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S J Kirk

Publications and source records attributed to S J Kirk.

At least 19 recordsLinked to original sources
PubMed2001

Tumour necrosis factor inhibitors reduce the acute-phase response in hapten-induced colitis.

BACKGROUND: Tumour necrosis factor (TNF) alpha has been implicated in the pathogenesis of inflammatory bowel disease. The aim of this study was to assess the contribution of TNF to the pathogenesis of hapten-induced colitis. METHODS: Colitis was induced in Wistar rats using intracolonic instillation of the hapten trinitrobenzenesulphonic acid (TNBS) in ethanol. Animals were treated with monoclonal anti-TNF antibody (cTN3), an idiotype control antibody (CB0006) or pentoxifylline. Colonic and systemic inflammation was assessed quantitatively. RESULTS: The use of either TNF inhibitor attenuated the acute-phase response in the early stages of colitis. Median (interquartile range (i.q.r.)) alpha 2-macroglobulin levels were reduced in animals pretreated with cTN3 (421 (279-915) micromol/ml) or pentoxifylline (567 (253-1454) micromol/ml) compared with levels in untreated colitic animals (1552 (1406-1998) micromol/ml) (P < 0.001 and P = 0.006, respectively). In established colitis, administration of anti-TNF antibodies resulted in an increase in median (i.q.r.) weight gain (percentage change in body-weight): colitic animals -2.3 (- 5.5 to 9.2) per cent versus cTN3-treated rats 15 (7.5-16.7) per cent; P < 0.05. CONCLUSION: The systemic response to TNBS-induced colitis appears to be at least partially dependent on TNF. This study did not provide evidence to support a role for TNF in the pathogenesis of colonic inflammation in this model. Presented in part to the 86th meeting of the Surgical Research Society in Nottingham, UK, 9-11 July 1997, and published in abstract form as Br J Surg 1997; 84: 1613

Acute-Phase Reaction↗
PubMed2000

Interleukin 10-deficient colitis: new similarities to human inflammatory bowel disease.

BACKGROUND: Interleukin (IL) 10 is a potent anti-inflammatory cytokine. Disruption of the IL-10 gene in C57/Black6 mice results in enterocolitis in the presence of intestinal bacteria. This study investigated gut mucosal barrier function sequentially during the development of colitis in this model. METHODS: Animals were bred in specific pathogen-free conditions and transferred to conventional housing at 4 weeks. Mice were evaluated at 6, 8, 10, 12, 14 and 15 weeks of age. Barrier function was assessed by measuring intestinal permeability and antibody response to systemic endotoxaemia (antibody to the core glycolipid region of lipopolysaccharide; EndoCAb). Colons were harvested and a histological injury score (HIS) was calculated. RESULTS: The HIS increased progressively until 12 weeks, with an associated increase in intestinal permeability, and immunoglobulin (Ig) M and IgG EndoCAb. The HIS correlated positively with both intestinal permeability and IgM and IgG EndoCAb. Intestinal permeability showed a positive correlation with EndoCAb. CONCLUSION: IL-10 knockout mice develop colitis with an associated disturbance in gut mucosal barrier function, as measured by increased permeability and endotoxaemia. The colitis found in the IL-10 knockout mouse shares these histological, physiological and biochemical features with human inflammatory bowel disease and is therefore suitable for therapeutic trials. A measure of endotoxaemia correlated directly with intestinal permeability in this model.

Animals↗
PubMed2000

Probiotic therapy fails to improve gut permeability in a hapten model of colitis.

BACKGROUND: Studies in clinical and experimental inflammatory bowel disease (IBD) have shown disturbances in intestinal bacterial flora with an increase in potentially pathogenic and a decrease in protective organisms. It was hypothesized that Lactobacillus plantarum species 299 (LP299), a probiotic, would ameliorate colitis and improve intestinal permeability in experimental colitis. This study investigated the effect of LP299 in the trinitrobenzenesulfonic acid/ethanol (TNBS/E) rat model of colitis. METHODS: Twelve week old male Wistar rats were randomized to receive rectal instillates of either TNBS/E (n = 48) or saline (n = 16). For the next 7 days the animals were gavaged with 2.5 ml of oat fibre suspension containing 10(9) colony forming units (CFU) of LP299 (LP299/OF), oat fibre suspension alone (OF) or no treatment. At the end of the experiment rats received radiolabelled polyethylene glycol and urine was collected for 24 h to assess permeability. Animals were then anaesthetized and colons were harvested for colon macroscopic scoring (CMS). RESULTS: TNBS/E per rectum resulted in a greater CMS (P < 0.001) and gut permeability (P = 0.006) than saline. Administration of LP299/OF or oat fibre alone did not result in a reduction in CMS or gut permeability when compared to colitic controls. CONCLUSIONS: LP299/OF, when administered after TNBS instillation, does not reduce the severity of colitis or improve gut permeability in this hapten model of colitis.

