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At least 577 records · Page 32Linked to original sources
PubMed2005

Do prostatic infarction, prostatic inflammation and prostate morphology play a role in acute urinary retention?

OBJECTIVE: To investigate whether there is a role of prostatic infarction, prostatic inflammation and prostate morphology in acute urinary retention (AUR) etiology. METHODS: Ninety-eight consecutive male patients who were admitted to our clinic with either AUR or lower urinary tract symptoms (LUTS) were involved in the study. Patient age ranged from 43 to 88 years (median age 70). Group 1 consisted of 53 (54%) patients with AUR, and Group 2 consisted of 45 (46%) patients with LUTS. In Group 1 and Group 2, 58.4% (n:31) and 62.2% (n:28) of the patients underwent transurethral prostate resection, 41.6% (n:22) and 37.8% (n:17) of the patients underwent suprapubic transvesical prostatectomy, respectively. Each patient was asked about the factors: smoking habits, taking previous general anesthesia and preexisting cardiovascular disease such as hypertention and atherosclerotic coronary vascular disease which may lead to AUR via prostatic infarct. Prostatic infarction, prostatic inflammation and prostatic morphology were examined in the patients' specimen. RESULTS: Mean age, median serum prostate-specific antigen (PSA) level, and prostatic inflammation ratio were significantly higher in Group 1. There were not significant differences between the groups regarding prostate volume, prostatic infarction ratio and a type of prostatic morphology. In the present study, except for taking previous general anesthesia and preexisting cardiovascular disease, only prostatic inflammation was found important contributory factor on AUR. AUR risk was 3.03 times higher in the patients with prostatic inflammation (95%CI 1.28-7.15) (p = 0.01). CONCLUSIONS: No significant effect of prostatic infarction was found on occurrence of AUR which was more frequent in elderly patients. Prostatic inflammation may have an important risk factor in AUR etiology. Additionally, serum PSA levels were higher in AUR group. No association was found between a type of prostatic morphology and AUR.

Adult↗
PubMed2004

Physiologic correlates of distal lung inflammation in asthma.

BACKGROUND: The distal lung is an important site of inflammation in asthma. Maximal midexpiratory flows and the ratio of maximal:partial flows are purported to reflect distal lung function. OBJECTIVE: We obtained contemporaneous transbronchial biopsy, spirometry, and plethysmography to describe more accurately the relationship between physiology and distal lung inflammation in asthma. METHODS: Ten patients with severe, persistent asthma with mean +/- SE FEV(1) of 2.8 +/- 0.2 L and overnight fall in FEV(1) of 22.8% +/- 3.8% underwent transbronchial biopsy, spirometry, maximal midexpiratory flows, maximal:partial ratio, and lung volumes, all at 4 am. Morphometric analysis was performed after immunohistochemistry for eosinophils, lymphocytes, macrophages, mast cells, and neutrophils. RESULTS: Maximal midexpiratory flows, maximal:partial ratio, FEV(1), and forced vital capacity were not significantly correlated with alveolar tissue inflammation. However, the degree of eosinophilic alveolar inflammation was significantly and positively correlated with both total lung capacity (Spearman rho=0.70; P=.03) and thoracic gas volume (rho=0.62; P=.05). Correlation between eosinophils and other lung volumes was not observed. Other inflammatory cell types did not correlate with lung volumes. CONCLUSION: Purported physiologic measures of distal lung function are poorly correlated with histopathologic evidence of distal lung inflammation. Measurement of lung volumes more accurately reflects eosinophilic distal lung inflammation.

Adult↗
PubMed2006

Src homology 2 domain-containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung.

