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PubMed2007

Proteomic profiling of the amniotic fluid to detect inflammation, infection, and neonatal sepsis.

BACKGROUND: Proteomic analysis of amniotic fluid shows the presence of biomarkers characteristic of intrauterine inflammation. We sought to validate prospectively the clinical utility of one such proteomic profile, the Mass Restricted (MR) score. METHODS AND FINDINGS: We enrolled 169 consecutive women with singleton pregnancies admitted with preterm labor or preterm premature rupture of membranes. All women had a clinically indicated amniocentesis to rule out intra-amniotic infection. A proteomic fingerprint (MR score) was generated from fresh samples of amniotic fluid using surface-enhanced laser desorption ionization (SELDI) mass spectrometry. Presence or absence of the biomarkers of the MR score was interpreted in relationship to the amniocentesis-to-delivery interval, placental inflammation, and early-onset neonatal sepsis for all neonates admitted to the Newborn Special Care Unit (n = 104). Women with "severe" amniotic fluid inflammation (MR score of 3 or 4) had shorter amniocentesis-to-delivery intervals than women with "no" (MR score of 0) inflammation or even "minimal" (MR score of 1 or 2) inflammation (median [range] MR 3-4: 0.4 d [0.0-49.6 d] versus MR 1-2: 3.8 d [0.0-151.2 d] versus MR 0: 17.0 d [0.1-94.3 d], p < 0.001). Nonetheless, a "minimal" degree of inflammation was also associated with preterm birth regardless of membrane status. There was a significant association between the MR score and severity of histological chorioamnionitis (r = 0.599, p < 0.001). Furthermore, neonatal hematological indices and early-onset sepsis significantly correlated with the MR score even after adjusting for gestational age at birth (OR for MR 3-4: 3.3 [95% CI, 1.1 to 9.2], p = 0.03). When compared with other laboratory tests routinely used to diagnose amniotic fluid inflammation and infection, the MR score had the highest accuracy to detect inflammation (white blood cell count > 100 cells/mm3), whereas the combination of Gram stain and MR score was best for rapid prediction of intra-amniotic infection (positive amniotic fluid culture). CONCLUSIONS: High MR scores are associated with preterm delivery, histological chorioamnionitis, and early-onset neonatal sepsis. In this study, proteomic analysis of amniotic fluid was shown to be the most accurate test for diagnosis of intra-amniotic inflammation, whereas addition of the MR score to the Gram stain provides the best combination of tests to rapidly predict infection.

Adolescent↗
PubMed2005

Behavioural treatments for chronic systemic inflammation: effects of dietary weight loss and exercise training.

Persistent low-grade inflammation, as indicated by higher circulating levels of inflammatory mediators such as C-reactive protein, interleukin-6 and tumour necrosis factor-alpha, is a strong risk factor for several chronic diseases. There are data indicating that decreasing energy intake and increasing physical activity may be effective therapies for reducing overall inflammation. Evidence is strong that circulating levels of inflammatory markers are elevated with total and abdominal obesity, possibly owing to a higher secretion rate of cytokines by adipose tissue in obese people. Moreover, very-low-energy dietary weight loss reduces both circulating markers of inflammation and adipose-tissue cytokine production. Data from several large population-based cohorts show an inverse association between markers of systemic inflammation and physical activity or fitness status; small-scale intervention studies support that exercise training diminishes inflammation. Dietary weight loss plus exercise is likely more effective than weight reduction alone in reducing inflammation. To date, data from randomized, controlled trails designed to definitively test the effects of weight loss or exercise training, or both, on inflammation are limited. Future studies are required to define the amount of weight loss needed for clinically meaningful reductions of inflammation; in addition, fully powered and controlled studies are necessary to clarify the effect of exercise training on chronic, systemic inflammation.

C-Reactive Protein↗
PubMed2002

Is soft-tissue inflammation in pedal infection contained by fascial planes? MR analysis of compartmental involvement in 115 feet.

