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Results for “Inflammatory pathways”

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At least 127 records · Page 7Linked to original sources
PubMed1997

Tacrolimus (FK506) down-regulates free radical tissue levels, serum cytokines, and neutrophil infiltration after severe liver ischemia.

BACKGROUND: Liver ischemia and reperfusion injury is associated with activation of multiple inflammatory pathways, including free radicals, cytokines, and neutrophil-mediated tissue damage among others. Tacrolimus (FK506) has shown important regulatory effects on some inflammatory pathways, such as cytokines, neutrophils, and adhesion molecules. In this study, we explored a new potential protective mechanism for tacrolimus in the liver inflammatory response after ischemia and reperfusion, specifically its effect on liver tissue free radicals. METHODS: Total hepatic ischemia was produced in the rat for 90 min with an extracorporeal portosystemic shunt. Animals (n=96) were divided into four groups: group 1 comprised normal rats for reference values; group 2 comprised sham operated rats; in group 3, ischemic control rats received only the vehicle; and the experimental treatment group, group 4, received tacrolimus at a dose of 0.3 mg/kg, 4 hr before ischemia. Animal survival was followed up to 7 days. Liver function tests were performed and liver tissue free radicals and myeloperoxidase, serum cytokines (interleukin 1, tumor necrosis factor-alpha), and liver histology were measured 4 hr after reperfusion. RESULTS: Seven-day survival was significantly improved from only 20% in the control group to 55% in the tacrolimus group (P<0.01). Liver function tests, histology, and myeloperoxidase tissue values were significantly improved (P<0.05) with tacrolimus pretreatment. Furthermore, a significant (P<0.05) down-regulation of serum cytokines and liver tissue free radicals was observed. CONCLUSIONS: These data indicate a new and different protective mechanism for FK506 in regard to its ability to down-regulate free radical levels in livers subjected to severe ischemia and reperfusion. Tacrolimus, also confirmed to be a potent suppressor of the cytokine response, specifically interleukin 1 and tumor necrosis, decreased neutrophil tissue migration as well.

Animals↗
PubMed2006

Innate immunity in critical care.

Innate and adaptive immunity are required for effective control of infection. Numerous breakthroughs have been achieved in the last 15 years with regard to the functioning of the innate immune system. This article focuses on new paradigms of microorganism recognition, discusses recently described (or rediscovered) cytokines that provide further insight into the development of sepsis, and reviews both pro- and anti-inflammatory pathways for control of infection. Finally, it discusses what has and has not worked with regard to controlling inflammatory pathways in septic patients.

Child↗
PubMed2005

Epigallocatechin-3-gallate impairs chemokine production in human colon epithelial cell lines.

A major component in green tea, epigallocatechin-3-gallate (EGCG), is reported to interfere with different steps of a number of inflammatory pathways. After oral administration, EGCG is retained in the gastrointestinal tract, where it is thought to exert preventive functions against inflammatory bowel disease and colon cancer. In this study, the human colon adenocarcinoma cell lines HT29 and T84 were used to investigate the effect of EGCG on intestinal inflammation. HT29 and T84 cells were stimulated with tumor necrosis factor (TNF)-alpha to induce the inflammatory condition and to trigger the inflammatory cascade in vitro and treated with EGCG to study its effect on inflammatory processes. The secretion of the chemokines interleukin (IL)-8, macrophage inflammatory protein (MIP)-3alpha, and prostaglandin E2 (PGE2) was determined by enzyme-linked immunosorbent assay. The gene expression level was measured by quantitative real-time polymerase chain reaction. Treatment of TNF-alpha-stimulated HT29 cells with EGCG dose-dependently inhibited the synthesis of IL-8, MIP-3alpha, and PGE2. Treatment with EGCG also inhibited the production of IL-8 and MIP-3alpha in TNF-alpha-stimulated T84 cells. Gene expression analysis in both HT29 and T84 cells revealed that EGCG down-regulates genes involved in inflammatory pathways. This study shows that EGCG acts broadly on the production of chemokines and PGE2 in the chemokine and eicosanoid pathways of colon epithelial cells. Therefore, EGCG might prove useful for the prevention and/or attenuation of colonic disorders.

