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PubMed2006

Hepatocyte growth factor suppresses acute renal inflammation by inhibition of endothelial E-selectin.

Vascular endothelial activation, marked by de novo expression of E-selectin, is an early and essential event in the process of leukocyte extravasation and inflammation. Evidence suggests that hepatocyte growth factor (HGF) ameliorates inflammation in animal models of renal disease, implying that HGF might inhibit specific components of the inflammatory response. This study examined the effect of HGF on endothelial E-selectin expression in acute inflammation induced by tumor necrosis factor (TNF)-alpha. In vitro, HGF suppressed TNF-alpha-induced cell surface expression of E-selectin in human umbilical vein endothelial cells (HUVEC) and inhibited E-selectin mediated monocytic adhesion to endothelial monolayers. HGF activated phosphatidylinositol 3-kinase (PI3K)-Akt that in turn inhibited its downstream transducer glycogen synthase kinase (GSK)3. Blockade of the PI3K-Akt pathway with specific inhibitors abrogated HGF induced inhibitory phosphorylation of GSK3 and suppression of E-selectin. In addition, selective inhibition of GSK3 activity by lithium suppressed TNF-alpha-induced E-selectin expression and monocytic adhesion, reminiscent of the action of HGF. Moreover, ectopic expression of an uninhibitable mutant GSK3beta, in which the regulatory serine-9 is replaced by alanine, abolished HGF's suppressive effect on endothelial E-selectin. In vivo, administration of exogenous HGF reduced endothelial expression of E-selectin induced by bolus injection of TNF-alpha. This was associated with less sequestration of circulating fluorescence-labeled macrophages in the kidney. These findings suggest that HGF ameliorates acute renal inflammation in part by downregulating E-selectin mediated macrophage adhesion to the inflamed endothelium.

Acute Disease↗
PubMed1979

Differential effect of clofibrate on inflammation-induced alterations in plasma proteins in the rat.

Daily intramuscular injections of clofibrate begun 6h before the initiation of inflammation induced by the subcutaneous injection of turpentine exerted a differential, dose-dependent inhibition of the anticipated acute-phase globulin response. Specifically, clofibrate at 140mg/kg muted the increase in alpha(2)-macrofoetoprotein, but did not affect that of seromucoid or haptoglobin and only transiently inhibited the rise in copper and the rebound in transferrin. A higher dose, 280mg/kg, markedly suppressed alpha(2)-macrofoetoprotein appearance and the rebound in transferrin, somewhat inhibited the increase in seromucoid and haptoglobin and only transiently affected the rise in plasma copper; 420mg of clofibrate/kg very nearly abolished the appearance of alpha(2)-macrofoetoprotein, markedly suppressed the transferrin rebound and the increases in seromucoid and haptoglobin and again only transiently affected the increase in copper. Clofibrate did not diminish the localized inflammatory response, did not cause microscopically detectable liver damage and did not prevent the hypozincaemia, hypoalbuminaemia and enhanced amino acid uptake by liver usually associated with inflammation. Thus it is unlikely that clofibrate exerted its dose-dependent selective inhibition by muting the initial stimulus or by impairing hepatic metabolism. This seemingly selective action of clofibrate on plasma-protein alterations during inflammation may provide a means of elucidating the function of individual acute-phase globulin during disease. Clofibrate of itself, apart from inflammation, produced decreases in plasma zinc, copper, transferrin and seromucoid and an increase in hepatic amino acid uptake that were to some extent dependent on the dose of the drug.

Amino Acids↗
PubMed2005

Signalling role of adipose tissue: adipokines and inflammation in obesity.

