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PubMed2002

Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia.

Depression is associated with increased cardiovascular disease, but the underlying mechanisms are not well understood. This study examines associations of depressive symptoms with inflammation and coagulation factors in persons aged > 65 years. Blood samples were obtained from 4,268 subjects free of cardiovascular disease (age 72.4 +/- 5.5 years, 2,623 women). Inflammation markers were C-reactive protein (CRP), white blood cell (WBC) count, total platelet count, and albumin; coagulation factors included factors VIIc and VIIIc and fibrinogen. Depression was assessed with the Center for Epidemiologic Studies Depression scale, and states of energy depletion with a validated exhaustion index. Statistical adjustments were made for risk factors (age, sex, race, systolic blood pressure, smoking status, diabetes mellitus) and physical measures of frailty (isometric handgrip, timed 15-feet walk test, activity level). Depression was associated with elevated CRP (3.31 +/- 0.10 vs 3.51 +/- 0.21 mg/L), WBC (6.14 +/- 0.03 vs 6.43 +/- 0.11 10(6)/L), fibrinogen (319 +/- 1 vs 326 +/- 3 mg/dl), and factor VIIc (124.6 +/- 0.6% vs 127.2 +/- 1.3%; all p <0.05). Exhaustion also was related to elevated inflammation and coagulation markers (p < 0.05). Exhausted men had markedly elevated CRP levels (6.82 +/- 2.10 mg/L) versus nonexhausted men (3.05 +/- 0.16: p = 0.007). After adjustment for control variables, exhaustion remained associated with albumin (p = 0.033), fibrinogen (p = 0.017), CRP (p = 0.066), and WBC (p = 0.060), whereas associations of depressive symptoms with biochemistry measures lost statistical significance. Thus, depression and exhaustion are associated with low-grade inflammation and elevated coagulation factors in persons aged > 65 years.

Aged↗
PubMed2005

Inflammation and extracellular matrix degradation mediated by activated transcription factors nuclear factor-kappaB and activator protein-1 in inflammatory acne lesions in vivo.

Acne is the most common skin disease, causing significant psychosocial problems for those afflicted. Currently available agents for acne treatment, such as oral antibiotics and isotretinoin (Accutane), have limited use. Thus, development of novel agents to treat this disease is needed. However, the pathophysiology of acne inflammation is poorly understood. Before new therapeutic strategies can be devised, knowledge regarding molecular mechanisms of acne inflammation is required. We report here that transcription factors nuclear factor-kappaB and activator protein-1 are activated in acne lesions with consequent elevated expression of their target gene products, inflammatory cytokines and matrix-degrading metalloproteinases, respectively. These elevated gene products are molecular mediators of inflammation and collagen degradation in acne lesions in vivo. This new knowledge enables a rational strategy for development of pharmacological agents that can target the inflammation and matrix remodeling that occurs in severe acne.

Acne Vulgaris↗
PubMed2005

Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1.

Rheumatoid arthritis is characterized by an intermittent course of disease with alternate periods of remission and relapse. T cells, and in particular the T-cell cytokine interleukin-17 (IL-17), are expected to be involved in arthritic flares. Here, we report that neutralizing endogenous IL-17 during reactivation of antigen-induced arthritis prevents joint inflammation and bone erosion. Synovial IL-17 mRNA expression was clearly up-regulated during primary arthritis and was further enhanced after antigen rechallenge. Neutralization of IL-17 significantly prevented joint swelling at day 1 of flare and significantly suppressed joint inflammation and cartilage proteoglycan depletion at day 4, as assessed by histology. Blocking IL-17 also clearly reduced bone erosions. Cathepsin K, a marker of osteoclast-like activity, and synovial RANKL mRNA expression were both suppressed. The degree of bone erosions strongly correlated with the severity of joint inflammation, suggesting that anti-IL-17 treatment reduced bone erosion by suppressing joint inflammation. Interestingly, blocking IL-17 suppressed synovial expression of both IL-1beta and tumor necrosis factor-alpha, whereas blocking IL-1 did not affect tumor necrosis factor-alpha levels. These data indicate that IL-17 is an important upstream mediator in joint pathology during flare-up of experimental arthritis.

