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PubMed1987

Pathogenesis of trachoma: the stimulus for inflammation.

Active trachoma is characterized by chronic inflammation of the conjunctiva, and repeated episodes of reinfection are thought to be necessary to sustain this inflammation. It is currently believed that much of the tissue damage is immunologically mediated. To identify which antigens might be responsible for stimulating this continued inflammation, cynomolgus monkeys that had recovered from a previous ocular infection with Chlamydia trachomatis were challenged with various antigen preparations. Purified preparations of formalin- or UV-inactivated elementary bodies did not elicit any inflammation even with daily inoculation. In addition, neither purified chlamydial major outer membrane protein nor lipopolysaccharide, including recombinant organisms expressing the lipopolysaccharide group antigen, elicit inflammation. A soluble triton extract of the organism rapidly induced marked inflammation when inoculated in the eyes of immune monkeys but had no effect in naive animals. These studies suggest that the continual inflammation in trachoma may not be due to repeated exposure to chlamydial surface antigen(s) but rather to a labile product released by the living organisms.

Animals↗
PubMed1997

Inhibition of tumor necrosis factor-alpha action within the CNS markedly reduces the plasma adrenocorticotropin response to peripheral local inflammation in rats.

The present study tested the hypothesis that the cytokine tumor necrosis factor-alpha (TNF-alpha) is an important CNS mediator of the hypothalamo-pituitary-adrenal (HPA) axis response to local inflammation in the rat. Recombinant murine TNF-alpha administered directly into the cerebroventricles of normal rats produced a dose-dependent increase in plasma adrenocorticotropin (ACTH) concentration. Local inflammation induced by the intramuscular injection of turpentine (50 microl/100 gm body weight) also produced an increase in plasma ACTH, peaking at 160-200 pg/ml at 7.5 hr after injection (compared with 10-30 pg/ml in controls). Intracerebroventricular pretreatment with either 5 microl of anti-TNF-alpha antiserum or 1-50 microg of soluble TNF receptor construct (rhTNFR:Fc) reduced the peak of the ACTH response to local inflammation by 62-72%. In contrast, intravenous treatment with the same doses of anti-TNF-alpha or rhTNFR:Fc had no significant effect on the ACTH response to local inflammation. Although these data indicated an action of TNF-alpha specifically within the brain, no increase in brain TNF-alpha protein (measured by bioassay) or mRNA (assessed using either in situ hybridization histochemical or semi-quantitative RT-PCR procedures) was demonstrable during the onset or peak of HPA activation produced by local inflammation. Furthermore, increased passage of TNF-alpha from blood to brain seems unlikely, because inflammation did not affect plasma TNF-alpha biological activity. Collectively these data demonstrate that TNF-alpha action within the brain is critical to the elaboration of the HPA axis response to local inflammation in the rat, but they indicate that increases in cerebral TNF-alpha synthesis are not a necessary accompaniment.

Adrenocorticotropic Hormone↗
PubMed1997

Vaccination promotes TH1-like inflammation and survival in chronic Pseudomonas aeruginosa pneumonia. A new prophylactic principle.

