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Biomedical subjects

C J Dunn

Publications and source records attributed to C J Dunn.

At least 73 records · Page 4Linked to original sources
PubMed1989

Interleukin-1 induced vascular pathology "in vivo": a scanning electron-microscopy study.

Ethylene vinyl acetate (EVA) discs containing either 50 U interleukin-1 (IL-1) or 250 mg bovine serum albumin as control were implanted around the exposed jugular veins of rabbits. After 24 hr, the veins were examined by scanning electron-microscopy. Compared with minor changes in control vein lumena, those of EVA-IL-1 treated veins showed extensive endothelial cell denudation and exposure of basement membrane associated with platelet accumulation and adherence/subendothelial migration of leucocytes. These observations suggest that locally-released IL-1 provokes significant vascular pathological changes "in vivo" and emphasise the importance of this cytokine as a mediator of inflammatory and thrombotic/atherosclerotic diseases.

Animals↗
PubMed1989

Acute and chronic inflammatory responses to local administration of recombinant IL-1 alpha, IL-beta, TNF alpha, IL-2 and Ifn gamma in mice.

The contention that cytokines are important mediators of inflammation prompted the present studies which were designed to compare acute and chronic pathological effects of locally-administered recombinant (r) IL-1 alpha, IL-1 beta, TNF alpha, IL-2 and Ifn gamma. Acute (6 hr), resolving (48 hr) inflammation was induced by the following, in order of potency: rIL-1 alpha greater than rIL-1 beta greater than rTNF alpha greater than rIfn gamma = BSA (control) following a single sc. injection. However, only rIL-1 beta and rIL-2 initiated and maintained chronic granulomatous reactions when delivered locally from a sc. ethylene vinyl acetate (EVA) slow-release polymer. The predominance of macrophages in EVA-rIL-1 beta lesions contrasted with the proliferative lymphoid granulomata induced by EVA-rIL-2 implants. These "in vivo" observations reinforce the roles of both IL-1 beta and IL-2 as potent mediators of chronic immunoinflammatory disease.

Animals↗
PubMed1989

The effects of sensitization protocols on arthritic responses in antigen-induced arthritis.

Three different immunization protocols were studied for their effect on methylated bovine serum albumin (mBSA)-induced arthritis. Mice were immunized with mBSA in Freund's incomplete adjuvant containing dextran and challenged 3 weeks later with antigen in one knee. After 7-14 days a strong inflammatory reaction developed without significant erosions of articular cartilage or bone. The reaction resolved between 28 and 35 days. In contrast, mice immunized with mBSA and complete Freund's adjuvant (CFA) developed inflammation that was accompanied by erosive disease. However, this pathology also resolved after 28-35 days. Mice immunized with mBSA in modified CFA developed inflammation and co-incident erosive disease that persisted for 60 days. Thus, three distinct arthropathies can be evoked depending on the immunization protocol employed.

Animals↗
PubMed1989

Development of a delayed-type hypersensitivity granuloma model in the mouse for the study of chronic immune-mediated inflammatory disease.

A cutaneous model of delayed-type hypersensitivity granuloma (DTH GRA) was developed, using methylated bovine serum albumin (mBSA) which could be easily quantified and represented chronic cellular immune-mediated inflammation characteristic of rheumatoid arthritis (RA). Quantitative kinetics showed maximal DTH GRA "wet" tissue weights at d.5 post-induction, diminishing between d.15-22; DTH GRA "dry" tissue weights peaked between d.8-22. Histological evaluation revealed early extensive fibrin deposition, edema, mixed PMN/mononuclear leucocyte infiltration and angiogenesis (d.2-5), followed by increased macrophage recruitment, lymphocyte infiltration, angiogenesis and vasculitis (d.10-15). Fibrin resorption and replacement by fibrous tissue resulted in resolution by d.35. It is suggested that the DTH GRA reaction represents a relevant model for probing pathogenic mechanisms and potential therapeutics for RA.

Animals↗
PubMed1989

Local pathological responses to slow-release recombinant interleukin-1, interleukin-2 and gamma-interferon in the mouse and their relevance to chronic inflammatory disease.