Animals↗
PubMed2000

In vivo detection of vascular adhesion protein-1 in experimental inflammation.

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial glycoprotein which mediates leukocyte-endothelial cell interactions. To study the pathogenetic significance of VAP-1 in inflammatory disorders, an in vivo immunodetection method was used to detect the regulation of luminally expressed VAP-1 in experimental skin and joint inflammation in the pig and dog. Moreover, VAP-1 was studied as a potential target to localize inflammation by radioimmunoscintigraphy. Up-regulation of VAP-1 in experimental dermatitis and arthritis could be visualized by specifically targeted immunoscintigraphy. Moreover, the translocation of VAP-1 to the functional position on the endothelial surface was only seen in inflamed tissues. These results suggest that VAP-1 is both an optimal candidate for anti-adhesive therapy and a potential target molecule for imaging inflammation.

Amine Oxidase (Copper-Containing)↗
PubMed1998

Multiple controls in inflammation. Extracellular and intracellular phospholipase A2, inducible and constitutive cyclooxygenase, and inducible nitric oxide synthase.

Inflammation occurs as a defensive response to invasion of the host by foreign material, often of microbial nature. This response is normally a localized protective response that at the microscopic level involves a complex series of events including dilatation of arterioles, venules, and capillaries with increased vascular permeability, exudation of fluids including plasma proteins, and leukocyte migration into the inflammatory area. Since disease characterized by inflammation is an important cause of morbidity and mortality in humans, the processes involved in the host defense in inflammation have been and continue to be the object of several experimental studies. The role of several mediators such as histamine, serotonin, bradykinin, prostaglandins, and, more recently, cytokines and nitric oxide has been evaluated, and a contribution for each one of these mediators has been proposed. With the development of powerful molecular biology tools, it has become possible to study enzymes involved in this complex phenomenon by measuring the expression or evaluating the signaling pathways following a specific stimulus. These techniques have generated a proliferation of studies on the role of several enzymes and cytokines in inflammation. Most of these studies have been conducted in vitro on cell lines, and not many of the results have been confirmed by in vivo studies. This commentary does not pretend to analyze all of the studies and their possible in congruences, but endeavors to provoke in the reader a critical review of dogmas and current beliefs that most of the time are built on unilateral interpretation of the data.

Animals↗
PubMed2001

Parathyroid hormone-related protein (PTHrP) induction in reactive astrocytes following brain injury: a possible mediator of CNS inflammation.

PTHrP, a peptide induced in parenchymal organs during endotoxemia and in the synovium in rheumatoid arthritis, has recently been shown to be expressed in immature or transformed human astrocytes, but not in normal cells. This finding has led us to postulate that PTHrP might also be induced in reactive astrocytes in inflamed brain and, thus, act as a mediator of CNS inflammation. To test this hypothesis, PTHrP expression was examined following cortical stab wound injury in rats, a classical model of reactive gliosis. To determine whether PTHrP was induced in glia by TNF-alpha, a known mediator of inflammation in brain and of PTHrP induction in peripheral tissues, and to determine whether PTHrP, in turn, mediated inflammatory changes in glia, in vitro studies with rat astrocytes and glial-enriched mixed brain cells were also undertaken. Consistent with previous reports of PTHrP expression in normal brain, neurons were the primary site of immunoreactive PTHrP expression in the injured cortex 1 day after stab wound injury. Over the subsequent 3 days, specific immunostaining for PTHrP and for GFAP, a marker of reactive astrocytes, appeared in reactive astrocytes at the wound edge and in perivascular astrocytes, reaching a maximum level of expression at the last time point examined (day 4). TNF-alpha induced PTHrP expression in astrocyte and glial-enriched brain cells in vitro, suggesting that this pro-inflammatory peptide was a possible mediator of PTHrP expression in CNS inflammation. PTHrP(1-34) acted in an additive fashion with TNF-alpha to induced astrocyte expression of IL-6, a cytokine with demonstrated neuroprotective effects. Astrocyte proliferation was inhibited by PTHrP(1-34) and PTHrP(1-141), acting via a PTH/PTHrP receptor cAMP signaling pathway. These studies suggest that PTHrP, analogous to its regulatory functions in other non-CNS models of inflammation, may be an important mediator of the inflammatory response in brain.