The ongoing lung tissue damage in chronically Pseudomonas aeruginosa infected cystic fibrosis (CF) patients has been shown to be caused by elastase liberated from polymorphonuclear leukocytes (PMN), which dominate the chronic inflammation in these patients. Most CF patients, however, contract the chronic lung infection with P. aeruginosa after a one-year period (median) of intermittent colonization. Therefore, prevention of the onset of the chronic infection or prevention of the dominance of the inflammation by PMNs would be important goals for a vaccine strategy against P. aeruginosa in CF. In a rat model of acute P. aeruginosa pneumonia we studied whether it was possible to improve the initial bacterial clearance and diminish the inflammatory response by vaccination prior to challenge with free, live P. aeruginosa. The vaccines studied were PAO 579 sonicate, O-polysaccharide toxin A (TA) conjugate, depolymerized alginate (3064) TA conjugate (D-ALG TA), or P. aeruginosa alginate (6680 + 8839). The vaccines could, however, not improve the very efficient natural clearance of P. aeruginosa from the lungs of the rats. In a rat model of chronic P. aeruginosa lung infection we found that none of the vaccines could prevent chronic lung inflammation. After challenge, however, none of the rats immunized with D-ALG TA died in contrast to the other vaccine groups combined (p = 0.03). In addition, the inflammatory response changed from an acute type inflammation dominated by PMNs as in CF patients to a chronic type inflammation dominated by mononuclear leukocytes. This response was achieved within the first week after challenge in D-ALG TA immunized rats; in the controls, the inflammation was still acute 4 weeks after challenge. Rats immunized with D-ALG TA had a significantly reduced severity of the macroscopic lung inflammation compared to the other vaccination groups (p = 0.009). The same effect could be obtained by IFN-gamma treatment (p = 0.004). The chronic P. aeruginosa lung infection was established in two inbred mice strains C3H/HeN, known as TH1 responders, and Balb/c, known as TH2 responders. The mortality due to the infection was significantly lower in C3H/HeN mice compared to Balb/c mice (p < 0.0003). P. aerurinosa was cleared more efficiently by C3H/HeN mice and significantly more C3H/HeN mice showed normal lung histopathology than Balb/c mice (p < 0.025). Supernatants from Concanavalin A stimulated spleen cells from C3H/HeN mice contained three times higher IFN-gamma concentration but only half as high interleukin-4 concentration than those of Balb/c mice. These findings suggest that change from the TH2-like response seen in CF patients towards a TH1 response might improve their prognosis.

Animals↗
PubMed1997

Effects of ozone on normal and potentially sensitive human subjects. Part II: Airway inflammation and responsiveness to ozone in nonsmokers and smokers.

Exposure to ozone at levels near the National Ambient Air Quality Standard causes respiratory symptoms, changes in lung function, and airway inflammation. Although ozone-induced changes in lung function have been well characterized in healthy individuals, the relationship between airway inflammation and changes in pulmonary function have not been prospectively examined. The purpose of this study was to determine whether individuals who differ in, lung function responsiveness to ozone also differ in susceptibility to airway inflammation and injury. A secondary goal was to determine whether ozone exposure induces airway inflammation in smokers, a population known to have airway inflammation and an increased burden of toxic oxygen species. Healthy nonsmokers (n = 56) and smokers (n = 34) were exposed to 0.22 parts per million (ppm)* ozone for 4 hours, with intermittent exercise, for the purpose of selecting ozone "responders" (decrement in forced expiratory volume in 1 second [FEV1] > 15%) and "nonresponders" (decrement in FEV1 < 5%). Selected subjects then were exposed twice to ozone (0.22 ppm for 4 hours with exercise) and once to air (with the same exposure protocol), each pair of exposures separated by at least 3 weeks, in a randomized, double-blind fashion. Nasal lavage (NL) and bronchoalveolar lavage (BAL) were performed immediately after one ozone exposure and 18 hours after the other, and either immediately or 18 hours after the air exposure. Indicators of airway effects in lavage fluid included changes in inflammatory cells, proinflammatory cytokines, protein markers of epithelial injury and repair, and generation of toxic oxygen species. In the classification exposure, fewer smokers than nonsmokers were responsive to ozone (11.8% vs. 28.6%, respectively); an insufficient number of smoker-responders were identified to study as a separate group. In the BAL study, all groups developed a similar degree of airway inflammation, consisting of increases in interleukins 6 and 8 (maximal immediately after exposure), and increases in polymorphonuclear leukocytes (PMNs), lymphocytes, and mast cells (maximal 18 hours after exposure). The increase in PMNs was inversely correlated with age (p = 0.013), but gender, nonspecific airway responsiveness, and allergy history were not predictive of inflammation. Alveolar macrophage production of toxic oxygen species decreased after ozone exposure in nonsmokers; however, not in smokers. Findings from nasal lavage did not mirror lower airway inflammatory responses in these studies. We conclude that, in response to ozone exposure, smokers experienced smaller decrements in lung function and fewer symptoms than nonsmokers; however, the intensity of the airway inflammatory response was independent of smoking status or airway responsiveness to ozone. Furthermore, the burden of toxic oxygen species following ozone exposure was greater for smokers than for nonsmokers. Subjects were young, healthy, and able to sustain exercise; the results may not be representative of nonsmokers or smokers in general. Nevertheless, the findings indicate that measuring symptoms and spirometric changes is not sufficient to assess the potential risks associated with ozone exposure.

