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PubMed2001

Effect of indomethacin on gallbladder inflammation and contractility during acute cholecystitis.

OBJECTIVE: The aim of this study was to determine whether the prostaglandin synthase inhibitor indomethacin reverses the inflammation and abnormal gallbladder contractility that occur after common bile duct ligation (CBDL), a model of acute cholecystitis. METHODS: Gallbladder muscle contractility was studied in vitro in normal, CBDL, and sham-operated guinea pigs. Animals were treated with saline or indomethacin in vivo. Acetylcholine (ACh) was used to directly contract the muscle and electric field stimulation (EFS) to activate intrinsic nerves. Hematoxylin and eosin-stained slides of muscle strips were scored for inflammation. RESULTS: CBDL in saline-treated animals increased the inflammation score and decreased gallbladder muscle contractility to ACh and EFS. Indomethacin decreased the inflammation score and partly reversed the smooth muscle contractile response to ACh 6 and 24 h after CBDL, but not at 48 h. Indomethacin did not reverse the CBDL-induced decrease in nerve-evoked contractions. CONCLUSION: Gallbladder inflammation and contractile dysfunction after CBDL are partly reversed with indomethacin at 6 and 24 h, but not at 48 h. This suggests that, early in the course of CBDL, the inflammation and contractile dysfunction are, in part, prostaglandin-mediated.

Acute Disease↗
PubMed1996

Bacterial Cell Wall Polymer-Induced Granulomatous Inflammation

Local or systemic injection of peptidoglycan-polysaccharide polymers, which are the primary structural components of cell walls of nearly all bacteria, leads to acute inflammation, which can develop into chronic, spontaneously relapsing, granulomatous inflammation in a number of organs. Evolution into chronic granulomatous inflammation is dependent upon persistence of poorly biodegradable cell wall polymers within tissues, genetically determined host susceptibility, and generation of a T-lymphocyte-mediated immune response. Intraperitoneal injection of peptidoglycan-polysaccharide fragments from group A streptococci or selected intestinal bacteria into susceptible Lewis rats leads to chronic, spontaneously reactivating erosive arthritis and hepatic granulomas. Subserosal (intramural) injection of poorly biodegradable cell wall fragments into the distal intestine of Lewis rats induces chronic, spontaneously relapsing granulomatous enterocolitis with associated arthritis, hepatic granulomas, anemia, and leukocytosis. Chronic inflammation does not occur in T-lymphocyte-deficient rats and is prevented by cyclosporin-A therapy and degradation of peptidoglycan by the muralytic enzyme, mutanolysin. Moreover, resistant Buffalo and Fischer F344 rats, the latter sharing identical MHC antigens with Lewis rats, develop only acute inflammation with no chronic granulomatous response. Peptidoglycan-polysaccharide polymers activate almost every limb of the inflammatory response. Blockade of specific pathways suggests that interleukin-1, transforming growth factor-beta, plasma kallikrein, and T lymphocytes are dominant mediators of peptidoglycan-polysaccharide-induced arthritis, hepatic granulomas, and enterocolitis. Because of the similarity of immune mechanisms of these rat models to human disease, bacterial cell wall-induced inflammation provides unique opportunities to study pathogenic mechanisms of granuloma formation in response to ubiquitous microbial agents and to test novel therapeutic agents.

Journal Article↗
PubMed2002

Adenosine-mediated bronchoconstriction and lung inflammation in an allergic mouse model.

