Therapeutic interventions in gastrointestinal disease based on an understanding of inflammatory mediators

Whatever initiates inflammation, the final message mediating cellular invasion is chemical. This consideration allows rational development of anti-inflammatory treatments. Two main classes of chemotactic mediator are recognised. Water-soluble peptides, e.g. cytokines derived from macrophages and other cells, play an important integrating part in the early recruitment of neutrophils and mononuclear cells, and in the amplification of immune responses. Lipid-soluble mediators, of which leukotriene B₄ is the most highly chemotactic for neutrophils, are important in secondary amplification.In inflammatory bowel disease, we have shown evidence of increased synthesis of cytokines interleukin 1, 6 and 8. These are associated with activation of circulating monocytes in active Crohn's disease, of lamina propria macrophages in relapse of both ulcerative colitis and Crohn's disease, and development of adhesion molecules on vascular endothelium. Our studies show that interleukin 6 is selectively increased in Crohn's disease, whilst preliminary findings suggest that enhanced synthesis of interleukin 8 is particularly characteristic of ulcerative colitis.Patterns of cytokine synthesis may, therefore, be of diagnostic value. They also offer the potential for therapeutic strategies since cytokine antagonists are becoming available.We have also demonstrated increased synthesis of leukotrienes in active inflammatory bowel disease. Since leukotriene B₄ is quantitatively the main chemotactic signal in the mucosa in inflammatory bowel disease during relapse, we investigated the therapeutic effect of suppressing leukotriene B₄ synthesis by treating patients with fish oil (as Hi-EPA), giving 4.5 g daily of eicosapentaenoic acid. This competes for the 5-lipoxygenase enzymes, inhibiting leukotriene B₄ and promoting synthesis of the less chemotactic product, LTB₄. Ninety-six patients were treated for one year in a study structured to investigate both relapse and remission. Hi-EPA was well tolerated and compliance was good, since increased local tissue contractions of EPA were sustained whilst leukotriene synthesis of LTB₅ rose and of LTB₄ fell, by approximately 50%. Although fish oil had on overall effect on the number of days in remission, there was a significant steroidsparing effect during relapse. Recent studies with 5-lipoxygenase inhibitors also support the therapeutic value of modulating leukotriene synthesis in relapse.     

Therapeutic interventions in gastrointestinal disease based on an understanding of inflammatory mediators

Whatever initiates inflammation, the final message mediating cellular invasion is chemical. This consideration allows rational development of anti-inflammatory treatments. Two main classes of chemotactic mediator are recognised. Water-soluble peptides, e.g. cytokines derived from macrophages and other cells, play an important integrating part in the early recruitment of neutrophils and mononuclear cells, and in the amplification of immune responses. Lipid-soluble mediators, of which leukotriene B₄ is the most highly chemotactic for neutrophils, are important in secondary amplification.In inflammatory bowel disease, we have shown evidence of increased synthesis of cytokines interleukin 1, 6 and 8. These are associated with activation of circulating monocytes in active Crohn's disease, of lamina propria macrophages in relapse of both ulcerative colitis and Crohn's disease, and development of adhesion molecules on vascular endothelium. Our studies show that interleukin 6 is selectively increased in Crohn's disease, whilst preliminary findings suggest that enhanced synthesis of interleukin 8 is particularly characteristic of ulcerative colitis.     

Therapeutic effects of Ligularia stenocephala against inflammatory bowel disease by regulating antioxidant and inflammatory mediators

In this report, we studied the effect of leaf extracts of Ligularia stenocephala (LS) on inflammatory bowel disease (IBD) by regulating antioxidant and inflammatory mediators. The water extracts (LSW) exhibited more antioxidant activity than that of ethanol extracts (LSE). The extracts suppress the formation of nitric oxide by down-regulating the inducible nitric oxide synthase and pro-inflammatory cytokines (eg tumor necrosis factor alpha, interleukin (IL)-6, IL-10 and IL-1β expression) through the suppression of nuclear factor-?β activation and mitogen-activated protein kinases phosphorylation in lipopolysaccharide-stimulated macrophage cells. Our in vivo study reveals that the extracts could suppress tissue damage significantly in mice colon. The expression regarding immune-related cytokines was also down-regulated by the extracts of LS leaf. Thus, it is concluded that the extracts could be used as a functional food, which could reduce the formation of oxidants, inflammation and IBD effectively.     