BACKGROUND: Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP-1) controls the intracellular level of the phosphoinositide 3-kinase product phosphotidylinositol-3,4,5-trisphosphate and functions as a negative regulator of cytokine and immune receptor signaling. Emerging evidence suggests that the phosphoinositide 3-kinase pathway might be involved in allergic inflammation in the lung. However, the functional relevance of SHIP-1 in the T(H)2 activation pathway has not been established. SHIP-1(-/-) mice have spontaneous myeloproliferative inflammation in the lung, the nature of which has not been elucidated. We hypothesized that SHIP-1 plays an important role as a regulator in pulmonary allergic inflammation and in maintaining lung homeostasis. OBJECTIVE: To test our hypothesis, we characterized the pulmonary phenotype of SHIP-1(-/-) mice. RESULTS: Analyses of lung histopathology and bronchoalveolar lavage cellularity revealed that the majority of SHIP-1(-/-) mice had progressive and severe pulmonary inflammation of macrophages, lymphocytes, neutrophils, and eosinophils; mucous hyperplasia; airway epithelial hypertrophy; and subepithelial fibrosis. These pathologic changes were accompanied by exaggerated production of T(H)2 cytokines and chemokines, including IL-4, IL-13, eotaxin, and monocyte chemoattractant protein 1, in the lung. Furthermore, the number of mast cells significantly increased, and many of these cells were undergoing degranulation, which was correlated with increased content and spontaneous release of histamine in the lung tissue of SHIP-1(-/-) mice. CONCLUSION: These findings provide strong evidence that mice lacking SHIP-1 have an allergic inflammation in the lung, suggesting that SHIP-1 plays an important role in regulating the T(H)2 signaling pathway and in maintaining lung homeostasis. CLINICAL IMPLICATIONS: SHIP-1 as a regulator might be a potential therapeutic target for controlling allergic inflammation in diseases such as asthma.

Animals↗
PubMed2006

Neonatal urinary bladder inflammation produces adult bladder hypersensitivity.

UNLABELLED: Inflammatory events experienced during early development may permanently alter sensory processing. Because urinary tract infections frequently occur during early development in females and painful bladder disorders have a high female prevalence, the present studies were undertaken to determine whether inflammation of the bladder in female rats could lead to altered sensory processing later in life. Female rat pups were anesthetized and treated as neonates (14th-16th days of life) or as adolescents (28th-30th days of life) with either intravesical zymosan (yeast cell wall component that produces robust inflammation), intravesical normal saline, or only with anesthesia. As adults, rats that had their bladders inflamed as neonates exhibited increased spontaneous micturition frequency and, after reinflammation of the bladder, increased cardiovascular and abdominal muscle contractile responses to urinary bladder distension when compared with controls. Similar effects were not observed in rats which did not experience inflammation of the bladder until adolescence. Evan's blue extravasation, a measure of the magnitude of inflammatory changes, was also greater in rats treated as neonates with intravesical zymosan. Thermal and mechanical hindpaw sensitivity was not altered by bladder inflammation. Altogether, this suggests that neonatal bladder inflammation increases bladder sensitivity and may be a cause of the hypersensitivity of painful bladder syndromes. PERSPECTIVE: The present study observed that bladder inflammation experienced in a neonatal rat led to accentuated responses to urinary bladder distension when tested as adults. This suggests that events experienced during development may permanently sensitize visceral sensory systems and so represent one of the causes of painful bladder disorders.

Abdominal Muscles↗
PubMed2006

Atrial fibrillation in athletes: implicit literature-based connections suggest that overtraining and subsequent inflammation may be a contributory mechanism.

Research on atrial fibrillation (AF), a common heart arrhythmia in the elderly, over many decades has resulted in a literature of more than 16,000 articles indexed in Medline. An exploratory Medline search was conducted in which the subheadings for epidemiology and etiology of AF were combined to form a small subset of the initial records. Further computer-assisted selection led to a few articles that reported an unexpectedly high prevalence of AF in groups of otherwise healthy middle-aged endurance runners and other athletes. Why athletes should be unusually susceptible to AF is mysterious and puzzling. Because relatively few articles are about both AF and endurance exercise, a computer was used first to create a list of important terms that these two separate literatures had in common. Several inflammation-related terms, including C-reactive protein (CRP) and interleukin-6, were on that list. Further searching and literature analysis revealed that excessive endurance exercise or overtraining can lead to chronic systemic inflammation and, separately, that there is a solid association between CRP and AF and that anti-inflammatory agents have been reported to lower CRP and ameliorate AF. No articles were found that brought together all three concepts - AF, inflammation, and exercise. The following hypothesis is plausible, readily testable, and apparently novel: Older athletes diagnosed with AF but otherwise healthy who have engaged in rigorous aerobic endurance exercise for more than a decade will have CRP levels that are higher than those of a similar population of athletes without AF. Corroboration of this hypothesis would then justify a prospective clinical trial of anti-inflammation therapy. It is of particular interest to extend recent studies of inflammation in AF to athletes; athletic behavior that can induce inflammation may contribute to understanding the origins of AF.