In this study, we studied the role of adenosine on airway responsiveness and airway inflammation using an allergic mouse model. Mice were sensitized by two i.p. injections of ragweed and three consecutive ragweed aerosol challenges. It was found that inhalation of adenosine causes a dose-related bronchoconstriction in this model. Ragweed sensitized and challenged mice showed increased sensitivity to airway challenge to adenosine compared to control animals. Theophylline, a non-selective adenosine receptor antagonist, blocked adenosine-induced bronchoconstriction, but was unable to inhibit bronchoconstrictor response to methacholine. Mice systemically sensitized and airway challenged with allergen showed a marked airway inflammation manifesting increases in eosinophils, lymphocytes and neutrophils, and decrease in macrophages. Twenty-four hours after airway challenge with allergen, aerosolization of adenosine further potentiated the allergen-induced airway inflammation. Cells in bronchoalveolar lavage fluid after adenosine aerosolization increased by 3.07-fold as compared to control mice, and by 1.8-fold compared to ragweed sensitized and challenged mice. The increases in eosinophils, lymphocytes, and neutrophils caused by allergen were potentiated after adenosine challenge. Unexpectedly, macrophages significantly decreased after adenosine challenge. Theophylline attenuated adenosine-enhanced airway inflammation, but could not reverse allergen-induced airway inflammation. These findings suggested that specific adenosine receptors contribute to airway responsiveness and airway inflammation associated with this model of allergic asthma.

Adenosine↗
PubMed1994

The relationship between the degree of chronic middle ear inflammation and tympanic bulla pneumatization in the pig as animal model.

The relationship between the degree of chronic middle ear inflammation and pneumatization was investigated in the pig as an animal model, since its tympanic bulla closely resembles the human mastoid air cell system. Ten piglets (sire: Landrace-Hampshire crossbreed; dam: Duroc) were used for this experiment. Four ears of two animals served as the normal control group and 16 ears of eight animals were the experimental group. In this latter group, otitis media was induced by injecting glycerin into the middle ear clefts 1 months after birth, and the degree of inflammation was varied by administering or withholding antibiotics (cefamandole and dibekacin) and adjusting the dosage regimen. The animals were sacrificed 6 months after birth and examined for the relationship between the degree of chronic middle ear inflammation present and tympanic bulla pneumatization. Various degrees of inflammation were successfully induced by injecting the antibiotics: the more severe the inflammation found, the greater was the inhibition of pneumatization. Findings demonstrated that the degree of inhibition of pneumatization produced was directly proportional to the severity of chronic middle ear inflammation.

Animals↗
PubMed1993

Dynamic changes in the receptive field properties of spinal cord neurons with ankle input in rats with chronic unilateral inflammation in the ankle region.

The aim of this study was to determine the discharge and receptive field properties of spinal cord neurons with ankle input in spinal segments L4-6 in the rat, both under control conditions and during the course of an adjuvant-induced unilateral inflammation in the ankle. The extent of receptive fields in the skin and deep tissue was assessed using brush, pinch and compression stimuli. Neurons were categorized as nociceptive-specific or wide-dynamic-range neurons on the basis of their response thresholds and responses to suprathreshold stimuli. At all stages of inflammation (2, 6, 13 and 20 days post inoculation) the population of neurons with ankle input showed differences from the population of neurons with ankle input in control rats. There was a reduction in the number of neurons that appeared as nociceptive specific and a concomitant increase in the number of neurons showing a wide-dynamic-range response profile. The receptive fields of the neurons with ankle input were markedly larger in rats with inflammation in the ankle region and mainly spread proximally on the ipsilateral hindlimb and also to the abdomen and tail in some cases. There was also an increase in the number of neurons with contralateral excitatory inputs. The mechanical thresholds at the ankle joint and proximal parts of the ipsilateral hindlimb were less in arthritic rats than in controls. The proportion of spontaneously active neurons was also increased in rats during the initial and later stages of inflammation, although there was no significant increase in the mean spontaneous discharge frequency. These data show that there are long-term changes in the receptive field and response properties of neurons in intact rats with chronic unilateral adjuvant-induced inflammation similar to those described previously in spinal cats with acute inflammation (Neugebauer and Schaible 1990). It is presumed that similar afferent and spinal mechanisms are at work under acute and chronic inflammatory conditions which produce hyperexcitability in spinal neurons with joint input.

Animals↗
PubMed1989

Pulmonary inflammation and fibrosis in a murine model of asbestosis and silicosis. Possible role of tumor necrosis factor.