Adolescent↗
PubMed2003

Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68.

OBJECTIVE: Low-dose weekly methotrexate therapy remains a mainstay in the treatment of inflammatory arthritis. Results of previous studies demonstrated that adenosine, acting at one or more of its receptors, mediates the antiinflammatory effects of methotrexate in animal models of both acute and chronic inflammation. We therefore sought to establish which receptor(s) is involved in the modulation of acute inflammation by methotrexate and its nonpolyglutamated analog MX-68 (N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]-carbonyl]-L-homoglutamic acid). METHODS: We studied the effects of low-dose methotrexate (0.75 mg/kg intraperitoneally [IP] every week for 5 weeks), MX-68 (2 mg/kg IP 2 days and 1 hour before induction of inflammation), dexamethasone (1.5 mg/kg IP 1 hour before induction of inflammation), or vehicle control on acute inflammation in an air-pouch model in A(2A) and A(3) receptor knockout mice. RESULTS: Low-dose weekly methotrexate treatment increased the adenosine concentration in the exudates of all mice studied and reduced leukocyte and tumor necrosis factor alpha accumulation in the exudates of wild-type mice, but not in those of A(2A) or A(3) receptor knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was equally effective at suppressing leukocyte accumulation in A(2A) knockout, A(3) knockout, and wild-type mice, indicating that the lack of response was specific for methotrexate and MX-68. CONCLUSION: These findings confirm that adenosine, acting at A(2A) and A(3) receptors, is a potent regulator of inflammation. Moreover, these results provide strong evidence that adenosine, acting at either or both of these receptors, mediates the antiinflammatory effects of methotrexate and its analog MX-68.

2-Aminoadipic Acid↗
PubMed2003

Inflammation and angiogenesis in osteoarthritis.

OBJECTIVE: To quantify the relationship between inflammation and angiogenesis in synovial tissue from patients with osteoarthritis (OA). METHODS: Hematoxylin and eosin staining and histologic grading for inflammation were performed for 104 patients who met the American College of Rheumatology criteria for OA and had undergone total joint replacement or arthroscopy. A purposive sample of synovial specimens obtained from 70 patients was used for further analysis. Vascular endothelium, endothelial cell (EC) proliferating nuclei, macrophages, and vascular endothelial growth factor (VEGF) were detected by immunohistochemical analysis. Angiogenesis (EC proliferation, EC fractional area), macrophage fractional area, and VEGF immunoreactivity were measured using computer-assisted image analysis. Double immunofluorescence histochemical analysis was used to determine the cellular localization of VEGF. Radiographic scores for joint space narrowing and osteophyte formation in the knee were also assessed. RESULTS: Synovial tissue samples from 32 (31%) of 104 patients with OA showed severe inflammation; thickened intimal lining and associated lymphoid aggregates were often observed. The EC fractional area, EC proliferation, and VEGF immunoreactivity all increased with increasing histologic inflammation grade and increasing macrophage fractional area. In the synovial intimal lining, VEGF immunoreactivity was localized to macrophages and increased with increasing EC fractional area and angiogenesis. No inflammation or angiogenic indices were significantly correlated with radiographic scores. CONCLUSION: Inflammation and angiogenesis in the synovium are associated with OA. The angiogenic growth factor VEGF generated by the inflamed synovium may promote angiogenesis, thereby contributing to inflammation in OA.

