disease (CD). Colonic injury was induced by intracolonic instillation of trinitrobenzensulfonic acid (TNBS). Rats were fed with different diets during 30 days before TNBS instillation and 2 weeks before killing: (i) standard, (ii) PE 250 mg/kg/day, (iii) PE 500 mg/kg/day, (iv) EA 10 mg/kg/day and (v) EA 10 mg/kg/day enriched-PE 250 mg/kg/day. Inflammation response was assessed by histology and MPO activity and TNF-α production. Besides, colonic expressions of iNOS, COX-2, p38, JNK, pERK1/2 MAPKs, IKBα and nuclear p65 NF-κB were studied by western blotting. MPO activity and the TNF-α levels were significantly reduced in dietary fed rats when compared with TNBS group. Similarly, PE and an EA-enriched PE diets drastically decreased COX-2 and iNOS overexpression, reduced MAPKs phosporylation and prevented the nuclear NF-κB translocation. Dietary supplementation of EA contributes in the beneficial effect of PE in this experimental colitis model and may be a novel therapeutic strategy to manage inflammatory bowel disease (IBD). PMID:22677088

  4. New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis.

    PubMed

    Hugo, Honor J; Saunders, C; Ramsay, R G; Thompson, E W

    2015-12-01

    The medicinal use of aspirin stretches back to ancient times, before it was manufactured in its pure form in the late 19th century. Its accepted mechanistic target, cyclooxygenase (COX), was discovered in the 1970s and since this landmark discovery, the therapeutic application of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has increased dramatically. The most significant benefits of NSAIDs are in conditions involving chronic inflammation (CI). Given the recognized role of CI in cancer development, the use of long-term NSAID treatment in the prevention of cancer is an enticing possibility. COX-2 is a key driver of CI, and here we review COX-2 expression as a predictor of survival in various cancer types, including breast. Obesity and post-partum involution are natural inflammatory states that are associated with increased breast cancer risk. We outline the COX-2 mediated mechanisms contributing to the growth of cancers. We dissect the cellular mechanism of epithelial-mesenchymal transition (EMT) and how COX-2 may induce this to facilitate tumor progression. Finally we examine the potential regulation of COX-2 by c-Myb, and the possible interplay between c-Myb/COX-2 in proliferation, and hypoxia inducible factor-1 alpha (HIF1α)/COX-2 in invasive pathways in breast cancer. PMID:26193871

  5. Rabbit chronic ileitis leads to up-regulation of adenosine A1/A3 gene products, oxidative stress, and immune modulation.

    PubMed

    Sundaram, Uma; Hassanain, Hamdy; Suntres, Zacharias; Yu, Jun Ge; Cooke, Helen J; Guzman, Jorge; Christofi, Fievos L

    2003-05-01

    A rabbit model of chronic ileitis has helped decipher the mechanism of alteration of multiple electrolyte and nutrient malabsorptions in inflammatory bowel disease (IBD). This study examined alterations in the adenosine A1/A3 receptor, oxidant, antioxidant, and immune-inflammatory pathways in chronic ileitis. Chronic ileal inflammation was induced 13-15 days after infection with 10,000 Eimeria magna oocytes. Quantitative analysis in 16 rabbits was done for oxidants, antioxidants, A1 and A3 transcripts, transport, injury, and inflammatory mediators. Inflamed gut had villus blunting, crypt hyperplasia and fusion, and immune cell infiltration. Alkaline phosphatase and Na-glucose co-transport were reduced by 78% (P=0.001) and 89% (P=0.001), respectively. Real-time fluorescence monitoring (TaqMan)-polymerase chain reaction revealed a transcriptional up-regulation of 1.34-fold for A1 and 5.40-fold for A3 receptors in inflamed gut. Lipid peroxidation increased in the mucosa (78%, P=0.012), longitudinal muscle-myenteric plexus (118%, P=0.042), and plasma (104%, P=0.001). Mucosal antioxidants were altered by inflammation: reductions occurred in superoxide dismutase (32%, P=0.001) and catalase (43%, P=0.001), whereas increases occurred in glutathione (75%, P=0.0271) and glutathione reductase (86%, P=0.0007). Oxidant enzyme activities were elevated by 21% for xanthine oxidase (P=0.004), 172% for chloramine (P=0.022), 47% for gelatinase (P=0.041), and 190% for myeloperoxidase (P=0.002). Mast cell tryptase increased by 79% (P=0.006). Increases occurred in the plasma concentration of leukotriene B(4) (13-fold, P=0.003), thromboxane B(2) (61-fold, P=0.018), and tumor necrosis factor-alpha (9-fold, P=0.002). In conclusion, chronic ileitis and tissue injury are associated with discrete alterations in complex multi-level oxidant, antioxidant, and immune inflammatory components. The rabbit ileitis model is a suitable model to gain further insight into chronic inflammation and IBD. We

  6. Chronic Stress, Inflammation, and Glucose Regulation in U.S. Hispanics from the HCHS/SOL Sociocultural Ancillary Study

    PubMed Central

    McCurley, Jessica L.; Mills, Paul J.; Roesch, Scott C.; Carnethon, Mercedes; Giacinto, Rebeca E.; Isasi, Carmen R.; Teng, Yanping; Sotres-Alvarez, Daniela; Llabre, Maria M.; Penedo, Frank J.; Schneiderman, Neil; Gallo, Linda C.

