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PubMed2000

Nitric oxide and intestinal inflammation.

Inflammation of the intestinal tract remains a very serious concern in the clinical setting. Unfortunately, to date, the mechanisms underlying many inflammatory conditions such as sepsis or inflammatory bowel diseases are poorly understood and our therapeutic interventions are less than ideal. Over the past decade, an abundance of research has been directed toward the role of nitric oxide (NO) in intestinal inflammation. It has become apparent that NO might have a dichotomous role as both a beneficial and detrimental molecule. Nitric oxide is a weak radical produced from L-arginine via the enzyme nitric oxide synthase (NOS). NOS exists in three distinct isoforms; constitutively (cNOS) expressed neuronal NOS (NOS1 or nNOS) and endothelial NOS (NOS3 or eNOS) or an inducible isoform (NOS2 or iNOS) capable of high production output of NO during inflammation. Constitutively expressed NOS has been shown to be critical to normal physiology and inhibition of these enzymes (nNOS or eNOS) caused damage. It has been proposed that the high output production of NO from iNOS causes injury, perhaps through the generation of potent radicals such as peroxynitrite and hence may explain the apparent dichotomous role of NO. However, recent studies have challenged this simple paradigm providing evidence that iNOS may have some protective role in some inflammatory models. Moreover, the importance of peroxynitrite has been questioned. In this review we discuss the role of cNOS and iNOS in intestinal inflammation and provide an overview of peroxynitrite in intestinal inflammation, highlighting some of the controversy that exists.

Antioxidants↗

PubMed2004

Interleukin-18 promotes joint inflammation and induces interleukin-1-driven cartilage destruction.

Interleukin (IL)-18 is a member of the IL-1 family of proteins that exerts proinflammatory effects and is a pivotal cytokine for the development of Th1 responses. The goal of the present study was to investigate whether IL-18 induces joint inflammation and joint destruction directly or via induction of other cytokines such as IL-1 and tumor necrosis factor (TNF). To this end we performed both in vitro and in vivo kinetic studies. For in vivo IL-18 exposure studies C57BL/6, TNF-deficient, and IL-1-deficient mice were injected intra-articularly with 1.10(7) pfu mIL-18 adenovirus followed by histopathological examination. Local overexpression of IL-18 resulted in pronounced joint inflammation and cartilage proteoglycan loss in control mice. Of high interest, IL-18 gene transfer in IL-1-deficient mice did not show cartilage damage, although joint inflammation was similar to that in wild-type animals. Overexpression of IL-18 in TNF-deficient mice showed that TNF was partly involved in IL-18-induced joint swelling and influx of inflammatory cells, but cartilage proteoglycan loss occurred independent of TNF. In vitro cartilage degradation by IL-18 was found after a 72-hour culture period. Blocking of IL-1 with IL-1Ra or an ICE-inhibitor resulted in complete protection against IL-18-mediated cartilage degradation. The present study demonstrated that IL-18 induces joint inflammation independently of IL-1. In addition, we showed that IL-1beta generation, because of IL-18 exposure, was essential for marked cartilage degradation both in vitro and in vivo. These findings implicate that IL-18, in contrast to TNF, contributes through separate pathways to joint inflammation and cartilage destruction.

Adenoviridae↗

PubMed2000

Preoperative evaluation to predict technical difficulties of laparoscopic cholecystectomy on the basis of histological inflammation findings on resected gallbladder.