White adipose tissue (WAT) is a major endocrine and secretory organ, which releases a wide range of protein signals and factors termed adipokines. A number of adipokines, including leptin, adiponectin, tumour necrosis factor alpha, IL-1beta (interleukin 1beta), IL-6, monocyte chemotactic protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor 1 and haptoglobin, are linked to inflammation and the inflammatory response. Obesity is characterized by a state of chronic mild inflammation, with raised circulating levels of inflammatory markers and the expression and release of inflammation-related adipokines generally rises as adipose tissue expands (adiponectin, which has anti-inflammatory action is an exception). The elevated production of inflammation-related adipokines is increasingly considered to be important in the development of diseases linked to obesity, particularly Type II diabetes and the metabolic syndrome. WAT is involved in extensive cross-talk with other organs and multiple metabolic systems through the various adipokines.

Adipose Tissue↗
PubMed2006

Controlling inflammation: the cholinergic anti-inflammatory pathway.

Innate immune responses and inflammation are regulated in part by neural mechanisms. In the present paper, we summarize experimental evidence that reveals that innate immunity and inflammation are controlled by the vagus nerve, previously known as a regulator of other vital physiological functions. Activation of vagus nerve cholinergic signalling inhibits TNF (tumour necrosis factor) and other pro-inflammatory cytokine overproduction through 'immune' alpha7 nicotinic receptor-mediated mechanisms. This efferent vagus nerve-based 'cholinergic anti-inflammatory pathway' has been elucidated as a critical regulator of inflammation in several experimental models of diseases. Our recent observations have shown that activation of central (brain) cholinergic transmission by selective muscarinic receptor ligands results in lower systemic TNF levels in rodents and indicate that the efferent vagus nerve may provide a functional brain-to-immune connection. Thus central cholinergic signalling is implicated in the activation of the cholinergic anti-inflammatory pathway. Electrical vagus nerve stimulation is clinically approved for the treatment of epilepsy and depression and current knowledge suggests that it could be utilized to control inflammation. Advances in understanding the receptor and molecular mechanisms of cholinergic anti-inflammatory signalling indicate that selective alpha7 nicotinic receptor agonists and centrally acting cholinergic enhancers can be used in the treatment of pathological conditions characterized by cytokine overproduction.

Brain↗
PubMed2004

Inflammation and endothelial dysfunction: intimate companions in the pathogenesis of vascular disease?

There is increasing evidence to implicate inflammation as an important precursor of endothelial dysfunction. This mechanistic link is apparent across the entire spectrum of inflammatory status, i.e. endothelial function is apparent following acute infection, and in subjects with chronic high-grade inflammation and, perhaps most importantly, persistent low-grade inflammation. The recognition of this relationship has present therapeutic ramifications, but also requires that future longitudinal studies determining the predictive ability of endothelial function measures for vascular events should incorporate markers of inflammation as potential confounders. In this issue of Clinical Science, Fichtlscherer and co-workers describe a link between endothelial function and sPLA(2) (secretory non-pancreatic type II phospholipase A(2)) serum activity.

C-Reactive Protein↗
PubMed2001

Effects of anti-tumour necrosis factor, interleukin-10 and antibiotic therapy in the indometacin-induced bowel inflammation rat model.

BACKGROUND: The administration of indometacin to rats increases intestinal permeability and induces inflammatory pathology of the small bowel. This represents a potential model for Crohn's disease. AIMS: To analyse the pathogenic role of T cells, tumour necrosis factor and bacterial flora in indometacin-induced changes in small bowel permeability and inflammation. METHODS: Rats were given indometacin, 13 mg/kg, on day 1 and day 2. The effects of antibiotic (metronidazole, aztreonam and amoxicillin/clavulanic acid), anti- tumour necrosis factor and interleukin-10 therapy were evaluated. The parameters used were weight change, serum haemoglobin, chromium-51 ethylenediaminetetra-acetate permeability and macro-and microscopic score on day 5. Results in conventionally harboured rats were compared with those in T-cell-free rats. Additional in vitro experiments were carried out to test the effect of metronidazole on tumour necrosis factor production. RESULTS: Indometacin administration resulted in small bowel ulcers and inflammation, independently of T cells. Metronidazole was more potent than amoxicillin/clavulanic acid and anti-tumour necrosis factor in improving the indometacin-induced small bowel inflammation. Only part of the efficacy was through improvement of increased intestinal permeability. Aztreonam and interleukin-10 had no effect. Metronidazole also suppressed in vitro lipopolysaccharide-induced tumour necrosis factor production, suggesting a therapeutic effect of this drug through the inhibition of tumour necrosis factor. CONCLUSIONS: These data implicate anaerobic bacteria and tumour necrosis factor production, but not T cells, as essential elements of the pathogenesis of indometacin-induced small bowel inflammation. Tumour necrosis factor is also involved in the change in intestinal permeability. Metronidazole was the most efficacious drug in this model, probably because it suppressed anaerobic bacteria and directly inhibited tumour necrosis factor production.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed1999