OBJECTIVE: The purpose of this study was to analyze compartmental involvement and patterns of spread of soft-tissue inflammation in pedal infection. MATERIALS AND METHODS: We reviewed 115 contrast-enhanced 1.5-T MR examinations of the foot in 41 women and 74 men with a mean age of 58.4 years who had undergone bone biopsy or surgery for suspected osteomyelitis. Presence of inflammation (contrast enhancement, fat signal intensity loss on T1-weighted images, and high signal intensity on T2-weighted images) was noted by two musculoskeletal radiologists in the following foot compartments: toes, medial, central, lateral, interosseous, dorsal, hindfoot, malleoli, and lower leg. Proximal and distal extension of soft-tissue inflammation was analyzed. The compartment closest to the ulcer that showed MR signs of direct contiguous infection was designated the primarily infected compartment. RESULTS: Spread of inflammation across fascial planes into neighboring compartments originated from the following primary compartments: medial (3/10, 30%), central (7/16, 44%), and lateral (16/20, 80%). Spread from the hindfoot and malleoli into adjacent compartments was seen in only 7% of such cases (2/24). Inflammation from toe infections spread in 34% of cases to forefoot compartments (15/44). Inflammation from forefoot or toe infections spread in 4.5% of cases to the midfoot and in 2% of cases to the hindfoot; ascension into the calf was rare (1% of cases). Spread of inflammation into neighboring compartments was not correlated with the presence of diabetes (p = 0.81) or with osteomyelitis (p = 0.34). CONCLUSION: Soft-tissue inflammation of the forefoot tends to spread into neighboring compartments, with little respect for fascial planes. Hindfoot inflammation tends to stay confined. Spread from the foot to the lower leg is rare.

Adult↗
PubMed1976

Experimental inflammation induced by naturally occurring microcrystalline calcium salts.

Inflammation caused by insoluble microcrystalline calcium salts was compared with inflammation elicited by soluble carrageenan and monosodium urate crystals, in rats' paws. Local and systemic responses to four calcium crystals, viz. pyrophosphate, triphosphate, oxalate, and tartrate were studied. Changes in liver function, reflected in reduced serum albumin and increased sleep times in response to barbiturates, indicative of systemic inflammation, occurred despite the localized nature of the crystal induced inflammation. Serum thiol levels were also reduced. These altered functions were similar to, but less pronounced than, those accompanying the severe systemic inflammation produced by Freund's adjuvant. A copper glycine complex was effective in reducing foot swelling due to triphosphate, and edema due to oxalate. Colchicine had very little effect on the inflammation caused by the insoluble calcium salts but inhibited inflammation due to sodium urats crystals and soluble carrageenan. Crystal-induced inflammation that is outwardly localized may induce biochemical changes that are similar to changes found in systemic inflammation.

Animals↗
PubMed2005

Inflammation and infection: imaging properties of 18F-FDG-labeled white blood cells versus 18F-FDG.

UNLABELLED: (18)F-FDG and (18)F-FDG-labeled white blood cells ((18)F-FDG-WBCs) are valuable radiopharmaceuticals for imaging focal sites of inflammation and infection. In the present study, the imaging properties of both radiotracers were compared in sterile and septic inflammation models. METHODS: Groups of adult male Sprague-Dawley rats (100-120 g) were injected in the left posterior thigh muscle with saline solution (group 1: controls, n = 15), 0.100 mL of turpentine oil (group 2: sterile inflammation, n = 26), 10(9) viable Escherichia coli bacteria (group 3: E. coli septic inflammation, n = 29), or 10(8) viable Pseudomonas aeruginosa bacteria (group 4: P. aeruginosa septic inflammation, n = 25). Twenty-four hours later, the animals were divided into 2 groups: One received (18)F-FDG intravenously and the other received human white blood cells (WBCs) labeled in vitro with (18)F-FDG injected intravenously. Biodistribution and microPET studies were performed 1 h after radiotracer injection. One hour after injection with cell-associated or free (18)F-FDG, phosphorimaging of abscess and contralateral muscle was performed in specimens collected from animals in groups 1, 2, and 3. The region of interest was selected within the abscess wall and values were converted to kBq/g using a (14)C calibration standard curve. Thin-layer radiochromatography (TLRC) was performed to study the chemical forms of (18)F within the WBCs. RESULTS: Whole-body biodistribution demonstrated a significantly higher uptake ratio of (18)F-FDG-WBCs compared with (18)F-FDG in all sterile and septic inflammation models (t test: sterile, P = 0.048; E. coli, P = 0.040; P. aeruginosa, P = 0.037). microPET imaging confirmed the greater performance of (18)F-FDG-WBCs versus (18)F-FDG in the sterile inflammation model and in both E. coli and P. aeruginosa septic models. Phosphorimaging analysis showed higher (18)F-FDG-WBC uptake than (18)F-FDG in the sterile inflammation and P. aeruginosa septic models and similar tissue uptake in the E. coli septic model. Time course labeling and TLRC of lysed WBCs demonstrated that (18)F-FDG was retained as (18)F-FDG-6-phosphate inside WBCs for at least 2 h, corresponding to the time frame of analysis. CONCLUSION: (18)F-FDG-WBCs gave better results compared with (18)F-FDG in all sterile and septic inflammation models. These data suggest that (18)F-FDG-WBC PET may be a useful technique for tracking focal inflammatory lesions in the body.