BACKGROUND: No papers have heretofore documented histological studies of cases involving the inflammation of resected gallbladder or examined surgical difficulties on the basis of pathological findings. METHODS: On the basis of the histological inflammation findings on the resected gallbladders of 437 patients who underwent laparoscopic cholecystectomy (LC), the factors affecting the technical difficulty of the operation were examined through preoperative clinical findings (13 items), diagnostic imaging (22 items), and blood test findings (6 items), using multivariate analysis. RESULTS: In accordance with the four-stage classification of inflammation findings for the resected gallbladder, the inflammation findings on the resected gallbladder indicated a higher correlation with the time required for gallbladder dissection (30.2 +/- 16.3 minutes) than with the operation time (77.6 +/- 32.7 minutes). Thus, the technical difficulty of the operation was judged according to the time required for gallbladder dissection. For the preoperative findings on 418 patients who underwent successful LC, the most influential factors on the time required for gallbladder dissection were the presence of abnormal findings on computed tomography, the degree of fever, obesity index, nonvisualized gallbladder cholangiography, and cystic duct length. According to the multiple regression equation of these five factors, the gallbladder dissection for the 19 patients who underwent conversion to open cholecystectomy (OC) due to extreme inflammation was calculated to require 61.9 +/- 12.3 minutes, and the patients who showed a gallbladder dissection time longer than 49.6 minutes were judged to have high technical difficulty predicted from the preoperative evaluation. In the preoperative evaluation, sensitivity was 79.6%, specificity was 97.6%, accuracy was 95.0%, positive predictive value was 85.0%, and negative predictive value was 96.6%. Next, each finding was scored on the basis of a multiple regression equation of five factors, and the technical difficulty of the operation was quantified using these scores. The score of the patients who underwent conversion to OC was 8.0 +/- 2.0, and the patients who showed a score higher than 6 were judged to have high technical difficulty. Almost the same results as in the aforementioned preoperative evaluation were obtained using these scores. CONCLUSION: The judgment using the scores was satisfactory in terms of the simplicity of evaluating the technical difficulties associated with each patient and the ease of obtaining information for each factor. The quantification of technical difficulty using the scores is useful for preoperative prediction of which patients will have difficulties in gallbladder dissection and the conversion to OC in LC. Our results suggest that the consideration of technical difficulties is important for conducting safe operations with avoiding intraoperative complications.

Adult↗

PubMed1996

Spinal NK1 receptors contribute to the increased excitability of the nociceptive flexor reflex during persistent peripheral inflammation.

Hyperalgesia is a characteristic of inflammation and is mediated, in part, by an increase in the excitability of spinal neurons. Although substance P does not appear to mediate fast synaptic events that underlie nociception in the spinal cord, it may contribute to the hyperalgesia and increased excitability of spinal neurons during inflammation induced by complete Freund's adjuvant. We examined the role of endogenous substance P in changes in the excitability of spinal neurons during adjuvant-induced, peripheral inflammation by determining the effect of a selective NK1 receptor antagonist (RP67580) on the nociceptive flexor reflex in adult rats. Experiments were conducted 2 or 3 days after injection of adjuvant. Animals exhibited moderate thermal hyperalgesia at this time. The flexor reflex was evoked by electrical stimulation of the sural nerve and was recorded in the ipsilateral hamstring muscles. The flexor reflex ipsilateral to the inflamed hindpaw was enhanced approximately two-fold compared to the flexor reflex evoked in untreated animals as determined by the number of potentials and the duration of the reflex. The enhanced reflex in adjuvant-treated animals was most likely due to an increase in the excitability of spinal interneurons because short-latency activity in the hamstring muscles did not differ between untreated animals and adjuvant-treated animals following electrical stimulation of the L5 dorsal root or the nerve innervating the muscle with a stimulus that was 1.3-1.5 times the threshold for excitation of A-fibers. Intrathecal administration of RP67580 (2.3 and 6.8 nmol) attenuated the flexor reflex evoked in adjuvant-treated animals, but had no effect in untreated animals. Intravenous or intraplantar injection of RP67580 (6.8 nmol) did not affect the flexor reflex in adjuvant-treated animals indicating a spinal action of the drug following intrathecal administration. RP68651, the enantiomer of RP67580, was without effect at doses up to 6.8 nmol, indicating that the effects of comparable doses of RP67580 were due to an action of the drug at NK1 receptors. However, intrathecal administration of 23 nmol of both drugs attenuated the reflex in adjuvant-treated and control animals indicating that effects of RP67580 at this dose were not mediated entirely by its action at NK1 receptors. Overall, these data suggest that endogenous substance P has a role in the increased excitability of spinal interneurons observed during persistent inflammation and support the hypothesis that substance P released in the spinal cord contributes to the hyperalgesia that accompanies adjuvant-induced persistent, peripheral inflammation.