Animals↗
PubMed1997

Expression of mRNA for brain-derived neurotrophic factor in the dorsal root ganglion following peripheral inflammation.

It is well known that the nerve growth factor (NGF) may serve as a link between inflammation and hyperalgesia. Recent experiments showed that systemic injection of NGF dramatically stimulated the expression of brain-derived neurotrophic factor (BDNF) mRNA in the dorsal root ganglion (DRG). In the present study, we evaluated the change of BDNF mRNA in the DRG following peripheral inflammation and also observed colocalization of BDNF and trkA mRNAs by means of in situ hybridization histochemistry in rats. Peripheral tissue inflammation produced by an intraplantar injection of Freund's adjuvant into the paws significantly increased BDNF mRNA levels in the DRG and many neurons expressing trkA mRNA showed increased expession of BDNF mRNA. Intraplantar injection of antibody to NGF together with Freund's adjuvant prevented the increase in BDNF mRNA. These findings suggest that peripheral inflammation induces an increased expression of BDNF mRNA which is mediated by NGF in DRG.

Animals↗
PubMed1997

Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation.

Our recent study showed that peripheral inflammation induced an increased expression of brain-derived neurotrophic factor (BDNF) mRNA which was mediated by nerve growth factor (NGF) in the dorsal root ganglion (DRG). In the present study, we evaluated the change of BDNF immunoreactivity in the DRG and spinal cord following peripheral inflammation by means of immunohistochemistry. Significant increases in the percentage of BDNF-immunoreactive (IR) neuron profiles in the L5 DRG and marked elevation in the expression of BDNF-IR terminals in the spinal dorsal horn were observed following peripheral tissue inflammation produced by an intraplantar injection of Freund's adjuvant into the rat paws. These findings suggest that peripheral tissue inflammation induces an increased BDNF synthesis in the DRG and an elevated anterograde transport of BDNF to the spinal dorsal horn. The functional role of this increased BDNF was discussed briefly.

Animals↗
PubMed1999

Inflammation-induced changes in peripheral glutamate receptor populations.

The ionotropic glutamate receptors N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) have been localized on subpopulations of unmyelinated and myelinated sensory axons in normal skin. Behavioral studies indicate that activation of these receptors results in nociceptive behaviors and contributes to inflammatory pain. The goal of the present study was to determine if these glutamate receptors might contribute to the peripheral hypersensitivity observed in inflammation. The major findings were that 48 h following complete Freund's adjuvant (CFA)-induced inflammation, the proportions of unmyelinated axons labeled for NMDA, AMPA or KA receptors were 61%, 43% and 48%, respectively, in cutaneous nerves in the inflamed paw compared to 48%, 22% and 27%, respectively, in the non-inflamed paw. The proportions of myelinated axons labeled for NMDA, AMPA or KA receptors were 61%, 61% and 43%, respectively, compared to 43%, 42% and 28%, respectively, in the non-inflamed hindpaw. These increases were all significant. These data indicate that the number of sensory axons containing ionotropic glutamate receptors increases during inflammation, and this may be a contributing factor to peripheral sensitization in inflammation.

Animals↗
PubMed2002

Activation of spinal kainate receptors after inflammation: behavioral hyperalgesia and subunit gene expression.