Animals↗
PubMed2000

Oral administration of inducible nitric oxide synthase inhibitors reduces nitric oxide synthesis but has no effect on the severity of experimental colitis.

BACKGROUND: Increased concentrations of nitrate and nitrite (the breakdown products of nitric oxide) in the serum and faeces of patients with inflammatory bowel disease (IBD) suggests that increased synthesis of nitric oxide occurs in IBD. The aim of this study was to assess aminoguanidine (AMG), a selective inhibitor of inducible nitric oxide synthase, with regard to its effectiveness as a nitric oxide inhibitor and as a modulator of inflammation in trinitrobenzene sulfonic acid (TNBS)-induced colitis. MATERIALS AND METHODS: Colitis was induced in Wistar rats. Selective (AMG) and non-selective (1-nitroso-arginine methyl ester (1-NAME)) inhibitors of nitric oxide synthase were given in the drinking water. Colonic citrulline and arginine concentrations were assessed using high-performance liquid chromatography. The severity of colitis was assessed by a macroscopic scoring system. RESULTS: Both 1-NAME and AMG successfully reduced nitric oxide synthesis. There was no evidence of substrate depletion in the colonic wall. Neither of the agents reduced the severity of colonic inflammation. CONCLUSIONS: Oral administration of nitric oxide synthase inhibitors reduced nitric oxide synthesis in the colonic wall. This study does not provide evidence to support a role for nitric oxide in the pathogenesis of colonic inflammation in TNBS colitis.

Administration, Oral↗
PubMed2000

Pregnancy associated endometriosis with pronounced stromal myxoid change.

A case of endometriosis presenting as a mass in the groin of a pregnant woman is described. The mass increased in size during the pregnancy and the radiological features were suspicious of malignancy. Histological examination showed atrophic glands set in an abundant stroma. This was not typical of normal endometrial stroma but had a pronounced myxoid appearance with areas of decidualization. The atypical site of the endometriosis together with the unusual stromal changes resulted in diagnostic confusion. Although stromal decidualization is well recognized in endometriosis in pregnancy, pronounced myxoid change appears unusual. The myxoid change in this case may be a degenerative phenomenon related to pregnancy.

Adult↗
PubMed1999

Characterization of the Kupffer cell response to exogenous endotoxin in a rodent model of obstructive jaundice.

BACKGROUND: Sepsis and endotoxaemia occur frequently in biliary obstruction. Impaired Kupffer cell endocytosis is implicated in these events. Tumour necrosis factor and interleukin 6, secreted by Kupffer cells, are important mediators of sepsis. Kupffer cell clearance of endotoxin and secretion of cytokines in experimental obstructive jaundice were investigated. METHODS: Wistar rats were randomized to bile duct ligation, sham operation or control. Groups (n = 8) were studied 1 and 3 weeks after operation. Kupffer cell function was assessed using in situ hepatic perfusion. RESULTS: Clearance of endotoxin was significantly depressed 1 week (median (interquartile range) 20.3 (10.5-27.1) per cent) and 3 weeks (22.1 (20.2-23.2) per cent) after bile duct ligation compared with that in respective sham animals (35.5 (29.9-41.6) and 40.9 (37.7-47.0) per cent) and controls (39.5 (37.3-46.8) per cent). Secretion of tumour necrosis factor was significantly greater 1 week (1113.7 (706.5-1436. 8) pg/ml) and 3 weeks (1118.2 (775.7-1484.1) pg/ml) following bile duct ligation compared with that in respective sham animals (114.3 (0-178.5) and 107.6 (63.7-166.4) pg/ml) and controls (0 (0-20.7) pg/ml). Interleukin 6 was not secreted by sham or control animals but was present in the perfusate from jaundiced animals at 1 and 3 weeks (52.5 (9.9-89.5) and 66.2 (60.2-193.1) pg/ml). CONCLUSION: These data demonstrate simultaneous impairment of Kupffer cell clearance of endotoxin and increased secretion of proinflammatory cytokines in experimental obstructive jaundice. These diverse responses may contribute to the development of sepsis-related complications in biliary obstruction.