Animals↗
PubMed1986

Influence of chronic inflammation on the level of mRNA for acute-phase reactants in the mouse liver.

Systemic injuries provoke a coordinate change in the hepatic synthesis and circulating concentration of plasma proteins. To assess the effect of a transition from acute to chronic inflammation on the expression of the plasma protein genes, the qualitative and quantitative changes of liver mRNA were measured in males of the inbred strain C57BL/6 of Mus musculus during a 14-day period of inflammation. Inflammation was induced and maintained by repeated injections of the irritants, turpentine, lipopolysaccharides, and celite. At various times, total RNA was extracted from the liver. The concentration of specific mRNA was quantitated by cellfree translation and by blot hybridization with cDNA. The mRNA for the increased plasma proteins serum amyloid A, alpha 1-acid glycoprotein, haptoglobin, and alpha-fibrinogen showed essentially the same time course of changes. The concentrations were maximal 24 hr after initiation of inflammation and then declined gradually during the following days. During the progression from acute to chronic inflammation, there was a switch from a predominant expression of the gene for alpha 1-acid glycoprotein-1 to one of alpha 1-acid glycoprotein-2. The prolonged inflammation had an inverse effect on the two major negative acute-phase reactants, albumin and major urinary proteins. The concentration of albumin mRNA was reduced to 50% after 24 hr of inflammation but returned to the control level within 5 days. The mRNA for major urinary proteins, however, were lowered within 2 to 5 days of inflammation to 10 to 20% and were maintained at that level. These results suggest that different regulatory factors, humoral and/or cellular, are involved in controlling the expression of the genes for positive and negative acute-phase plasma proteins during acute and chronic inflammation.

Animals↗
PubMed2006

Fcgamma receptors directly mediate cartilage, but not bone, destruction in murine antigen-induced arthritis: uncoupling of cartilage damage from bone erosion and joint inflammation.

OBJECTIVE: To determine the relationship between synovial inflammation and the concomitant occurrence of cartilage and bone erosion during conditions of variable inflammation using various Fcgamma receptor knockout (FcgammaR(-/-)) mice. METHODS: Antigen-induced arthritis (AIA) was introduced in the knee joints of various FcgammaR(-/-) mice and wild-type controls. Joint inflammation and cartilage and bone destruction levels were determined by histologic analysis. Cathepsin K, RANKL, and osteoprotegerin (OPG) levels were detected by immunolocalization. RESULTS: In FcgammaRIIb(-/-) mice, which lack the inhibiting Fcgamma receptor IIb, levels of joint inflammation and cartilage and bone destruction were significantly higher (infiltrate 93%, exudate 200%, cartilage 100%, bone 156%). AIA in mice lacking activating FcgammaR types I, III, and IV, but not FcgammaRIIb (FcR gamma-chain(-/-) mice), prevented cartilage destruction completely. In contrast, levels of bone erosion and joint inflammation were comparable with their wild-type controls. Of great interest, in arthritic mice lacking activating FcgammaR types I, II, and III, but not IV (FcgammaRI/II/III(-/-) mice), levels of joint inflammation were highly elevated (infiltrate and exudate, 100% and 188%, respectively). Cartilage destruction levels were decreased by 92%, whereas bone erosion was increased by 200%. Cathepsin K, a crucial mediator of osteoclasts, showed a strong correlation with the amount of inflammation but not with the amount of activating FcgammaR, which was low in osteoclasts. RANKL, but not OPG, levels were higher in the inflammatory cells of arthritic knee joints of FcgammaRI/II/III(-/-) mice versus wild-type mice. CONCLUSION: Activating FcgammaR are crucial in mediating cartilage destruction independently of joint inflammation. In contrast, FcgammaR are not directly involved in bone erosion. Indirectly, FcgammaR drive bone destruction by regulating joint inflammation.