We determined whether neural responses to inflammation and hyperalgesia involve activation of kainate receptors, a subgroup of glutamate receptors. Inflammation was introduced into the hind paw by intraplantar injection of complete Freund's adjuvant. The inflammation-induced thermal hyperalgesia was attenuated by intrathecal administration of a non-selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium (NBQX), as well as by selective kainate receptor antagonists, 6,7,8,9-tetrohydro-5-nitro-1H-benz[g]indole-2,3-dione 3-oxime (NS-102) and 3S,4aR,6S,8aR-6-(4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-deca-hydroisoquinoline-3-carboxylic acid (LY382884). Reverse transcription-polymerase chain reaction (RT-PCR) indicated that the GluR5 and GluR6, but not the GluR7, KA1 and KA2 subunits, exhibited increased mRNA expression at 2 h to 3 days following inflammation (P<0.05). Western blot showed an increase in GluR6 protein levels (P<0.01) with a time course consistent with the changes in its mRNA levels. cDNA sequence and BbvI endonuclease digestion of the GluR6 PCR product revealed that the upregulated GluR6 mRNAs were predominantly the unedited form (Q). These results suggest that a selective upregulation of kainate receptor subunit expression contributes to inflammatory hyperalgesia.

Amino Acid Sequence↗
PubMed2003

Interleukin-1beta, interleukin-6, tumour necrosis factor-alpha and interferon-gamma released by a viral infection and an aseptic inflammation reduce CYP1A1, 1A2 and 3A6 expression in rabbit hepatocytes.

Inflammation reduces activity and expression of hepatic cytochrome P450 (P450) and therefore diminishes drug biotransformation. This study aimed to identify the serum mediators triggered by a viral infection and an aseptic inflammation that downregulate P450 isoforms. Incubation of hepatocytes with serum from rabbits with a turpentine-induced inflammation or humans with a viral infection decreased the amount of cytochrome 1A1 (CYP1A1), 1A2 and 3A6 mRNA and apoproteins. By serum fractionation and immuno-neutralization, we showed that in the aseptic inflammation, interleukin-6 and, to a lesser degree, interleukin-1beta are involved in the downregulation of all three isoforms. In serum from humans with a viral infection, interleukin-1beta, interleukin-6, interferon-gamma and tumour necrosis factor-alpha contribute to the downregulation of P450 isoforms. CYP1A1 and 1A2 are regulated by serum mediators at the transcriptional level, while the expression of CYP3A6 appears to be under the control of pre- and posttranscriptional mechanisms.

Animals↗
PubMed1979

Antiinflammatory substances appearing during an acute inflammation and the alteration of their properties by isoproterenol (ISO). An in vivo investigation in rats.

It could be demonstrated that antiinflammatory substances appear during the course of an acute inflammation. The inhibition of leucocyte immigration into the site of inflammation (caused by Sephadex) was taken as criterion for the antiinflammatory property. The highest quantity or effect of the antiinflammatory substances was found on the 3rd day after inflammation has started. Not only the absolute number of cells but also the composition of the cellular exudate (compared with a fresh inflammation) was changed: The percentage rate of the neutrophils was reduced, whereas the portion of the eosinophils and the lymphocytes was increased. A permanent ISO application on the animals altered the quantity of the composition of these substances, in consequence of which the immigration of eosinophils and lymphocytes was promoted. The reaction of the neutrophils was unaffected.

Animals↗
PubMed2003

Hepatic expression of PPARalpha, a molecular target of fibrates, is regulated during inflammation in a gender-specific manner.

Dyslipidemia, inflammation and gender are major risk factors in cardiovascular disease. Here we show that hepatic expression of Peroxisome proliferator-activated receptor alpha (PPARalpha), a nuclear receptor that regulates lipid metabolism and inflammation, is regulated in a gender-specific manner during lipopolysaccharide (LPS)-induced systemic inflammation. Immediately following LPS-induced systemic inflammation, hepatic PPARalpha mRNA level decreased dramatically in mice. It was restored to baseline within 24 h in females but remained below baseline for >72 h in male mice. In gonadectomized mice of both sexes, PPARalpha mRNA level was restored to baseline within 48 h after the initial decrease.