Mast cell tryptase in dermal neurogenic inflammation.

BACKGROUND: Mast cell activation has been assumed to play a role in dermal neurogenic inflammation: C fibre-derived neuropeptides activating mast cells and releasing histamine, which in turn would activate C fibres. OBJECTIVE: To test this hypothesis mast cell tryptase (MCT) was measured inside the axon reflex flare area. Axon reflexes were elicited by histamine or compound 48/80, a polyanionic mast cell-degranulating substance. The time course of plasma extravasation and release of histamine and MCT from dermal mast cells in neurogenic inflammation was measured in vivo by intradermal microdialysis in humans. METHODS: Single hollow plasmapheresis fibres (pore cutoff size: 3000 kDa) were inserted intracutaneously at the volar forearm and perfused with Ringer's solution (4 microL/min) with one microdialysis fibre located at the planned stimulation site and a second inside the axon reflex area. Neurogenic inflammation was induced by intraprobe delivery of either histamine or the mast cell-degranulating agent compound 48/80. Mediator release was measured at the stimulation sites and inside the arising axon reflex flare area. RESULTS: Mast cell degranulation induced marked plasma protein extravasation (PPE 0.25 +/- 0.04-1.31 +/- 0.6 mg/mL; pre- and post-stimulation, mean +/- sem, n = 7) and release of histamine (2.0 +/- 0.9-38.7 +/- 1.4 ng/mL) and MCT (9.84 +/- 2.4-92.2 +/- 21.6 ng/mL). Interestingly, in addition to increasing PPE (0.33 +/- 0. 11-1.85 +/- 0.9 mg/mL), histamine also induced a slight but significant increase in MCT (11.3 +/- 3.0-12.4 +/- 2.3 ng/mL). No evidence for mast cell activation was observed inside the axon reflex areas, where PPE (0.34 +/- 0.03-0.25 +/- 0.02 mg/mL), histamine (1.64 +/- 0.5-1.46 +/- 0.4 ng/mL) and MCT concentration (11.6 +/- 3.1-7.6 +/- 1.7 ng/mL) gradually decreased. CONCLUSION: It is concluded that dermal neurogenic inflammation does not degranulate mast cells.

Adult↗
PubMed2001

Induction, distribution and modulation of upper airway allergic inflammation in mice.

