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Results for “INFLAMMATORY MECHANISMS”

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PubMed2003

Differential efficacy of intrathecal NMDA receptor antagonists on inflammatory mechanical and thermal hyperalgesia in rats.

Spinal cord dorsal horn N-methyl-D-aspartate (NMDA) receptors have been implicated in central sensitization, enhanced responsiveness to peripheral stimuli following peripheral injury. Since hyperalgesia is a behavioral consequence of central sensitization, it should be attenuated at the level of the dorsal horn with NMDA receptor antagonists. However, responsiveness to thermal and mechanical hyperalgesia may be distinct, and have thus far not been directly compared in chronic inflammatory pain models. In the present study, inflammation was induced with complete Freund's adjuvant (CFA) injected into the rat hind paw and NMDA receptor antagonists dizocilpine (MK-801) or 2-amino-5-phosphonovaleric acid (AP-5) were intrathecally injected in rats to determine the effects on both mechanical and thermal hyperalgesia. Locomotor tests and reflexes were also conducted to evaluate potential motor side effects. The NMDA receptor antagonists dose-dependently ameliorated mechanical hyperalgesia, but had marginal effects on thermal hyperalgesia. In ranges near antihyperalgesic doses, significant disruption of motor coordination was observed for both antagonists. These results suggest that, depending on the stimulus, NMDA receptors may have variable significance for central sensitization-mediated hyperalgesia, and that NMDA receptor antagonists may have therapeutic potential for some, but not all components in the clinical manifestation of inflammatory pain.

Animals↗
PubMed1983

Glucocorticosteroids I: anti-inflammatory mechanisms.

Although progress in understanding how steroids work has accelerated in the past few years, several important factors have eluded definitive analysis. Broadly, the mechanisms affect leukocyte traffic and function: Glucocorticoids inhibit the availability of leukocytes to the inflammatory site, interfere with their function at the site, and thus suppress the normal inflammatory response.

Anti-Inflammatory Agents↗
PubMedDate not supplied

Inflammatory mechanisms associated with brain damage induced by kainic acid with special reference to the interleukin-1 system.

The evidence of inflammatory processes in the clinical manifestations and neuropathological sequelae of epilepsy have accumulated in the last decade. Administration of kainic acid, an analogue of the excitatory amino acid glutamate, induces a characteristic behavioural syndrome and a reproducible pattern of neurodegeneration in several brain areas, closely resembling human temporal lobe epilepsy. Results from studies using the kainic acid model indicate that manipulation of pro- and anti-inflammatory cytokines can modify the outcome with regard to the behavioural syndrome as well as the neuropathological consequences. Interleukin-1 is one of the most important cytokines and has several actions in the brain that are critical for the host defense against injury and infection, and it is involved in the initiation of early stages of inflammation. It is believed that interleukin-1 plays a pivotal role in the neuroinflammation associated with certain forms of neurodegeneration, including cerebral ischemia, trauma and excitotoxic brain injury. In this review, we have summarized the experimental data available with regard to the involvement of the interleukin-1 system in kainic acid-induced changes in the brain and emphasized the modulatory role of interleukin-1beta in this model of epilepsy

Animals↗
PubMed2004

Inflammatory mechanisms contributing to pancreatic cancer development.

OBJECTIVE: Pancreatic cancer is the most deadly of all gastrointestinal (GI) malignancies, yet relatively little is known regarding mechanisms of tumor development including the role of inflammation. SUMMARY BACKGROUND DATA: Chronic pancreatitis (CP) increases the risk of developing cancer by 10- to 20-fold; mediators of the chronic inflammatory process and the surrounding fibrotic stroma likely support a transformation to malignancy, yet the exact mechanisms remain undefined. The purpose of our present study was to determine potential inflammatory components in epithelial and stromal cells that may contribute to both CP and pancreatic cancers. METHODS: Specimens of normal pancreas, CP, and pancreatic cancer were examined using laser-capture microdissection (LCM), gene array, and immunohistochemistry. RESULTS: Gene array analysis from LCM-dissected tissues demonstrated: (i) increased expression of interleukin-8 (IL-8), an activator of the inflammatory factor nuclear factor-kappaB (NF-kappaB), and (ii) decreased expression of IkappaB (an inhibitor of NF-kappaB) in CP ductal cells compared with normal ducts. Compared with CP, cancers demonstrated: (i) increased expression of tumor related genes including S100A4, cyclin E1, and epidermal growth factor (EGF) receptor, and (ii) expression of matrix metalloproteinase 2, a pro-invasive factor for tumor cells, which was not present in the CP stroma. Increased staining of both the p50 NF-kappaB subunit and IKKalpha kinase (a protein that allows activation of NF-kappaB) was noted in CP and cancers. CONCLUSIONS: Our results demonstrate that similar inflammatory components and downstream effectors are present in CP and pancreatic cancers. Importantly, these findings suggest that a common pathway for pancreatic cancer development may be through a chronic inflammatory process including stroma formation. These findings may lead to novel strategies for pancreatic cancer prophylaxis based on inhibition of inflammatory mediators.