Animals↗
PubMed2002

Sunset glow fundus in Vogt-Koyanagi-Harada disease with or without chronic ocular inflammation.

BACKGROUND: Sunset glow fundus is considered an important ocular finding for diagnosing and understanding the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. In this study, we investigated the association between the incidence of chronic ocular inflammation in VKH disease and the appearance of sunset glow fundus. METHODS: The study was a retrospective noncomparative interventional case series. Eighty patients with VKH disease treated with high-dose corticosteroid therapy from initial onset were included in the study. We compared the incidence of sunset glow fundus between patients with VKH disease with chronic ocular inflammation lasting more than 6 months and those without chronic ocular inflammation. RESULTS: Chronic ocular inflammation was seen in 14 of 80 patients (17.5%). The presence of severe anterior uveitis were significantly more frequent in the chronic group. Forty-one patients (62%) without chronic ocular inflammation showed sunset glow fundus, while 13 patients (93%) with chronic ocular inflammation developed sunset glow fundus. Duration from disease onset to appearance of sunset glow fundus was significantly shorter in patients with than in patients without chronic inflammation. CONCLUSIONS: There is a significant association between the incidence of chronic ocular inflammation lasting more than 6 months and the appearance of sunset glow fundus. In addition, more severe disease at onset might be associated with chronic ocular inflammation in VKH disease.

Adult↗
PubMed2005

Serum surfactant protein D is increased in acute and chronic inflammation in mice.

Surfactant protein A (SP-A) and surfactant protein D (SP-D) are important components of innate immunity that can modify the inflammatory response. However, alterations and regulation of SP-A and SP-D in acute and chronic inflammation are not well defined. In addition, serum SP-D may serve as a biomarker of lung inflammation. We determined the expression of SP-A and SP-D in murine models. To study acute inflammation, we instilled bleomycin intrabronchially. To study chronic lung inflammation, we used a transgenic mouse that overexpresses tumor necrosis factor (TNF)-alpha under the control of the SP-C promoter. These mice have a chronic mononuclear cell infiltration, airspace enlargement, pulmonary hypertension, and focal pulmonary fibrosis. In acute inflammation model, levels of mRNA for all surfactant proteins were reduced after bleomycin administration. However, serum SP-D was increased from days 7 to 28 after instillation. In chronic inflammation model, SP-D mRNA expression was increased, whereas the expression of SP-A, SP-B and SP-C was reduced. Both serum and lung SP-D concentrations were increased in chronic lung inflammation. These data clarified profile of SP-A and SP-D in acute and chronic inflammation and indicated that serum SP-D can serve as a biomarker of lung inflammation in both acute and chronic lung injury in mice.

Acute Disease↗
PubMed2005

Neointimal inflammation and adventitial angiogenesis correlate with severity of cardiac allograft vasculopathy in pediatric recipients.