Microparticles as mediators of cellular cross-talk in inflammatory disease

Microparticles are a heterogeneous population of membrane-coated vesicles which can be released from virtually all cell types during activation or apoptosis. Release occurs from the cell surface in an exogenous budding process involving local rearrangement of the cytoskeleton. Given their origin, these particles can be identified by staining for cell surface markers and annexin V. As shown in in vitro studies, microparticles may represent a novel subcellular element for intercellular communication in inflammation. Thus, microparticles can transfer chemokine receptors and arachidonic acid between cells, activate complement, promote leukocyte rolling and stimulate the release of pro-inflammatory mediators. Under certain conditions, however, microparticles may also exert anti-inflammatory properties by inducing immune cell apoptosis and the production of anti-inflammatory mediators. Microparticles may play an important role in the pathogenesis of rheumatologic diseases as evidenced by their elevation in diseases such as systemic sclerosis (SSc), systemic vasculitis and antiphospholipid antibody syndrome and correlation with clinical events. A role in inflammatory arthritis is suggested by the finding that leukocyte-derived microparticles induce the production of matrix metalloproteinases and cytokines by synovial fibroblasts. Together, these findings point to novel signaling pathways of cellular cross-talk that may operate along the spectrum of soluble cytokines and mediators of direct cell-cell contact.     

Microparticles as mediators of cellular cross-talk in inflammatory disease

Microparticles are a heterogeneous population of membrane-coated vesicles which can be released from virtually all cell types during activation or apoptosis. Release occurs from the cell surface in an exogenous budding process involving local rearrangement of the cytoskeleton. Given their origin, these particles can be identified by staining for cell surface markers and annexin V. As shown in in vitro studies, microparticles may represent a novel subcellular element for intercellular communication in inflammation. Thus, microparticles can transfer chemokine receptors and arachidonic acid between cells, activate complement, promote leukocyte rolling and stimulate the release of pro-inflammatory mediators. Under certain conditions, however, microparticles may also exert anti-inflammatory properties by inducing immune cell apoptosis and the production of anti-inflammatory mediators. Microparticles may play an important role in the pathogenesis of rheumatologic diseases as evidenced by their elevation in diseases such as systemic sclerosis (SSc), systemic vasculitis and antiphospholipid antibody syndrome and correlation with clinical events. A role in inflammatory arthritis is suggested by the finding that leukocyte-derived microparticles induce the production of matrix metalloproteinases and cytokines by synovial fibroblasts. Together, these findings point to novel signaling pathways of cellular cross-talk that may operate along the spectrum of soluble cytokines and mediators of direct cell–cell contact.     

Annexin A1 based inflammation resolving mediators and nanomedicines for inflammatory bowel disease therapy

Inflammatory bowel diseases (IBD) such as Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic, progressive, and relapsing disorders of the gastrointestinal tract (GIT), characterised by intestinal epithelial injury and inflammation. Current research shows that in addition to traditional anti-inflammatory therapy, resolution of inflammation and repair of the epithelial barrier are key biological requirements in combating IBD. Resolution mediators include endogenous lipids that are generated during inflammation, e.g., lipoxins, resolvins, protectins, maresins; and proteins such as Annexin A1 (ANXA1). Nanoparticles can specifically deliver these potent inflammation resolving mediators in a spatiotemporal manner to IBD lesions, effectively resolve inflammation, and promote a return to homoeostasis with minimal collateral damage. We discuss these exciting and timely concepts in this review.     

Immunologic and inflammatory mediators and cognitive decline in Alzheimer's disease

Local up-regulation of immune mediators is implicated in the development of AD; however, the systemic cell-mediated immune response in patients with AD may be impaired. Progression of AD from moderate to severe stages is accompanied by a progressive decline in cognitive function, independence, and behavioral and motor impairments and by the occurrence of recurrent infections, such as bronchitis and pneumonia. Several factors, including malnutrition, may be implicated in the reduced ability to mount an adequate immune response against invading pathogens in advanced stages of AD. The immune system has an important role in the development, progression, and potential treatment of AD and is involved in determining the subsequent sequelae and morbidity outcomes in patients with advanced-stage AD. A better understanding of the immune mediators that are involved in the local and systemic immune response in AD may assist in mediating the development of AD, halting its progression, and treating patients with anti-inflammatory drugs and immunization strategies.     