Afferent Pathways↗

PubMed1989

Treatment with 16,16'-dimethyl prostaglandin E2 before and after induction of colitis with trinitrobenzenesulfonic acid in rats decreases inflammation.

Colitis was induced in rats by intrarectal administration of trinitrobenzene sulfonic acid (80 mg/kg, in 30% ethanol). An acute inflammation with ulcers and neutrophil infiltration developed that evolved into a chronic inflammation and luminal narrowing with attendant smooth muscle hypertrophy. We assessed the effects of 16,16-dimethyl prostaglandin E2, administered either before or after trinitrobenzene sulfonic acid, on the development of inflammation. Inflammation was assessed by gross appearance using a grading scale (0-4) and by histology. The number of neutrophils present in inflamed colonic tissue was quantitated by the myeloperoxidase assay. The production of lipoxygenase products was monitored by incubation of colonic specimens with [14C]arachidonic acid and separation of the products by thin-layer chromatography and high-pressure liquid chromatography. Levels of leukotriene B4 were measured in tissue extracts by high-pressure liquid chromatography and ultraviolet absorbance. Eicosanoid production was also assayed by incubating colonic specimens and assaying the media for prostaglandin E2, leukotriene B4, and leukotriene C4 by radioimmunoassay. Trinitrobenzene sulfonic acid treatment resulted in a greatly increased amount of leukotriene B4 in the media. Treatment with 16,16-dimethyl prostaglandin E2 before administration of trinitrobenzene sulfonic acid resulted in a lower inflammation index, lower myeloperoxidase activity, and decreased production of leukotriene B4. Administration of 16,16-dimethyl prostaglandin E2 24 h after administration of trinitrobenzene sulfonic acid was also effective in reducing the inflammatory response. Treatment with 16,16-dimethyl prostaglandin E2 also prevented the development of long-term architectural changes 3 wk after administration of trinitrobenzene sulfonic acid. Rectal administration of dimethyl prostaglandin E2 also diminished the colitis induced by direct injection of trinitrobenzene sulfonic acid into the colonic wall.

16,16-Dimethylprostaglandin E2↗

PubMed1982

Full crown restorations and gingival inflammation in a controlled population.

The volume of crevicular fluid around full crown restorations was measured with a Periotron instrument to compare the gingival inflammation between restored and nonrestored teeth in the same patient. Thirty-eight full crown restorations were compared to nonrestored teeth used as controls in 26 patients. Forty-six full crown restorations in 28 patients were also evaluated according to gingival margin placement to determine if there was a difference in inflammation in gingival tissues. The highly motivated patients were selected from a private practice because of their interest and investment in long-term dental health. The results revealed the following findings. 1. Full crown restorations have the potential for causing gingival inflammation. However, they need not be associated with a significant increase in gingival inflammation when placed in the oral environment of a highly motivated patient in a rigid dental recall program. 2. Gingival inflammation surrounding full crown restorations may be controlled regardless of gingival margin placement when the gingiva is healthy, the restorations are adequate, and the patient is in a strict recall program.

Adult↗

PubMed2000

Elevated serum leptin concentrations induced by experimental acute inflammation.

