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PubMed1994

[Mechanisms of microcrystalline inflammation].

The inflammatory mechanisms which take place in microcrystalline arthropathies can be divided into several stages, each of them being characterized by the activation of a set of mediators. The process begins with activation by crystals of resident cells in the synovial fluid which release various pro-inflammatory factors including several cytokines. Among these, interleukin 1 (IL-1) and tumor-necrosis factor alpha (TNF-alpha) have multiple effects and play a predominant role in the starting of inflammation. With the contribution of humoral factors, also activated by the crystals, IL-1 and TNF-alpha activate notably the endothelial cells to allow leucocyte extravasation. The attraction and massive activation of polymorphonuclear neutrophils (PMNs) which then occurs and characterizes acute microcrystalline arthropathies mainly depend on IL-8, another cytokine secreted by synoviocytes. At the same time, an acute phase systemic reaction principally induced by IL-6 develops. When inflammation is prolonged mechanisms of tissue destruction begin to act, notably by releasing proteases induced by IL-1 and TNF-alpha. These mechanisms are counterbalanced by release of antiproteases, notably those induced by the transforming growth factor beta (TGF-beta) and by IL-6. Finally, these inflammatory processes may limit themselves or even stop spontaneously, due to a series of control mechanisms including cytokines with anti-inflammatory effects, ACTH release and physico-chemical changes in crystals.

Acute Disease↗
PubMed2001

New insights into mechanism of inflammatory and allergic diseases in mucosal tissues.

The gastrointestinal immune system is a major component of the mucosal barrier to foreign antigens including microbial and dietary antigens. Under normal circumstances, the mucosal immune system employs tightly regulated dynamic mucosal intra- and internets for the maintenance of an appropriate immunological balance between the host and gut environments. For example, mucosally induced tolerance is usually induced against enteric commensal bacterial and/or dietary antigens. However, in some cases, the break down of these tightly regulated mucosal immune responses led to hyper-responsiveness against these gut environmental antigens. To this end, numerous disorders could evoke in the gastrointestinal tissues, such as inflammatory bowel disease (IBD) and allergic gastroenteropathy. Recently, many studies have described possible molecular and cellular mechanisms of those dysfunctions in the gastrointestinal tissues. In this review, we have briefly summarized some of the current interesting and exciting findings for gastrointestinal diseases, especially IBD and intestinal allergic diseases from our group, which can be applied for the development of new mucosal immune therapy.

Animals↗
PubMed2001

Botulinum toxin therapy for pain and inflammatory disorders: mechanisms and therapeutic effects.

Botulinum toxin (BTX) injections are a well-recognised therapeutic modality for the treatment of regional involuntary muscle disorders and recently BTX has been used for treatment of pain and inflammatory disorders. The primary purpose of this review is to discuss the mechanism of action of therapeutic BTX in light of both the traditional understanding of BTX pharmacological effects as well as new observations. The review will deal with clinical observations and relevant animal experimentation. The data and hypotheses presented are not only relevant to botulinum toxin technology but will certainly prove important in the basic mechanisms of some of the diseases where botulinum toxin has been successfully applied. BTX used clinically comprises botulinum neurotoxin (BoNT) complexed with non-toxic proteins. The non-toxic components of the BTX complexes stabilise the labile BoNT during purification and formulation as a therapeutic. The complex proteins may also have unrecognised clinical significance such as slowing diffusion in tissues or imparting stability. The mechanisms of BTX formulations acting on SNARE proteins are briefly reviewed providing a basis for BTX clinical applications. The potential for design of improved botulinum toxins and formulations is addressed.

Animals↗
PubMed2003

Cytokine profile of the rheumatoid nodule suggests that it is a Th1 granuloma.

OBJECTIVE: To define the cytokine profile within rheumatoid subcutaneous nodules, and to determine whether the destructive inflammatory process in this lesion displays features of a lymphocyte-driven Th1 or Th2 granuloma. METHODS: Subcutaneous nodules excised from 10 patients with rheumatoid arthritis were examined. Transcripts for interleukin 1beta (IL-1beta) IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-15, IL-18, and for tumor necrosis factor alpha (TNFalpha) and interferon-gamma (IFNgamma) were detected by reverse transcription-polymerase chain reaction of extracted RNA. RESULTS: Nine of 10 nodules contained transcripts for IFNgamma. We observed no evidence for the expression of IL-2, IL-4, or IL-5 among the lymphokine genes analyzed. Transcripts for TNFalpha, IL-1beta, IL-10, IL-15, and IL-18 were present in all 10 nodules. Transcripts for IL-12 were present in all but one nodule. Expression of IL-13 messenger RNA was observed in only 5 nodules. CONCLUSION: The cytokine profile within the rheumatoid nodule (i.e., presence of IFNgamma but not IL-2, and prominent expression of IL-1beta and TNFalpha together with IL-12, IL-18, IL-15, and IL-10) is similar to the profile of cytokines in the synovial lesion of rheumatoid arthritis, which is generally accepted as being attributable to a Th1-mediated inflammatory mechanism. Our results suggest that damage to affected synovial membrane or subcutaneous tissue is caused by the same inflammatory mechanisms, and that the nodule is a Th1 granuloma.

