Browsing by Author "Morck, Douglas W."
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Item Embargo Anti-inflammatory effects of retinoids and carotenoid derivatives on caspase-3–dependent apoptosis and efferocytosis of bovine neutrophils(American Journal of Veterinary Research, 2014-12) Duquette, Stephanie C.; Fischer, Carrie D.; Feener, Troy D.; Muench, Gregory P.; Morck, Douglas W.; Barreda, Daniel R.; Nickerson, James G.; Buret, Andre G.Objective—To evaluate immunomodulatory properties of all-trans retinoic acid and a fully oxidized β-carotene dietary product in calves with Mannheimia haemolytica–induced pneumonia. Animals—Twenty-five 6- to 10-week-old male Holstein calves for experimental inoculations and three 8- to 30-week-old Angus heifers for blood donations. Procedures—In vitro, neutrophils and monocyte-derived macrophages isolated from blood of healthy Angus heifers were treated with all-trans retinoic acid (1μM) or fully oxidized β-carotene (8.3 μg/mL) for various times and assessed for markers of cellular death, antimicrobial function, and production of proinflammatory leukotriene B4. Following 28 days of dietary supplementation with fully oxidized β-carotene, Holstein calves were experimentally inoculated with M haemolytica. Bronchoalveolar lavage fluid was collected at 3 and 24 hours after challenge inoculation and analyzed for markers of apoptosis. Results—In vitro, all-trans retinoic acid and fully oxidized β-carotene induced cell-selective, caspase-3–dependent apoptosis in neutrophils, which subsequently enhanced efferocytosis in macrophages. Conversely, neither treatment altered phorbol 12-myristate 13-acetate–induced oxidative burst, phagocytosis of nonopsonized zymosan (complement or antibody independent), or M haemolytica–induced leukotriene B4 production in bovine neutrophils. In vivo, fully oxidized β-carotene enhanced leukocyte apoptosis in bronchoalveolar lavage fluid as well as subsequent efferocytosis by macrophages without altering numbers of circulating leukocytes. Conclusions and Clinical Relevance—Neutrophil apoptosis and subsequent efferocytosis by macrophages are key mechanisms in the resolution of inflammation. Findings for the present study indicated that all-trans retinoic acid and fully oxidized β-carotene could be novel nutraceutical strategies that may confer anti-inflammatory benefits for cattle with respiratory tract disease.Item Open Access Distribution of Treponema species and antimicrobial resistance genes in digital dermatitis lesions(2018-08-04) Beninger, Caroline; De Buck, Jeroen M.; Orsel, Karin; Morck, Douglas W.Digital dermatitis lesions are ulcerative or proliferative masses between the heel bulbs. The most significant clinical outcome of digital dermatitis (DD) is lameness, leading to animal welfare concerns and economic loss for dairy producers worldwide due to premature culling, milk loss, and decreased fertility. While there is insufficient evidence to determine the etiological agent(s) responsible for DD, it is widely accepted that DD is a polymicrobial disease significantly associated with anaerobic bacteria, Treponema. Difficulties in obtaining pure cultures and the nearly exclusive presence of Treponema in diseases as members of a polytreponemal or polymicrobial communities has led to insufficient species identification within lesions and incomparable prevalence estimates based on phylotype. Our primary research objectives were to develop a diagnostic tool to identify Treponema spp. within DD lesions to associate presence and abundance with DD lesion grades. Further, we examined the distribution of antimicrobial resistance genes (AMGs) within sequenced isolates of DD-associated Treponema and designed targeted PCR for Treponema AMGs (AMGsTrep) within lesions. We provide significant evidence that the absolute quantities of Treponema and AMGsTrep are lower in chronic and early, active DD lesions suggesting Treponema spp. within these lesions may be more susceptible to antimicrobials (AMs) compared to species in advanced, active lesions. We have identified potential interactions among Treponema spp. that may facilitate DD progression and enhance pathogenicity and may affect AM susceptibility and lesion chronicity. With the novel diagnostic tool developed here, future research should elucidate interactions among Treponema spp. and in vitro susceptibility profiles and the efficacy of treating early and chronic lesions compared to advanced, active lesions on infection resolution.Item Open Access Immuno-Modulating Properties of Tulathromycin in Porcine Reproductive and Respiratory Syndrome Virus-Infected Macrophages In Vitro.