BACKGROUND: Chronic inflammation and angiogenesis have been implicated in the pathogenesis of both cardiac allograft vasculopathy (CAV) and age-related vasculopathy. Because concurrent atherosclerosis does not complicate assessment of CAV in children, we sought to characterize the spectrum of coronary lesions in this population and determine whether inflammatory infiltrates and angiogenesis correlate with severity of CAV. METHODS: In 18 pediatric heart specimens CAV was graded 1 to 4 (none to severe). Each case was assigned to either: Group I, no inflammation; Group II, perivascular inflammation; or Group III, perivascular and neointimal inflammation. Inflammatory infiltrates were immunophenotyped using anti-CD3, anti-CD20 and HAM 56. Angiogenesis was assessed by determining microvascular density (MVD) in 5 high-power fields (HPFs) per section. RESULTS: CAV was evident in 94% of cases, and inflammation in 61%. Cases with neointimal inflammation had significantly more severe CAV compared with cases without inflammation (2.7 +/- 0.16 vs 1.9 +/- 0.2, p = 0.002). MVD was significantly higher in both inflammation groups (Groups II and III) compared with Group I (4.1 +/- 0.5 per HPF and 5.9 +/- 0.5 vs 3.1 +/- 0.7, p = 0.018 and p = 0.002) and correlated with the degree of CAV (p = 0.007). The perivascular infiltrates (Group II, n = 5) contained lymphocytes, macrophages and plasma cells, and 67% of neointimal infiltrates (Group III, n = 6) also contained eosinophils. CONCLUSIONS: CAV in children is more common than previously reported. Our data indicate that CAV is often associated with inflammation and that adventitial angiogenesis correlated with the severity of CAV.

Adolescent↗
PubMed2006

Joint mobilization reduces hyperalgesia associated with chronic muscle and joint inflammation in rats.

UNLABELLED: Joint mobilization is a common treatment used by healthcare professions for management of a variety of painful conditions, including inflammatory joint and muscle pain. We hypothesized that joint mobilization would reduce the bilateral hyperalgesia induced by muscle and joint inflammation. Mechanical hyperalgesia was measured by examining the mechanical withdrawal threshold of the rat's paw before and after induction of inflammation with 3% carrageenan (gastrocnemius muscle) or 3% kaolin/carrageenan (knee joint), and for 1 hour after knee joint mobilization. The mobilization consisted of rhythmically flexing and extending the knee joint to the end of range of extension while the tibia was simultaneously moved in an anterior to posterior direction. A bilateral decrease in mechanical withdrawal thresholds occurred 1, 2, and 4 weeks after inflammation of the knee joint or muscle. In animals with muscle inflammation, mobilization of the knee joint increased the mechanical withdrawal threshold bilaterally when given 1, 2, or 4 weeks after inflammation. However, in animals with knee joint inflammation, mobilization of the knee joint at 4 weeks increased the mechanical withdrawal threshold but had no effect when administered 1 or 2 weeks after inflammation. Therefore, joint mobilization reduces hyperalgesia induced by chronic inflammation of muscle and joint. PERSPECTIVE: This article shows that unilateral joint mobilization reduces bilateral hyperalgesia induced by chronic muscle or joint inflammation. Understanding the pain conditions in which mobilization produces an analgesic effect should assist the clinician in selecting appropriate treatment techniques. The bilateral effect suggests that central mechanisms could mediate the analgesia.

Animals↗
PubMed2003

Effect of subclinical prostatic inflammation on serum PSA levels in men with clinically undetectable prostate cancer.

OBJECTIVES: To examine whether subclinical prostatic inflammation might influence serum prostate-specific antigen (PSA) levels in men with clinically undetectable prostate cancer. METHODS: A total of 461 patients who underwent prostate biopsy at our hospital were studied between January 1996 and December 1999. Of these patients, a total of 125 patients without detectable prostate cancer or a history or symptoms of prostatitis, with serum PSA levels of less than 20.0 ng/mL and other specified exclusion criteria, were included in the study. Inflammation observed at biopsy was scored for inflammation extent and inflammatory aggressiveness, and the effects of these morphologic aspects of inflammation on serum PSA levels were examined. RESULTS: The extent of inflammation tended to increase as the prostate volume increased (P = 0.006). Patients with a PSA greater than 2.5 ng/mL had a greater extent and aggressiveness of inflammation than those with PSA levels of 2.5 ng/mL or less (P = 0.004 and P = 0.050, respectively). However, no statistically significant differences were found in terms of the extent of inflammation or inflammatory aggressiveness between patients with PSA levels greater than 4.0 ng/mL and those with PSA levels of 4.0 ng/mL or less. Furthermore, the extent of inflammation did not account for PSA levels greater than 2.5 or 4.0 ng/mL by multivariate analysis. CONCLUSIONS: Our results indicate that subclinical prostatic inflammation is not the etiology of a serum PSA greater than 4.0 ng/mL in men without clinically detectable prostate cancer.