Aged↗
PubMed2006

Alterations in behavior in adult offspring mice following maternal inflammation during pregnancy.

Maternal intrauterine inflammation during pregnancy poses a major threat of neurodevelopmental brain damage in offspring and may cause poor cognitive and perceptual outcomes. In mice, we have previously shown that maternal inflammation induced by lipopolysaccharide (LPS) at gestation day 17th increased the levels of the pro-inflammatory cytokine IL-6 in the fetal brain. In this study, we used the same system and examined the effect of short, systemic maternal inflammation on anxiety and social behavior of the offspring. Adult offspring from the maternal inflammation group showed increased anxiety, as indicated by the elevated plus maze. Social interaction among offspring from the test groups was examined when two unfamiliar mice from different litters were introduced into a new home-cage. Offspring from the maternal inflammation group showed reduced activity, indicating increased fear. In addition, offspring from the maternal inflammation group were less aggressive towards their cagemates and they spent a significantly longer time trimming the whiskers of their cagemates during the first 30 min of their interaction, compared to offspring from the control group. Our data suggest that short systemic maternal inflammation have long-lasting consequences on the adult mouse stress and social behavior.

Age Factors↗
PubMed1993

Mechanisms of acute and chronic intestinal inflammation induced by indomethacin.

The objective of this study was to characterize the mechanisms of acute and chronic intestinal mucosal injury and inflammation induced by subcutaneously injected indomethacin (Indo). One injection of Indo (7.5 mg/kg) produced acute injury and inflammation in the distal jejunum and proximal ileum that were maximal at three days and completely resolved within one week. Two daily subcutaneous injections of Indo produced a more extensive and chronic inflammation that lasted in an active form in more than 75% of the rats for at least two weeks. Epithelial injury, as measured by enhanced mucosal permeability, was significantly elevated only at one day in the acute model (one injection) but was persistently elevated in the chronic model (two injections). Bile duct ligation completely attenuated increased mucosal permeability in the acute model, however, depletion of circulating neutrophils had no effect. Neither Indo (0-0.1 mg/ml) nor normal bile was cytotoxic to cultured rat intestinal epithelial cells; however, they synergistically promoted significant cytotoxicity. Bile collected from rats treated with Indo was cytotoxic towards the epithelial cells in a dose-dependent manner. Sulfasalazine and metronidazole (100 mg/kg/day, both) attenuated enhanced mucosal permeability in the chronic model. Massive bacterial translocation into the mesenteric lymph nodes, liver, and spleen following two injections of Indo was significantly attenuated by metronidazole. We conclude that: (1) a single injection of Indo produces acute intestinal mucosal injury and inflammation that resolve completely within three to seven days, whereas two daily injections of Indo produce both acute and chronic injury and inflammation, (2) enterohepatic circulation of Indo is important in promoting the acute phases of injury and inflammation, (3) circulating neutrophils do not play a role in the pathogenesis of this model, and (4) endogenous bacteria play an important role in exacerbating and/or perpetuating the chronic phases of injury and inflammation.

Acute Disease↗
PubMed1995

Anal canal inflammation after ileal pouch-anal anastomosis. The need for treatment.

UNLABELLED: One technique used during restorative proctocolectomy to prevent loss of continence involves preservation of the anal canal. This technique retains a small amount of colonic mucosa and transitional mucosa that may become inflamed or develop dysplastic or neoplastic changes. PURPOSE: This study was designed to determine the presence and severity of anal canal inflammation and the need for treatment. METHOD: Records of 217 patients with mucosal ulcerative colitis who underwent restorative proctocolectomy with a stapled ileal pouch-anal anastomosis without anal mucosectomy from 1987 through 1990 were retrospectively reviewed. RESULTS: Anal canal inflammation was evident on both endoscopy and biopsy in 48 patients (22.11 percent); 18 patients (8.29 percent) had a normal ileal pouch (9 had symptoms; 5 required topical treatment), and 30 patients (13.82 percent) had associated ileal pouch inflammation (23 with symptoms requiring systemic treatment because of pouchitis; 10 patients had concomitant topical treatment). CONCLUSION: Symptomatic inflammation of the retained mucosa occurred in 32 (14.7 percent) patients. Nine (4.1 percent) patients had inflammation of the anal canal alone, and 23 (10.6 percent) had pouchitis in addition. The need for treatment occurred in 28 (12.9 percent) of the total ((2.3 percent) patients with anal canal inflammation and 23 (10.6 percent) with anal canal inflammation plus pouchitis).