Prolonged asbestos and silica inhalation is associated with pulmonary inflammation and fibrosis. Several studies suggest that TNF may play a role in the development of inflammation and fibrosis. We studied TNF production in a murine model of asbestosis and silicosis. Asbestos fibers caused a significant inflammatory response at two weeks and pulmonary fibrosis beginning at one month. Pulmonary inflammation was principally caused by an accumulation of neutrophils (0.88 x 10(5) neutrophils/compared to 0.05 x 10(5) in controls). TNF production by bronchoalveolar cells was higher in asbestos-instilled mice at two weeks, but was significantly diminished in older mice. Pulmonary inflammation was observed until six months in silica-instilled mice. Neutrophils were also the principal protagonists of the inflammation. In this group, severe fibrosis was observed at two weeks. TNF production in silica-instilled mice was similar to controls, possibly due to the presence of large numbers of neutrophils (3.3 x 10(5)/lavage) that could adsorb TNF. In vitro experiments showed an augmentation of TNF production by bronchoalveolar cells in the presence of silica. Taken together, our data suggest that asbestos and silica stimulate alveolar macrophages to produce TNF, which can be involved in pulmonary inflammation and fibrosis.

Animals↗
PubMed1995

Dermal inflammation in primates, mice, and guinea pigs: attenuation by second-generation leukotriene B4 receptor antagonist, SC-53228.

Granulocyte infiltration is a prominent feature of human psoriasis. Psoriatic lesional skin contains abnormally high amounts of immunoreactive leukotriene B4 (LTB4), a potent granulocyte chemotaxin in vivo and in vitro. SC-53228 [(+)-(S)-7-(3-}2-(cyclopropylmethyl)-3-methoxy-4- [(methylamino)carbonyl]phenoxy}propoxy}-3,4-dihydro-8-propyl-2H-1- benzopyran-2-propanoic acid], a second-generation LTB4 receptor antagonist, was tested topically and orally in phorbol ester-induced dermal inflammation in three species. Skin inflammation was induced by topical application of phorbol-12-myristate-13-acetate-(PMA/TPA) and assessed by ear thickness, levels of the neutrophil marker enzyme myeloperoxidase (MPO) and histological examination. In mice, SC-53228 inhibited inflammation with a topical ED50 value of 200 +/- 18 micrograms. When applied to guinea pigs, SC-53228 (100 micrograms) inhibited the MPO increase by 86%, while 1000 micrograms abrogated inflammation in rhesus macaques with no plasma accumulation of the drug. A 1% gel formulation was also efficacious in guinea pig PMA-induced epidermal inflammation. Furthermore, single oral dose administration to mice was efficacious (ED50 < 2.5 mg/kg) as was multidose administration to rhesus macaques. PMA-induced skin inflammation possesses some of the attributes of human psoriasis and an agent such as SC-53228 may have utility in the medical management of this condition.

Administration, Cutaneous↗
PubMed1993

Cyclooxygenase inhibitors acetylsalicylic acid and indomethacin do not affect capsaicin-induced neurogenic inflammation in human skin.

Neurogenic inflammation is evoked by neuropeptides released from primary afferent terminals and, presumably, by other secondarily released inflammatory mediators. This study examines whether prostaglandins might participate in the development of neurogenic inflammation in humans and whether cyclooxygenase inhibitors have any anti-inflammatory effect on this type of inflammation. In healthy volunteers, neurogenic inflammation was elicited by epicutaneously applied capsaicin (1%), after systemic pretreatment with acetylsalicylic acid, or topically applied indomethacin compared to pretreatment with saline or vehicle, respectively. The extent of neurogenic inflammation was quantified by planimetry of visible flare size and recording the increase of superficial cutaneous blood flow (SCBF) with a laser Doppler flowmeter. Capsaicin-induced flare sizes and outside SCBF (both representing neurogenically evoked inflammation) were unaffected by acetylsalicylic acid or indomethacin. Only the capsaicin-induced increase of inside SCBF was attenuated by local pretreatment with indomethacin, reflecting the participation of prostaglandins in the inflammatory response of those areas which were in direct contact with capsaicin.

