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D J Ormrod

Publications and source records attributed to D J Ormrod.

At least 19 recordsLinked to original sources
PubMed2001

Temporal expression of heat shock proteins 60 and 70 at lesion-prone sites during atherogenesis in ApoE-deficient mice.

In the study, we investigate whether the expressions of heat shock protein (hsp)60 (a potential autoantigen) and the stress-inducible form of cytoprotector hsp70 are correlated with the development of atherosclerotic lesions in the aortic tree of apolipoprotein E-deficient (apoE(-/-)) mice. The apoE(-/-) mouse model is advantageous because the stress-inducible form of hsp70 is not constitutively expressed in mice, unlike primates; hence, tissues under stress can be clearly defined. Both mammalian hsps were detected newly expressed (before mononuclear cell infiltration) on aortic valves and endothelia at lesion-prone sites of 3-week-old apoE(-/-) mice. In 8- and 20-week-old mice, they were strongly and heterogeneously expressed in early to advanced fibrofatty plaques, with levels correlating with lesion severity. Expression was markedly downregulated in advanced collagenous, acellular, calcified plaques of 40- and 69-week-old mice and was absent in control aortas of normocholesterolemic wild-type (apoE(+/+)) mice. Western blot analysis of tissue homogenates confirmed the temporal expression of the hsps. Double immunostaining revealed that both hsps were expressed by lesional endothelial cells, macrophages, smooth muscle cells, and CD3(+) T lymphocytes. This study provides evidence that hsp60 and hsp70 are temporally expressed on all major cell types in lesion-prone sites during atherogenesis, suggesting that few cells escape the toxic environment of the atherosclerotic plaque.

Animals↗
PubMed1998

An anti-inflammatory component derived from milk of hyperimmunised cows reduces tight junction permeability in vitro.

OBJECTIVE AND DESIGN: Effects of hyperimmune milk factor (HIMF), an anti-inflammatory factor from milk of hyperimmunised cows, on tight junction permeability and cell growth were studied in vitro. MATERIAL OR SUBJECTS: Mammary (HC11) and kidney (MDCK) epithelial cell lines were used. TREATMENT: HIMF was used at a final concentration of 2 mg/ml. METHODS: Tight junction permeability was assessed by measuring transepithelial electrical resistance (TER) across confluent monolayers, following the addition of HIMF with or without an inflammatory challenge. Cell growth was assessed by measuring total DNA of cultures with and without HIMF. Data were analysed by analyses of variance. RESULTS: HIMF promoted tight junction formation and prevented loss of TER following a challenge in both epithelia. Post-challenge recovery of TER was also faster with HIMF. HIMF inhibited cell growth. CONCLUSIONS: HIMF stimulates tight junction maintenance and formation, and its previously reported anti-inflammatory properties may be mediated by restricting the extravasation of white blood cells through tight junctions.

Animals↗
PubMed1998

Dietary chitosan inhibits hypercholesterolaemia and atherogenesis in the apolipoprotein E-deficient mouse model of atherosclerosis.

Chitosan, the deacetylated form of chitin, is extracted from the shells of crustaceans. The strong positive charge carried by the chitosan molecule causes it to bind negatively charged substrates such as lipids. Orally administered chitosan binds fat in the intestine, blocking absorption, and has been shown to lower blood cholesterol in animals and humans. As a result it has been proposed that dietary supplementation with chitosan may inhibit the formation of atherosclerotic plaque. We have tested this hypothesis using the apolipoprotein E-deficient mouse model of atherosclerosis. This hypercholesterolaemic animal develops atherosclerosis without the need for dietary or surgical intervention. The apolipoprotein E-deficient mouse therefore provides an ideal model in which to study the effects of dietary chitosan on both blood cholesterol and atherosclerosis. Animals were fed for 20 weeks on a diet containing 5% chitosan or on a control diet. Blood cholesterol levels were significantly lower in the chitosan fed animals throughout the study, and at 20 weeks were 64% of control levels. When the area of aortic plaque in the two groups was compared a highly significant inhibition of atherogenesis, in both the whole aorta and the aortic arch, was observed in the chitosan fed animals--42 and 50%, respectively. Body growth was significantly greater in the chitosan fed animals. This study is the first to show a direct correlation between lowering of serum cholesterol with chitosan and inhibition of atherogenesis, and suggests that the agent could be used to inhibit the development of atherosclerosis in individuals with hypercholesterolaemia.