Animals↗
PubMed2002

Treatment of the chronic inflammation in peripheral target tissue improves the crushed nerve recovery in the rat: histopathological assessment of the nerve recovery.

An experimental study was performed to investigate the influence of subsidence of chronic inflammation in peripheral target tissue on the recovery of crushed nerve. Seventy-eight male Wistar rats weighing 300-370 g were used. The sciatic nerve was operatively crushed unilaterally with an aneurysm clip (250 gf) applied for 5 min. Chronic inflammation, localized to the ankle, was induced by intra-articular injection of complete Freund's adjuvant 1 week preoperatively. Prednisolone farnesylate (PNF-21) 1.4% gel was applied on the ankle as an anti-inflammatory agent for consecutive days after the operation. The animals were divided into five groups as follows: crush injury with ipsilateral arthritis (CIA); crush injury with ipsilateral arthritis and PNF-21 gel applied on the ipsilateral ankle (CIA + IPNF); crush injury with ipsilateral arthritis and PNF-21 gel applied on the contralateral ankle (CIA + CPNF); crush injury with contralateral arthritis (CCA); crush injury without arthritis (C). Specimens for histopathological examination were taken from the nerve at a site 5 mm distal to the crush lesion at 4 weeks postoperatively. The average axon diameter was significantly larger in the CIA + IPNF group than in the CIA group (p < 0.01). No significant difference was observed between the CIA + CPNF group and the CIA group. In conclusion, chronic inflammation in peripheral target tissue suppresses recovery of the crushed nerve, and subsidence of this chronic inflammation improves this suppression histopathologically.

Animals↗
PubMed2001

Activity of body energy regulatory pathways in inflammation-induced anorexia.

Previous research has shown that reductions in body weight prior to induction of acute inflammation can attenuate inflammation-induced anorexia in male rats. In the current study, potential mechanisms responsible for this observation were examined. Specifically, the effect of a 12% prior reduction in body weight on serum leptin, insulin, and corticosterone; levels of interleukin-1 (IL-1), interleukin-6 (IL-6) in the serum, liver, and spleen; neuropeptide Y (NPY) and POMC mRNA levels in the arcuate nucleus (ARC) of the hypothalamus were examined 8 h after induction of acute inflammation. Rats with prior weight reduction had significantly lower serum leptin levels and gene expression of POMC in the ARC than normal-weight rats. In contrast, prior weight reduction altered neither NPY mRNA in the ARC, nor IL-1alpha, IL-1beta, and IL-6 levels in the serum, liver, and spleen. These results suggest that the attenuation of inflammation-induced anorexia by prior weight reduction is not due to altered cytokine activity, but rather to changes in energy regulatory systems that moderate the anorexic actions of IL-1beta and IL-6. One potential change may be reduced activity of the CNS melanocortin system induced by decreased circulating leptin.

Adipose Tissue↗
PubMed2005

[Inflammation and ischaemic stroke: current status and future perspectives].

INTRODUCTION: Inflammation may play an important role in acute ischemic stroke. Experimental and clinical data suggest that post-stroke inflammatory responses are complex cascade phenomena, which may have detrimental or beneficial effects on outcome. This review focuses on the current understanding of inflammation effector pathways in focal cerebral ischemia and on therapeutic perspectives. STATE OF ARTS/PERSPECTIVES: Somatic markers, such as admission body temperature or C-reactive protein, seem to be correlated with outcome, but data are heterogeous and contradictory, perhaps because their kinetics are complex during the first hours of a stroke. The most studied effectors of inflammation are cellular adhesion molecules--CAM (including integrins, selectins and members of the immunoglobulin superfamily), leucocytes, microglia, and blood brain barrier permeability. Evidence from animal data has lead to some clinical trials investigating anti adhesion molecules and hypothermia. However, current results remain disappointing. Recent experimental data also suggest a possible beneficial role of insulin and statins, which may be mediated by their effects on the inflammatory response. CONCLUSION: Inflammation is an important avenue of therapeutic research in acute stroke. A better understanding of the inflammatory pathophysiology may help to a better design of clinical trials.