Adult↗
PubMed2002

99mTc-Hynic-annexin V imaging to evaluate inflammation and apoptosis in rats with autoimmune myocarditis.

Inflammation and cell death are two important components of myocarditis. We evaluated the distribution of inflammation and apoptotic cell death in rats with autoimmune myocarditis using two radiotracers - technetium-99m Hynic-annexin V ((99m)Tc-annexin) as a marker of apoptotic cell death and carbon-14 deoxyglucose ((14)C-DG) as a marker of inflammation - in comparison with histologic findings. Three, 7 and 14 weeks after immunization with porcine cardiac myosin (acute, subacute, and chronic phases, respectively) (99m)Tc-annexin and (14)C-DG were injected. The uptake in the total heart was determined as the percentage of injected dose per gram (% ID/g) by tissue counting. Dual-tracer autoradiography with (99m)Tc-annexin and (14)C-DG was performed. The distribution of each of these agents was compared with the results of hematoxylin and eosin staining to identify areas of inflammation, and TUNEL staining to identify areas of apoptosis. Total cardiac uptake of (99m)Tc-annexin in the acute phase of myocarditis was significantly higher than that in normal rats (1.28%+/-0.30% vs 0.46%+/-0.01%; P<0.0001); it then decreased in the subacute phase and reached normal levels (0.56%+/-0.08% vs 0.60%+/-0.08%; P=NS). Total cardiac uptake of (14)C-DG in the acute phase of myocarditis was significantly higher than that in normal rats (2.78%+/-0.95% vs 1.02%+/-0.25%; P<0.0001); it then decreased in the subacute phase, but still remained higher than in controls (2.06%+/-0.52% vs 1.37%+/-0.46%; P<0.05). Using autoradiography and staining of tissue specimens, it was found that most histologic inflammatory foci corresponded to areas of high (14)C-DG uptake; some also corresponded to areas of high (99m)Tc-annexin uptake in the acute phase of myocarditis. (99m)Tc-annexin localization was strongly correlated with the number of TUNEL-positive cells (P<0.0001, r=0.83), but the uptake of (14)C-DG showed no relationship with it. There is a marked difference in the distribution of inflammation and apoptotic cell death in the myocardium of animals with immune myocarditis. These changes are mirrored by the localization of (14)C-DG and (99m)Tc-annexin. Sites of inflammation and zones of apoptotic cell death change over the course of immune myocarditis.

Animals↗
PubMed2005

Localization of Eutr2, a locus controlling susceptibility to DES-induced uterine inflammation and pyometritis, to RNO5 using a congenic rat strain.

In some rat strains chronic administration of exogenous estrogens induces pyometritis, an inflammation of the uterus associated with infection, suggesting that there is genetic variation in susceptibility to estrogen-induced inflammation and pyometritis. In this article we report that following 10 weeks of treatment with the synthetic estrogen diethylstilbestrol (DES), Fisher 344 (F344) rats exhibit modest uterine inflammation and a 0% incidence of pyometritis. By contrast, under identical experimental conditions, Brown Norway (BN) rats exhibit significant inflammation and a 100% incidence of pyometritis. Similarly, we also observed profound uterine inflammation and a 100% incidence of pyometritis in a congenic rat strain in which a segment of RNO5 from the BN strain is carried on the F344 strain. These data suggest that a locus on RNO5 controls both the magnitude of DES-induced uterine inflammation and susceptibility to DES-induced pyometritis. This locus, designated Eutr2, resides within the same segment of RNO5 as the Eutr1 locus, which confers susceptibility to E2-induced pyometritis in an F2 population generated in a cross between the BN and August x Copenhagen 9935, Irish (ACI) strains.