Leptin is a pleiotropic hormone that regulates body weight and energy expenditure. Recent findings suggest that leptin may be involved in acute and/or chronic inflammation, however only limited results are available describing the effects of in vivo models of acute inflammation on leptin secretion. The aim of this study was to evaluate serum leptin levels in response to two well-established models of acute inflammation in rats: carrageenan rat paw induced oedema and carrageenan induced pleurisy. Our results clearly show that leptin levels rise in rats in which both oedema and pleurisy were induced. Serum leptin levels in carrageenan induced paw oedema were 3.86+/-0.16 microg/L in comparison to 1.83+/-0.17 microg/L of control animals (p<0.001). A similar result was observed in carrageenan induced pleurisy animals in which leptin levels were 4.87+/-0.27 microg/L in comparison to 2.19+/-0.16 microg/L of control animals (p<0.001). The increase in leptin levels induced following carrageenan-induced pleurisy appears to be dependent on adrenal function and it is markedly blunted in adrenalectomized rats. Leptin levels in carrageenan induced pleurisy, carried out on adrenalectomized rats, were lower than intact inflamed animals, suggesting a possible involvement of endogenous glucocorticoids. In summary the results here presented show that: a) an elevated plasma leptin concentration was induced during experimental models of inflammation b) this increase is mediated to a large extent by glucocorticoids. In conclusion, acute experimental models of inflammation are associated with changes in circulating leptin suggesting a possible involvement of this hormone in the anorexia/cachexia that is frequently associated with inflammatory processes. Furthermore, our data indicate the existence of a feedback loop among glucocorticoids and leptin which might contribute to the immune response to lace the inflammatory process.

Acute Disease↗

PubMed1997

The non-peptide NK-1 receptor antagonist LY303870 inhibits neurogenic dural inflammation in guinea pigs.

LY303870 is a competitive, high affinity NK-1 receptor antagonist. It was tested in the trigeminal stimulation-induced neurogenic dural inflammation model of migraine. The neurogenic inflammation theory of migraine pain proposes that substance P, acting through NK-1 receptors, causes dural inflammation which enhances migraine pain. LY303870 administration potently inhibited neurogenic dural inflammation as measured by plasma protein extravasation caused by electrical stimulation of the trigeminal ganglion in guinea pigs. It was active in this model when administered via intravenous, oral or inhalation routes. LY306155, the enantiomer of LY303870 with lower affinity for the NK-1 receptor, was much less potent than LY303870 in this model. LY303870, at oral doses of 1, 10 and 100 microg/kg, produced a long, dose-dependent inhibition of dural inflammation, demonstrating a suitable duration of action for a potential use in acute migraine and migraine prophylaxis.

Animals↗

PubMed2001

Obesity and preeclampsia: the potential role of inflammation.

OBJECTIVE: Systemic inflammation might contribute to the pathogenesis of preeclampsia. In addition, the association between obesity and inflammation in preeclampsia has not been examined in detail. We determined whether first-trimester elevation of serum C-reactive protein, an index of systemic inflammation, was associated with preeclampsia. METHODS: We conducted a prospective, nested case-control study among women enrolled in the Massachusetts General Hospital Obstetrical Maternal Study cohort. High-resolution C-reactive protein assays were performed on first-trimester (11 +/- 2 weeks' gestation) serum samples in 40 women in whom preeclampsia developed (blood pressure [BP] greater than 140/90 mmHg, and proteinuria, either 2+ or more by dipstick or greater than 300 mg per 24 hours), and in 80 matched controls. This sample size had greater than 80% power to detect a difference in C-reactive protein levels between cases and controls. We used nonparametric tests to compare C-reactive protein levels and conditional logistic regression to control for confounding variables. RESULTS: First-trimester C-reactive protein levels were significantly higher among women in whom preeclampsia subsequently developed compared with controls (4.6 compared with 2.3 mg/L, P =.04). When women were subdivided into C-reactive protein quartiles, the odds ratio (OR) of being in the highest quartile of C-reactive protein was 3.2 (95% confidence interval [CI] 1.1, 9.3, P =.02) among cases of preeclampsia compared with controls. When body mass index (BMI) was added to the multivariable model, the highest quartile of C-reactive protein was no longer associated with increased risk of preeclampsia (OR 1.1, 95% CI.3, 4.3, P =.94). In the same model without BMI, the highest quartile of C-reactive protein was associated with increased risk of preeclampsia (OR 3.5, 95% CI 1.3, 9.5, P =.01). CONCLUSION: In women with preeclampsia, there was evidence of increased systemic inflammation in the first trimester. Inflammation might be part of a causal pathway through which obesity predisposes to preeclampsia.