Administration, Rectal↗
PubMed2005

Serologic responses in indeterminate colitis patients before ileal pouch-anal anastomosis may determine those at risk for continuous pouch inflammation.

PURPOSE: Although acute pouchitis after ileal pouch-anal anastomosis is common and easily treated, continuous pouch inflammation seen clinically as chronic, antibiotic-dependent pouchitis, and/or Crohn's disease remains a difficult management problem. Compared with ulcerative colitis, indeterminate colitis patients undergoing ileal pouch-anal anastomosis have a higher incidence of continuous pouch inflammation, which may represent persistent immune reactivity to microbial antigens. Antibody responses to three microbial antigens (oligomannan anti-Saccharomyces cerevisiae, outer membrane porin C of Escherichia coli, and an antigen (I2) from Pseudomonas flourescens) are more commonly seen in Crohn's disease, whereas antibodies to a cross-reactive antigen (perinuclear antineutrophil cytoplasmic antibodies) is more suggestive of ulcerative colitis. We examined whether preoperative serologic responses to these antigens were associated with Crohn's disease in indeterminate colitis patients after ileal pouch-anal anastomosis. METHODS: Twenty-eight indeterminate colitis patients undergoing ileal pouch-anal anastomosis were prospectively assessed for the development of pouchitis or Crohn's disease. Serologic responses were determined by enzyme-linked immunosorbent assay and immunofluorescence. Patients were classified based on four predominant profiles of antibody expression. Antibody profiles were determined before knowledge of clinical outcome. RESULTS: Median follow-up was 38 (range, 3-75) months. Of 16 patients (61 percent) who developed pouch inflammation, 4 (25 percent) had acute pouchitis and 12 (75 percent) had continuous pouch inflammation (9 had chronic pouchitis, 3 had Crohn's disease). No preoperative clinical factor predicted the development of these pouch complications. Overall, 16 patients (57 percent) had a positive antibody reactivity profile. Serologic expression of any marker alone did not predict the development of continuous pouch inflammation. However, continuous pouch inflammation developed in 10 of 16 patients (63 percent) who had a positive antibody reactivity profile compared with only 2 of 12 patients (17 percent) who had a negative antibody reactivity profile (P = 0.015). CONCLUSIONS: Indeterminate colitis patients who have a positive antibody reactivity profile before ileal pouch-anal anastomosis have a significantly higher incidence of continuous pouch inflammation after surgery than those with a negative profile.

Adolescent↗
PubMed2007

The murine bronchopulmonary microcirculation in hapten-induced inflammation.

OBJECTIVE: The clinical observation of central bronchial artery hypertrophy in chronic lung inflammation suggests the possibility that the bronchial circulation may also participate in adaptive responses in peripheral lung inflammation. METHODS: To investigate the potential role of the bronchial microcirculation in peripheral lung inflammation, we developed a murine model of lung inflammation using the intratracheal instillation of the peptide-hapten trinitrophenol in presensitized mice. RESULTS: Clinical parameters indicated a peak inflammatory response at 96 hours. Similarly, gross and microscopic evidence of inflammation was observed 96 hours after antigen instillation. Using a forced oscillation technique to probe peripheral lung mechanics at 96 hours, we detected no change in central airway resistance (P > .05), but a significant increase in peripheral tissue resistance (P < .05). The structure of the bronchial circulation was investigated by microsphere occlusion of the pulmonary circulation and corrosion casting of the bronchial circulation. SEM of the bronchial artery casts demonstrated (1) the presence of the peripheral bronchial circulation in mice, (2) interconnections of the two systems in the distal bronchial arteries and at the level of alveolar capillaries, and (3) functional evidence of increased bronchial perfusion of alveolar capillaries during mononuclear inflammation. CONCLUSION: These results suggest an important adaptive role of the bronchial circulation in pulmonary inflammation.