Aged↗
PubMed1998

Inflammation in high-grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilization.

BACKGROUND AND PURPOSE: Inflammatory mechanisms have been implicated in the pathogenesis of atherosclerosis. In this study, we investigated whether the extent of inflammatory infiltration in high-grade stenoses of the internal carotid artery (ICA) correlates to clinical features of plaque destabilization. METHODS: Endarterectomy specimens from 37 consecutive patients undergoing surgery for high-grade ICA stenosis were stained immunocytochemically for macrophages (CD68) and T cells (CD3). The staining was quantified by planimetry of immunostained areas (CD68) or counting individual cells (CD3). Clinical evidence of plaque instability was provided by the preoperative assessment of recent ischemic symptoms attributable to the stenosis and of the occurrence of cerebral microembolism in transcranial Doppler ultrasound monitoring of the ipsilateral middle cerebral artery. RESULTS: The percentage of macrophage-rich areas and number of T cells per mm2 section area were larger in recently symptomatic patients than in asymptomatic patients (macrophages: 18+/-10% versus 11+/-4%, P=0.005; T cells: 71.2+/-34.4 versus 40.5+/-31.4 mm2, P=0.005). The presence of microembolism was associated with an increase in macrophage-rich areas (P=0.011). Macrophage (19+/-10% versus 9+/-3%, P=0.0009) and T cell (71.5+/-39.0 versus 46.4+/-22 mm2, P=0.045) infiltration were more pronounced in predominantly atheromatous than in fibrous plaques, but did not correlate significantly to the presence of surface ulceration or luminal thrombosis. CONCLUSIONS: Our data suggest a role of plaque-infiltrating macrophages and T cells in the clinical destabilization of high-grade ICA stenoses. Inflammatory mechanisms may be a therapeutic target in patients with symptomatic ICA disease.

Adult↗
PubMed1996

Mechanisms of inflammatory liver injury: adhesion molecules and cytotoxicity of neutrophils.

During recent years, increasing experimental evidence has suggested that hepatic nonparenchymal cells, in particular Kupffer cells and neutrophils, can contribute significantly to the pathogenesis of liver injury in various chemical toxicities. Neutrophils are central to the mechanism of injury after hepatic ischemia reperfusion and endotoxemia. In this symposium summary, an overview of critical aspects of neutrophil-dependent liver injury is presented. A general introduction to the involvement of adhesion molecules in neutrophil rolling and transendothelial migration is provided. Mediators and mechanisms of neutrophil sequestration in the liver vasculature, extravasation, and adherence-dependent cytotoxicity are discussed using the examples of endotoxin-induced hepatic failure and ischemia-reperfusion injury. These processes involve a complex network of inflammatory mediators including cytokines, chemokines, and lipid-derived compounds. The role of neutrophil-derived cytotoxic mediators, e.g., reactive oxygen and proteases, in the molecular mechanisms of parenchymal cell injury is discussed. Furthermore, interactions between neutrophils and contractile, perisinusoidal, stellate cells that influence microvascular blood flow in the liver are discussed. Results of these and other investigations are leading to increased understanding of the complex interactions between neutrophils and tissues that result in injury.

Animals↗
PubMed2005

Inflammation, blood pressure, and stroke: an opportunity to target primary prevention?

Promising findings suggest that systemic inflammation and neuroinflammation are central features in cerebrovascular disease. Inflammatory mechanisms are also important participants in the pathophysiology of hypertension. Markers of inflammation have been shown to be upregulated in different forms of cerebrovascular disease, and to correlate with vascular risk. The inhibitor nuclear factor-kB/nuclear factor-kB system is considered a major intracellular inflammatory pathway, mediating most of the vascular inflammatory responses. Increasing evidence indicates that hypertension, through the vasoactive peptides angiotensin and endothelin-1, promotes and accelerates the atherosclerotic process via inflammatory mechanisms. Proinflammatory properties of angiotensin II have been demonstrated. The identification of useful markers of inflammation, of new therapeutic targets to interfere with these mechanisms, and the evaluation of the efficacy of anti-inflammatory treatments will allow progress in our ability to combat cerebrovascular disease and the complications of hypertension. Whether these targets will be useful in the development of risk prediction strategies or therapies for the treatment of stroke in humans is far from clear.

Biomarkers↗
PubMed2004

Interaction between a rat model of cerebral ischemia and beta-amyloid toxicity: inflammatory responses.