Adenocarcinoma↗
PubMed1999

High-grade inflammation in prostate cancer as a prognostic factor for biochemical recurrence after radical prostatectomy. Pathologist Multi Center Study Group.

OBJECTIVES: To assess the prognostic value of prostatic stromal inflammation in surgically treated localized prostate carcinoma for biochemical recurrence-free survival. METHODS: Stromal prostatic inflammation grading was studied in 161 patients who underwent radical prostatectomy for prostate cancer without involvement of the lymph nodes and who did not receive preoperative or postoperative radiotherapy or hormonal therapy until recurrence occurred. Inflammation was graded as high-grade inflammation if confluence of inflammatory cell infiltrate and/or glandular epithelium disruption associated with interstitial inflammatory infiltrate were present and as low-grade inflammation otherwise. Each specimen was graded separately first in the stroma surrounding nonmalignant glands and second in the stroma surrounding malignant glands. Biochemical recurrence based on serum prostate-specific antigen (PSA) level was defined as two successive PSA measurements greater than 1 ng/mL. RESULTS: Malignant tissue was significantly less involved in high-grade inflammation than benign adjacent tissue (9.3% and 19.9%, respectively; P <0.01). In a univariate Kaplan-Meier analysis, the 5-year recurrence-free survival rate for patients with high-grade and low-grade classified prostates was 61.0% and 66.7% in benign tissue and 27.0% and 65.3% in malignant tissue, respectively, with a significant difference between grades only in malignant tissue (P <0.02). In a multivariate analysis controlling for Gleason grade, preoperative serum PSA, pathologic stage, and inflammation grade in malignant tissue, the latter factor remained significantly predictive of biochemical recurrence (P = 0.03). CONCLUSIONS: Patients with high-grade inflammation surrounding malignant glands in radical prostatectomy specimens had significantly more postoperative biochemical recurrence than patients with low-grade inflammation.

Aged↗
PubMed1997

Differential roles of neurokinin 1 and neurokinin 2 receptors in the development and maintenance of heat hyperalgesia induced by acute inflammation.

1. Following induction of acute inflammation by intraarticular injection of kaolin and carrageenan into the knee joint in rats, there was a significant decrease in the withdrawal latency to radiant heat applied to the paw (i.e. heat hyperalgesia), an increased joint circumference and increased joint temperature. 2. A neurokinin1 (NK1) receptor antagonist (CP-99,994, 10 mM) had no effect on the paw withdrawal latency when it was administered spinally through a microdialysis fibre before the induction of inflammation. Pretreatment with a NK2 receptor antagonist (SR48968, 1 mM) administered spinally through the microdialysis fibre prevented the heat hyperalgesia from developing in the early stages of the inflammation. 3. Post-treatment through the microdialysis fibre with the NK1 receptor antagonist (0.01-10 mM) was effective in reversing the heat hyperalgesia. In contrast, post-treatment spinally with the NK2 receptor antagonist (0.01-1 mM) had no effect on the heat hyperalgesia. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 4. Pretreatment systemically with the NK1 receptor antagonist (30 mg kg-1) had no effect on the heat hyperalgesia or pain-related behaviour ratings where 0 is none and 5 is non weight bearing and complete avoidance of limb contact. Pretreatment with a NK2 receptor antagonist (10 mg kg-1) systemically prevented the heat hyperalgesia and pain-related behaviour ratings from developing in the early stages of the inflammation. The inactive stereoisomers of NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 5. Post-treatment systemically with either the NK1 (0.1-30 mg kg-1) or the NK2 (0.1-10 mg kg-1) receptor antagonist resulted in a dose-dependent reversal of the heat hyperalgesia. Pain-related behaviour ratings were reduced by post-treatment only with the NK1 receptor antagonist. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the behavioural responses. 6. Direct pretreatment of the knee joint with either the NK1 (30 mg) or the NK2 (10 mg) receptor antagonist prevented the heat hyperalgesia from developing without affecting joint swelling. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 7. There appears to be a differential role for the spinal tachykinin receptors in the development and maintenance of the heat hyperalgesia associated with acute joint inflammation. The NK2 receptors appear to be activated early in the development of the heat hyperalgesia and NK1 receptors are involved in the maintenance of the heat hyperalgesia. 8. Peripherally, both NK1 and NK2 receptors are involved in the development of heat hyperalgesia and pain-related behaviour ratings induced by acute inflammation.