Animals↗
PubMed1999

Kupffer cell blockade, tumour necrosis factor secretion and survival following endotoxin challenge in experimental biliary obstruction.

BACKGROUND: Gram-negative sepsis and its sequelae frequently complicate invasive procedures in patients with obstructive jaundice. In response to endotoxin, Kupffer cells secrete tumour necrosis factor (TNF), a pivotal early mediator of sepsis. An investigation was carried out into the specific role of Kupffer cell TNF secretion following endotoxin challenge in obstructive jaundice. METHODS: Survival following intraperitoneal administration of endotoxin (2.0, 0.02 and 0.0002 mg per 100 g) was determined in rats following bile duct ligation (BDL) or sham operation. Plasma TNF concentration was quantified following endotoxin administration (0.0002 mg per 100 g) at 1, 2 and 6 h. Subsequently, the effect of Kupffer cell blockade by gadolinium chloride on survival and plasma TNF concentration was assessed. RESULTS: Jaundiced animals showed a significantly increased mortality rate following intraperitoneal injection of endotoxin 2.0 mg per 100 g (BDL 100 per cent versus sham 0 per cent) and 0.02 mg per 100 g (BDL 70 per cent versus sham 0 per cent; P = 0. 002, Fisher's exact test). Median plasma TNF concentration was significantly greater in jaundiced animals 1 h after endotoxin administration (BDL 943 (interquartile range (i.q.r.) 211-3900) pg/ml versus sham 64 (i.q.r. 47-127) pg/ml; P = 0.002, Mann-Whitney U test). Kupffer cell blockade with gadolinium chloride increased the survival rate following endotoxin administration in BDL animals (BDL-GdCl3 100 per cent versus BDL-saline 40 per cent; P = 0.0003, Fisher's exact test) and decreased median plasma levels of TNF (BDL-GdCl3 88 (i.q.r. 0-1065) pg/ml versus BDL-saline 16 550 (1255-29 360) pg/ml; P = 0.002, Mann-Whitney U test). CONCLUSION: Kupffer cell blockade improved survival and suppressed systemic TNF activity after endotoxin challenge. In obstructive jaundice, hypersecretion of TNF by Kupffer cells may supplement systemic cytokine production and be responsible for significant complications.

Animals↗
PubMed1999

Fine needle aspiration cytology (FNAC) of mammary granular cell tumour: a report of three cases.

This report describes the FNAC findings in three cases of granular cell tumour of the breast. The patients comprised two females aged 59 and 62 years and one male aged 28 years. All patients presented with a breast lump which was clinically and radiologically suspicious of malignancy. FNAs yielded moderately cellular specimens which on cytologic examipation consisted of groups of cells and single cells with small regular nuclei and abundant granular cytoplasm. Bare nuclei were also present but these did not have the characteristic bipolar appearance of myoepithelial cells. In two cases there was a granularity to the background. The aspirates were reported as equivocal or atypical, probably benign, and surgical biopsy was performed. Histological examination showed typical benign granular cell tumours with strong positive staining for S-100 protein. Pathologists should be aware that granular cell tumour may occur in or around the breast and should consider this diagnosis in aspirates containing a population of cells with regular nuclei and abundant granular cytoplasm. The main cytologic differential diagnoses are likely to be apocrine cells and histiocytes. The suspicion of a granular cell tumour should be heightened when these features are present in an aspirate from a clinically and radiologically suspicious mass. These cases highlight the role of the triple approach encompassing clinical, radiological and cytological features in the assessment of a breast lesion.

Adult↗
PubMed1997

Tumour necrosis factor and inflammatory bowel disease.