BACKGROUND: To further elucidate mechanisms of human allergic rhinosinusitis, we studied the induction, distribution and modulation of allergen-induced upper airway inflammation in a BALB/c mouse model. METHODS: Allergic inflammation induced with ovalbumin (OVA) by intraperitoneal (IP) injection in alum was compared to repeated intranasal instillation. The type and distribution of inflammatory cells was compared in the respiratory and olfactory epithelial compartments. Eosinophil distribution was assessed using Scarlet Red stain and a polyclonal antibody recognizing eosinophil major basic protein (MBP). The role of interleukin (IL)-5 in upper airway inflammation was tested by administration of polyclonal anti-IL-5 antibody during the sensitization protocol. RESULTS: Unsensitized control mice receiving saline failed to develop upper airway eosinophil infiltration. IP OVA-sensitized mice developed marked upper airway mucosal eosinophil infiltration after aerosol OVA challenge, whereas repeated intranasal instillation of OVA produced qualitatively similar, but less intense eosinophil infiltration. Using either sensitization protocol, eosinophil infiltration was seen in areas of the lower portion of the nasal septum, the floor and the lower lateral walls of the mid-caudal region of the nasal cavity. Immunofluorescence staining for MBP confirmed this distribution of eosinophils but also demonstrated some eosinophils in the maxillary sinuses and in circumscribed regions of the ethmoturbinates. All areas of eosinophil infiltration were lined by respiratory epithelium. The selective infiltration of respiratory but not olfactory epithelium by eosinophils was unassociated with a measurable induction of epithelial ICAM-1 or eotaxin expression. OVA-induced upper airway eosinophil infiltration was found to be IL-5 dependent, since administration of a polyclonal anti-IL-5 antibody (TRFK-5) during OVA sensitization resulted in a marked modulation (80% decrease) in eosinophil infiltration in response to subsequent OVA challenge. CONCLUSION: The mouse upper airway, specifically in areas containing respiratory epithelium, is a target for OVA-induced allergic inflammation. This selective infiltration of respiratory, but not olfactory, epithelium is, in part, dependent upon IL-5. This model is useful for further dissection of the inflammatory response with genetic manipulations and targeted immunological approaches.

Administration, Inhalation↗
PubMed2000

Entamoeba histolytica cysteine proteinases with interleukin-1 beta converting enzyme (ICE) activity cause intestinal inflammation and tissue damage in amoebiasis.

The protozoan parasite Entamoeba histolytica causes intestinal inflammation and ulceration. Amoebic trophozoites activate the transcription factor NF-kappa B in human intestinal epithelial cells, initiating an inflammatory response programme with resultant damage to the intestinal tissue. Amoebic cysteine proteinases have been proposed as important virulence factors for amoebiasis. To test the role of amoebic cysteine proteinases in the pathogenesis of amoebic colitis, human intestinal xenografts in SCID mice were infected with E. histolytica trophozoites expressing an antisense message to ehcp5. The cysteine proteinase-deficient amoeba failed to induce intestinal epithelial cell production of the inflammatory cytokines interleukin (IL)-1B and IL-8, and caused significantly less gut inflammation and damage to the intestinal permeability barrier. The critical role of amoebic cysteine proteinases in human gut inflammation and tissue damage may be explained by our discovery that amoebic cysteine proteinases possess IL-1B converting enzyme (ICE) activity. This ICE activity could contribute to intestinal inflammation by activating human pIL-1B released by damaged intestinal cells. These results demonstrate for the first time that amoebic cysteine proteinases are a key virulence factor in amoebic colitis, and provide a novel mechanism for their activity.

Amebiasis↗
PubMed2002

Alterations of neurokinin receptors and interstitial cells of Cajal during and after jejunal inflammation induced by Nippostrongylus brasiliensis in the rat.

Substance P (SP) and its receptors NK1 and NK2 are widely expressed in the intestinal wall by neurones, interstitial cells of Cajal (ICC) and smooth muscle cells. Changes in SP and/or its NK receptors have been documented during experimental inflammation in animals or inflammatory bowel diseases in humans, but the data concern the acute phase of the inflammatory process. We determined immunohistochemically whether NK receptors and SP were altered in the muscle coat during jejunal inflammation induced by the nematode Nippostrongylus brasiliensis and whether these alterations persisted when inflammation had spontaneously resolved 30 days postinfection. An ultrastructural analysis was also conducted on ICC, nerves and muscle. At day 14, when inflammation peaked, there was a reduction in NK1 receptors in myenteric neurones and in SP-immunoreactive nerve endings. There were also ultrastructural anomalies in synaptic vesicles and NK2 receptor loss in the circular muscle layer. The SP decrease persisted at day 30, whereas neurones and circular muscle cells re-expressed NK1 and NK2 receptors, respectively. The ICC at the deep muscular plexus, located near to the inflammatory site, underwent alterations leading to their complete loss at day 30. These morphological changes are probably associated with impairment in tachykinergic control of jejunal functions leading to the alterations of motility and sensitivity to distension already described in these animals.