Animals↗
PubMed1993

Anti-inflammatory activity of glycogen extracted from Perna canaliculus (NZ green-lipped mussel).

Previous laboratory based investigations of a commercially prepared freeze-dried extract of the NZ green-lipped mussel (Perna canaliculus) showed that the material had the capacity to inhibit experimentally induced inflammation. The activity was thought to reside within an aqueous fraction containing high molecular weight material, possibly a polysaccharide. In the present study, a polysaccharide (glycogen) has been extracted from Perna canaliculus and its anti-inflammatory activity examined in an attempt to characterise further the high molecular weight components of this mollusc. Glycogen extracts administered i.v. demonstrated a dose-dependent anti-inflammatory effect in rats with carrageenin-induced footpad oedema. Mobilisation of neutrophils to the site of an inflammatory stimulus was also significantly reduced. This activity was lost if the glycogen extract was treated with KOH or proteinase K, suggesting that the anti-inflammatory properties resided within a protein moiety associated with the glycogen.

Animals↗
PubMed1993

Milk from hyperimmunized dairy cows as a source of a novel biological response modifier.

Laboratory investigations have established that hyperimmunization of dairy cows with a polyvalent bacterial vaccine results in the secretion of biologically active substances into the milk. One of these factors, a low molecular weight anti-inflammatory agent (HIMF), has been studied in detail. The evidence supports the hypothesis that HIMF suppresses inflammation by inhibiting neutrophil emigration. Additionally, the experiments suggested that HIMF was capable of modifying the host response to infection and lymphocyte function. These effects have considerable clinical potential and were therefore investigated further. Intravenous administration of HIMF to rats with subcutaneous E. coli infection reduced the influx of neutrophils in the early phase of infection by as much as 73%. HIMF suppressed the host vs. graft but not the graft vs. host reaction and resulted in an increase in spleen weight and the number of splenic lymphocytes. The lymphocyte response to concanavalin A was also abrogated by the agent. These data indicate that HIMF may be useful for the inhibition of tissue destructive infectious processes, and in situations where suppression of lymphocyte function is desirable.

Animals↗
PubMed1992

A low molecular weight component derived from the milk of hyperimmunised cows suppresses inflammation by inhibiting neutrophil emigration.

An earlier study demonstrated that hyperimmunisation of dairy cows with a polyvalent bacterial vaccine stimulated the secretion of a small molecular weight anti-inflammatory moiety in the milk. This hyperimmune milk factor (HIMF) has been further investigated in the present experiments. HIMF was found to suppress the cellular phase of the response to carrageenin and also the neutrophil-dependent reverse passive Arthus reaction. These results, together with the observation that the administration of HIMF led to an increase in the number of circulating neutrophils, suggested that the agent might inhibit inflammation by interfering with the ability of neutrophils to emigrate from the vasculature. In vivo studies carried out to evaluate this possibility demonstrated that HIMF suppressed neutrophil emigration by up to 75%. In vitro experiments established that the ability of neutrophils to respond to chemotactic stimuli or adhere to endothelial cells was not affected by HIMF. It is possible, therefore, that the agent modulates inflammation by down-regulating the synthesis of inducible pro-inflammatory cytokines or adhesion molecules. Attempts are presently being made to isolate the active moiety to allow the activity of the agent at the molecular level to be studied in more detail.

Animals↗
PubMed1992

Suppression of inflammation by cyclosporin A is mediated via a T lymphocyte-independent process.

An athymic mutant rat strain was used to examine the hypothesis that modification of diseases with an inflammatory component by cyclosporin A (CsA) results from the suppression of nonspecific inflammatory mechanisms, rather than T-lymphocyte function, as is commonly inferred. Confirmation that the animal host was grossly depleted of T cells was obtained from anatomic and morphologic examination and functional tests of T-lymphocyte responsiveness. The experimental approach was to determine the effect of CsA on the course of experimentally induced infection with Escherichia coli, and extracellular pathogen. Host protection against this microorganism is dependent on an effective nonspecific inflammatory response. CsA administration prior to bacterial challenge resulted in a highly significant increase in bacterial numbers in the kidneys of both euthymic and athymic hosts. The data have provided a direct demonstration that modulation of the nonspecific inflammatory response by CsA can occur via a T lymphocyte-independent process.

Animals↗
PubMed1991

The anti-inflammatory activity of a low molecular weight component derived from the milk of hyperimmunized cows.