BACKGROUND AND PURPOSE: Clinical data suggest that Alzheimer disease (AD) and stroke together potentiate cognitive impairment. Inflammatory mechanisms are involved in AD pathology and stroke and may be the mediator between AD and stroke toxicity. METHODS: AD was modeled by cerebroventricular injections of beta-amyloid (Abeta[25-35]) and subcortical lacunar infarcts by striatal endothelin injections. Inflammatory mechanisms were examined using immunohistochemical analysis. Memory and motor tasks were assessed using the Montoya staircase test. RESULTS: Abeta injections elicited increases in pathological and inflammatory correlates of AD in multiple forebrain sites. Increases in astrocytosis and reactive microglia in the hippocampus were enhanced with the combination of endothelin and Abeta(25-35). Abeta(25-35) treatment decreased performance in the Montoya staircase behavioral test. CONCLUSIONS: The enhanced inflammatory response with Abeta toxicity and ischemia may mediate the inability to improve behavioral performance caused by the stroke. Anti-inflammatory treatment may ameliorate the pathological and behavioral deficits associated with the combination of AD and stroke.

Alzheimer Disease↗
PubMed2006

Spontaneous coronary dissection as a cause of acute coronary syndrome: evidence for non-inflammatory underlying mechanisms.

Myocardial infarction in patients without atherosclerotic coronary artery disease is a rare syndrome. Several pathophysiologic mechanisms have been proposed, such as spontaneous coronary dissection, intramural hematoma, coronary vasospasm and thrombosis. Diagnosis can be confirmed by coronary angiography and intravascular ultrasound, while the presence of an inflammatory process within the coronary artery wall can be detected from local heat production by intracoronary thermography. We present two women with acute coronary syndrome, due to a limited spontaneous coronary dissection and an intramural hematoma detected by coronary angiography and intravascular ultrasound.

Acute Disease↗
PubMed2004

Indomethacin blocks the nucleus pulposus-induced effects on nerve root function. An experimental study in dogs with assessment of nerve conduction and blood flow following experimental disc herniation.

Inflammatory mechanisms have been suggested to be involved in the basic pathophysiologic events leading to nerve root injury after local application of nucleus pulposus. To assess if these nucleus pulposus-induced effects could be blocked by anti-inflammatory treatment, 41 dogs were exposed to either incision of the L6-7 disc to induce experimental disc herniation with (n=12) or without (n=14) indomethacin treatment per os (5 mg/kg per day), and no incision with (n=5) or without (n=10) indomethacin. Intraneural blood flow and nerve conduction velocity were assessed after 7 days to evaluate the degree of nerve injury. Disc incision induced a reduction in nerve root and dorsal ganglion blood flow as well as nerve function, similarly to previous studies. However, simultaneous treatment with indomethacin efficiently blocked the negative effects on both blood flow and nerve conduction but had no effects per se. The present study thus indicates that inflammatory mechanisms may be of relevance in the pathophysiology of nucleus pulposus-induced nerve root injury and thereby also for sciatica.

Animals↗
PubMed2005

Immunology of ischemic vascular disease: plaque to attack.

Interest and studies focused on the role of immune and inflammatory mechanisms in vascular disease have advanced in synchrony with the advances in the understanding of innate immune system regulation and the interplay between innate and adaptive immunity. Clinical studies have implicated immune and inflammatory mechanisms in stroke and acute coronary syndromes. Analyses of genetically modified mice and in vitro and in vivo preclinical ischemia models have yielded insights into pathobiological mechanisms. Deciphering the role of innate immune mechanisms that confer tolerance to ischemia might guide translation of more effective therapies. Antigen-targeted and other forms of focused immunomodulation that can suppress vessel activation and protect ischemic tissue might ultimately find a niche in the prevention and treatment of vascular disease.

Animals↗
PubMed2003

Modulation of macrophage activity by proteolytic enzymes. Differential regulation of IL-6 and reactive oxygen intermediates (ROIs) synthesis as a possible homeostatic mechanism in the control of inflammation.

Inflammatory foci are rich in proteases released by neutrophils (serine proteases) and macrophages (metalloproteases). These enzymes can degrade extracellular matrix proteins and cell membrane bound proteins thus contributing to the development and progression of inflammatory reaction. In this study we have investigated the influence of collagenase (metalloprotease) and trypsin (serine protease) on murine resident and oil-induced peritoneal macrophages (Mf). Short in vitro treatment of Mf, not affecting cell viability, significantly reduced the release of reactive oxygen intermediates (ROIs) and at the same time triggered the increase of IL-6 production and to lesser extent of TNF-alpha production. Both these effects were dependent on enzyme concentration used and were particularly well pronounced in resident macrophages. In addition both enzymes cleaved a number of cell-membrane molecules, including CD23, CD14, CD95L, and Mac-3. We hypothesize that the enzymatic digestion of certain Mf surface receptor proteins in inflammatory foci may be responsible for modification of cell behaviour either by preventing the generation of specific signal or alternatively by delivering a mock substitute signal to the cell interior. In effect inhibition of ROIs production limits their destructive effects and the increase in the secretion of IL-6 stimulates the synthesis of acute phase proteins and triggers other anti-inflammatory mechanisms thus directing Mf present in inflammatory foci into regulatory pathway rather than allowing them to perform solely the effector function.