Biomarkers, Tumor↗
PubMed1996

Inhibition of phagocyte-endothelium interactions by oxidized fatty acids: a natural anti-inflammatory mechanism?

Diets rich in marine fish oil may protect against cardiovascular disease. Although the mechanisms involved in such protection are not known, fish oils have been reported to exert anti-inflammatory actions. For example, dietary fish oil supplementation was observed to profoundly decrease the numbers of monocytic cells adherent to endothelium overlying atherosclerotic lesions in pigs. We have therefore investigated the possibility that fish oil components-particularly n-3 polyunsaturated fatty acids (PUFAs)-might inhibit phagocyte-endothelium interactions. We have found that binding of a monocytic cell line (U937) to cultured endothelium (with cell adhesion molecules up-regulated by exposure to lipopolysaccharide (LPS), interleukin-1 alpha, tumor necrosis factor-alpha, or phorbol myristate acetate (PMA) is greatly decreased by pre-exposure of endothelial cells to n-3 and other PUFAs that are incidentally or purposefully oxidized; unoxidized PUFAs are completely ineffective. Decreased monocyte adherence probably derives from diminished up-regulation of endothelial cell adherence molecules VCAM-1 and ELAM-1. Oxidized n-3 PUFAs prevent LPS- or PMA-induced activation of transcription factor NF-kappa B and the consequent induction of mRNA for both cell adhesion molecules. Hydroperoxy fatty acids are the active principle in oxidized PUFAs because the activity (1) is predominantly organic soluble, (2) is obliterated by pretreatment of oxidized material with chemical reducing agents, and (3) is diminished by enzymatic reduction of organic hydroperoxides with glutathione/glutathione peroxidase. We speculate that this suppression of phagocyte-endothelium interactions by oxidized PUFAs may help explain the anti-inflammatory and possible anti-atherogenic effects of diets rich in fish oil. Perhaps more importantly, this modulation of endothelial cell adhesion molecule expression by oxidized lipids may represent a natural mechanism whereby inflammation-mediated oxidation of endothelial PUFAs may retard ingress of phagocytes and thereby prevent unrestrained phlogistic responses.

Animals↗
PubMed2004

MC-3 receptor and the inflammatory mechanisms activated in acute myocardial infarct.

Investigation of the mechanisms activated by endogenous inhibitory pathways can lead to identification of novel targets for cardiovascular inflammatory pathologies. Here we exploited the potential protective role that melanocortin receptor type 3 (MC3-R) activation might play in a myocardial ischemia-reperfusion injury model. In resting conditions, mouse and rat heart extracts expressed MC3-R mRNA and protein, without changes following ischemia-reperfusion. At the cellular level heart macrophages, but not fibroblasts or cardiomyocytes, expressed this receptor, as demonstrated by immunogold labeling. In vivo, administration of the melanocortin agonist MTII (10 microg per mouse equivalent to 9.3 nmol) 30 min prior to ischemia (25 min) attenuated mouse heart 2 h reperfusion injury by approximately 40%, an effect prevented by the mixed MC3/4-R antagonist SHU9119 but not by the selective MC4-R antagonist HS204. Similar results were obtained when the compound was given at the beginning of the reperfusion period. Importantly, delayed myocardial damage as measured 24 h post-reperfusion was equally protected by administration of 10 microg MTII. The focus on MC3-R was also substantiated by analysis of the recessive yellow (e/e) mouse, bearing a mutated (inactive) MC1-R, in which MTII was fully protective. Myocardial protection was associated with reduced markers of systemic and local inflammation, including cytokine contents (interleukin-1 and KC) and myeloperoxidase activity. In conclusion, this study has highlighted a previously unrecognized protective role for MC3-R activation on acute and delayed heart reperfusion injury. These data may open new avenues for therapeutic intervention against heart and possibly other organ ischemia-reperfusion injury.