Animals↗
PubMed2006

Muscle inflammation induces a rapid increase in calcitonin gene-related peptide (CGRP) mRNA that temporally relates to CGRP immunoreactivity and nociceptive behavior.

Recent data support an important role for calcitonin gene-related peptide (CGRP) in deep tissue nociceptive processing. Using real-time reverse transcriptase polymerase chain reaction (RT-PCR), radioimmunoassay, immunohistochemistry and behavioral testing, we studied the early time course of CGRP mRNA and protein expression as well as nociceptive behavior following muscle inflammation. A rapid and significant increase in CGRP mRNA occurred in the mandibular division (V3) of the ipsilateral trigeminal ganglion at 30 minutes, 4 and 24 h after the injection of complete Freund's adjuvant as an inflammatory agent into rat masseter muscle. No change in mRNA occurred in the ipsilateral ophthalmic and maxillary divisions (V1/V2) or in the contralateral V3. The levels of immunoreactive calcitonin gene-related peptide (iCGRP) in the ipsilateral V3 significantly increased at 1, 4 and 24 h following muscle inflammation. In contrast, no change occurred in iCGRP levels in either the ipsilateral V1/V2 or contralateral V3. When saline was injected into the masseter muscle, the levels of mRNA or iCGRP did not change in the ipsilateral V3 suggesting that the biochemical changes are specific to CFA-induced muscle inflammation. The number of muscle afferent neurons immunoreactive for CGRP was significantly reduced compared with control at 1, 4 and 24 h in the ipsilateral but not in the contralateral trigeminal ganglion following inflammation. This decrease in the ipsilateral ganglion may indicate a loss of intrasomatic CGRP as a result of increased axonal transport away from the neuronal cell body and/or release of CGRP. Behavioral testing showed a reduction in head withdrawal thresholds bilaterally from 30 min through 24 h following muscle inflammation. Thus upregulation of CGRP mRNA and iCGRP levels are temporally related to the development of inflammation and lowered pain thresholds. The present data support the hypothesis that CGRP is upregulated during deep tissue inflammation and suggest that gene transcription is involved in this upregulation.

Animals↗
PubMed2005

Transcutaneous electrical nerve stimulation (TENS) reduces chronic hyperalgesia induced by muscle inflammation.

Transcutaneous electrical nerve stimulation (TENS) reduces pain through central mechanisms involving spinal cord and brainstem sites. Since TENS acts through central mechanisms, we hypothesized that TENS will reduce chronic bilateral hyperalgesia produced by unilateral inflammation when applied either ipsilateral or contralateral to the site of muscle inflammation. Sprague-Dawley rats were injected with carrageenan in the left gastrocnemius muscle belly. Mechanical withdrawal threshold was tested bilaterally before and 2 weeks after carrageenan injection. After testing withdrawal thresholds at 2 weeks, rats received TENS treatment either ipsilateral or contralateral to the site of inflammation. In each of these groups, rats were randomized to control (no TENS), low frequency (4 Hz), or high frequency (100 Hz) TENS treatment. TENS was applied for 20 min at sensory intensity under light halothane anesthesia. Mechanical withdrawal thresholds were re-assessed after TENS or 'no TENS' treatment. Unilateral injection of carrageenan to the gastrocnemius muscle significantly reduced the mechanical withdrawal threshold (mechanical hyperalgesia) bilaterally 2 weeks later. Either low or high frequency TENS applied to the gastrocnemius muscle ipsilateral to the site of inflammation significantly reversed mechanical hyperalgesia, both ipsilateral and contralateral to the site of inflammation. Low or high frequency TENS applied to the gastrocnemius muscle contralateral to the site of inflammation also significantly reduced mechanical hyperalgesia, both ipsilateral and contralateral to the site of inflammation. Since ipsilateral or contralateral TENS treatments were effective in reducing chronic bilateral hyperalgesia in this animal model, we suggest that TENS act through modulating descending influences from supraspinal sites such as rostral ventromedial medulla (RVM).