Atrial Fibrillation↗
PubMed2006

Inflammation and atrial fibrillation: is Chlamydia pneumoniae a candidate pathogen of atrial fibrillation?

Atrial fibrillation is the most common arrhythmia, however, the mechanism of atrial fibrillation is not well explained. It has been considered that inflammation plays a role in atrial fibrillation, recently. Patients undergoing coronary artery bypass graft are at high risk for developing postoperative atrial fibrillation. The peak levels of C-reactive protein (CRP) were paralleled to the incidence of postoperative atrial fibrillation. In general population, CRP was also higher in patients with atrial fibrillation than in control people. Persistent atrial fibrillation patients had a higher CRP level than paroxysmal atrial fibrillation patients. CRP was not only associated with the presence of atrial fibrillation but may also predict patients at increased risk for future development of atrial fibrillation. Why inflammation markers in atrial fibrillation are high is a puzzling problem. We hypothesized that Chlamydia pneumoniae infection is a possible cause of atrial fibrillation by initiating inflammation response. It was demonstrated that infection of endothelial cells with C. pneumoniae elicited the production of Monocyte Chemoattractant Protein-1, interleukin-1, interleukin-8, interleukin-18, tumor necrosis factor, interferon and soluble intercellular adhesion molecule. Most of these cytokines play a crucial role in inflammation response that associate with the initiating and maintenance of atrial fibrillation. There are so many pathogens that can trigger inflammation. Some evidences showed that C. pneumoniae was the most likely pathogen of atrial fibrillation. In epidemic study, the incidence of atrial fibrillation increased from younger to elder and atrial fibrillation was more common in men than in women. C. pneumoniae has the same epidemic trend as the incidence of atrial fibrillation. Hypertension, myocardial infarction and reduced lung function are predictors of atrial fibrillation. C. pneumoniae infection is high in the patients with the above diseases. C. pneumoniae was found in endomyocardial biopsy samples, which supported C. pneumoniae was the candidate pathogen, too. Chlamydia infection can cause myocardial interstitial fibrosis and inflammation cells infiltration. The pathology characters of C. pneumoniae infection are similar to that found in atrial fibrillation. Seroepidemic study should be carried out to evaluate if there is relationship between C. pneumoniae and atrial fibrillation. If the hypothesis is confirmed, macrocyclic lactone antibiotics may be used to eliminate the pathogen. It will be a new target point to treat atrial fibrillation.

Atrial Fibrillation↗
PubMed2005

Inflammation alters sodium currents and excitability of temporomandibular joint afferents.

Inflammation-induced changes in voltage-gated sodium currents (I(Na)) in primary afferent neurons may contribute to hyperexcitability and pain. The present study was designed to test the hypothesis that persistent inflammation of the temporomandibular joint (TMJ) increases I(Na) in TMJ afferents. Acutely dissociated retrogradely labeled TMJ afferents were studied using whole-cell patch clamp techniques three days following Complete Freund's Adjuvant-induced inflammation of the TMJ. Inflammation was associated with a decrease in tetrodotoxin (TTX)-sensitive Na+ conductance and no significant change in slowly inactivating TTX-resistant Na+ conductance. However, inflammation increased the excitability of TMJ afferents. These results suggest that changes in ion channels other than those underlying TTX-sensitive and the slowly inactivating TTX-resistant Na+ conductance are likely to account for the inflammation-induced increase in the excitability of TMJ afferents.

Action Potentials↗
PubMed2005

Specific neurodevelopmental damage in mice offspring following maternal inflammation during pregnancy.

Intrauterine inflammation is a major risk for offspring neurodevelopmental brain damage and may result in cognitive limitations and poor cognitive and perceptual outcomes. Pro-inflammatory cytokines, stimulated during inflammatory response, have a pleotrophic effect on neurons and glia cells. They act in a dose-dependent manner, activate cell-death pathways and also act as trophic factors. In the present study, we have examined in mice the effect of short, systemic maternal inflammation on fetal brain development. Maternal inflammation, induced by lipopolysaccharide (LPS) at gestation day 17, did not affect morphogenic parameters and reflex development during the first month of life. However, maternal inflammation specifically increased the number of pyramidal and granular cells in the hippocampus, as well as the shrinkage of pyramidal cells, but not of the granular cells. No additional major morphological differences were observed in the cerebral cortex or cerebellum. In accordance with the morphological effects, maternal inflammation specifically impaired distinct forms of learning and memory, but not motor function or exploration in the adult offspring. The specific deficiency observed, following maternal inflammation, may suggest particular sensitivity of the hippocampus and other associated brain regions to inflammatory factors during late embryonic development.