Adult↗

PubMed1995

Minimal persistent inflammation is present at mucosal level in patients with asymptomatic rhinitis and mite allergy.

The natural exposure to house dust mites causes sensitization in genetically susceptible patients. Persistent exposure of sensitized patients causes chronic inflammation, and consequently, hyperreactivity, thus promoting the development of clinical features. Recently, intercellular adhesion molecule-1 (ICAM-1)/CD54 expression on epithelial cells triggered by allergen has been demonstrated and related to the inflammation caused by the allergic reaction. Therefore we evaluated the possible presence of inflammation (i.e., inflammatory cell infiltrate and ICAM-1/CD54 expression on epithelium) at conjunctival and nasal levels in patients with asymptomatic allergic rhinitis caused by mites, in their relatives living in the same environment, and in healthy volunteers. In addition, the possible relationship between inflammation and house dust mite allergen exposure was evaluated. Conjunctival and nasal scrapings of allergic subjects enrolled in the study showed many inflammatory cells. A mild ICAM-1/CD54 expression on conjunctival and nasal epithelium was detectable in allergic subjects, whereas relatives and healthy volunteers showed few inflammatory cells and no ICAM-1/CD54 expression on epithelial cells. A detectable level of house dust mite, sufficient to cause sensitization, was found in all houses. This study demonstrates a minimal persistent inflammation at conjunctival and nasal levels constantly detectable in patients without symptoms who are sensitized to mites and continuously exposed to the natural allergens.

Adolescent↗

PubMed1987

Blood and protein loss via small-intestinal inflammation induced by non-steroidal anti-inflammatory drugs.

Nearly three-quarters of patients on long-term treatment with non-steroidal anti-inflammatory drugs (NSAIDs) have small-intestinal inflammation, the consequences of which are largely unknown. Two potentially important complications, blood and protein loss from the small intestine, have been studied. 49 patients on NSAIDs underwent study with an indium-111 labelled leucocyte technique which localises and measures intestinal inflammation. 32 patients underwent simultaneous study with technetium-99m labelled red blood cells (RBC), which showed identical sites of localisation to 111In-leucocytes in 19. Intestinal blood loss was measured in 8 patients by use of chromium-51 labelled RBC, and a significant correlation between blood loss and intestinal inflammation was found. Intestinal protein loss was assessed in 9 patients with 51Cr-labelled proteins; patients with NSAID-induced small-intestinal inflammation were found to have a protein-losing enteropathy. These studies show that small intestinal inflammation caused by NSAIDs is associated with blood and protein loss, both of which may contribute to the general ill-health of rheumatic patients.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1996

Pretreatment with topical diclofenac sodium to decrease postoperative inflammation.

