Veterinary Biosciences - Research Publications
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ItemNo Preview AvailableH5N1 infection causes rapid mortality and high cytokine levels in chickens compared to ducks(ELSEVIER, 2014-06-24)Infection with H5N1 influenza virus is often fatal to poultry with death occurring in hours rather than days. However, whilst chickens may be acutely susceptible, ducks appear to be asymptomatic to H5N1. The mechanisms of disease pathogenesis are not well understood and the variation between different species requires investigation to help explain these species differences. Here we investigated the expression of several key proinflammatory cytokines of chickens and ducks following infection with 2 highly pathogenic H5N1 (A/Muscovy duck/Vietnam/453/2004 (Vt453) and A/Duck/Indramayu/BBVW/109/2006 (Ind109)) and a low-pathogenic H5N3 influenza virus (A/Duck/Victoria/1462/2008 (Vc1462)). H5N1 viruses caused fatal infections in chickens as well as high viral loads and increased production of proinflammatory molecules when compared to ducks. Cytokines, including Interleukin 6 (IL6) and the acute phase protein Serum Amyloid A (SAA), were rapidly induced at 24h post infection with H5N1. In contrast, low induction of these cytokines appeared in ducks and only at later times during the infection period. These observations support that hypercytokinemia may contribute to pathogenesis in chickens, whilst the lower cytokine response in ducks may be a factor in their apparent resistance to disease and decreased mortality.
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ItemIncreased Inducible Nitric Oxide Synthase Expression in Organs Is Associated with a Higher Severity of H5N1 Influenza Virus Infection(PUBLIC LIBRARY SCIENCE, 2011-01-19)BACKGROUND: The mechanisms of disease severity caused by H5N1 influenza virus infection remain somewhat unclear. Studies have indicated that a high viral load and an associated hyper inflammatory immune response are influential during the onset of infection. This dysregulated inflammatory response with increased levels of free radicals, such as nitric oxide (NO), appears likely to contribute to disease severity. However, enzymes of the nitric oxide synthase (NOS) family such as the inducible form of NOS (iNOS) generate NO, which serves as a potent anti-viral molecule to combat infection in combination with acute phase proteins and cytokines. Nevertheless, excessive production of iNOS and subsequent high levels of NO during H5N1 infection may have negative effects, acting with other damaging oxidants to promote excessive inflammation or induce apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: There are dramatic differences in the severity of disease between chickens and ducks following H5N1 influenza infection. Chickens show a high level of mortality and associated pathology, whilst ducks show relatively minor symptoms. It is not clear how this varying pathogenicty comes about, although it has been suggested that an overactive inflammatory immune response to infection in the chicken, compared to the duck response, may be to blame for the disparity in observed pathology. In this study, we identify and investigate iNOS gene expression in ducks and chickens during H5N1 influenza infection. Infected chickens show a marked increase in iNOS expression in a wide range of organs. Contrastingly, infected duck tissues have lower levels of tissue related iNOS expression. CONCLUSIONS/SIGNIFICANCE: The differences in iNOS expression levels observed between chickens and ducks during H5N1 avian influenza infection may be important in the inflammatory response that contributes to the pathology. Understanding the regulation of iNOS expression and its role during H5N1 influenza infection may provide insights for the development of new therapeutic strategies in the treatment of avian influenza infection.
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ItemLYMPHOCYTE SUBSETS SHOW MARKED DIFFERENCES IN THEIR DISTRIBUTION BETWEEN BLOOD AND THE AFFERENT AND EFFERENT LYMPH OF PERIPHERAL LYMPH-NODES(ROCKEFELLER UNIV PRESS, 1988-06-01)The surface phenotypes (CD1, CD4, CD5, CD8, SBU-T19, MHC class I, MHC class II, and sIg) of cells in blood, lymph nodes, and lymph were determined to examine simultaneously the distribution of lymphocyte subsets circulating in blood, afferent lymph, and efferent lymph of a peripheral lymph node. Marked differences in the percentage of certain lymphocyte subsets were apparent within the compartments examined, suggesting that lymphocyte subsets leave the blood with differing efficiencies. Lymphocyte subsets also appeared to be extracted from the blood at different rates by lymph node as opposed to subcutaneous vascular endothelium. Endothelial cells in different vascular beds may express different numbers of molecules complementary to a set of migration-related cell surface molecules specific for each lymphocyte subset. Accordingly, the vascular endothelium would be the key factor in regulating nonrandom cell migration.