Animals↗
PubMed2002

Exposure and nasal inflammation in workers heating polyurethane.

OBJECTIVE: To test the hypothesis that exposure to thermal-degradation products of polyurethane (PUR), particularly isocyanates, induced nasal inflammation. METHODS: Thirty-eight workers -14 with a history of work-related nasal symptoms (WRS/Nose), and 15 referents without such history - exposed to sprayed and heated PUR glue, were studied with regard to biomarkers of isocyanate exposure [4,4'-diphenylmethane diisocyanate (4,4'-methylenediphenyl diisocyanate; MDI) and 2,4- and 2,6-toluene diisocyanate (TDI), determined as 4,4'-diphenylmethane (U-MDX) and 2,4- and 2,6-toluene (U-2,4 and U-2,6-TDX) diamine in hydrolysed urine and nasal lavage fluid (NAL)], inflammation [albumin; eosinophilic cationic protein (ECP); myeloperoxidase (MPO) and cells in NAL], serum IgG specific for MDI (S-IgG-MDI) and TDI (S-IgG-TDI), and nose symptoms. Nine unexposed office workers were also examined. RESULTS: The exposure to sprayed and heated PUR glue, especially when heated by gun, was associated with the presence of biomarkers of isocyanate exposure in urine; after work the levels [median (range)] in all workers were: U-MDX 0.32 (<or=0.1-1.5); U-2,6-TDX 0.33 (<or=0.1-0.71) microg/g creatinine. Also, 5/38 workers had detectable levels in NAL. Furthermore, the biomarkers of inflammation in NAL - albumin ( P<or=0.05; Kendall), MPO ( P=0.01), and neutrophils ( P<or=0.01) - showed similar patterns of relationships with the exposure to glue heated by guns. After work, workers who had complained of WRS/Nose had higher levels of albumin (medians 3.5 vs. 1.9 mg/l; P=0.05, Mann-Whitney U-test) and MPO (14 vs. 11 microg/l; P<or=0.05) in NAL than those who had had no such complaints. U-2,6-TDX, as well as S-IgG-MDI and S-IgG-TDI, were associated with increased levels of the inflammation biomarkers, U-2,6-TDX also with the symptoms. As expected, acute symptoms after exposure were associated with the inflammation biomarkers. CONCLUSIONS: The present data indicate that thermal degradation products of PUR induced a 'chronic' rhinitis. At exposure, there was an accentuation of symptoms; the signs of acute inflammation were less obvious.

Automobiles↗
PubMed2004

Does asymptomatic inflammation increase PSA? A histopathological study comparing benign and malignant tissue biopsy specimens.

AIM: To determine the effect of inflammation on postage-specific antigen (PSA) levels in patients who were performed transrectal ultrasonography (TRUSG) guided prostate biopsy because of high PSA levels. MATERIALS AND METHOD: 376 tissue specimens of 47 patients with BPH and 176 tissue specimens of 22 patients with prostate adenocancer were analysed histopathologically. Digital rectal examination, TRUSG, and PSA measurements were performed to all the patients before biopsy. Sextant biopsy was performed. Two pathologists examined all the biopsy specimens in blinded fashion. Inflammation pattern was categorized as glandular, periglandular, stromal and perivascular and intensity of inflammation graded from 1 to 3. RESULTS: The mean age of the patients was 66.2 years. The mean serum PSA level of the initial biopsy was 8.7 ng/ml in the BPH and 13.4 ng/ml in the prostate Ca. No relation was found between the serum total PSA levels and prostate volume or patient's age in BPH patients (P = 0.258). In BPH patients stromal, periglandular, glandular inflammations did not increase PSA levels. Perivascular inflammation increased PSA levels significantly. CONCLUSION: The inflammation in perivascular field increases serum PSA levels (P = 0.007). Although high serum PSA levels shows correlation with cancer in biopsy, there is no such significant relation with rebiopsy results and PSA levels at last studies. Because of this, these patients' biopsy samples must be reinspected for infection findings and atipic biopsy or high grade PIN. The result of our study showed that histological perivascular infection within the prostatic gland is a significant factor to serum PSA levels in BPH. If you have negative biopsy sample, pathology must indicate the place of the infection. Follow up of this patient and rebiopsy time are decided according to the result of this negative biopsy sample.