Acute Disease↗
PubMed2001

Endothelial atheroprotective and anti-inflammatory mechanisms.

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, whereas laminar flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF), have been shown to stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent data suggest that steady laminar flow decreases EC apoptosis and blocks TNF-mediated EC activation. EC apoptosis is likely important in the process termed "plaque erosion" that leads to platelet aggregation. Steady laminar flow inhibits EC apoptosis by preventing cell cycle entry, by increasing antioxidant mechanisms (e.g., superoxide dismutase), and by stimulating nitric oxide-dependent protective pathways that involve enzymes PI3-kinase and Akt. Conversely, our laboratory has identified nitric oxide-independent mechanisms that limit TNF signal transduction. TNF regulates gene expression in EC, in part, by stimulating mitogen-activated protein kinases (MAPK) which phosphorylate transcription factors. We hypothesized that fluid shear stress modulates TNF effects on EC by inhibiting TNF-mediated activation of MAP kinases. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm2) on TNF-stimulated activity of two MAP kinases: extracellular signal regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK). Flow alone stimulated ERK1/2 activity, but decreased JNK activity compared to static controls. TNF (10 ng/ml) alone activated both ERK1/2 and JNK maximally at 15 minutes in human umbilical vein EC (HUVEC). Pre-exposing HUVEC for 10 minutes to flow inhibited TNF activation of JNK by 46%, but it had no significant effect on ERK1/2 activation. Incubation of EC with PD98059, a specific mitogen-activated protein kinase kinase inhibitor, blocked the flow-mediated inhibition of TNF activation of JNK. Flow-mediated inhibition of JNK was unaffected by 0.1 mM L-nitroarginine, 100 pM 8-bromo-cyclic GMP, or 100 microM 8-bromo-cyclic AMP. Transfection studies with dominant negative constructs of the protein kinase MEK1 and MEK5 suggested an important role for BMK1 in flow-mediated regulation of TNF signals. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms.

Animals↗
PubMed2003

Regulation and function of spinal and peripheral neuronal B1 bradykinin receptors in inflammatory mechanical hyperalgesia.

Activation of either B1 or B2 bradykinin receptors by kinins released from damaged tissues contributes to the development and maintenance of inflammatory hyperalgesia. Whereas B2 agonists activate sensory neurones directly, B1 agonists were thought only to have indirect actions on sensory neurones. The recent discovery of constitutive B1 receptor expression in the rat nervous system lead us to re-investigate the role of neuronal B1 receptors in inflammatory hyperalgesia. Therefore we have examined B1 bradykinin receptor regulation in rat dorsal root ganglia in a model of inflammatory hyperalgesia, and correlated it with hyperalgesic behaviour. Twenty-four hours after injection of Freund's complete adjuvant into one hindpaw, there was a significant increase in B1 protein expression (measured by immunohistochemistry) in both ipsilateral and contralateral dorsal root ganglion neurones, whereas axotomy resulted in reduction of B1 protein in ipsilateral dorsal root ganglia. In behavioural experiments, the B1 antagonist desArg10HOE140, administered by either intrathecal or systemic routes, attenuated Freund's complete adjuvant-induced mechanical hyperalgesia in the inflamed paw, but did not affect mechanical allodynia. The B1 agonist, desArg9BK, did not affect paw withdrawal thresholds in nai;ve rats following intraplantar administration into the paw, whilst intrathecal administration elicited mechanical hyperalgesia. However, after Freund's complete adjuvant-induced inflammation, desArg9BK caused a marked mechanical hyperalgesia, by either route, of the contralateral, uninflamed hindpaw, correlating with the observed contralateral and ipsilateral increases in receptor levels. Our results suggest a functional role for B1 receptors expressed both in the periphery and in the spinal cord, in mechanical hyperalgesia during inflammation.

Animals↗
PubMed2002

Hallmarks of atherosclerotic lesion development with special reference to immune inflammatory mechanisms.