PURPOSE: Anti-inflammatory medications are traditionally administered to the eye only postoperatively for control of inflammation. Because the presumed mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) is to inhibit the formation of prostaglandin mediators of inflammation, the author studied the effect that pretreatment with an NSAID had on postoperative inflammation. METHODS: In a prospective study, 60 patients scheduled for phacoemulsification with silicone lens implantation were randomly assigned to receive either (1) pretreatment with one drop of diclofenac sodium 0.1% four times per day for the 3 days before surgery plus one drop of diclofenac sodium 0.1% every 15 minutes for four doses, beginning 1 hour before surgery along with the dilating drops; (2) no pretreatment, but one drop of diclofenac sodium 0.1% every 15 minutes for four doses beginning 1 hour before surgery along with the dilating drops; or (3) no diclofenac sodium drops at all before surgery. No anti-inflammatory medications were given either during or immediately after surgery, and all patients were begun on a regimen of one drop of diclofenac sodium 0.1% to the operated eye four times per day after being examined on the first postoperative day. Postoperative inflammation was measured on the first postoperative day and at 1 week with a laser cell and flare meter. RESULTS: On the first postoperative day, the mean flare score for group A was 25.59 photons/millisecond; for group B, 29.69 photons/millisecond; and for group C, 33.07 photons/millisecond. The difference between groups A and C was statistically significant. The differences between groups A and B and between groups B and C were not statistically significant. There was no statistically significant difference for cell scores at 1 day or for cell or flare scores at 1 week. CONCLUSIONS: The pretreatment with an NSAID before cataract surgery can reduce the amount of initial postoperative inflammation.

Administration, Topical↗

PubMed1997

A novel procedure for mediastinal vagotomy inhibits neurogenic inflammation in rat bronchial tree.

Tachykinin-containing sensory axons originating from the cervical vagal nerves and the first several pairs of thoracic spinal nerves are involved in neurogenic inflammation evoked by capsaicin in the bronchial tree. Unilateral degeneration of the cervical vagal trunk by surgical lesion inhibits neurogenic inflammation in the ipsilateral bronchial airways. The vagal trunk has two main branches, the thoracic vagus nerve and recurrent laryngeal nerve in the thorax. The main purpose of this study was to determine whether the thoracic vagus nerve or recurrent laryngeal nerve was significantly involved in the neural control of bronchial inflammation in the rat. A novel and safe surgical procedure was used for selectively cutting the right thoracic vagal trunk, thoracic vagus nerve, or recurrent laryngeal nerve by introducing the surgical instrument through an aperture between the first and second ribs in the ventral wall of the rostral mediastinum. This surgical operation could be completed without causing a pneumothorax. After 2 postoperative weeks, the effects of denervation on capsaicin-induced plasma extravasation in the respiratory tract were tested. Either right thoracic vagal trunk transection or thoracic vagus section significantly decreased plasma extravasation in the right bronchial tree. Thoracic vagus section was obviously more effective. Evans blue extravasation in the right lobar bronchi was reduced by 44-78% after thoracic vagal trunk transection, while that in the right mainstem and lobar bronchi was reduced by 58-81% after thoracic vagus section. Area densities of India ink-labeled leaky blood vessels in the right lobar bronchi were reduced by 40-65% after thoracic vagal trunk transection, and those in the right mainstem and lobar bronchi were reduced by 83-88% after thoracic vagus neurectomy. Recurrent laryngeal neurectomy did not change the plasma extravasation induced by capsaicin in the trachea and bronchi. These results suggest that capsaicin-sensitive fibers running in the vagal trunk, which largely mediated neurogenic inflammation in the bronchial tree, were projected into the thoracic vagus nerve which, in turn, sent these nerve fibers to the ipsilateral bronchial tree. For the trachea, the remaining sensory fibers surviving denervation might provide sufficient tachykinins to trigger neurogenic inflammation.

Animals↗

PubMed1996

Differential effects of transforming growth factor-beta 1 on interleukin-1-induced cellular inflammation and vascular permeability in the rabbit retina.