BACKGROUND: Tumour necrosis factor (TNF) is a pleiotropic cytokine produced largely by macrophages and T lymphocytes. It has been implicated in the pathogenesis of numerous immunoinflammatory processes. Recently, a number of studies have indicated that anti-TNF antibodies may be of value in the treatment of inflammatory bowel disease. METHODS: The literature is reviewed regarding the role of TNF in the pathogenesis of inflammatory bowel disease and the results of administering TNF inhibitors. RESULTS AND CONCLUSIONS: TNF may have a role in the pathogenesis of inflammatory bowel disease. The effects of TNF inhibitors are complex and incompletely understood. Anti-TNF antibody strategies may have a role in the treatment of acute exacerbations of the disease but are unlikely to be appropriate therapies for long-term management.

Antibodies↗
PubMed1995

Manipulation of the L-arginine-nitric oxide pathway in experimental colitis.

The role of the L-arginine-nitric oxide pathway in the pathogenesis of colonic inflammation was assessed using L-arginine and its competitive analogue N omega-nitro-L-arginine methyl ester (L-NAME) in a rat model of colitis. In the first study oral L-arginine 2 per cent (control: 3.4 per cent L-glycine) was administered with and without L-NAME 100 mg/l. Orally administered L-arginine increased colonic inflammation (P = 0.004) and decreased thymic weight (P = 0.0007). Addition of L-NAME reduced the colonic inflammation and prevented loss of body-weight (P < 0.04). In the second study L-NAME was administered orally in concentrations of 100, 200 and 500 mg/l (control: no L-NAME). L-NAME 500 mg/l reduced colonic inflammation and increased thymic weight and body-weight (P < 0.01). Thymic weight and body-weight correlated positively with the concentration of L-NAME administered orally (rs > or = 0.3, P = 0.04). L-NAME l g/l was administered topically as an enema (control: suspension agent). Topical L-NAME reduced colonic inflammation and increased thymic weight (P < 0.05). These results suggest that the L-arginine-nitric oxide pathway mediates colonic inflammation in this model.

Administration, Oral↗
PubMed1995

Endotoxaemia and cytokine production in experimental colitis.

Systemic endotoxaemia is a well recognized feature of inflammatory bowel disease but its pathogenic role remains uncertain. This study examined plasma endotoxin and cytokine concentrations and the acute-phase protein response in a hapten-induced model of experimental colitis. On days 2, 8 and 14 after induction of colitis with trinitrobenzenesulphonic acid in ethanol (TNBS-E), plasma endotoxin, immunoglobulin (Ig) G and IgM endotoxin-core antibody (EndoCAb), tumour necrosis factor (TNF), interleukin (IL) 6 and alpha 2-macroglobulin (alpha 2M) concentrations and colon macroscopic inflammation score were determined. At all time points there was significant colonic inflammation when compared with control values (P < 0.0001). Animals treated with TNBS-E had raised concentrations of endotoxin at all time points (P < 0.04). In TNBS-E-treated animals EndoCAb concentrations were reduced on day 2 (P < 0.0001) and later increased. There were increases in IL-6 and alpha 2M concentrations in TNBS-E-treated animals but no significant change in TNF concentrations. Endotoxin concentrations correlated with macroscopic inflammation score, IL-6 and alpha 2M concentrations. There was a less consistent correlation between EndoCAb concentrations and these parameters. These results suggest that endotoxin is a mediator of the systemic response in this model of experimental colitis.

Animals↗
PubMed1994

Modulation of immune function and weight loss by L-arginine in obstructive jaundice in the rat.

Jaundiced surgical patients have a high incidence of postoperative complications. Many causative factors have been identified including cachexia and immune suppression. The amino acid L-arginine has anabolic and immunostimulatory properties. It was hypothesized that dietary supplementation with L-arginine would diminish the weight loss and immune suppression of obstructive jaundice. Sixteen male Wistar rats rendered jaundiced by bile duct ligation were allocated to two groups. The test group (n = 8) received drinking water supplemented with 1.8 percent L-arginine ad libitum and the control group (n = 8) received a solution of isonitrogenous glycine. Both groups had free access to standard chow. Body-weight, and fluid and food intake were recorded. After 21 days, delayed-type hypersensitivity to 2,4-dinitrofluorobenzene was assessed. Animals receiving L-arginine consumed more food than controls (mean(s.e.m.) 414(16) versus 360(13) g, P < 0.05) and lost less weight (mean(s.e.m.) proportion of initial body-weight lost 7.8(1.2) versus 14.8(1.4) percent, P < 0.05). The delayed-type hypersensitivity response was significantly greater in rats receiving L-arginine (mean(s.e.m.) increase in ear thickness 23.9(2.7) versus 9.4(2.1) percent, P < 0.05). In this animal model of obstructive jaundice dietary supplementation with L-arginine diminished both weight loss and immune suppression.