Animals↗
PubMed2004

The expression and role of Fas ligand in intestinal inflammation.

Fas ligand (FasL) is involved in the pathogenesis of inflammatory diseases and immune privilege. We examined the expression of FasL in the enteric nervous system (ENS) in murine colitis and guinea-pig ileitis. We studied FasL immunoreactivity, functional integrity of the ENS, severity of colitis, and distribution of neutrophils in wild type and B6/gld mice that lack functional FasL. In ileitis, the distribution of FasL, CD4+ and CD8+ T cells was examined. FasL expression was increased in the ENS of wild type mice with colitis, but decreased labelling of nerve fibres was noted in B6/gld mice. Neutrophils were more abundant and widely distributed in B6/gld mice. Colitis was more severe and persistent in B6/gld mice 7 days after induction. Functional parameters of intestinal secretion and motility in B6/gld mice were the same as controls. In ileitis, FasL expression was increased in the guinea-pig ENS and returned to control levels following the resolution of inflammation. While T cells were not present in the ENS of controls, they were observed during inflammation, but were excluded from ganglia. The number of enteric neurons was unchanged over the course of inflammation. The expression of FasL is altered in intestinal inflammation and contributes to its resolution in experimental colitis.

Animals↗
PubMed2003

Cyclooxygenase-2 is induced in the endothelial cells throughout the central nervous system during carrageenan-induced hind paw inflammation; its possible role in hyperalgesia.

Inflammation is often accompanied with hyperalgesia. This hyperalgesia is mediated partly by prostaglandin(s) produced in the CNS through the cyclooxygenase-2 (COX-2) dependent pathway. However, it remains unclear where COX-2 is induced in the CNS during inflammation, and how it is involved in hyperalgesia. We studied the precise site of COX-2 induction in the CNS, the relation between the time course of COX-2 induction and that of hyperalgesia, and the effect of COX-2-selective inhibitor by using a carrageenan model. Carrageenan injection induced expression of COX-2-like immunoreactivity in vascular endothelial cells throughout the CNS. This response became evident by 3 h, and was most prominent at 6 h after carrageenan injection. This COX-2 induction was associated with an elevation of prostaglandin E2 in the cerebrospinal fluid, being evident at 3 h, larger at 6 h, and alleviated by a COX-2-selective inhibitor. Thermal hyperalgesia became evident at 1 h, further increased thereafter, and remained elevated until 6 h. Intrathecal administration of COX-2-selective inhibitor 2 h after the carrageenan injection exerted a prominent therapeutic effect on hyperalgesia. These results demonstrate that, during carrageenan-induced inflammation, endothelial cells are the major source of prostaglandin(s) in the CNS, and this endothelial expression of COX-2 is involved in the inflammation-induced hyperalgesia.

Animals↗
PubMed2000

Impaired monocyte CD11b expression in interstitial inflammation in hemodialysis patients.