"Immune" milk has been utilized as a source of biologically active compounds for many years. In the present study, a low molecular weight fraction, isolated from the milk of dairy cows hyperimmunized with a multivalent bacterial vaccine (HIMF), has been evaluated for anti-inflammatory activity. Analysis was carried out using the rat hind-paw oedema assay. HIMF was shown to have a marked anti-inflammatory effect in this model and carrageenin-induced oedema was suppressed by up to 80% in individual experiments. The agent was active following oral, subcutaneous, intramuscular, intraperitoneal or intravenous administration. Intravenous injection was particularly effective and amounts as small as 1 mg significantly reduced the inflammatory response to carrageenin. The experiments have established that milk from hyperimmunized cows contains a highly active anti-inflammatory compound and form a basis for further studies, which will attempt to isolate and further characterize the active moiety.

Animals↗
PubMed1991

Assessment of antiinflammatory agents using 125I-labeled human serum albumin to quantify footpad edema volume in the rat.

Intravenously injected human serum albumin, labeled with radioactive iodine ([125I]HSA), accumulates at inflammatory foci in proportion to the volume of the exudate, making it possible to quantify the volume of edema. This paper describes the use of [125I]HSA to measure edema formation in the carrageenin rat-footpad model, both continuously and at a single time point. In assessing antiinflammatory agents, the method was shown to be more sensitive than the most commonly used technique of thickness measurement. Because anesthetics are known to suppress inflammation, the comparative effect of five anesthetic agents on the inflammatory response was determined. Ether was the only anesthetic tested that did not substantially inhibit the accumulation of edema. The technique overcomes many of the limitations of previously used procedures and has the potential to become the method of choice when assessing edema in the rat footpad.

Anesthetics↗
PubMed1990

Cyclosporin A modulation of the acute inflammatory response: an explanation for the effect of CsA on host defences in infection.

Previous studies have shown that the administration of cyclosporin A (CsA) to animals with experimentally induced pyelonephritis resulted in considerable exacerbation of infection. T-lymphocytes are not involved in the host response to pyelonephritis but neutrophils are known to be a key component in the pathogenesis of this infection, so the effect of CsA on this inflammatory component was investigated. CsA administration did not affect the metabolic activity of neutrophils in vitro nor their ability to phagocytose and kill microorganisms. However, the ability of neutrophils to mobilize to a sterile inflammatory focus in vivo was significantly impaired. Further experiments, using models of pyelonephritis and subcutaneous infection, demonstrated that the CsA-induced suppression of neutrophil mobilization was directly related to the observed increase in bacterial numbers and exacerbation of tissue damage. Additionally, the actual effect of CsA on host defences and the outcome of infection was found to be dependent on the level of the initial infectious challenge. The results of this study provide an explanation for the current pattern of infectious disease in patients treated with CsA, in whom infection with extracellular pathogens is still common. It is also clear that the effect of CsA on inflammatory mechanisms may explain the efficacy of the agent in inflammatory diseases such as rheumatoid arthritis. This suggests a wider therapeutic role for CsA than is currently recognized.

Acute-Phase Reaction↗
PubMed1987

Inhibition of neutrophil myeloperoxidase activity by selected tissues.

Myeloperoxidase, a polymorphonuclear leukocyte-specific enzyme, has been used previously to quantify the number of polymorphonuclear leukocytes in tissue. When this method was employed in an attempt to measure polymorphonuclear leukocyte numbers in infected kidneys, it was found that myeloperoxidase could not be demonstrated, although significant numbers of neutrophils were present in the pyelonephritic lesions. Further studies were carried out to determine the effect of other tissues on free and cell-bound exogenous myeloperoxidase. We have shown that while skin had little effect on enzyme levels, liver and spleen totally destroyed myeloperoxidase activity within 30 sec. Cardiac and striated muscle had an intermediate effect. When intact neutrophils were added to fresh cardiac tissue 72.5% myeloperoxidase activity was destroyed during the enzyme solubilization procedure. These findings indicate that the technique can only be used for the quantification of polymorphonuclear leukocytes in selected tissues and that appropriate controls are essential. Previous studies in which myeloperoxidase levels have been used to estimate polymorphonuclear leukocyte numbers in cardiac tissue will need reevaluation.

Animals↗
PubMed1987

An animal model for chronic infection of the unobstructed urinary tract.

Chronic cystitis due to Escherichia coli is frequently associated with anatomical or functional abnormalities of the lower urinary tract, but there is no satisfactory animal model available to help resolve biological and management problems. We have induced chronic infection of the unobstructed urinary tract in the rat by implanting a small polyurethane sponge into the dome of the bladder, 14 days before bacterial challenge. This manipulation provides a focus of infected urine and leads to the establishment of a chronic cystitis. Both the predisposing factor and the pathological details mimic important features of the disease in man.