Animals↗
PubMed2006

Protease-activated receptor-4: a novel mechanism of inflammatory pain modulation.

BACKGROUND AND PURPOSE: Protease-activated receptor-4 (PAR(4)), the most recently discovered member of the PARs family, is activated by thrombin, trypsin and cathepsin G, but can also be selectively activated by small synthetic peptides (PAR(4)-activating peptide, PAR(4)-AP). PAR(4) is considered a potent mediator of platelet activation and inflammation. As both PAR(1) and PAR(2) have been implicated in the modulation of nociceptive mechanisms, we investigated the expression of PAR(4) in sensory neurons and the effects of its selective activation on nociception. EXPERIMENTAL APPROACH AND KEY RESULTS: We demonstrated the expression of PAR(4) in sensory neurons isolated from rat dorsal root ganglia by reverse transcription-polymerase chain reaction and immunofluorescence. We found that PAR(4) colocalized with calcitonin gene-related peptide and substance P. We also showed that a selective PAR(4)-AP was able to inhibit calcium mobilization evoked by KCl and capsaicin in rat sensory neurons. Moreover, the intraplantar injection of a PAR(4)-AP significantly increased nociceptive threshold in response to thermal and mechanical noxious stimuli, while a PAR(4) inactive control peptide had no effect. The anti-nociceptive effects of the PAR(4)-AP were dose-dependent and occurred at doses below the threshold needed to cause inflammation. Finally, co-injection of the PAR(4)-AP with carrageenan significantly reduced the carrageenan-induced inflammatory hyperalgesia and allodynia, but had no effect on inflammatory parameters such as oedema and granulocyte infiltration. CONCLUSIONS AND IMPLICATIONS: Taken together, these results identified PAR(4) as a novel potential endogenous analgesic factor, which can modulate nociceptive responses in normal and inflammatory conditions.

Animals↗
PubMed2005

[Effect of sinomenine on adjuvant arthritis and its mechanisms].

OBJECTIVE: To discuss the anti-inflammatory mechanism of sinomenine on inflammatory media in joint of adjuvant arthritis rats. METHOD: Rats were randomly divided into the normal group and the model group, the prednisone group, the small, medium, large of sinomenine group (30, 60, 120 mg x kg(-1)). Except for the rats in the normal group, animals were modeled to adjuvant arthritiswith freund's complete adjuvant. The arthritis index (AI) and the swelling degree of paws were recorded, and the activity of IL-1, TNF and the levels of NO, PGE2 in joint fluids of secondary arthritis were determined. RESULT: Compared with the normal group, the activity of IL-1, TNF and the levels of NO, PGE2 in joint fluids of secondary arthritis were increased significantly in the model group (P < 0.05). Compared with the model group, it was shown to exert a dramatic inhibitory effect on secondary reaction of freund's adjuvant arthritis of rats, and the activity of IL-1, TNF and the levels of NO, PGE2 in joint fluids of secondary arthritis were significantly decreased in the sinomenine group (P < 0.05). CONCLUSION: Sinomenine has a remarkable treatment effect on RA. It is via NO to inhibit the activity of cytokines and decrease the level of inflammation mediators, which may be one of its curing RA mechanism.

Animals↗
PubMed2003

Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA.

The human gut microflora is important in regulating host inflammatory responses and in maintaining immune homeostasis. The cellular and molecular bases of these actions are unknown. Here we describe a unique anti-inflammatory mechanism, activated by nonpathogenic bacteria, that selectively antagonizes transcription factor NF-kappaB. Bacteroides thetaiotaomicron targets transcriptionally active NF-kappaB subunit RelA, enhancing its nuclear export through a mechanism independent of nuclear export receptor Crm-1. Peroxisome proliferator activated receptor-gamma (PPAR-gamma), in complex with nuclear RelA, also undergoes nucleocytoplasmic redistribution in response to B. thetaiotaomicron. A decrease in PPAR-gamma abolishes both the nuclear export of RelA and the anti-inflammatory activity of B. thetaiotaomicron. This PPAR-gamma-dependent anti-inflammatory mechanism defines new cellular targets for therapeutic drug design and interventions for the treatment of chronic inflammation.

Animals↗