Antioxidants↗
PubMed2003

The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment.

The pattern recognition receptor, RAGE (receptor for advanced glycation endproducts), propagates cellular dysfunction in several inflammatory disorders and diabetes. Here we show that RAGE functions as an endothelial adhesion receptor promoting leukocyte recruitment. In an animal model of thioglycollate-induced acute peritonitis, leukocyte recruitment was significantly impaired in RAGE-deficient mice as opposed to wild-type mice. In diabetic wild-type mice we observed enhanced leukocyte recruitment to the inflamed peritoneum as compared with nondiabetic wild-type mice; this phenomenon was attributed to RAGE as it was abrogated in the presence of soluble RAGE and was absent in diabetic RAGE-deficient mice. In vitro, RAGE-dependent leukocyte adhesion to endothelial cells was mediated by a direct interaction of RAGE with the beta2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with beta1-integrins. The RAGE-Mac-1 interaction was augmented by the proinflammatory RAGE-ligand, S100-protein. These results were corroborated by analysis of cells transfected with different heterodimeric beta2-integrins, by using RAGE-transfected cells, and by using purified proteins. The RAGE-Mac-1 interaction defines a novel pathway of leukocyte recruitment relevant in inflammatory disorders associated with increased RAGE expression, such as in diabetes, and could provide the basis for the development of novel therapeutic applications.

Animals↗
PubMed2002

Viral respiratory infection therapy: historical perspectives and current trials.

Attempts to relieve the misery of the common cold have been made since long before current understanding of its viral origin. Although current symptomatic therapies provide some relief, any effective treatment must incorporate an antiviral to address the infection. Symptom production is related not only to viral cytopathic effect but also to the early activation of several inflammatory pathways. Antiviral treatment alone may not be able to prevent these events. Combining an antiviral with selected therapeutic agents that block these inflammatory pathways has been shown to improve the effectiveness of cold treatment. Early diagnosis and initiation of treatment combined with regular dosing until symptoms subside appears to be the most effective treatment strategy to maximize therapeutic outcomes. This strategy reduces viral shedding in nasal fluid, provides treatment for the period of maximum symptom burden, and may reduce the frequency and severity of the sinus disease that accompanies colds.

Antiviral Agents↗
PubMed2002

Understanding pathogenesis and treatment of HIV dementia: a role for magnetic resonance?

HIV dementia (HIVD) is among the most common and most feared neurological complications of AIDS. In vitro studies have identified a constellation of potentially neurotoxic inflammatory and non-inflammatory pathways, one or more of which could underlie HIVD. Magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) studies can distinguish between inflammatory and non-inflammatory pathways in vivo and suggest that either or both might be active in different patients or at different times in the same patient. This could perhaps explain the variability in HIVD development, progression and response to therapy. These findings also suggest that MRI and MRS can identify patients at risk for HIVD and predict response to therapy.

AIDS Dementia Complex↗
PubMed2006

Statin therapy of calcific aortic stenosis: hype or hope?

Calcific aortic stenosis, with a prevalence of 3-9%, is the most frequent heart valve disease and the main cause for valve replacement in patients over 60 years of age. Once thought to be caused by a passive calcium precipitate within the aortic valve leaflets, there is now increasing evidence that development and progression of calcific aortic valve disease may be triggered by underlying genetic and cardiovascular risk factors, and is regulated by an active cellular process involving inflammatory pathways. Targeted drug therapy to prevent the progression of calcific aortic valve disease should ideally be based on the knowledge of risk factors and the molecular pathogenesis of the disease. Conflicting data exists on the potency of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e. statins) to influence both risk factors and inflammatory pathways by lowering lipid levels and exerting anti-inflammatory properties, respectively. In this review, various aspects of the molecular pathogenesis of calcific aortic stenosis will be summarized and connected with recent experimental and clinical studies that address the potential benefit of the targeted drug therapy by statins in order to prevent the progression of the disease.