    2015-01-01

    Diabetes prevalence is rising rapidly, and diabetes disproportionately affects Hispanics and other underserved groups. Chronic stress may contribute to diabetes risk, but few studies have examined this relationship in U.S. Hispanics. We examined associations of chronic stress with fasting glucose, glucose tolerance, and glycosylated hemoglobin (HbA1c) in Hispanics without diabetes, and also assessed indirect effects of stress through inflammation (CRP). Participants were 3923 men and women, aged 18-74, without diabetes, from the four U.S. field centers (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA) of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)-Sociocultural Ancillary study. Participants completed a measure of chronic life stress and a physical exam with oral glucose tolerance test. In a multivariate regression analysis with adjustment for demographic and health covariates, higher chronic stress was related to higher fasting glucose (standardized regression coefficient: β=.09, p<0.01), post load glucose (β=.07, p<0.05), and HbA1c levels (β=.08, p<0.01). However, there was no indirect effect of stress through inflammation. Findings suggest that higher chronic stress is associated with poorer glucose regulation in Hispanics, prior to the onset of a clinical diabetes diagnosis. PMID:25898909

  7. Chronic stress, inflammation, and glucose regulation in U.S. Hispanics from the HCHS/SOL Sociocultural Ancillary Study.

    PubMed

    McCurley, Jessica L; Mills, Paul J; Roesch, Scott C; Carnethon, Mercedes; Giacinto, Rebeca E; Isasi, Carmen R; Teng, Yanping; Sotres-Alvarez, Daniela; Llabre, Maria M; Penedo, Frank J; Schneiderman, Neil; Gallo, Linda C

    2015-08-01

    Diabetes prevalence is rising rapidly, and diabetes disproportionately affects Hispanics and other underserved groups. Chronic stress may contribute to diabetes risk, but few studies have examined this relationship in U.S. Hispanics. We examined associations of chronic stress with fasting glucose, glucose tolerance, and glycosylated hemoglobin (HbA1c) in Hispanics without diabetes, and also assessed indirect effects of stress through inflammation (CRP). Participants were 3,923 men and women, aged 18-74, without diabetes, from the four U.S. field centers (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA) of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Sociocultural Ancillary study. Participants completed a measure of chronic life stress and a physical exam with oral glucose tolerance test. In a multivariate regression analysis with adjustment for demographic and health covariates, higher chronic stress was related to higher fasting glucose (standardized regression coefficient: β = .09, p < .01), postload glucose (β = .07, p < .05), and HbA1c levels (β = .08, p < .01). However, there was no indirect effect of stress through inflammation. Findings suggest that higher chronic stress is associated with poorer glucose regulation in Hispanics, prior to the onset of a clinical diabetes diagnosis. PMID:25898909

  8. Inflammatory bowel disease related innate immunity and adaptive immunity

    PubMed Central

    Huang, Yuan; Chen, Zhonge

    2016-01-01

    Inflammatory bowel disease (IBD) is a chronic nonspecific intestinal inflammatory disease, including ulcerative colitis (UC) and Crohn’s disease (CD). Its pathogenesis remains not yet clear. Current researchers believe that after environmental factors act on individuals with genetic susceptibility, an abnormal intestinal immune response is launched under stimulation of intestinal flora. However, previous studies only focused on adaptive immunity in the pathogenesis of IBD. Currently, roles of innate immune response in the pathogenesis of intestinal inflammation have also drawn much attention. In this study, IBD related innate immunity and adaptive immunity were explained, especially the immune mechanisms in the pathogenesis of IBD. PMID:27398134

  9. Angiotensin-(1-7) attenuates airway remodelling and hyperresponsiveness in a model of chronic allergic lung inflammation

    PubMed Central

    Magalhães, G S; Rodrigues-Machado, M G; Motta-Santos, D; Silva, A R; Caliari, M V; Prata, L O; Abreu, S C; Rocco, P R M; Barcelos, L S; Santos, R A S; Campagnole-Santos, M J

    2015-01-01

    Background and Purpose A long-term imbalance between pro- and anti-inflammatory mediators leads to airway remodelling, which is strongly correlated to most of the symptoms, severity and progression of chronic lung inflammation. The Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor axis of the renin-angiotensin system is associated with attenuation of acute and chronic inflammatory processes. In this study, we investigated the effects of Ang-(1-7) treatment in a model of chronic allergic lung inflammation. Experimental Approach Mice were sensitized to ovalbumin (OVA; 4 injections over 42 days, 14 days apart) and were challenged three times per week (days 21–46). These mice received Ang-(1-7) (1 μg·h−1, s.c.) by osmotic mini-pumps, for the last 28 days. Histology and morphometric analysis were performed in left lung and right ventricle. Airway responsiveness to methacholine, analysis of Ang-(1-7) levels (RIA), collagen I and III (qRT-PCR), ERK1/2 and JNK (Western blotting), IgE (elisa), cytokines and chemokines (elisa multiplex), and immunohistochemistry for Mas receptors were performed. Key Results Infusion of Ang-(1-7) in OVA-sensitized and challenged mice decreased inflammatory cell infiltration and collagen deposition in the airways and lung parenchyma, and prevented bronchial hyperresponsiveness. These effects were accompanied by decreased IgE and ERK1/2 phosphorylation, and decreased pro-inflammatory cytokines. Mas receptors were detected in the epithelium and bronchial smooth muscle, suggesting a site in the lung for the beneficial actions of Ang-(1-7). Conclusions and Implications Ang-(1-7) exerted beneficial attenuation of three major features of chronic asthma: lung inflammation, airway remodelling and hyperresponsiveness. Our results support an important protective role of Ang-(1-7) in lung inflammation. PMID:25559763

  10. Chronic inflammation and est