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ItemAntigen-independent maturation of CD2, CD11a/CD18, CD44, and CD58 expression on thymic emigrants in fetal and postnatal sheep(HARWOOD ACAD PUBL GMBH, 1995)We have compared the expression of CD2, CD11a/CD18, CD44, and CD58 and alpha beta and gamma delta T cells emigrating from the fetal and postnatal thymus. We report that both gamma delta and the CD4+CD8- and CD4-CD8+ subsets of alpha beta T cells express mature levels of the adhesion molecules CD11a/CD18, CD44, and CD58 upon emigration from the thymus. Whereas CD44 is up-regulated on gamma delta + thymocytes prior to export, down-regulation of both CD11a/CD18 and CD58 occurs prior to emigration from the thymus, suggesting that down-regulation of these molecules may be a final maturational step taken by developing gamma delta T cells before their export from the thymus. In contrast, there is continued up-regulation of CD2 on gamma delta and alpha beta T cells upon emigration from the thymus and as they move into the mature peripheral T-cell pool. There was also a marked reduction in the number of CD2+ gamma delta T cells exported during fetal development that was associated with a marked reduction in the percentage of CD2+ gamma delta thymocytes exported. The postthymic maturation of CD2 and the other changes in adhesion-molecule expression appear to be independent of extrinsic antigen, as the same changes were observed in the antigen-free environment of the fetus as in the postnatal lamb, which has been exposed to extrinsic antigen. It thus appears that these changes in adhesion-molecule expression are as a result of the normal maturation pathway from a developing thymocyte to a mature peripheral T cell.
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ItemStructural and functional correlations in a large animal model of bleomycin-induced pulmonary fibrosis(BMC, 2015-07-31)BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a severe and progressive respiratory disease with poor prognosis. Despite the positive outcomes from recent clinical trials, there is still no cure for this disease. Pre-clinical animal models are currently largely limited to small animals which have a number of shortcomings. We have previously shown that fibrosis is induced in isolated sheep lung segments 14 days after bleomycin treatment. This study aimed to determine whether bleomycin-induced fibrosis and associated functional changes persisted over a seven-week period. METHODS: Two separate lung segments in nine sheep received two challenges two weeks apart of either, 3U bleomycin (BLM), or saline (control). Lung function in these segments was assessed by a wedged-bronchoscope procedure after bleomycin treatment. Lung tissue, and an ex vivo CT analysis were used to assess for the persistence of inflammation, fibrosis and collagen content in this model. RESULTS: Fibrotic changes persisted up to seven weeks in bleomycin-treated isolated lung segments (Pathology scores: bleomycin12.27 ± 0.07 vs. saline 4.90 ± 1.18, n = 9, p = 0.0003). Localization of bleomycin-induced injury and increased tissue density was confirmed by CT analysis (mean densitometric CT value: bleomycin -698 ± 2.95 Hounsfield units vs. saline -898 ± 2.5 Hounsfield units, p = 0.02). Masson's trichrome staining revealed increased connective tissue in bleomycin segments, compared to controls (% blue staining/total field area: 8.5 ± 0.8 vs. 2.1 ± 0.2 %, n = 9, p < 0.0001). bleomycin-treated segments were significantly less compliant from baseline at 7 weeks post treatment compared to control-treated segments (2.05 ± 0.88 vs. 4.97 ± 0.79 mL/cmH20, n = 9, p = 0.002). There was also a direct negative correlation between pathology scores and segmental compliance. CONCLUSIONS: We show that there is a correlation between fibrosis and correspondingly poor lung function which persist for up to seven weeks after bleomycin treatment in this large animal model of pulmonary fibrosis.
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ItemDevelopment of an ovine efferent mammary lymphatic cannulation model with minimal tissue damage(BIOMED CENTRAL LTD, 2016-12-12)BACKGROUND: Two mammary lymphatic cannulation models in sheep have been described with minimal use in the past 50 years. The purpose of this study was to investigate a new surgical technique to allow long term monitoring of mammary lymph flow and composition from the mammary glands, with rapid ewe recovery and minimal complications post-surgery. RESULTS: We developed a modified methodology for cannulating the efferent mammary lymphatic from the mammary lymph node with minimum tissue damage. Compared to the previous models, our method required only a small incision on the aponeurosis of the external abdominal oblique muscles and thus reduced the difficulties in suturing the aponeurosis. It allowed for lymph collection and assessment for at least one week post-surgery with concurrent milk collection. CONCLUSION: This method allows for good ewe recovery post-surgery and in vivo sampling of efferent mammary lymph from the mammary lymph nodes in real-time and comparison with milk parameters.
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ItemCharacterisation of ovine lymphatic vessels in fresh specimens(PUBLIC LIBRARY SCIENCE, 2019-01-16)BACKGROUND AND AIM: The development and use of experimental models using lymphatic cannulation techniques have been hampered by the lack of high-quality colour imaging of lymphatic vessels in situ. Most descriptions of lymphatic anatomy in sheep have historically depended on schematic diagrams due to limitations in the ability to publish colour images of the lymphatic vessels with decent resolution. The aim of this work was to encourage more widespread use of the ovine cannulation model by providing clear photographic images identifying the location and anatomical layout of some major lymphatic ducts and their in situ relationship to surrounding tissues. METHODS: The cadavers of the sheep were collected after they had been euthanized at the end of animal trials not associated with this study. The lymphatics were dissected and exposed to show their appearance in the surrounding tissues and their relationship to other organs. Patent Blue was used to locate lymphatic vessels in exploratory preparations. However, in order to present the natural appearance of the vessels, we used minimal dissection and dye was not used for the photographed examples. Instead, we have indicated the course of the vessels with lines where their position is less clear. RESULTS AND CONCLUSION: In this paper, we have used sheep specimens as examples to show characteristic images of lymphatic vessels. The images of in situ lymphatics and lymph nodes combined with schematic summaries provide a concise illustration of the lymphatic drainage scheme in sheep.