Animals↗
PubMed1993

Sepsis impairs gut amino acid absorption.

Sepsis has been shown to adversely affect the barrier and metabolic functions of the small intestine as well as to reduce mesenteric blood flow and cause histologic damage. However, the effect of sepsis on gut absorptive function has been largely ignored. In this study, intestinal absorption of arginine and an amino acid analogue, aminoisobutyric acid, was studied using in vivo and in vitro techniques in an experimental model of sepsis. In vivo studies showed a significant impairment in the absorption of both amino acids from the intestinal lumen 24 and 72 hours after cecal ligation and puncture. Uptake of these amino acids by everted gut sacs prepared from septic animals was also significantly reduced. This reduction in absorptive capacity of the gut may limit the ability of enteral feeding alone to supply nutritional requirements during sepsis and may also contribute to the associated morbidity and mortality.

Aminoisobutyric Acids↗
PubMed1993

Arginine stimulates wound healing and immune function in elderly human beings.

BACKGROUND: Experimentally, arginine enhances immune function and promotes wound healing. In this randomized double-blind study we investigated the effect of oral arginine supplementation on wound healing and T-cell function in elderly human beings (more than 65 years of age). METHODS: Thirty elderly, healthy, human volunteers (15 men and 15 women) received daily supplements of 30 gm arginine aspartate (17 gm free arginine). Fifteen volunteers (nine men and six women) received a placebo syrup. Fibroplastic wound responses were assessed by inserting a polytetrafluoroethylene catheter subcutaneously into the right deltoid region. Epithelialization was examined by creating a 2 x 2 cm split thickness wound on the lateral aspect of the upper thigh. Mitogenic response of peripheral blood lymphocytes to concanavalin A, phytohemagglutinin, pokeweed mitogen, and allogeneic stimuli was assayed at the beginning and end of supplementation. Polytetrafluoroethylene catheters were analyzed for alpha-amino nitrogen (assessment of total protein accumulation), hydroxyproline (index of reparative collagen synthesis), and DNA accumulation (index of cellular infiltration). RESULTS: Arginine supplementation for 2 weeks significantly enhanced wound catheter hydroxyproline accumulation (26.49 +/- 2.39 nmol/cm vs 17.41 +/- 2.04 nmol/cm) and total protein content (43.47 +/- 3.85 micrograms/cm vs 21.95 +/- 2.5 micrograms/cm). Arginine did not influence the DNA content of the catheters or the rate of epithelialization of the skin defect. Peripheral blood lymphocyte responses to mitogenic and allogenic stimulation were greater in the arginine supplemented group. Serum insulin-like growth factor-1 levels were significantly elevated in the arginine group. CONCLUSIONS: The data suggest that arginine supplementation may improve wound healing and immune responses in the elderly.

Aged↗
PubMed1993

Tumor necrosis factor-alpha inhibits in vivo collagen synthesis.

In this study we sought to determine the in vivo role of tumor necrosis factor-alpha (TNF-alpha) at the wound-healing site. In vivo abrogation of endogenous TNF-alpha activity in experimental wounds by administration of anti-murine TNF-alpha rabbit serum resulted in a significant 77.5% increase in wound collagen deposition, as assessed by wound sponge granuloma hydroxyproline content. Administration of pharmacologic doses of recombinant murine TNF-alpha into subcutaneously inserted polyvinyl alcohol sponges resulted in an increase in collagen deposition (1594 +/- 117 vs 1014 +/- 49 and 1588 +/- 135 vs 1014 +/- 49 micrograms/100 mg sponge, for TNF-alpha in situ administration at a dose of 0.05 and 0.5 micrograms, respectively). This effect could be abolished by the simultaneous systemic treatment of the animals with the antiinflammatory drug indomethacin. The data suggest that the enhanced collagen deposition after TNF-alpha administration is a consequence of a nonspecific inflammatory activity that indirectly promotes collagen synthesis. The data also support the hypothesis that endogenous wound TNF-alpha down-regulates collagen synthesis during normal wound healing.

Animals↗