Animals↗
PubMed2005

The involvement of nitric oxide in the enhanced expression of mu-opioid receptors during intestinal inflammation in mice.

Intestinal inflammation enhances the potency of mu-opioid receptor (MOR) agonists inhibiting gastrointestinal transit and increases the expression of MOR in mice intestine. The precise mechanisms implicated in the increased expression of MOR during intestinal inflammation are not known. The aim of the study is to evaluate if nitric oxide released during intestinal inflammation could modulate MOR gene expression and affect gastrointestinal transit. Intestinal inflammation was induced by the intragastric administration of croton oil. In CD-1 mice, with and without inflammation, we evaluated the anti-transit effects of morphine in animals treated with NOS inhibitors (L-NAME and L-NIL) and the intestinal levels of iNOS enzyme mRNA. The anti-transit effects of morphine and the expression of MOR mRNA in the gut of wild-type (WT) and iNOS-/- mice were also assessed. Gastrointestinal transit was measured with charcoal meal and mRNA levels determined by real-time PCR. In CD-1 mice, inflammation induced a 10-fold increase (P<0.0001) in iNOS mRNA levels in the gut. The absence of iNOS gene and treatment of CD-1 mice with L-NAME or L-NIL abolished the increased antitransit effects of morphine observed during inflammation. Moreover, although the basal levels of MOR mRNA were similar in WT and iNOS animals (-/-), intestinal inflammation only increased the MOR expression in the gut of WT (P<0.01) but not in iNOS-/- mice. The results suggest that nitric oxide derived from the increased expression of iNOS is implicated in the enhanced effects of morphine and in the upregulation of MOR gene transcription observed during intestinal inflammation.

Animals↗
PubMed2002

New insights into the relationship between airway inflammation and asthma.

Asthma is a condition characterized by variable airflow obstruction, airway hyper-responsiveness (AHR) and airway inflammation which is usually, but not invariably, eosinophilic. Current thoughts on the pathogenesis of asthma are focused on the idea that it is caused by an inappropriate response of the specific immune system to harmless antigens, particularly allergens such as cat dander and house dust mite, that result in Th2-mediated chronic inflammation. However, the relationship between inflammation and asthma is complex, with no good correlation between the severity of inflammation, at least as measured by the number of eosinophils, and the severity of asthma. In addition, there are a number of conditions, such as eosinophilic bronchitis and allergic rhinitis, in which there is a Th2-mediated inflammatory response, but no asthma, as measured by variable airflow obstruction or AHR. Bronchoconstriction can also occur without obvious airway inflammation, and neutrophilic inflammation can in some cases be associated with asthma. When we compared the immunopathology of eosinophilic bronchitis and asthma, the only difference we observed was that, in asthma, the airway smooth muscle (ASM) was infiltrated by mast cells, suggesting that airway obstruction and AHR are due to an ASM mast cell myositis. This observation emphasizes that the features that characterize asthma, as opposed to bronchitis, are due to abnormalities in smooth muscle responsiveness, which could be intrinsic or acquired, and that inflammation is only relevant in that it leads to these abnormalities. It also emphasizes the importance of micro-localization as an organizing principle in physiological responses to airway inflammation. Thus, if inflammation is localized to the epithelium and lamina propria, then the symptoms of bronchitis (cough and mucus hypersecretion) result, and it is only if the ASM is involved -- for reasons that remain to be established -- that asthma occurs.