Acute Disease↗
PubMed2005

Glucuronidase deconjugation in inflammation.

This chapter focuses on deglucuronidation by beta-glucuronidase in inflammation. We investigated whether glucuronides were converted to free parent compounds by beta-glucuronidase released from human-stimulated neutrophils in inflammation. Beta-glucuronidase activity was assayed using 4-methylumbelliferyl-glucuronide and methanol extracts of rat plasma containing luteolin monoglucuronide as a substrate. The released 4-methylumbelliferone, a fluorescent molecule, was quantitated on a microplate fluorometer. Deglucuronidation of luteolin monoglucuronide was examined by high-performance liquid chromatography (HPLC) analysis. The beta-glucuronidase activity in mouse plasma after iv injection of lipopolysaccharide (LPS) increased with time, as did the levels of inflammation marker, tumor necrosis factor-alpha, and soluble intercellular adhesion molecule-1. Four kinds of human cell (neutrophils, human umbilical vein endothelial cells, IMR-90, and Caco-2) possess beta-glucuronidase activity. Among these, Caco-2 cells showed the highest level of beta-glucuronidase activity. Supernatants obtained from neutrophils stimulated with cytochalasin B and ionomycin showed higher levels of beta-glucuronidase activity than those of nonstimulated neutrophils. HPLC analyses also showed that supernatants obtained from stimulated neutrophils hydrolyzed luteolin monoglucuronide to free luteolin. As reported previously (Shimoi et al., 1998), two main peaks (free luteolin and luteolin monoglucuronide) were observed in plasma of rats administered with luteolin. In LPS-treated rats, the peak of luteolin monoglucuronide decreased to about half and the ratio of luteolin to luteolin monoglucuronide increased. These results suggest that beta-glucuronidase released from neutrophils or certain injured cells may hydrolyze glucuronide conjugates to free aglycones at the site of inflammation.

Administration, Oral↗
PubMed1996

Depletion of CD8+ T cells enhances pulmonary inflammation but not airway responsiveness after antigen challenge in rats.

BACKGROUND: CD8+ (OX-8+) T cells may suppress airway inflammation and airway responsiveness after allergen challenge. OBJECTIVE: We studied the effects of depletion of OX-8+ T cells on allergen-induced lung eosinophilia and airway responsiveness in the Sprague-Dawley rat. METHODS: Sprague-Dawley rats were sensitized to ovalbumin and challenged by aerosol 14 days later. Test animals received either low-dose (2 mg, n = 9) or high-dose (3 mg, n = 7) OX-8 monoclonal antibody (mAb), whereas controls (n = 8) received BALB/c ascites fluid. A fourth group of animals (n = 10) was not sensitized to ovalbumin and also received ascites fluid. Twenty-four hours after ovalbumin challenge, responsiveness to methacholine was measured, and lung inflammation was assessed in the large airways and small airways and parenchyma. RESULTS: Circulating and airway CD8+ T cells were decreased by OX-8 mAb administration with greatest changes in animals treated with high-dose OX-8 mAb compared with controls (blood: 1.0% +/- 3.6% vs 18.7% +/- 3.9%, p < 0.05); (large airways: 2.5% +/- 1.2% vs 13.8% +/- 1.2%, p < 0.05). Ovalbumin challenge resulted in increases in macrophages and neutrophils in the small airways and parenchyma of sensitized compared with unsensitized rats (p < 0.05). High-dose OX-8 mAb further increased total leukocytes, attributable to increases in neutrophils and eosinophils, retrieved from the large airways and small airways and parenchyma compared with other groups (p < 0.05). Airway responsiveness to methacholine was not significantly different between control and ovalbumin-challenged animals and was not augmented by OX-8 pretreatment. CONCLUSION: CD8+ T cells modulate the extent of allergen-induced airway inflammation. However, the enhancement of inflammation was not sufficient to affect airway responsiveness.

Animals↗