Age Factors↗
PubMed2003

Reduction of glycine receptor-mediated miniature inhibitory postsynaptic currents in rat spinal lamina I neurons after peripheral inflammation.

Peripheral inflammation may induce long-lasting sensitization in the central nociceptive system. Neurons in lamina I of the spinal dorsal horn play a pivotal role in the integration and relay of pain-related information. In rats we studied whether changes in passive and active membrane properties and/or alteration of glycine receptor-mediated inhibitory control of spinal lamina I neurons may contribute to central sensitization in a model of peripheral long-lasting inflammation (complete Freund's adjuvant, hindpaw). Spontaneously occurring glycine receptor-mediated miniature inhibitory postsynaptic currents (GlyR-mediated mIPSCs) were recorded in lumbar spinal lamina I neurons. Miniature IPSC rise, decay kinetics and mean GlyR-mediated mIPSC amplitude were not affected by peripheral inflammation. The mean frequency of GlyR-mediated mIPSCs of lamina I neurons ipsilateral to the inflamed hindpaw was, however, significantly reduced by peripheral inflammation when compared with neurons from noninflamed animals. Principal passive and active membrane properties and firing patterns of spinal lamina I neurons were not changed by inflammation. These results indicate that long-lasting peripheral inflammation leads to a reduced glycinergic inhibitory control of spinal lamina I neurons by a presynaptic mechanism.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2004

The correlation between epithelial cell proliferation and inflammation in odontogenic keratocyst.

The objective of this study was to investigate the effect of inflammation on Ki-67 and PCNA labeling indices of odontogenic keratocysts. The study included 45 cases of OKC. From each case, three 5-microm sections were cut and stained with hematoxylin and eosin and with monoclonal antibodies for PCNA and Ki-67. In 10 high power fields (HPF), the type of epithelial lining was recorded separately for each field (metaplastic squamous or classic parakeratinized). Labeling indices for Ki-67 and PCNA and the inflammatory infiltrate density in the depth of 1 HPF adjacent to the basement membrane were recorded for each HPF. Parameters were compared between fields, and for each case the average inflammatory score and average labeling indices were calculated, and cases compared. No inflammation was observed in 24.5% of cases, mild in 30.5% and moderate to severe in 45%. Foci of metaplastic non-keratinizing epithelium were observed in 64% of cases, which were twice as common in inflamed cysts (90%) than in non-inflamed cysts (44%). The average labeling indices for PCNA and Ki-67 yielded no significant differences between inflamed and non-inflamed cysts. When compared between HPF's, there was an increase in the Ki-67 labeling index in metaplastic epithelium in areas with moderate to severe inflammation score (p=0.036). PCNA labeling index did not significantly change between areas with low and high inflammation. No differences in labeling indices were observed between areas of classic and metaplastic epithelium with equal inflammation density. A focal increase in Ki-67 expression adjacent to moderate to severe inflammation was found, with no significant effect on the overall proliferation activity of the cysts.

Cell Division↗
PubMed2004

Inflammation persistently enhances nocifensive behaviors mediated by spinal group I mGluRs through sustained ERK activation.

Group I metabotropic glutamate receptors (mGluRs) and their downstream signaling pathways, which involve the extracellular signal-regulated kinases (ERKs), have been implicated as mediators of plasticity in several pain models. In this study, we report that inflammation leads to a long-lasting enhancement of behavioral responses induced by activation of spinal group I mGluRs. Thus, the nocifensive response to intrathecal injection of the group I mGluR agonist (RS)-3,5-Dihydroxyphenylglycine (DHPG) is significantly potentiated seven days following Complete Freund's Adjuvant (CFA)-induced inflammation of the hind paw. This potentiation is not associated with increased mGlu1 or mGlu5 receptor expression but is associated with increased levels of phosphorylated ERK in dorsal horn neurons. We also tested whether the increased behavioral response to DHPG following inflammation may be explained by enhanced coupling of the group I mGluRs to ERK activation. DHPG-induced ERK phosphorylation in the dorsal horn is not potentiated following inflammation. However, inhibiting ERK activation using a MEK inhibitor, U0126, following inflammation attenuates the intrathecal DHPG-induced behavioral responses to a greater extent than in control animals. The results from this study indicate that persistent ERK activation is required for the enhanced behavioral responses to spinal group I mGluR activation following inflammation and suggest that tonic modulation of ERK activity may underlie a component of central sensitization in dorsal horn neurons.