Animals↗
PubMed2005

Role of inflammation in cardiopulmonary health effects of PM.

The relationship between increased exposure to PM and adverse cardiovascular effects is well documented in epidemiological studies. Inflammation in the lungs, caused by deposited particles, can be seen as a key process that could mediate adverse effects on the cardiovascular system. There are at least three potential pathways that could lead from pulmonary inflammation to adverse cardiovascular effects. Firstly, inflammation in the lung could lead to systemic inflammation, which is well known to be linked to sudden death from cardiovascular causes. Systemic inflammation can lead to destabilization by activation of inflammatory processes in atheromatous plaques. Secondly, inflammation can cause an imbalance in coagulation factors that favor propagation of thrombi if thrombosis is initiated. Thirdly, inflammation could affect the autonomic nervous system activity in ways that could lead to alterations in the control of heart rhythm which could culminate in fatal dysrhythmia.

Air Pollutants↗
PubMed1999

Neurochemical evidence for inflammation-induced activation of the coeruleospinal modulation system in the rat.

By using the microdialysis technique, the concentration of noradrenaline (NA) in the dorsal horn during unilateral hindpaw inflammation was compared between rats receiving bilateral lesions of the locus coeruleus (LC) and non-operated control rats. Bilateral lesions of the LC were made using an anodal current one week before testing. Unilateral hindpaw inflammation was produced by a subcutaneous injection of carrageenan (6 mg in 0.15 ml saline). Under conditions of sodium pentobarbital anesthesia, the microdialysis probe was inserted into the dorsal horn either ipsilateral or contralateral to the site of inflammation. The NA concentration in the dialysate was measured by high-performance liquid chromatography with electrochemical detection. Prior to carrageenan injection, the NA level (baseline level) did not differ between the LC-lesioned and the non-operated groups. After carrageenan injection, in the non-operated rats, the NA level increased significantly compared to the baseline level only in the dorsal horn ipsilateral to the site of inflammation, but not in the dorsal horn contralateral to the site of inflammation. An increase of the NA level was not observed in the LC-lesioned rats and in rats receiving an injection of saline. The result suggests that unilateral hindpaw inflammation produces excitation of descending NA-containing neurons from the LC, resulting in an increase of the NA level in the dorsal horn ipsilateral to the site of inflammation.

Animals↗
PubMed1994

Relationships between bladder inflammation and other clinical features in interstitial cystitis.

OBJECTIVES: Interstitial cystitis (IC) has been considered possibly to represent more than one disease process. If so, patients would be expected to form distinct subgroups. The degree of mononuclear inflammation on bladder biopsy can be objectively quantified and might be a useful parameter for subgroup division. The hypothesis of this study was that patients with mild versus severe inflammation would differ with regard to other clinical features of IC. METHODS: Sixteen patients who met the original National Institute of Diabetes, Digestive and Kidney Diseases criteria for IC underwent cystoscopy with bladder distention and biopsy. The degree of mononuclear inflammation on bladder biopsy was classified as mild, with less than 100 mononuclear cells/high power field (HPF), or severe (100 or more mononuclear cells/HPF or lymphoid aggregates). Associations were sought between degree of inflammation and other subjective and objective clinical features. RESULTS: Five patients had severe inflammation and 11 had mild inflammation. The major finding was that the patients with severe inflammation experienced better symptom relief after cystoscopy with bladder distention under anesthesia. This difference was highly significant (Fisher's exact test, p = 0.0014). For the other clinical features studied, these two groups did not differ significantly. CONCLUSIONS: Two distinct IC patient groups were identified by bladder biopsy findings. These two groups had significantly different treatment responses. If this difference is confirmed with a larger number of patients, it would suggest that these two patient groups may have different underlying disease processes.