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ItemImmunoselected STRO-3+ mesenchymal precursor cells reduce inflammation and improve clinical outcomes in a large animal model of monoarthritis(BMC, 2017-02-07)BACKGROUND: The purpose of this study was to investigate the therapeutic efficacy of intravenously administered immunoselected STRO-3 + mesenchymal precursor cells (MPCs) on clinical scores, joint pathology and cytokine production in an ovine model of monoarthritis. METHODS: Monoarthritis was established in 16 adult merino sheep by administration of bovine type II collagen into the left hock joint following initial sensitization to this antigen. After 24 h, sheep were administered either 150 million allogeneic ovine MPCs (n = 8) or saline (n = 8) intravenously (IV). Lameness, joint swelling and pain were monitored and blood samples for leukocytes and cytokine levels were collected at intervals following arthritis induction. Animals were necropsied 14 days after arthritis induction and gross and histopathological evaluations were undertaken on tissues from the arthritic (left) and contralateral (right) joints. RESULTS: MPC-treated sheep demonstrated significantly reduced clinical signs of lameness, joint pain and swelling compared with saline controls. They also showed decreased cartilage erosions, synovial stromal cell activation and angiogenesis. This was accompanied by decreased infiltration of the synovial tissues by CD4+ lymphocytes and CD14+ monocytes/macrophages. Over the 3 days following joint arthropathy induction, the numbers of neutrophils circulating in the blood and plasma concentrations of activin A were significantly reduced in animals administered MPCs. CONCLUSIONS: The results of this study have demonstrated the capacity of IV-administered MPCs to mitigate the clinical signs and some of the inflammatory mediators responsible for joint tissue destruction in a large animal model of monoarthritis.
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ItemChanges in duodenal CD163-positive cells in dogs with chronic enteropathy after successful treatment(SAGE PUBLICATIONS LTD, 2018-10)Chronic enteropathy (CE) in dogs is characterized retrospectively per treatment response as food-responsive enteropathy (FRE), antibiotic-responsive enteropathy (ARE), and immunosuppressant-responsive enteropathy (IRE) - the latter most resembling inflammatory bowel disease in people. The aim of this study was to characterize duodenal macrophages (Mϕ) in CE using immunohistochemistry; with calprotectin (CAL) as a marker of early differentiated Mϕ and CD163 expression as a marker for resident Mϕ in the duodenum before and after treatment. Prior to treatment, dogs with FRE and IRE had a lower CD163+/CAL+ ratio than control dogs (CTRL) in crypts; this increased significantly and normalized compared with CTRL after treatment. Conversely, the CD163+/CAL+ ratio in dogs with ARE was comparable to that in healthy dogs before and after treatment. In summary, these results suggest that Mϕ play a role in the pathogenesis of CE in FRE and IRE, with a decrease in resident Mϕ and an increase in early differentiated Mϕ, but not in ARE dogs. Mϕ normalize after successful treatment.
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ItemNo Preview AvailableClinical and histopathological characterization of a large animal (ovine) model of collagen-induced arthritis(Elsevier BV, 2014)Collagen induced arthritis (CIA) is the most studied and used rheumatoid arthritis (RA) model in animals, as it shares many pathological and immunological features of the human disease. The aim of this study was to characterize clinical and immunological aspects of the ovine CIA model, and develop lameness and histopathological scoring systems, in order to validate this model for use in therapeutic trials. Sheep were sensitized to bovine type II collagen (BCII), arthritis was induced by injection of bovine collagen type II into the hock joint and the response was followed for two weeks. Clinical signs of lameness and swelling were evident in all sheep and gross thickening of the synovium surrounding the tibiotarsal joint and erosion on the cartilage surface in the arthritic joints. Leucocyte cell counts were increased in synovial fluid and there was synovial hyperplasia, thickening of the intimal layer, inflammation and marked angiogenesis in the synovial tissue. There was a large influx of monocytes and lymphocytes into the synovial tissue, and increased expression of TNF-α and IL-1β in arthritic intima, angiogenesis and upregulation of VCAM-1. CIA in sheep appears to be an excellent large animal model of RA and has the potential for testing biological therapeutics for the treatment of rheumatoid arthritis. © 2014 Elsevier B.V. All rights reserved.