Animals↗
PubMed1986

Sustained release of a corticosteroid using polymeric implants.

An effective sustained release method of drug administration, using methylprednisolone incorporated into acrylic bone cement, has been developed. The effect of this form of treatment on peripheral blood leukocytes, lymphoid tissue weight and the inflammatory response has been evaluated. This mode of methylprednisolone administration was compared with conventional systemic therapy and was found to produce rapid and prolonged pharmacological effects at very low plasma levels of drug. A dose response relationship was established and we determined that, for a given quantity of drug, the level and duration of suppression was greater using sustained release therapy. The inflammatory response was also depressed using this mode of administration. These results, coupled with the commercial availability and existing clinical approval of SIMPLEX P bone cement, suggest that further development may lead to useful clinical protocols.

Adrenal Cortex Hormones↗
PubMed1986

Mucosal mast cells as a component of the inflammatory response to lower-urinary tract infection.

Globule cells have been observed in mucosae for many years. Recently, a subpopulation of these globule cells in the intestinal mucosa of man and rodents have been identified as unique mast cells. In this communication, intraepithelial globule cells and some lamina-propria mast cells found in the normal rat urinary-bladder wall have been characterized as mucosal mast cells, similar to intestinal mast cells, and differentiated morphologically and histochemically from rat peritoneal mast cells. The number of mast cells in the bladder wall increased significantly during various bladder manipulations, including mechanical trauma, parasitic infestation and bacterial infection. The origin and function of the mucosal mast cells remains unknown.

Animals↗
PubMed1985

Extended immunosuppression with cyclophosphamide using controlled-release polymeric implants.

An effective method of prolonged immunosuppressive therapy using cyclophosphamide incorporated into acrylic bone cement has been developed. We have studied the effect of this form of administration of cyclophosphamide on circulating immune cells and the inflammatory response. When the slow release mode of cyclophosphamide administration was compared with conventional systemic therapy, it was found to produce a more rapid and prolonged immunosuppression. A dose-response relationship was established and the biological effects of varying the composition and surface area of the implant were determined. The inflammatory response, assessed by measuring the mobilisation of cells into subcutaneously implanted sponges, was also depressed using this mode of administration. These results, coupled with the commercial availability and existing clinical approval of Simplex P bone cement, suggest that the procedure could lead to useful clinical protocols.

Animals↗
PubMed1985

Host immune status in uraemia. VI. Leucocytic response to bacterial infection in chronic renal failure.

Infection often complicates renal failure and frequently causes death, but the association between renal failure, impaired immunity and infection has not been proved. A recent study showed that patients on dialysis did not show an expected leucocytic response to infection, suggesting that the blunted response was evidence of the immunocompromised state of the uraemic patient. In this study, the relationship between leucocytic responses and infectious challenge was investigated in an animal model of chronic renal failure. Bacteraemia, peritonitis and a chronic lung infection were induced in normal and uraemic rats; the leucocytic response was then monitored. In all three infections, the total white blood cell response was significantly less in the uraemic animals. Neutrophil numbers actually increased, but this response was disguised by a pronounced depression in lymphocyte numbers. Our conclusion is that, although the leucocytic response of the uraemic host to infection may be depressed, the changes to individual leucocyte components in the peripheral blood are sufficiently characteristic to provide useful evidence of infection.

Animals↗
PubMed1985

Immunopotentiation in infectious disease, I. Effect of bestatin on the immune response.

Few immunomodulators are available for the control of infectious disease. One reason has been the lack of a suitable protocol for evaluating such agents. We have presented a series of assays of immune function that will allow a standardized approach to this problem. The value of this protocol has been established using long-term low dose, and short-term high dose, administration of bestatin, a small molecular weight microbial product. The experiments were done using both normal and immunocompromised animals. Bestatin had no effect on circulating leukocytes or the reticuloendothelial system. Leukocyte mobilization and T cell responsiveness in immunocompromised animals were enhanced following bestatin treatment. The antibody response to SRBC doubled in normal animals while the same treatment schedule resulted in a marked reduction in the response to Escherichia coli lipopolysaccharide. These results have established the value of the protocol and identified some new immunomodulating properties of bestatin which may be useful in the control of infectious disease.

Adjuvants, Immunologic↗