Animals↗
PubMed2006

Induction of CB1 cannabinoid receptor by inflammation in primary afferent neurons facilitates antihyperalgesic effect of peripheral CB1 agonist.

Cannabinoids act on various regions in the nervous system to modulate neuronal activity including nociception. Here, we investigated CB1 receptor expression in primary afferent neurons in the dorsal root ganglion (DRG) and the efficacy of a local (intraplantar) application of the selective CB1 agonist, 2-arachidonyl-2-chloroethylamide (ACEA), on inflammatory thermal hyperalgesia. In situ hybridization showed normal CB1 mRNA expression in 28% of DRG neurons. Peripheral inflammation by CFA (complete Freund's adjuvant) significantly increased the ratio of CB1 mRNA-positive neurons to 43%, primarily with increase in NF200-negative C-fiber nociceptors. Furthermore, CB1 and TRPV1 (transient potential receptor vanilloid subtype-1) co-localization was increased from 41% before inflammation to 67% two days after inflammation. Inflammation also increased CB1 immunoreactivity in DRG neurons and in nerve fibers of the hindpaw dermis, indicating increased CB1 transport from the cell body to the peripheral nerve. The intraplantar application of ACEA attenuated CFA-induced thermal hyperalgesia. The antinociceptive properties of ACEA became more prominent at 2 days after inflammation, compared with those in non-inflamed and inflamed animals at 8 h. These results suggest that CB1 expression in primary afferent neurons is increased by inflammation and that the subsequent increase in CB1 transport to peripheral axons contributes to the increased antihyperalgesic efficacy of locally administered CB1 agonist.

Analysis of Variance↗
PubMed2006

Evaluation of oral corticosteroids and phosphodiesterase-4 inhibitor on the acute inflammation induced by inhaled lipopolysaccharide in human.

BACKGROUND: Endotoxins are pro-inflammatory substances present in the environment. In man, inhalation of its purified derivative lipopolysaccharide (LPS) induces inflammation related to macrophages and neutrophils. Corticosteroids and phosphodiesterase (PDE)-4 inhibitors have inhibiting effects on macrophages and neutrophils, respectively. This study investigated the effect of prednisolone and of the PDE-4 inhibitor cilomilast on the LPS-induced acute inflammation. METHODS: The study was a placebo-controlled, double-blind crossover design. On three occasions, at 2 weeks interval, 16 healthy subjects inhaled 50 microg LPS after a 6-day treatment with cilomilast (15 mg bd), prednisolone (10 mg bd) or placebo. For the assessment of the inflammatory response, induced sputum was obtained before inclusion and 6h post-LPS while blood samples were collected before, 6 and 24 h post-LPS. RESULTS: Inhaled LPS induced an increase in sputum neutrophils (p<0.0001), logMMP-9 (p<0.05), logMMP-9/TIMP-1 (p<0.01) and logTNF-alpha (p<0.02). At the blood level there were significant rise in neutrophilia (p<0.001), E-selectin (p<0.02), C-reactive protein (CRP) (p<0.001) and LPS-binding protein (p<0.001). There was both a slight, but not significant, increase in body temperature and decrease in forced expiratory volume in 1 s (FEV(1)). Neither prednisolone nor cilomilast had protective effect on the LPS-induced airways' inflammation. The LPS-induced CRP acute-phase protein of inflammation (0.58+/-0.13 and 3.52+/-0.41 mg/dL, before and after LPS, respectively) was significantly inhibited by a pre-treatment with prednisolone (1.39+/-0.32 mg/dL, p<0.01) and attenuated (2.65+/-0.30 mg/dL, p=0.09) with cilomilast. CONCLUSION: In healthy subjects, while the LPS-induced airways' inflammation was not modified either by oral prednisolone or by PDE-4 inhibitor cilomilast (at actual dosage), the LPS-induced acute phase of blood inflammation was reduced by prednisolone.