1. The present study describes the pathological responses to local administration of recombinant cytokines in subcutaneously implanted slow-release ethylene vinyl acetate (EVA) co-polymer in mice. 2. EVA-recombinant human interleukin-1 beta (10(4) units) implants induced the formation of chronic granulomatous inflammatory tissue between 4 and 7 days after implantation, characterized by predominant macrophage infiltration, neovascularization and fibrosis which persisted up to 21 days after-implantation. EVA-recombinant human interleukin-1 alpha (10(4)-10(5) units) implants induced a qualitatively similar but less intense response. 3. In contrast, recombinant human interleukin-2 (10(2)-10(4) units) implants resulted in early lymphocytic vasculitis (4 days) and the development of a predominantly lymphoid lesion comprised of lymphoblasts and significant mononuclear cell proliferation by 7 days. 4. EVA-recombinant gamma-interferon (10(3)-10(4) units) implants failed to elicit a significant tissue response; with the exception of multinucleate giant cell formation the characteristics of these lesions closely resembled the mild fibrotic responses observed for EVA-bovine serum albumin (0.5-12.5 mg) implants. 5. These observations suggest that continuous endogenous local release of interleukin-1 or interleukin-2 in vivo is sufficient for the development of specific pathological features characterizing chronic immuno-inflammatory diseases.

Animals↗
PubMed1989

Interleukin-1 potentiates the development of collagen-induced arthritis in mice.

1. The subcutaneous administration of recombinant human interleukin-1 beta (rhIL-1 beta) was found to induce an increased incidence and earlier onset of collagen-induced arthritis in mice. 2. The rhIL-1 beta had different effects, depending on when it was administered after collagen-immunization. 3. The effect of rhIL-1 beta may be due, in part, to augmentation of the immune response to type II collagen. 4. Interleukin-1-accelerated, collagen-induced arthritis will provide a useful model for investigating the role of interleukin-1 in the regulation of arthritic diseases, and the development of anti-arthritic therapeutics.

Animals↗
PubMed1989

Effect of the selective leukotriene B4 antagonist U-75302 on antigen-induced bronchopulmonary eosinophilia in sensitized guinea pigs.

The selective leukotriene B4 (LTB4) antagonist, U-75302, 6-(6-(3-hydroxy-1E,5Z-undecadien-1-yl)-2-pyridinyl)-1,5-hexa nediol) was examined for its ability to inhibit the "late-phase" bronchopulmonary eosinophilia that occurs 6 to 24 h after inhalation of specific antigen in sensitized guinea pigs. Groups of 6 male guinea pigs, sensitized with ovalbumin, were pretreated with U-75302, 1.0, 10.0, or 30.0 mg/kg, or vehicle 1 h before and 7 h after antigen inhalation. Twenty-four hours after antigen provocation, the lungs were lavaged for the enumeration of inflammatory cell populations. Doses of U-75302 (1.0, 10.0 and 30.0 mg/kg) administered orally produced 12.2%, (p greater than 0.05), 43.2% (p less than 0.05), and 61.1% (p less than 0.05) inhibition, respectively, of the antigen-induced influx of eosinophils into the bronchial lumen. Neutrophil populations were not significantly affected by treatment with U-75302. In a separate study, we compared the histopathological changes that occurred following antigen challenge in U-75302-treated or vehicle-treated guinea pigs. Vehicle-treated, sensitized animals exhibited marked changes in the airway at 8 min, 6 h, and 24 h after antigen challenge. U-75302 treatment produced a significant reduction in eosinophil adherence to peribronchial/peribronchiolar capillaries followed by a dramatic and specific reduction of peribronchial eosinophil infiltration (81% reduction at 6 h and 79% reduction at 24 h). Neutrophil migration appeared unaffected. These data implicate LTB4 as a mediator of antigen-induced bronchopulmonary eosinophilia in the guinea pig.

Animals↗
PubMed1988

Evaluation of angiogenesis in chronic inflammation by laser-Doppler flowmetry.

1. A non-invasive method is described for the assessment of angiogenesis in chronic inflammation using laser-Doppler flowmetry. 2. Significant increases in capillary blood flow were seen on days 5 and 7 after induction of subcutaneous granulomatous lesions, as compared with control skin. 3. Changes in blood flow were accompanied by changes in pulsatile flow pattern and by an intense angiogenic response observed by light microscopy. 4. The potential application of laser-Doppler flowmetry to quantitative and qualitative studies of evolving angiogenesis in pathological responses is discussed.

Animals↗
PubMed1988

Development of a prolonged eosinophil-rich inflammatory leukocyte infiltration in the guinea-pig asthmatic response to ovalbumin inhalation.