Aged↗
PubMed1990

Influence of the nervous system on experimentally induced urethral inflammation.

We have studied the contribution of the nervous system on experimentally induced urethral inflammation in the rat. Urethral inflammation was induced by inserting latex strips into the urethra. The effects of different experimental procedures was assessed by using a 4-graded inflammation scale based on the histological findings. Attenuation of urethral inflammation was produced by administration of capsaicin at birth. A more complete attenuation was produced by sympathectomy prior to application of the latex strip. Urethral inflammation was also severe in the spontaneous hypertensive rat. Injection of morphine into the third ventricle of the brain significantly reduced the experimentally induced urethral inflammation. These data taken together indicate that the sensory and postganglionic innervation of the urethral mucosa as well as the central nervous system is critically involved in the inflammatory reaction of the urethra following exposure to latex strips.

Adrenergic Fibers↗
PubMed1994

Intraspinal release of immunoreactive calcitonin gene-related peptide during development of inflammation in the joint in vivo--a study with antibody microprobes in cat and rat.

This study addressed the intraspinal release of immunoreactive calcitonin gene-related peptide in vivo during mechanical stimulation of the normal joint and during the development of an acute experimental inflammation in the knee joint in the anaesthetized cat (spinalized) and rat (not spinalized). Release was assessed using microprobes coated with antibody to calcitonin gene-related peptide; inhibition of binding of [125I]calcitonin gene-related peptide to these probes following insertion into the spinal cord is equated with intraspinal release of the endogenous (unlabelled) peptide. Probes inserted prior to inflammation showed marked basal release of immunoreactive calcitonin gene-related peptide in the dorsal horn with a maximum in the superficial dorsal horn in the absence of intentional stimulation. The pattern of binding of [125I]calcitonin gene-related peptide was not or only minimally changed by innocuous mechanical stimuli (flexion of and innocuous pressure to the knee in the cat and innocuous pressure to the knee of the rat) but was significantly altered by electrical stimulation of the tibial nerve in the cat (sufficient to excite unmyelinated afferent fibres), indicating release of the peptide by the latter stimulus. During the first hours of the development of an experimental inflammation in the knee joint induced by intra-articular injections of kaolin and carrageenan, the pattern of binding of [125I]calcitonin gene-related peptide changed. In the cat, the level of immunoreactive calcitonin gene-related peptide showed a persistent increase in the gray matter and up to the surface of the cord and release was slightly increased by innocuous stimuli. In the rat, increased levels of immunoreactive calcitonin gene-related peptide were mainly seen in the superficial and deep dorsal horn during innocuous pressure (this stimulus did not evoke release of the peptide prior to inflammation) and noxious pressure applied to the injected knee, whereas increased basal levels were only observed at later stages. These data show that the development of an acute experimental inflammation in the joint is associated with an enhancement of the intraspinal release of immunoreactive calcitonin gene-related peptide. Since the changes in the release were noted at an early stage, within the first hours, they could contribute to the generation of inflammation-evoked changes of the responsiveness of spinal cord neurons and hence to the mechanisms inducing inflammatory pain.

Animals↗
PubMed1992

Alpha-MSH peptides inhibit acute inflammation induced in mice by rIL-1 beta, rIL-6, rTNF-alpha and endogenous pyrogen but not that caused by LTB4, PAF and rIL-8.