Aortic Valve Stenosis↗
PubMed1993

Blocking periodontal disease progression with anti-inflammatory agents.

Recent advances in the identification of specific immuno-inflammatory pathways of periodontal disease have encouraged investigators to attempt to modulate some of these host responses in an attempt to slow the periodontal disease process. Some of the best known mediators of these immuno-inflammatory pathways are prostaglandins. The action of prostaglandins can be inhibited through the use of non-steroidal anti-inflammatory drugs (NSAIDs). This review examines research over the last two decades during which the effect of several NSAIDs on the progression of gingival inflammation and alveolar bone loss was explored.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Inflammation in coronary artery disease: potential role for immunomodulatory therapy.

Understanding of the mechanisms underlying atherosclerotic disorders has evolved beyond the view of a progressive collection of lipids and cellular debris in the vascular wall. Current evidence has implicated inflammatory pathways as an important pathogenic mechanism in atherogenesis and plaque destabilization. Although not necessarily the primary event, inflammation and cytokine activation during plaque formation and destabilization may represent a common final pathway to various stimuli. Thus, it seems that not only 'new' risk factors, such as infections with various microorganisms, but also classic risk factors for cardiovascular disease, such as hyperlipidemia, hypertension and diabetes, may promote their atherogenic effects through inflammatory responses. Indeed, recent reports have suggested that traditional cardiovascular medications may attenuate atherogenesis and enhance plaque stability, at least partly through anti-inflammatory mechanisms. However, uncovering the inflammatory pathways in atherosclerosis has raised the possibility that newer treatment modalities should be more directly targeted against inflammatory mediators. Recently, a series of experimental studies have reported reduction of atherosclerosis by immunomodulatory therapy, such as chemokine blockade, interleukin-10 and immunization/vaccination against oxidized low-density lipoprotein and heat-shock protein. It is conceivable that some of these approaches will be tested clinically and, if successful, they could provide novel treatment strategies in coronary artery disease in humans.

Animals↗
PubMed2004

Quercetin protects against linoleic acid-induced porcine endothelial cell dysfunction.

Consumption of plant phenolics, such as quercetin, may be associated with decreased risk of cardiovascular disease by stabilizing and protecting vascular endothelial cells against oxidative and proinflammatory insults. The present study focused on the effect of quercetin on linoleic acid-induced oxidative stress and the inflammatory pathways of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). Because the transcription factor peroxisome proliferator activated receptor gamma (PPARgamma) was reported to downregulate inflammatory pathways, we further investigated the effect of quercetin on PPARgamma. Porcine pulmonary-arterial endothelial cells were activated with linoleic acid in the presence or absence of quercetin. Oxidative stress was markedly induced by endothelial cell exposure to linoleic acid and diminished by treatment with quercetin as measured via the oxidation of 2',7'-dichlorofluorescin. Quercetin reduced linoleic acid-mediated binding activity of NF-kappaB and AP-1 and mRNA levels of inflammatory genes such as interleukin-6 (IL-6) and vascular cell adhesion molecule-1 (VCAM-1). Cotreatment of linoleic acid plus quercetin or vitamin E also decreased linoleic acid-induced binding activity of PPARgamma. These data suggest that quercetin has potent antioxidative and anti-inflammatory properties and protects endothelial cells against linoleic acid-mediated cell dysfunction.

Animals↗
PubMed2006

The potential role of phosphodiesterase inhibitors in the management of asthma.