Considerable attention has recently focused on the role of inflammation in the pathophysiology of asthma, with special emphasis on "late-phase" bronchoconstriction and increased airway hyperreactivity after antigen challenge in sensitized subjects. The present report describes the histopathologic changes in guinea-pig lung and trachea at various time intervals after ovalbumin inhalation in nonsensitized (control) and sensitized animals. Bronchoalveolar lavage (BAL) was also used to assess the accompanying accumulation of intraluminal leukocytes. A distinct leukocyte margination, consisting of neutrophils and eosinophils, was observed in the peribronchial vasculature as early as 8 min postchallenge in sensitized guinea pigs. At 6 h, the eosinophils predominated and migrated to the peribronchiolar smooth muscle layer. Between 6 h and 18 h, eosinophils were seen in tracts between the smooth muscle cell layers, accumulating in large numbers in the bronchial mucosal epithelium. This pattern persisted for at least 7 days postchallenge during which eosinophils remained the dominant cell type present. Peribronchiolar accumulation of neutrophils and mononuclear cells was minimal at all time points studied. Intraluminal mucus eosinophilia developed between 18 h and 7 days. A similar pattern of eosinophil infiltration was observed in the tracheal epithelium. Control, nonsensitized, guinea-pig lungs showed minor changes with little or no eosinophil infiltration at any time after antigen challenge. These findings correlated well with the BAL study in which sensitized guinea pigs exhibited a marked delayed increase in eosinophil counts between 18 h and 7 days compared with that in nonsensitized animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

The effects of cyclosporin A on leucocyte infiltration and procoagulant activity in the mouse delayed hypersensitivity response in vivo.

A model of delayed type hypersensitivity (DTH) to methylated bovine serum albumin was established and characterised in the mouse pleural cavity. Fluid exudate formation was delayed, peaking around 24 h and diminishing by 48-72 h. Exudate leucocyte accumulation was also delayed, rising by 24 h and reaching maximal levels between 24-72 h. Significant PMN leucocyte infiltration was observed early on, although macrophages dominated the reaction from 24 h onwards. Small numbers of lymphoid cells were also observed. Treatment with cyclosporin A (CsA) at 100 mg/kg p.o. around the time of antigen challenge significantly reduced fluid exudate volume but consistently failed to reduce either leucocyte infiltration or the PMN: mononuclear cell ratio throughout the reaction. CsA treatment enhanced DTH exudate leucocyte procoagulant activity (PCA) although leucocyte morphology remained unaltered. The development of carrageenan edema in the hind paws of mice was unaffected by CsA treatment (50-200 mg/kg p.o.). These results suggest that (1) CsA selectively suppresses DTH vascular permeability responses without affecting leucocyte accumulation and (2) CsA does not affect the lymphokine-mediated induction of leucocyte PCA associated with DTH reactions in vivo.

Animals↗
PubMed1986

The role of cyclooxygenase and lipoxygenase pathways in the adhesive interaction between bovine polymorphonuclear leukocytes and bovine endothelial cells.

The effects of arachidonic acid metabolites, analogues and cyclooxygenase/lipoxygenase inhibitors were tested on an "in vitro" bovine model of endothelial cell (EC)-polymorphonuclear leukocyte (PMN) adhesion. Arachidonic acid blocked adhesion at 10(-5)M, a dose which also induced aggregation of PMN. Lower doses did not affect either EC-PMN adhesion or PMN aggregation. Various cyclooxygenase pathway metabolites were inactive in the EC-PMN adhesion assay, with the exception of prostaglandin A2 and prostaglandin B2 which significantly suppressed adhesion at 10(-5)M. Of the synthetic analogs tested, 6 alpha-carbaprostacyclin I2, (5Z)-9 beta-ethynyl-calcium salt (U-64,567E) was inhibitory at 10(-5)M. The cyclooxygenase inhibitors acetylsalicylic acid, indomethacin and ibuprofen were inactive. Products of the lipoxygenase pathways, leukotriene B4 (LTB4), 5-hydroxyeicosatetraenoic acid (5-HETE) and 15-hydroperoxyeicosatetraenoic acid (15-HPETE) exhibited variable inhibitory activity at 10(-5)M only. Paradoxical effects were observed with the putative lipoxygenase inhibitors 4,7,10,13-eicosatetraynoic acid (4,7,10,13 ETYA), 5,8,11,14-eicosatetraynoic acid (5,8,11,14 ETYA) and nordihydroguairetic acid (NDGA), which also suppressed EC-PMN adhesion at 10(-5)M. The dual cyclooxygenase-lipoxygenase inhibitor, BW755C was inactive. Bovine PMNs did not respond chemotactically to LTB4 although they were able to synthesize the 5-lipoxygenase products LTB4 and 5-HETE.

Adhesiveness↗
PubMed1986

A pro-inflammatory role of lymphoid cells in acute pleurisy in rats.