BACKGROUND: It is not known to what extent intravascular phenotypic alterations in adhesion molecule expression induced by hemodialysis influence the recruitment of monocytes and their ability to up-regulate CD11b at the local site of inflammation in the interstitium. Using a skin suction chamber technique, we addressed these issues in eight hemodialysis patients and in eight healthy subjects. METHODS: Two skin blisters were raised on the forearm of each individual and blister exudate collected. The blisters were then stimulated with autologous serum (active blister, intense inflammation) or buffer (control blister, intermediate inflammation), respectively. Thereafter the patients were treated with Cuprophan hemodialysis for four hours. After 10 hours, the exudate was aspirated from each chamber in all subjects. Monocyte count and expression of CD11b were analyzed in serum and blister fluid by flow cytometry. Then, monocytes from healthy blood donors were incubated in blister fluid from patients and healthy subjects in order to determine the local chemotactic activity in terms of CD11b up-regulation. Monocyte chemotactic protein-1 (MCP-1), a marker of systemic monocyte chemotactic activity, was also analyzed in serum at 0 and 10 hours in all individuals. RESULTS: The number of monocytes at the site of inflammation in the interstitium in hemodialysis patients correlated with the expression of CD11b on transmigrated cells (r = 0.78, P < 0.001). Monocytes collected in the active blister fluid of dialysis patients expressed equal levels of CD11b as cells collected from healthy subjects. By contrast, monocytes collected from the control blisters of patients expressed lower levels of CD11b than cells from healthy subjects (P < 0.01), despite equal interstitial biological activity of CD11b-mobilizing factors in blister fluid from patients and healthy subjects and the fact that patients had higher systemic chemotactic activity in terms of MCP-1 concentration in serum (P < 0.001). CONCLUSION: Monocytes from hemodialysis patients have the capacity to mobilize CD11b to the same extent as cells from healthy individuals at the inflammatory spot, but more intense stimuli are required for such actions, probably because of a transient refractoriness.

Adult↗
PubMed2001

A malnutrition-inflammation score is correlated with morbidity and mortality in maintenance hemodialysis patients.

Malnutrition inflammation complex syndrome (MICS) occurs commonly in maintenance hemodialysis (MHD) patients and may correlate with increased morbidity and mortality. An optimal, comprehensive, quantitative system that assesses MICS could be a useful measure of clinical status and may be a predictor of outcome in MHD patients. We therefore attempted to develop and validate such an instrument, comparing it with conventional measures of nutrition and inflammation, as well as prospective hospitalization and mortality. Using components of the conventional Subjective Global Assessment (SGA), a semiquantitative scale with three severity levels, the Dialysis Malnutrition Score (DMS), a fully quantitative scoring system consisting of 7 SGA components, with total score ranging between 7 (normal) and 35 (severely malnourished), was recently developed. To improve the DMS, we added three new elements to the 7 DMS components: body mass index, serum albumin level, and total iron-binding capacity to represent serum transferrin level. This new comprehensive Malnutrition-Inflammation Score (MIS) has 10 components, each with four levels of severity, from 0 (normal) to 3 (very severe). The sum of all 10 MIS components ranges from 0 to 30, denoting increasing degree of severity. These scores were compared with anthropometric measurements, near-infrared-measured body fat percentage, laboratory measures that included serum C-reactive protein (CRP), and 12-month prospective hospitalization and mortality rates. Eighty-three outpatients (44 men, 39 women; age, 59 +/- 15 years) on MHD therapy for at least 3 months (43 +/- 33 months) were evaluated at the beginning of this study and followed up for 1 year. The SGA, DMS, and MIS were assessed simultaneously on all patients by a trained physician. Case-mix-adjusted correlation coefficients for the MIS were significant for hospitalization days (r = 0.45; P < 0.001) and frequency of hospitalization (r = 0.46; P < 0.001). Compared with the SGA and DMS, most pertinent correlation coefficients were stronger with the MIS. The MIS, but not the SGA or DMS, correlated significantly with creatinine level, hematocrit, and CRP level. During the 12-month follow-up, 9 patients died and 6 patients left the cohort. The Cox proportional hazard-calculated relative risk for death for each 10-unit increase in the MIS was 10.43 (95% confidence interval, 2.28 to 47.64; P = 0.002). The MIS was superior to its components or different subversions for predicting mortality. The MIS appears to be a comprehensive scoring system with significant associations with prospective hospitalization and mortality, as well as measures of nutrition, inflammation, and anemia in MHD patients. The MIS may be superior to the conventional SGA and the DMS, as well as to individual laboratory values, as a predictor of dialysis outcome and an indicator of MICS.

Adult↗
PubMed2003

Hyperhomocysteinemia and its relationship to cardiovascular disease in ESRD: influence of hypoalbuminemia, malnutrition, inflammation, and diabetes mellitus.