Atherosclerosis is a complex disease that starts during childhood and becomes clinically evident later in life. Atherosclerosis results from an interaction between diverse factors including lipid metabolism, blood coagulation elements, cytokines and hemodynamic stress. Humoral and cellular immune reactions are key events in pathogenesis with the balance between pro-inflammatory and anti-inflammatory stimuli being crucial for the development of atherosclerotic lesions. Atherosclerotic lesions are characterised by the presence of immune competent cells including T-cells and dendritic cells. Dendritic cell interactions with T-cells might be responsible for T-cell activation in atherogenesis. Despite increasing acknowledgment that immune-inflammatory processes participate in atherogenesis, the immune mechanisms remain incompletely defined.

Arteriosclerosis↗
PubMed1993

Immunological aspects and inflammatory mechanisms of allergic reactions.

The tissue changes and symptoms that occur during an allergic reaction in the upper respiratory tract are due to inflammatory reactions. The authors give a survey of the different allergic reactions and discuss the different components of the IgE mediated hypersensitivity which is the most important type of hypersensitivity in the upper airways. The production of IgE, the immunoglobulin of the immediate hypersensitivity reaction, is modulated by T-cells through the activity of cytokines. Antigen presenting cells, including Langerhans cells, play an important role in the sensitisation phase. Mast cells and basophils degranulate as a result of a complex enzymatic pathway, in which phosphatidylinositol plays an important role. The mediators released by these cells include vasoactive substances, chemotactic agents and inflammatory proteases; these mediators and those liberated by secondary recruited cells, such as eosinophils and basophils will be responsible for the early and late symptoms.

Basophils↗
PubMed2006

Interleukin 1 genetics, inflammatory mechanisms, and nutrigenetic opportunities to modulate diseases of aging.

Inflammation plays a central role in many diseases of aging, and genetic differences in the inflammatory response appear to influence different disease courses among individuals. Variations in the genes for the family of interleukin 1 (IL-1) proteins are inherited together in a small set of patterns and provide an example of the role of inflammatory genetics as a modifier of diseases of aging. The IL-1 genetic variations are associated with variation in both the inflammatory response and the clinical presentation of a range of diseases, including coronary artery disease, Alzheimer disease, gastric cancer, and periodontitis. This growing understanding of the role of genetic variation in inflammation and chronic disease presents opportunities to identify healthy persons who are at increased risk of disease and to potentially modify the trajectory of disease to prolong healthy aging. Nutrition represents one of the promising approaches to modulation of the risk of diseases of aging because of the effects of certain nutrients on gene expression. One of the most practical applications of nutritional modulation of chronic disease may be nutrients that regulate the expression of key inflammatory genes.

Aged↗
PubMed2006

Anti-inflammatory mechanisms of isoflavone metabolites in lipopolysaccharide-stimulated microglial cells.

The microglial activation plays an important role in neurodegenerative diseases by producing several proinflammatory cytokines and nitric oxide (NO). We found that three types of isoflavones and their metabolites that are transformed by the human intestinal microflora suppress lipopolysaccharide (LPS)-induced release of NO and tumor necrosis factor (TNF)-alpha in primary cultured microglia and BV2 microglial cell lines. The inhibitory effect of the isoflavone metabolites (aglycon form) was more potent than that of isoflavones (glycoside form). The RNase protection assay showed that the isoflavone metabolites regulated inducible nitric oxide synthase (iNOS) and the cytokines at either the transcriptional or post-transcriptional level. A further molecular mechanism study was performed for irisolidone, a metabolite of kakkalide, which had the most potent anti-inflammatory effect among the six isoflavones tested. Irisolidone significantly inhibited the DNA binding and transcriptional activity of nuclear factor (NF)-kappaB and activator protein-1. Moreover, it repressed the LPS-induced extracellular signal-regulated kinase (ERK) phosphorylation without affecting the activity of c-Jun N-terminal kinase or p38 mitogen-activated protein kinase. The level of NF-kappaB inhibition by irisolidone correlated with the level of iNOS, TNF-alpha, and interleukin (IL)-1beta suppression in LPS-stimulated microglia, whereas the level of ERK inhibition correlated with the level of TNF-alpha and IL-1beta repression. Overall, the repression of proinflammatory cytokines and iNOS gene expression in activated microglia by isoflavones such as irisolidone might have therapeutic potential for various neurodegenerative diseases including ischemic cerebral disease.

Animals↗