The effect of viable splenic lymphoid cells and their constituents (filtrate) on carrageenan-induced acute pleurisy was investigated in rats. Suspensions of lymphoid cells administered intravenously to recipients just prior to initiation of pleurisy enhance both the volume of exudate and cell accumulation in the pleural cavity 3 h after the irritation. Similar results were observed when filtrate of disrupted lymphoid cells was injected either 30 or 5 min before the carrageenan, but not when administered 30 min afterwards. Suspensions of bone marrow cells, on the contrary, were ineffective in producing an enhancement of the parameters studied. When administered into the pleural cavity together with carrageenan, the lymphoid cell filtrate augmented the inflammatory response to the irritant. Nevertheless, it was ineffective, per se, to elicit any local change. It is suggested that lymphoid cells may play a pro-inflammatory role in the initiation of the process by enhancing both the fluid and the cellular components of inflammation.

Acute Disease↗
PubMed1984

Prolonged treatment with D-penicillamine: effects on adjuvant arthritis in the rat.

The effects of long term D-penicillamine treatment on adjuvant arthritis in the rat were determined in order to establish a possible approach to the laboratory evaluation of anti-rheumatic drugs. Oral pretreatment (1-3 months) followed by continued through-treatment on a daily basis (100 mg/kg p.o.) failed to modify the parameters tested: viz. (a) body weight changes; (b) primary paw lesions; (c) secondary hind paw lesions; (d) secondary forepaw, ear and tail lesions; (e) the number of 'responders'. Autopsy showed no macroscopic abnormalities in the lungs, heart, thymus, liver, spleen, adrenal glands, kidneys and gastro-intestinal tract. These results are discussed in relation to previous findings whereby rat adjuvant arthritis, in addition to other experimental immune reactions, has been suggested as an indicator for D-penicillamine activity.

Administration, Oral↗
PubMed1984

Antrafenine: anti-inflammatory activity with respect to oedema and leucocyte infiltration in the rat.

Antrafenine effectively suppressed carrageenan paw oedema in the rat (ED 40 = 24 mg/kg p.o) in the dose range of 10-40 mg/kg p.o, approximating that of phenylbutazone. Antrafenine was superior to phenylbutazone with respect to inhibition of exudate volume and total leucocyte infiltration in carrageenan and calcium pyrophosphate dihydrate crystal pleurisies. The effect of antrafenine on leucocytes was most striking, significant suppression being observed at each dose tested (10, 20, 40 mg/kg p.o), whereas phenylbutazone showed significant activity only at the relatively elevated dose of 40 mg/kg p.o. These observations suggest that antrafenine merits further investigation with respect to its anti-inflammatory effects.

Animals↗
PubMed1984

Legionella pneumophila serogroup 9: a cause of human pneumonia.

A new serogroup of Legionella pneumophila was isolated from bronchoscopic washings and an open-lung biopsy specimen of a patient from California with pneumonia. A serologically identical isolate was obtained from tap water of a hospital ward in the Netherlands, and a fatal case of pneumonia in a patient from Virginia was shown retrospectively to have been caused by this new organism. The type strain of what is now serogroup 9 of L. pneumophila is IN-23-G1-C2 (American Type Culture Collection no. 35289). Disease caused by L. pneumophila serogroup 9 is not apparently different from that caused by other L. pneumophila serogroups.

Agglutination Tests↗
PubMed1984

Increased adhesion of polymorphonuclear leukocytes to vascular endothelium by specific interaction of endogenous (interleukin-1) and exogenous (lipopolysaccharide) substances with endothelial cells 'in vitro'.

Cultured human endothelial cells exposed to interleukin-1 (IL-1) exhibited increased adhesiveness for human polymorphonuclear leukocytes (PMNs). This phenomenon was dose-dependent, maximal increased adhesion being observed at 0.25 U/ml IL-1. ECs required a minimum exposure time of 30 min. with IL-1 followed by at least 1-2 hours incubation for expression of increased adhesiveness. Incubation for shorter periods of time did not induce significant changes in EC-PMN adhesion compared with cultures having received no IL-1. No change in adhesion was observed when IL-1 was co-incubated with ECs and PMNs. Similar results were observed using lipopolysaccharide (LPS) as stimulus. It is concluded that increased adhesion of PMNs to vascular endothelium is mediated by the direct interaction of endogenous (IL-1) and exogenous (LPS) substances with ECs, the expression of which requires a latent period of 1-2 hours and is protein synthesis-dependent. The implications of these novel findings in pathological disease states are discussed.

Cell Adhesion↗