Asthma is a chronic inflammatory condition characterised by reversible airflow obstruction and airway hyperreactivity. The course of the illness may be punctuated by exacerbations resulting in deterioration in quality of life and, in some cases, days lost from school or work. That asthma is common and increasingly prevalent magnifies the importance of any potential economic costs, and promoting asthma control represents an important public health agenda. While lifestyle changes represent a valuable contribution in some patients, the majority of asthmatic patients require therapeutic intervention. The recognition of the role of inflammation in the pathogenesis of asthma has led to an emphasis on regular anti-inflammatory therapy, of which inhaled corticosteroid treatment remains the most superior. In selected patients, further improvements in asthma control may be gained by the addition of regular inhaled long-acting beta(2)-adrenoceptor agonists or oral leukotriene receptor antagonists to inhaled corticosteroid therapy. However, a significant minority of patients with asthma remain poorly controlled despite appropriate treatment, suggesting that additional corticosteroid nonresponsive inflammatory pathways may be operative. Furthermore, some patients with asthma display an accelerated decline in lung function, suggesting that active airway re-modeling is occurring. Such observations have focused attention on the potential to develop new therapies which complement existing treatments by targeting additional inflammatory pathways. The central role of phosphodiesterase (PDE), and in particular the PDE4 enzyme, in the regulation of key inflammatory cells believed to be important in asthma - including eosinophils, lymphocytes, neutrophils and airway smooth muscle - suggests that drugs designed to target this enzyme will have the potential to deliver both bronchodilation and modulate the asthmatic inflammatory response. In vivo studies on individual inflammatory cells suggest that the effects are likely to be favorable in asthma, and animal study models have provided proof of concept; however, first-generation PDE inhibitors have been poorly tolerated due to adverse effects. The development of second-generation agents such as cilomilast and roflumilast heralds a further opportunity to test the potential of these agents, although to date only a limited amount of data from human studies has been published, making it difficult to draw firm conclusions.

Adrenal Cortex Hormones↗
PubMed2004

Alzheimer's associated inflammation, potential drug targets and future therapies.

Alzheimer's disease is the most common cause of dementia in the elderly population. The most widely used treatment for Alzheimer's disease at present is acetylcholinesterase inhibitors, which aim to prolong cognitive function through increased synaptic activity, without providing neuroprotection. This treatment is only symptomatic and provides modest outcomes for patients. The recent elucidation of the inflammatory pathways involved in Alzheimer's disease however, has opened doors for better treatment and prevention by identification of areas of therapeutic intervention that target the cause of the disease rather than the symptoms. This review describes the inflammatory pathways that are thought to be present in Alzheimer's disease and some of the new therapies that have shown promise, via alteration or inhibition of these pathways. Some of the therapies included in this review, which have already demonstrated beneficial effects in the treatment of Alzheimer's disease, or have the potential to do so, are nonsteroidal anti-inflammatory drugs, statins, RAGE antagonists and antioxidants.

Alzheimer Disease↗
PubMed1990

Effect of resiniferatoxin pretreatment on the inflammatory response to phorbol-12-myristate-13-acetate in mouse strains with different susceptibilities to phorbol ester tumor promotion.

All tumor-promoting phorbol esters induce inflammation in mouse skin. The correlation between promoting and inflammatory activities is only partial, however, indicating that only some events in inflammation may be closely coupled to the process of tumor promotion. Resiniferatoxin (RTX), an extremely inflammatory phorbol-related diterpene, acts as an ultrapotent analog of capsaicin to stimulate and then to block the neurogenic inflammatory pathway. In CD-1 mice, we have used pretreatment with RTX to show that the erythema and edema responses to phorbol and 12-deoxyphorbol esters in significant part involve this neurogenic inflammatory pathway. We report here that mouse strains with differing sensitivities to phorbol-ester-induced promotion displayed marked differences in the effect of pretreating with RTX on the edema response following phorbol-12-myristate-13-acetate (PMA) application. In the highly promotion-sensitive SENCAR mouse, RTX pretreatment had little inhibitory effect; the edema response to PMA was similar with or without RTX pretreatment 6 h before PMA application. On the other hand, in C57BL/6J mice, which are resistant to promotion by phorbol esters under the usual protocols, the edema response to PMA was totally eliminated by RTX pretreatment during the first 8 h after PMA administration. DBA/2J mice, which are similar to CD-1 mice in their susceptibility to PMA promotion, responded similarly to CD-1: the edema response was blocked partially by RTX pretreatment during the early phase (up to 8 h) of inflammation. Our results suggest that the RTX-resistant component of PMA-induced edema may correlate better with the sensitivity to promoting action than does the overall inflammatory response.