BACKGROUND: In the general population, a mildly elevated plasma total homocysteine (tHcy) level is an independent and graded risk factor for cardiovascular disease (CVD). In patients with end-stage renal disease (ESRD), CVD is highly prevalent and a major cause of premature mortality, and plasma tHcy levels are as much as three to four times greater than in the general population. Several other risk factors, such as diabetes mellitus (DM), inflammation, and malnutrition, also are prevalent and contribute to CVD in patients with ESRD, and there are strong associations between inflammation, malnutrition, and hypoalbuminemia in these patients. Several investigations in patients with ESRD have shown the important role of vitamin status for plasma tHcy, but little attention has been given to the influence of nutritional status. However, it is obvious that hypoalbuminemia is of interest because a substantial fraction of tHcy (>70%) is protein bound, mainly to albumin. RESULTS: In studies of patients with ESRD in whom the prevalence of hyperhomocysteinemia was very high (>90%), tHcy level was strongly related to serum albumin level, and patients with malnutrition had lower levels of both tHcy and serum albumin than those with normal nutritional status. Furthermore, inflammation, DM, and CVD are associated with hypoalbuminemia and therefore a lower degree of hyperhomocysteinemia. In our studies, in different groups of patients with ESRD, we showed that greater tHcy levels were associated with lower CVD mortality. However, this apparently paradoxical association between lower CVD mortality and lower plasma tHcy levels (although still abnormally high) does not refute the concept that hyperhomocysteinemia is a risk factor for CVD because almost all patients may have had long-standing elevated plasma tHcy levels within a range that makes them prone to develop atherosclerosis. Instead, a potentially detrimental effect of hyperhomocysteinemia on CVD in patients with ESRD may be obscured by the influence of hypoalbuminemia, whatever the cause, because hypoalbuminemia and its causes are strong predictors of mortality. CONCLUSION: Our findings imply that nutritional status and serum albumin level, as well as the presence of inflammation and DM, should be taken into consideration when evaluating tHcy as a risk factor for CVD in patients with ESRD.

Cardiovascular Diseases↗
PubMed2004

Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: the chronic renal impairment in Birmingham (CRIB) study.

BACKGROUND: Studies in the general population suggest that low-grade inflammation, endothelial dysfunction, and platelet activation are associated with an increased risk of cardiovascular events. METHODS: Markers of inflammation, endothelial dysfunction, and platelet activation were measured in 334 patients with chronic kidney disease (serum creatinine >1.47 mg/dL [>130 micromol/L] at screening) and compared with 2 age- and sex-matched control groups, 1 comprising 92 patients with coronary artery disease and the other comprising 96 apparently healthy individuals with no history of cardiovascular or kidney disease. RESULTS: There was evidence of low-grade inflammation in the chronic renal impairment group compared with healthy controls, with higher concentrations of C-reactive protein (3.70 versus 2.18 mg/L, P < 0.01) and fibrinogen (3.48 versus 2.67 g/L, P < 0.001) and lower serum albumin concentration (41.8 versus 44.0 g/dL [418 versus 440 g/L], P < 0.001). More severe renal impairment was associated with a trend towards higher fibrinogen and lower albumin concentrations (both P < 0.001), although there was no association with higher C-reactive protein level. As compared to healthy controls, plasma von Willebrand factor (142 versus 108 IU/dL, P < 0.001) and soluble P-selectin concentrations (57.0 versus 43.3 ng/mL, P < 0.001) were also higher in the chronic renal impairment group. More severe renal impairment was associated with a trend towards higher levels of von Willebrand factor (P < 0.001) and of soluble P selectin (P < 0.05). CONCLUSION: This cross-sectional analysis demonstrates that chronic kidney disease is associated with low-grade inflammation, endothelial dysfunction, and platelet activation, even among patients with moderate renal impairment.