The neuropeptide alpha-melanocyte stimulating hormone [alpha-MSH(1-13)] occurs in the pituitary, brain, skin and other tissues and receptors for this molecule are likewise widespread. In previous research, this tridecapeptide, which shares its amino acid sequence with ACTH(1-13), was shown to have both potent antipyretic activity and a role in the endogenous control of the febrile response. alpha-MSH(1-13) and its COOH-terminal tripeptide were subsequently found to inhibit inflammation induced by general stimuli such as topical application of an irritant. The aim in the present experiments was to determine if these peptides can inhibit acute inflammatory responses induced in mice by injection of individual cytokines, endogenous pyrogen (EP), a natural cytokine mixture, and other mediators of inflammation. Inflammation induced in the mouse ear by rIL-1 beta, rIL-6 or rTNF-alpha was inhibited by alpha-MSH and a D-valine-substituted analog of alpha-MSH(11-13) whereas substantial doses of alpha-MSH(1-13) did not alter inflammation induced by LTB4, PAF and IL-8. Both peptides inhibited edema caused in the mouse paw by local injection of EP. The results indicate that alpha-MSH molecules antagonize the actions of certain cytokine mediators of inflammation, consistent with previous observations of anti-cytokine activity of these peptides. Failure to inhibit edema caused by LTB4, PAF and IL-8 suggests that, in inflammation induced by general stimuli, such as EP, the peptides act prior to the release of these mediators of the inflammatory response. Because of the anticytokine/anti-inflammatory actions of the alpha-MSH molecules they may be useful in understanding the cytokine network and for treatment of inflammatory diseases.

Animals↗
PubMed2006

Effects of gastrointestinal inflammation on enteroendocrine cells and enteric neural reflex circuits.

Inflammation of the gastrointestinal (GI) tract has pronounced effects on GI function. Many of the functions of the GI tract are subject to neural regulation by the enteric nervous system (ENS) and its extrinsic connections. Therefore, it is possible that inflammatory effects on the ENS contribute to altered function during GI inflammation. The reflex circuitry of the ENS is comprised of sensory transducers in the mucosa (enteroendocrine cells), afferent neurons, interneurons and motor neurons. This review focuses on recent data that describe inflammation-induced changes to the ENS and mucosal enteroendocrine cells. Studies of tissues from patients with inflammatory bowel disease (IBD) and from animal models of IBD have demonstrated marked changes in mucosal enteroendocrine cell signaling. These changes, which have been studied most intensely in 5-HT-containing enterochromaffin cells, involve changes in the number of cells, their signaling molecule content or their means of signal termination. Morphological evidence of enteric neuropathy during inflammation has been obtained from human samples and animal models of IBD. The neuropathy can reduce the number of enteric neurons in the inflamed region and is often accompanied by a change in the neurochemical coding of enteric neurons, both in the inflamed region and at distant sites. Electrophysiological recordings have been made from enteric neurons in inflamed regions of the colon of animal models of IBD. These studies have consistently found that inflammation increases excitability of intrinsic primary afferent neurons and alters synaptic transmission to interneurons and motor neurons. These data set the stage for a comprehensive examination of the role of altered neuronal and enteroendocrine cell signaling in symptom generation during GI inflammation.

Animals↗
PubMed2004

Markers of inflammation in patients with coronary artery disease are also associated with glycosylated haemoglobin A1c within the normal range.

AIMS: Diabetes is a risk factor for atherosclerosis and low-degree inflammation may play a central role in both diseases. Glycosylated haemoglobin A(1c) (HbA(1c)) is an established measure of long-term glycaemic control but data on its correlation with markers of inflammation are limited, especially in patients with atherosclerotic manifestations. The aim of the present study was thus to investigate the associations between HbA(1c) and a panel of inflammation-sensitive parameters in patients with and without diabetes. METHODS AND RESULTS: This single centre cross-sectional study comprised 314 consecutive subjects who underwent coronary angioplasty for stable coronary artery disease. Sixty-six patients had diabetes mellitus. Haemoglobin A(1c) and markers of inflammation, i.e., plasma levels of CRP, fibrinogen, and albumin, erythrocyte sedimentation rate and white blood cell count were measured. All inflammation markers were altered in a more inflammatory direction in diabetic patients. Furthermore, when non-diabetic patients with HbA(1c) levels within the normal range were studied separately, all inflammation-sensitive parameters except albumin correlated significantly with HbA(1c). CONCLUSION: In subjects with known coronary atherosclerosis, low-degree inflammatory activity is not only increased in diabetic patients, but also increased with increasing HbA(1c) in non-diabetic individuals with HbA(1c) within the normal range, i.e., at a pre-diabetic level of glucose metabolism derangement.