Intra-vitreal injection of 300 U of interleukin (IL)-1 beta into the rabbit eye induces an inflammation of the retina characterized by hemorrhage, monocyte and neutrophil infiltration, and an increase in vascular permeability that peaks 24 h post-injection. Since the epiretinal vessels involved in this inflammation form part of the blood-retina barrier, we used this model to investigate the effects of the immunosuppressive cytokine TGF beta 1 on inflammation within the context of the central nervous system. We found that intra-vitreal injection of 1 microgram rh TGF beta administered concomitantly with rh IL-1 beta significantly reduced IL-1 beta-induced hemorrhage by 78%, and monocyte and neutrophil infiltration by 53% and 62%, respectively. In contrast, TGF beta did not reduce the IL-1 beta-induced increase in vascular permeability. However, TGF beta by itself caused a statistically significant increase in serum proteins in perfused tissues of the eye, to give a 3.1 +/- 0.4 fold increase in protein content over control values. No cellular inflammation accompanied this alteration in vascular permeability. These data indicate that whereas the local administration of TGF beta may be an effective inhibitor of cellular inflammation in the CNS, the effects on alterations in vascular permeability and accumulation of serum proteins may be more complex.

Animals↗

PubMed1996

Threshold effect of liver iron content on hepatic inflammation and fibrosis in hepatitis B and C.

BACKGROUND/AIMS: In hepatitis C, iron depletion may improve serum aminotransferases and the response to interferon, but it is not known whether inflammation and fibrosis correlate with hepatic iron content. Our aim was to establish whether hepatic iron content correlates with histological and serum indices of hepatic inflammation and fibrosis in hepatitis B and C. METHODS: Total hepatic iron was measured using computerized histomorphometry, and hepatic inflammation and fibrosis using a modified Knodell score, on histological slides from 31 patients with chronic hepatitis B and 38 with hepatitis C. RESULTS: Total hepatic iron was similar in the hepatitis B and C groups (0.82 +/- 1.72% and 0.56 +/- 1.12%; mean +/- SD). No iron was detectable in 11 patients with hepatitis B and 13 with hepatitis C. Alanine aminotransferase (85.96 +/- 67.1 vs 44.2 +/- 39.7 p < 0.05), aspartate aminotransferase (93.8 +/- 75.6 vs 47 +/- 33.5 IU/ml p < 0.05) and histological inflammatory score (9.33 +/- 3.51 vs 7.79 +/- 3.3 p = 0.07) were increased in those with stainable hepatic iron compared to those without. However, where iron was present, no association was found between the amount of hepatic iron and inflammatory or fibrosis scores. In hepatitis C, fibrosis was minimal in 77% of patients if iron was absent vs 24% with iron present, while marked fibrosis was present in 56% with iron vs 15% without iron (p < 0.01, Fisher's exact test). CONCLUSION: Hepatic iron is associated with increased hepatic inflammation in chronic hepatitis B and hepatitis C and with high fibrosis scores in hepatitis C. There is a threshold effect, and once present, increasing iron does not correlate with increasing inflammation or fibrosis.

Adolescent↗

PubMed2002

Enhancement of antigen-induced eosinophilic inflammation in the airways of mast-cell deficient mice by diesel exhaust particles.

The present study was conducted to clarify the involvement of mast cells in the exacerbating effect of diesel exhaust particles (DEP) toward allergic airway inflammation and airway hyperresponsiveness (AHR). Airway inflammation by the infiltration of cosinophils with goblet cell proliferation and AHR, as well as by the production of antigen-specific IgG1 and IgE, in plasma were examined using mast cell-deficient mice (W/W(v)) and normal mice (W/W(+)). Both groups of mice received ovalbumin (OVA) or OVA+DEP intratracheally. The eosinophilic airway inflammation and goblet cell proliferation promoted by OVA were significantly greater in W/W(+) than in W/W(v). A similar result was observed in AHR, but was not significant among both groups of mice. DEP enhanced OVA induced-allergic airway inflammation, goblet cell proliferation, and development of AHR in W/W(v), but not in W/W(+). DEP decreased production of antigen-specific IgG1 and IgE in both groups of mice. Mast cells were observed in the submucosal layer of the main bronchus in W/W(v). The number of mast cells was significantly decreased by OVA treatment. The results indicate that mast cells are not necessary to enhance airway damage and development of AHR in W/W(v) by DEP. However, mast cells may be required for the OVA-induced cosinophilic inflammation, airway damage with goblet cell proliferation, and AHR in W/W(+).