Animals↗
PubMed2001

Redox-modulated pathways in inflammatory skin diseases.

Inflammatory skin diseases account for a large proportion of all skin disorders and constitute a major health problem worldwide. Contact dermatitis, atopic dermatitis, and psoriasis represent the most prevalent inflammatory skin disorders and share a common efferent T-lymphocyte mediated response. Oxidative stress and inflammation have recently been linked to cutaneous damage in T-lymphocyte mediated skin diseases, particularly in contact dermatitis. Insights into the pathophysiology responsible for contact dermatitis can be used to better understand the mechanism of other T-lymphocyte mediated inflammatory skin diseases, and may help to develop novel therapeutic approaches. This review focuses on redox sensitive events in the inflammatory scenario of contact dermatitis, which comprise for example, several kinases, transcription factors, cytokines, adhesion molecules, dendritic cell surface markers, the T-lymphocyte receptor, and the cutaneous lymphocyte-associated antigen (CLA). In vitro and animal studies clearly point to a central role of several distinct but interconnected redox-sensitive pathways in the pathogenesis of contact dermatitis. However, clinical evidence that modulation of the skin's redox state can be used therapeutically to modulate the inflammatory response in contact dermatitis is presently not convincing. The rational for this discrepancy seems to be multi-faceted and complex and will be discussed.

Dermatitis, Allergic Contact↗
PubMed2025

Impact of Maternal Aspirin Therapy on Neonatal Epigenetic Patterns.

BACKGROUND: Low-dose aspirin (LDA) is an intervention recommended to prevent the development of hypertensive disorders of pregnancy (HDP) in high-risk pregnancies. Maternal conditions such as HDP have been associated with cord blood epigenetic changes including those related to cardiovascular processes; however, it is unclear whether maternal aspirin therapy may impact neonatal epigenetics in otherwise healthy high-risk pregnancy. OBJECTIVE: This study aimed to determine if maternal LDA exposure in utero leads to altered DNA methylation in umbilical cord blood cells in term neonates compared with controls not exposed to aspirin, and to identify if these methylation changes alter key pathways in the development of chronic disease. METHODS: Umbilical cord blood was collected from 10 neonates without LDA exposure and 13 neonates with LDA exposure in utero. Patients with hypertensive disorders of pregnancy, COVID-19, and chorioamnionitis were excluded. Genomic DNA was isolated from umbilical cord blood cells and genome-wide DNA methylation was performed using Illumina Methylation EPIC assay. RESULTS: A total of 155 differentially methylated loci (81 genes were hypermethylated and 74 were hypomethylated) were identified in LDA-exposed neonatal umbilical cord blood compared with the control group. Important canonical pathways identified by Ingenuity Pathway Analysis (IPA) were related to Th1 and Th2 signaling and classical (M1) macrophage activation. The genes affected by LDA exposure were associated with cardiac and renal systems. CONCLUSION: LDA exposure led to differential DNA methylation in umbilical cord blood. The differentially methylated genes were related to inflammatory pathways as well as cardiac and renal toxicity pathways. LDA exposure in utero may promote altered health programming in the neonate in areas impacting cardiovascular health. KEY POINTS: &#xb7; Maternal aspirin exposure is associated with differential DNA methylation in cord blood.. &#xb7; Cord blood epigenetic changes associated with maternal aspirin relate to anti-inflammatory pathways.. &#xb7; Research on potential protective impact of maternal aspirin on neonatal epigenetics is warranted..