Adult↗
PubMed1997

The role of nerve growth factor in a model of visceral inflammation.

There is growing evidence that nerve growth factor may be an important mediator of the sensory disorders associated with inflammation. This hypothesis was tested in a rat model of cystitis. In this model, an experimental inflammation is created in anaesthetized rats with an irritant chemical. Within 1 h, bladder reflexes, activated by the sensory innervation of this viscus, become exaggerated, mimicking the disorders seen in humans with chronic cystitis. The development of this hyper-reflexia following experimental inflammation was quantified using the technique of repeated cystometrograms. By several measures, bladder reflex excitability increased about three-fold after 5 h. Firstly, the study investigated whether inflammatory changes can be prevented by pharmacological antagonism of nerve growth factor. A synthetic fusion protein was used, consisting of the extracelluar domain of the high-affinity nerve growth factor receptor, trkA, coupled to the Fc portion of an immunoglobulin. Previous work has shown that this molecule can sequester nerve growth factor and reduce its bioavailability both in vitro and in vivo. Treatment of animals with the fusion molecule at 1 mg/kg, immediately before inflammation of the bladder, largely, and very significantly, prevented the expected increases in reflex excitability of this organ. Pretreatment with a related fusion protein, capable of sequestering the neurotrophin brain-derived neurotrophic factor and neurotrophin-4/5, but not nerve growth factor, was without effect. Similarly, a control fusion molecule, without neurotrophin-sequestering capacity, did not reduce the inflammation-induced hyper-reflexia. Systemic treatment with the nerve growth factor-sequestering molecule, but not control molecules, partially and significantly reversed established inflammatory changes, by about 30-60%, depending on outcome measure. The nerve growth factor-sequestering protein had no significant effects on bladder reflex excitability in the uninflamed state. It was also without significant effect on capsaicin-induced contractions of the urinary bladder. Administration of exogenous nerve growth factor into the lumen of the urinary bladders of normal anaesthetized rats produced a rapid and marked bladder hyper-reflexia similar to that seen with experimental inflammation. These findings are consistent with other circumstantial evidence that nerve growth factor may interact with visceral sensory systems. Together, the data strongly suggest that nerve growth factor produced in inflamed tissues is a critical mediator of the sensory disorders associated with inflammation.

Animals↗
PubMed1994

Inflammation of the abdominal aortic aneurysm wall.

Inflammation and fibrosis do not only appear in an "inflammatory" aneurysm, but also in "ordinary" abdominal aortic aneurysms. In this study inflammatory changes in 130 abdominal aortic aneurysms were studied and related to patients' clinical records. According to histopathological criteria five different degrees of inflammation (Histological Inflammation Scale of Aneurysms) were found and patients were classified according to these criteria: grade A or mixed acute/chronic inflammation (4.5%); grade 0 or no inflammation (16.2%); grade 1 or mild chronic (57.7%); grade 2 or moderate chronic (16.2%); and grade 3 or severe chronic inflammation (5.4%) corresponding to an "inflammatory" aneurysm. Patients with grade 3 or an "inflammatory" aneurysm were younger (p = 0.013), were all symptomatic (p = 0.02), showed no associated iliac or femoral aneurysms (p = 0.03), were only recognised peroperatively and had elevated erythrocyte sedimentation rates (p = 0.0002). No other differences could be demonstrated between sex, risk factors, cardiovascular diseases, previous abdominal operations, bacterial culture, aneurysm diameter, white blood count, cholesterol level in-hospital mortality when compared to the degree of inflammation.

Adolescent↗