Acute Disease↗
PubMed2006

Myeloperoxidase as a marker of increasing systemic inflammation in smokers without severe airway symptoms.

BACKGROUND: There is increasing evidence of systemic inflammation in patients with chronic obstructive pulmonary disease (COPD), but there is very little information on the development of systemic inflammation in smokers without severe airway symptoms. In this longitudinal study, we examined whether smokers with mild or no airway symptoms develop signs of systemic inflammation by assessing inflammatory markers in blood over a 6-year period. METHODS: Forty smokers and 28 male never-smokers were investigated in 1995 (year 0) and 6 years later (year 6). At year 6, 11 smokers had stopped smoking (quitters); these subjects were analysed as a separate group. At year 0 and 6, we measured serum levels of myeloperoxidase (MPO), lysozyme and human neutrophil lipocalin (HNL), regarded as markers of activity in neutrophils plus monocyte-lineage cells, monocyte-lineage cells only and neutrophils only. RESULTS: All systemic markers of inflammation (MPO, HNL and lysozyme) were significantly higher in smokers than in never smokers at year 6. For MPO alone, smokers only displayed a unique pattern compared with the other groups; the concentration of MPO in blood increased among smokers during the 6-year period, and this increase was statistically significant compared with that observed in never-smokers. Even though quitters did not display any clear change in MPO, we observed a statistically significant negative correlation between the change in blood MPO and the duration of smoking cessation in this group. For HNL and lysozyme, the changes over time were similar in smokers and never-smokers, with no statistically significant difference compared with quitters. CONCLUSION: This study provides evidence that male smokers without severe airway symptoms develop an increasing systemic inflammation during a 6-year period. The study forwards both direct and indirect evidence that MPO may be an early marker of this systemic inflammation. However, our study also forwards indirect evidence that ongoing tobacco smoking may "drive" the level of systemic HNL and lysozyme. The origin of the increased MPO and its value as an easily measured predictor for future COPD deserves to be further evaluated.

Acute-Phase Proteins↗
PubMed2001

Role of novel markers of inflammation in patients with stable coronary heart disease.

The role of novel markers of inflammation in patients with coronary heart disease (CHD) is still unclear. We conducted a case-control study to assess the association between various markers of inflammation and the presence and severity of chronic stable CHD. We included 312 clinically stable patients with angiographically documented CHD, aged 40 to 68 years. Voluntary blood donors (n = 479) matched for age and gender served as controls. High-sensitivity C-reactive protein, serum amyloid A, plasminogen activator inhibitor-1 activity, von Willebrand factor, fibrinogen, plasma viscosity, albumin, and neutrophils were determined. The severity of CHD was evaluated by 3 coronary scoring systems: the clinical 1- to 3-vessel disease score, the American Heart Association extension score (1 to 15 segments), and the Gensini score. All markers of inflammation were highly significantly elevated (all p <0.005) in patients with stable CHD compared with controls. After multivariable adjustment by means of logistic regression analysis, the association between CHD and fibrinogen, plasma viscosity, von Willebrand factor, and plasminogen activator inhibitor-1 activity remained substantial, whereas it decreased in high-sensitivity C-reactive protein, serum amyloid A, and neutrophils. The combination of > or = 2 markers of inflammation was associated with a strongly increased risk of CHD. No association between markers of inflammation and any of the coronary scores applied was found. These results document an independent association between most of the markers of inflammation and chronic CHD, even in clinically stable patients. The combination of several of these biochemical markers, i.e., the determination of an "inflammatory risk profile," may be useful to further stratify cardiovascular risk.

Adult↗
PubMed2003

The inhibitory receptor FcgammaRII reduces joint inflammation and destruction in experimental immune complex-mediated arthritides not only by inhibition of FcgammaRI/III but also by efficient clearance and endocytosis of immune complexes.