Animals↗

PubMed2000

The role of nitric oxide and prostaglandin signaling pathways in spinal nociceptive processing in chronic inflammation.

Both nitric oxide (NO) and prostaglandins (PG) and their associated enzymes nitric oxide synthases (NOS) and cyclooxygenases (COX) (specifically COX-2) have been implicated in the development of hyperalgesia. This study examined the effects of naturally occurring chronic inflammation, chronic mastitis, on spinal nociceptive processing in sheep and focused on potential alterations in spinal PG and NO signaling pathways. Mechanical withdrawal thresholds were significantly lower in animals suffering from chronic inflammation (n=6) compared to control animals (n=6). Hyperalgesia was restricted to the side contralateral to the inflammation (decrease from ipsilateral side: hindlimb 33.2+/-5%, forelimb 19.4+/-5%). Neuronal NOS-immunoreactivity was significantly reduced bilaterally in lumbar and cervical spinal cord throughout laminae I-III (decrease 18.4+/-5% and 16.9+/-4%, respectively) and in lamina X (decrease 29.1+/-6% and 17.1+/-4%, respectively) in mastitic animals relative to control animals. No difference was detected in eNOS or iNOS-immunoreactivity or in NADPH-diaphorase staining, a marker of dynamically active NOS. RT-PCR failed to detect any change in levels of nNOS, eNOS, iNOS, COX-1 or COX-2 mRNAs. However, a marked increase in the PGE receptor, EP(3) (but not EP(2)) mRNA was detected in ipsilateral spinal cord tissue from animals with chronic inflammation. This increase in EP(3) receptor expression indicates that spinal PGs are important in the spinal response to chronic peripheral inflammation. Contralateral mechanical hyperalgesia may not be directly linked to changes in spinal EP(3) receptor mRNA expression, however, the bilateral changes in nNOS suggest that this pathway may contribute to the adaptive behavioural response observed.

Animals↗

PubMed2002

Therapeutic administration of nitric oxide synthase inhibitors reverses hyperalgesia but not inflammation in a rat model of polyarthritis.

Nitric oxide (NO) has been postulated to play a role in pain as well as in inflammation. In the present studies, the effects of NO synthase (NOS) inhibitors on both pain and inflammation were examined in a rat model of polyarthritis. Female Lewis rats were injected intraperitoneally (i.p.) with peptidoglycan/polysaccharide (PG/PS) or saline to induce arthritis. Hind paw volume, response latency to thermal nociceptive stimulus and mechanical threshold were measured daily for the next 35 days. Paw inflammation, thermal hyperalgesia and mechanical allodynia developed in all rats that received PG/PS compared to saline. On day 19 (chronic inflammation phase), rats were given either N(G)-nitro-L-arginine methyl ester (L-NAME, non-selective NOS inhibitor, 100 mg/l), L-N (6)-(1-iminoethyl) lysine (L-NIL, selective inducible NOS inhibitor, 10 mg/l) or no drug in drinking water. By day 21, L-NAME treatment reversed the thermal hyperalgesia completely and this effect remained until day 35. Similarly, L-NIL treatment reversed thermal hyperalgesia from days 24 to 34. Neither treatment affected mechanical allodynia. Paw volume was not different between PG/PS treated and PG/PS plus L-NAME treated rats. However, the PG/PS plus L-NIL treatment produced an increase in paw volume greater than did PG/PS alone. Other rats were treated with PG/PS plus the antiinflammatory agent indomethacin (days 19-35). Indomethacin treatment reversed all the measured parameters, although the reversal of mechanical allodynia was only partial. These results suggest that NO is involved in thermal, but not mechanical sensory pathways and that the selective inhibition of inducible NOS activity exacerbates established inflammation.

Animals↗