Pathobionts of the gastrointestinal microbiota and inflammatory disease

Our immune system is charged with the vital mission of identifying invading pathogens and mounting proper inflammatory responses. During the process of clearing infections, the immune system often causes considerable tissue damage. Conversely, if the target of immunity is a member of the resident microbiota, uncontrolled inflammation may lead to host pathology in the absence of infectious agents. Recent evidence suggests that several inflammatory disorders may be caused by specific bacterial species found in most healthy hosts. Although the mechanisms that mediate pathology remain largely unclear, it appears that genetic defects and/or environmental factors may predispose mammals to immune-mediated diseases triggered by potentially pathogenic symbionts of the microbiota. We have termed this class of microbes 'pathobionts', to distinguish them from acquired infectious agents. Herein, we explore burgeoning hypotheses that the combination of an immunocompromised state with colonization by pathobionts together comprise a risk factor for certain inflammatory disorders and gastrointestinal (GI) cancer.     

Moderators and mediators of treatment outcome for youth with ADHD: understanding for whom and how interventions work

OBJECTIVE: To present data on moderators and mediators of treatment response from the Multimodal Treatment Study of Children With ADHD (MTA). METHODS: Moderator variables (baseline factors that define subgroups with greater vs lesser intervention response) and mediator variables (factors occurring during treatment that explain how interventions "work") are described with specific application to the outcomes of the MTA Study. RESULTS: Key moderator variables (comorbid anxiety disorder, public assistance, severity of attention-deficit/hyperactivity disorder, parental depressive symptomatology, IQ) and mediator processes (negative/ineffective parental discipline) are reviewed. CONCLUSIONS: Treatment research in the future should explicitly consider the exploration of moderator and mediator variables, which can greatly aid the explanatory power of clinical trials and specify the critical next steps for intervention research.     

Effects of high-dose corticosteroids on post-traumatic inflammatory mediators

Objective  

Plasma concentrations of inflammatory mediators are substantially increased in major orthopaedic surgery. It was our hypothesis that corticosteroids would reduce the post-operative levels of inflammatory mediators in patients with ankylosing spondylitis, and we performed a single-centre randomised controlled trial.     

The concept of mediators in acute inflammatory reactions

The evolution of ideas about inflammation oscillates between two poles: sometimes the cell aspects of inflammation are described, with leucocyte adhesion to the vessel wall followed by migration into the tissues and phagocytosis - at other times it is the turn of the chemical intermediaries accounting for the damage to blood vessels, in which case vasodilatation, permeability and chemotaxis are given particular emphasis. The present tendency is to concentrate on the origin of these intermediaries and their relationship to the different cell populations found in situ. Before defining the relationship between cells and acute inflammatory mediators, an inventory needs to be drawn up of the latter. They can be divided into three main categories, according to the manner of their involvement at the site of inflammation: preformed agents, which are then released; mediators formed as a result of enzyme influences, cell-derived or not, from inactive precursors; the enzymes themselves which attack the structures involved in the lesion. These various mediators are thus traceable to specific mechanisms of formation or release, from cell populations that are now clearly identified. From an understanding of how the inflammatory focus has been colonised by the different leucocyte populations and a knowledge of their enzymatic potential, conclusions can be drawn not only about the mediators concerned but more especially about the pharmacological agents that must be mobilised in order to neutralise their clinically apparent effects.     

The role of innate mediators in inflammatory response

Cytokines produced by innate immune response can profoundly influence the subsequent adaptive immunity. IL-15 and -18 are two of several mediators produced by macrophages that perform such a function. Here we present recent data mainly from our own laboratory illustrating the important role of IL-15 and -18 in the induction and perpetuation of chronic inflammation during experimental and clinical rheumatoid synovitis.