Studies of FcgammaRII-/- mice identified the inhibitory function of this receptor in joint inflammation and cartilage destruction induced with immune complexes (ICs). To extend our insight in the role of FcgammaRII in arthritis, we explored the role of FcgammaRII in the absence of activating receptors I and III using FcgammaRI/III-/- as well as FcgammaRI/II/III-/- mice. When antigen-induced arthritis (AIA) was elicited, which is a mixture of T cell and IC-driven inflammation, arthritis was almost absent at day 7 in FcgammaRI/III-/- mice. Remarkably, in FcgammaRI/II/III-/- mice, this model induced a tremendously increased arthritis as compared to wild-type controls. This implies that FcgammaRII regulates joint inflammation also in the absence of activating FcgammaRI and III. To confirm the IC specificity of this finding, similar studies were done with ICs or zymosan as arthritogenic stimuli. Strongly elevated inflammation was found in FcgammaRI/II/III-/- mice with IC but not with zymosan. Clearance studies identified accumulation of IgG in the knee joint in the absence of FcgammaRII. Moreover, macrophages expressing only FcgammaRII showed prominent endocytosis of preformed soluble ICs not different from controls. In total absence of FcgammaR (FcgammaRI/II/III-/-), macrophages completely failed to endocytose ICs. Although joint inflammation was much higher in AIA arthritic knee joints of FcgammaRI/II/III-/- and the inflammatory cells still expressed an inflammatory phenotype, severe cartilage destruction (MMP-mediated neoepitopes in the matrix and chondrocyte death) was completely prevented in contrast to the marked destruction which was observed in the wild-type. Our study indicates that FcgammaRII reduces joint inflammation in the absence of activating FcgammaR by promoting endocytosis and clearance of ICs from the joint. Infiltrating cells, which fail to express activating FcgammaR although they still become stimulated are no longer capable of inducing severe cartilage destruction.

Animals↗
PubMed2003

Use of the A(2A) adenosine receptor as a physiological immunosuppressor and to engineer inflammation in vivo.

Inflammation must be inhibited in order to treat, e.g., sepsis or autoimmune diseases or must be selectively enhanced to improve, for example, immunotherapies of tumors or the development of vaccines. Predictable enhancement of inflammation depends upon the knowledge of the "natural" pathways by which it is down-regulated in vivo. Extracellular adenosine and A(2A) adenosine (purinergic) receptors were identified recently as anti-inflammatory signals and as sensors of excessive inflammatory tissue damage, respectively (Ohta A and Sitkovsky M, Nature 2001;414:916-20). These molecules may function as an important part of a physiological "metabolic switch" mechanism, whereby the inflammatory stimuli-produced local tissue damage and hypoxia cause adenosine accumulation and signaling through cyclic AMP-elevating A(2A) adenosine receptors in a delayed negative feedback manner. Patterns of A(2A) receptor expression are activation- and differentiation-dependent, thereby allowing for the "acquisition" of an immunosuppressive "OFF button" and creation of a time-window for immunomodulation. Identification of A(2A) adenosine receptors as "natural" brakes of inflammation provided a useful framework for understanding how tissues regulate inflammation and how to enhance or decrease (engineer) inflammation by targeting this endogenous anti-inflammatory pathway. These findings point to the need of more detailed testing of anti-inflammatory agonists of A(2A) receptors and create a previously unrecognized strategy to enhance inflammation and targeted tissue damage by using antagonists of A(2A) receptors. It is important to further identify the contributions of different types of immune cells at different stages of the inflammatory processes in different tissues to enable the "tailored" treatments with drugs that modulate the signaling through A(2A) purinergic receptors.

Adenosine↗
PubMed2003

Local inflammation increases vanilloid receptor 1 expression within distinct subgroups of DRG neurons.

Vanilloid receptor 1 (VR1) is essential to the development of inflammatory hyperalgesia. We investigated whether inflammation can increase in VR1 positive neuronal profiles in rat DRG neurons using histochemical methods. We also used size frequency analysis and double staining with several neuronal markers to investigate whether or not inflammation alters VR1 expression. Inflammation induced a 1.5-fold increase in percentage of VR1-like immunoreactivity (LI) positive profiles per total neuronal profiles, suggesting that the number of heat and pH sensitive neurons increase during inflammation. Area frequency histograms showed that VR1 expression increased in small and medium-sized neurons after inflammation. Double labeling of VR1 with NF200 showed that VR1 positive neurons with NF200 positive profiles significantly increased, indicating that the medium-sized VR1 positive neurons were neurons with myelinated A-fibers. Local inflammation thus increases in VR1 protein level within distinct subgroups of DRG neurons that may participate in the development and maintenance of inflammatory hyperalgesia.

Animals↗