Humans↗
PubMed1989

Human junctional epithelium as a pathway for inflammatory exudation.

Photographic montages of transmission electron micrographs of the dentogingival region have made it possible to assess the morphologic alterations that occur in the junctional and the oral sulcular epithelium as a result of mild gingival inflammation. Enlargements of the intracellular spaces in the junctional epithelium varied in size and shape from isolated alveolate enlargements, often containing isolated granulocytes, to channel-like pathways oriented in an apico-coronal direction and frequently filled with rows of granulocytes. In contrast to artifactitious spaces, these enlarged intercellular spaces failed to reveal the presence of ruptured intercellular bridges and contained well preserved undistorted granulocytes with round profiles. Moderately electron dense material within the enlarged intercellular spaces probably represented proteins from the fluid exudate, precipitated by the fixation process. The rate of normal junctional epithelial turnover appeared to be insufficient to compensate for the above morphological alterations brought about by the inflammatory process. Mononuclear cells, mostly lymphocytes, were preferentially located in the connective tissue side of the junctional epithelium. Their low numbers in the gingival sulcus suggest that they are passively carried into the sulcus as a result of normal turnover of the junctional epithelium, whereas granulocytes, which account for the majority of leucocytes in the sulcus, actively migrate through the junctional epithelium.

Bicuspid↗
PubMed2006

Signalling pathways mediating inflammatory responses in brain ischaemia.

Stroke causes neuronal necrosis and generates inflammation. Pro-inflammatory molecules intervene in this process by triggering glial cell activation and leucocyte infiltration to the injured tissue. Cytokines are major mediators of the inflammatory response. Pro-inflammatory and anti-inflammatory cytokines are released in the ischaemic brain. Anti-inflammatory cytokines, such as interleukin-10, promote cell survival, whereas pro-inflammatory cytokines, such as TNFalpha (tumour necrosis factor alpha), can induce cell death. However, deleterious effects of certain cytokines can turn to beneficial actions, depending on particular features such as the concentration, time point and the very intricate network of intracellular signals that become activated and interact. A key player in the intracellular response to cytokines is the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway that induces alterations in the pattern of gene transcription. These changes are associated either with cell death or survival depending, among other things, on the specific proteins involved. STAT1 activation is related to cell death, whereas STAT3 activation is often associated with survival. Yet, it is clear that STAT activation must be tightly controlled, and for this reason the function of JAK/STAT modulators, such as SOCS (suppressors of cytokine signalling) and PIAS (protein inhibitor of activated STAT), and phosphatases is most relevant. Besides local effects in the ischaemic brain, cytokines are released to the circulation and affect the immune system. Unbalanced pro-inflammatory and anti-inflammatory plasma cytokine concentrations favouring an 'anti-inflammatory' state can decrease the immune response. Robust evidence now supports that stroke can induce an immunodepression syndrome, increasing the risk of infection. The contribution of individual cytokines and their intracellular signalling pathways to this response needs to be further investigated.

Animals↗
PubMed1996

Role of the neuroendocrine system in cytokine pathways in inflammatory bowel disease.

The intestine is a rich venue for interactions between the neuroendocrine and immune systems. Functional regulation of mucosal immune responses can be exerted through local neuroendocrine paths by neuropeptides from the neurons of the enteric nervous system and peptide hormones. Immune regulation can also be exerted through influences in the central nervous system activating the hypothalamic-pituitary-adrenal axis, and through the activation of the autonomic nervous system. The integrity of these systems can alter the outcome of immune-mediated inflammation in the gut. The role of these pathways in the regulation of cytokines is examined, and the implications for Crohn's disease and ulcerative colitis are explored.

Animals↗