Aged↗
PubMed2004

ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry eye patients and Sjögrens syndrome-like MRL/lpr mice.

PURPOSE: We previously reported that immune-based inflammation occurs on the ocular surface of humans as well as canines with keratoconjunctivitis sicca (KCS). Intercellular adhesion molecule-1 (ICAM-1) was found to be upregulated on lymphocytes and/or vascular endothelial cells resulting in lymphocytic diapedesis to the lacrimal and conjunctival tissues. The purpose of the current study was to demonstrate the role of ICAM-1 in (1) resident epithelial cell response during ocular inflammation, (2) local and/or peripheral lymphocyte activation or accumulation in the ocular tissues, and (3) whether anti-ICAM-1 is effective to attenuate immune-mediated ocular inflammation. METHODS: ICAM-1 levels in various ocular tissues of human with KCS and/or MRL/lpr mouse were evaluated by immunohistochemistry and in situ hybridization for protein and messenger RNA (mRNA) expression, respectively. Soluble ICAM-1 concentrations in MRL/lpr mouse plasma over the course of disease development were measured by ELISA. Cell proliferation within ocular tissues was assessed by bromodeoxyuridine (BrdU) incorporation and immunohistochemical detection. The level of T cell activation was determined by IL-2 receptor (CD25, a marker of T cell activation and proliferation) and CD69 (a marker of T cell activation) immunoreactivity using FACS analysis. To examine the effectiveness of anti-ICAM-1/LFA-1 in elimination of lacrimal gland inflammation, MRL/lpr mice were injected intraperitoneally (i.p.) with or without monoclonal antibodies against ICAM-1 and LFA-1 at three or eight weeks of age. RESULTS: Increased endogenous ICAM-1 expression at the level of protein and mRNA was detected in the epithelial cells present in the conjunctival and accessory lacrimal tissues in dry eye patients. In MRL/lpr mice, ICAM-1 expression by lacrimal acinar epithelial cells and conjunctival epithelial cells were detected in addition to inflammatory infiltrates and vascular endothelial cells at 16 weeks of age. Soluble ICAM-1 levels were markedly increased concomitantly with disease progression over time as compared with the controls. No significant lymphocytic proliferation (a lack of BrdU and CD25 immunoreactivities) was detected within lacrimal glands of MRL/lpr mice at the disease onset. However, a population of the infiltrated T cells were CD69 positive, indicating the activation stage of a T cell subset. Treatment using monoclonal antibodies against murine ICAM-1 and LFA-1 resulted in a decrease in the number of inflammatory infiltrates in MRL/lpr mice. CONCLUSIONS: Our findings suggest that ICAM-1 upregulation locally and systemically promote lymphocyte activation and migration to the ocular surface (OS). Ocular resident epithelium is an active component of ocular surface and is capable of interacting with invasive lymphocytes by ICAM-1 production in response to immune activation and inflammation. ICAM-1 synthesized by epithelial cells may serve as a signaling molecule for predisposition of ocular surface inflammation and facilitate potential antigen presentation by epithelial cells. Lymphocytic infiltrates in the lacrimal gland of the MRL/lpr mouse appeared to be the result of the accumulation, but not proliferation of circulating lymphocytes diapodesed from the vasculature that had migrated into the local ocular tissues. The potential use of anti-ICAM-1 therapy in treating immune-based inflammatory diseases such as dry eye deserves further investigation.

Animals↗