Asthma↗
PubMed2004

Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis.

BACKGROUND & AIMS: Patients with ulcerative colitis are at increased risk of colorectal cancer. It is widely believed that this is secondary to colonic inflammation. However, the severity of colonic inflammation has never been shown to be a risk factor. METHODS: We devised a case-control study of patients with long-standing extensive ulcerative colitis to examine various potential risk factors for neoplasia. All cases of colorectal neoplasia detected from our surveillance program between January 1, 1988, and January 1, 2002, were studied (n = 68). Each patient was matched with 2 control patients from the same surveillance population (n = 136). Matching was for sex, colitis extent, age at onset, duration of colitis, and year of index surveillance colonoscopy. Segmental colonoscopic and histological inflammation was recorded by using a simple score (0, normal; 1, quiescent/chronic inflammation; and 2, 3, and 4, mild, moderate, and severe active inflammation, respectively). Other data collected included history of primary sclerosing cholangitis, family history of colorectal cancer, and smoking and drug history (mesalamine 5-aminosalicylic acid, azathioprine, and folate). RESULTS: Univariate analysis showed a highly significant correlation between the colonoscopic (odds ratio, 2.5; P = 0.001) and histological (odds ratio, 5.1; P < 0.001) inflammation scores and the risk of colorectal neoplasia. No other factors reached statistical significance. On multivariate analysis, only the histological inflammation score remained significant (odds ratio, 4.7; P < 0.001). CONCLUSIONS: In long-standing extensive ulcerative colitis, the severity of colonic inflammation is an important determinant of the risk of colorectal neoplasia. Endoscopic and histological grading of inflammation could allow better risk stratification for surveillance programs.

Adolescent↗
PubMed1996

The role of gut inflammation in the pathogenesis of spondyloarthropathies.

The concept of spondyloarthropathy (SpA) gathers together a group of chronic diseases with common clinical, biological, genetic and therapeutic characteristics. The concept forms a distinct entity, different from other rheumatic diseases. The target organs are not only the joint, but also the axial skeleton, the enthesis, the eye, the gut, urogenital tract, the skin and sometimes the heart. The prevalence of this entity in the general population is estimated 1%, equal to the prevalence of rheumatoid arthritis. Genetical predisposition (HLA-B27) is one of the clues to the pathogenesis of the disease. Since reactive arthritis is induced by specific urogenital or enterogenic bacteriae, and since the gut is implicated in different forms of spondyloarthropathies, especially in IBD, it was clear that the gut could play an important role by permitting exogenous factors to enter the body. This hypothesis was the rationale for investigating the gut in the spondyloarthropathies by performing ileocolonoscopies. In the first ileocolonoscopic studies of SpA patients, histological signs of gut inflammation were found in a relatively great number of patients, mostly without any clinical intestinal manifestations. These lesions were not seen in other inflammatory joint diseases. Further ileocolonoscopic studies confirmed the strong relationship between gut and joint inflammation. In patients in whom a second ileocolonoscopy was performed, remission of the joint inflammation was always connected with a disappearance of the gut inflammation, whereas persistence of locomotor inflammation was mostly associated to the persistence of gut inflammation. The hypothesis was proposed that some patients with a spondyloarthropathy had a form of subclinical Crohn's disease in which the locomotor inflammation was the only clinical expression. This hypothesis was confirmed in prospective long-term studies in which the ileocolonoscoped patients were reviewed 2 to 9 years later: about 6% of SpA patients not presenting any sign of Crohn's disease at first investigation but demonstrating gut inflammation on biopsy, developed full-blown Crohn's disease. The discovery of subclinical gut inflammation in the SpA had therapeutic consequences. Sulphasalazine (SASP) has been proven to be an active drug in the treatment of IBD. Since the gut could play a crucial role in SpA, it was logic to use this drug in the treatment of this disease. Multiple open and double-blind studies have proven the effectiveness of this drug in SpA; recent studies concluded that the beneficial effect of the drug in this disease entity is more prominent on the peripheral arthritis than on the axial disease.

Anti-Inflammatory Agents↗