Adult↗
PubMed2005

CpG motifs of bacterial DNA essentially contribute to the perpetuation of chronic intestinal inflammation.

BACKGROUND & AIMS: Recently, we demonstrated a proinflammatory effect of cytosin-guanosin dinucleotide (CpG)-oligodeoxynucleotide (ODN) treatment in established dextran sulphate sodium (DSS)-induced colitis. Here, we investigated whether DNA derived from luminal bacteria plays a role in the perpetuation of chronic intestinal inflammation. METHODS: Toll-like receptor (TLR9)-deficient and wild-type (wt) control mice were used for the induction of chronic DSS colitis. Moreover, mice with established chronic colitis using different experimental models were treated with adenoviral ODN (AV-ODN) known to block CpG effects. Colonic inflammation was scored and cytokine production was quantified both in colonic tissue and draining mesenteral lymph node cells (MLC). RESULTS: Eight weeks after induction of chronic DSS colitis in TLR9-deficient mice, intestinal inflammation was significantly lower (-68%), and proinflammatory cytokine production was drastically reduced. Treatment of wt mice with chronic DSS-induced colitis with AV-ODN resulted in a significant amelioration of disease with a reduced histologic score (-43%) and reduced cytokine production of MLC (interleukin [IL]-6: -68%; interferon [IFN]-gamma: -48%) and RNA expression of the T helper (Th)1-specific transcription factor T-bet (-62%) in colonic tissue. Qualitatively, the same results were obtained in the severe combined immunodeficiency disease (SCID) transfer model of colitis and in spontaneous colitis in IL-10-deficient mice. CONCLUSIONS: Bacterial DNA derived from luminal bacteria contributes significantly to the perpetuation of chronic intestinal inflammation. Inhibition of the immune-stimulating properties of bacterial DNA using AV-ODN may offer a novel and specific tool for the treatment of inflammatory bowel disease.

Animals↗
PubMed2005

NF-kappaB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis.

BACKGROUND & AIMS: We explored the roles of nuclear factor-kappaB (NF-kappaB) and tumor necrosis factor (TNF) alpha (TNF-alpha) as mediators of inflammation in a nutritional model of steatohepatitis. METHODS: Wild-type (wt), TNF null -/-, and TNF receptor (R)-1-/- mice were fed a methionine- and choline-deficient (MCD) diet for up to 5 weeks. Liver injury (serum alanine aminotransferase [ALT]), hepatic inflammation, triglycerides, and lipid peroxide levels were determined. Hepatic NF-kappaB activation and expression of TNF and intercellular adhesion molecule-1 (ICAM-1) were assayed. RESULTS: Irrespective of genotype, MCD diet-fed mice developed hepatic lipid peroxidation and serum ALT elevation; at day 10, livers from wt, TNF-/-, and TNFR-1-/- mice showed equivalent steatohepatitis. NF-kappaB/DNA binding was enhanced in hepatic nuclear fractions from MCD diet-fed wt mice compared with dietary controls; there were corresponding increases of ICAM-1 and TNF messenger RNA (mRNA). Likewise, NF-kappaB activation and ICAM-1 expression were enhanced by MCD dietary feeding in TNF-/- and TNFR-1-/- mice compared with respective controls. To establish whether NF-kappaB is a primary mediator of inflammation in experimental steatohepatitis, we over-expressed a mutant, nondegradable IkappaB (mIkappaB), delivered by adenovirus in vivo. As expected, hepatic mIkappaB expression reduced NF-kappaB/DNA binding induced by MCD dietary feeding, with resultant abrogation of ICAM-1 and TNF synthesis. Such blockade of NF-kappaB transcriptional activation substantially protected against development of steatohepatitis, with significant reductions in liver injury and hepatic inflammation. CONCLUSIONS: In the MCD dietary model of steatohepatitis, NF-kappaB is activated early and is an important proinflammatory mediator of lesion development, but steatohepatitis occurs independently of TNF synthesis and TNFR-1 activation.

Animals↗