(2018-08-10) Desmonts de Lamache, Dimitri; Buret, Andre G.; Morck, Douglas W.; Yates, Robin M.; Cobo, Eduardo R.With a total cost of productivity losses estimated at $600 million annually in the U.S alone, porcine reproductive and respiratory syndrome (PRRS) is a major concern in the swine industry. PRRS etiological agent, the porcine reproductive and respiratory syndrome virus (PRRSV) is a small positive-strand RNA virus that primarily grows in alveolar macrophages. Due to its high antigenic variability, and poorly understood immunopathogenesis, there is currently no treatment to control PRRSV infection. Commercially available vaccines are inefficient and cannot meet practical needs encouraging more researchers to explore different approaches to treat PRRSV infections. The common occurrence of PRRSV infection with bacterial infections as well as its inflammatory-driven pathobiology raises the question of the value of antibiotics for the treatment of the disease it causes. Tulathromycin (TUL), a macrolide antibiotic previously studied in our laboratory has been shown to exhibit potent anti-inflammatory and immunomodulatory actions in cattle and pigs. The aim of this study was to identify and characterize anti-viral and immunomodulating properties of TUL in PRRSV-infected porcine macrophages. Our findings indicate that blood monocyte-derived macrophages are readily infected by PRRSV and can be used as a cellular model to study PRRSV pathogenesis. TUL was found to not change viral titers and viral receptors (CD163 and CD169) expression suggesting that the drug does not possess direct antiviral effects against PRRSV. In addition, we showed that TUL acts synergistically with PRRSV to induce apoptosis but prevents virus-induced early necrosis. TUL was also found to attenuate PRRSV-induced macrophage pro-inflammatory signaling (CXCL-8 and mitochondrial ROS production) and prevent phagocytosis inhibition. Together, these data demonstrate that tulathromycin downregulates PRRSV-induced inflammatory response in macrophages which may in turn reduce virus-related tissue injury. More importantly, this study sheds the light on the potential clinical benefits of an antibiotic in the context of a virus-induced inflammation.Item Embargo Immuno-modulation and anti-inflammatory benefits of antibiotics: The example of tilmicosin(Canadian Journal of Veterinary Research, 2010-01) Duquette, Stephanie C.; Fischer, Carrie D.; Williams, Allison C.; Sajedy, Saman; Feener, Troy D.; Bhargava, Amol; Reti, Kristen L.; Muench, Gregory P.; Morck, Douglas W.; Allison, Jim; Lucas, Merlyn J.; Buret, Andre G.Exagerated immune responses, such as those implicated in severe inflammatory reactions, are costly to the metabolism. Inflammation and pro-inflammatory mediators negatively affect production in the food animal industry by reducing growth, feed intake, reproduction, milk production, and metabolic health. An ever-increasing number of findings have established that antibiotics, macrolides in particular, may generate anti-inflammatory effects, including the modulation of pro-inflammatory cytokines and the alteration of neutrophil function. The effects are time- and dose-dependent, and the mechanisms responsible for these phenomena remain incompletely understood. Recent studies, mostly using the veterinary macrolide tilmicosin, may have shed new light on the mode of action of some macrolides and their anti-inflammatory properties. Indeed, research findings demonstrate that this compound, amongst others, induces neutrophil apoptosis, which in turn provides anti-inflammatory benefits. Studies using tilmicosin model systems in vitro and in vivo demonstrate that this antibiotic has potent immunomodulatory effects that may explain why at least parts of its clinical benefits are independent of anti-microbial effects. More research is needed, using this antibiotic and others that may have similar properties, to clarify the biological mechanisms responsible for antibiotic-induced neutrophil apoptosis, and how this, in turn, may provide enhanced clinical benefits. Such studies may help establish a rational basis for the development of novel, efficacious, anti-microbial compounds that generate anti-inflammatory properties in addition to their antibacterial effects.Item Open Access Microarchitecture, but Not Bone Mechanical Properties, Is Rescued with Growth Hormone Treatment in a Mouse Model of Growth Hormone Deficiency(Hindawi Publishing Corporation, 2012-01-02) Kristensen, Erika; Hallgrímsson, Benedikt; Morck, Douglas W.; Boyd, Steven K.Item Open Access Microarchitecture, but Not Bone Mechanical Properties, Is Rescued with Growth Hormone Treatment in a Mouse Model of Growth Hormone Deficiency(2012-03-13) Kristensen, Erika; Hallgrímsson, Benedikt; Morck, Douglas W.; Boyd, Steven K.Growth hormone (GH) deficiency is related to an increased fracture risk although it is not clear if this is due to compromised bone quality or a small bone size. We investigated the relationship between bone macrostructure, microarchitecture and mechanical properties in a GH-deficient (GHD) mouse model undergoing GH treatment commencing at an early (prepubertal) or late (postpubertal) time point. Microcomputed tomography images of the femur and L4 vertebra were obtained to quantify macrostructure and vertebral trabecular microarchitecture, and mechanical properties were determined using finite element analyses. In the GHD animals, bone macrostructure was 25 to 43% smaller as compared to the GH-sufficient (GHS) controls (). GHD animals had 20% and 19% reductions in bone volume ratio (BV/TV) and trabecular thickness (Tb.Th), respectively. Whole bone mechanical properties of the GHD mice were lower at the femur and vertebra (67% and 45% resp.) than the GHS controls (). Both early and late GH treatment partially recovered the bone macrostructure (15 to 32 % smaller than GHS controls) and the whole bone mechanical properties (24 to 43% larger than GHD animals) although there remained a sustained 27–52% net deficit compared to normal mice (). Importantly, early treatment with GH led to a recovery of BV/TV and Tb.Th with a concomitant improvement of trabecular mechanical properties. Therefore, the results suggest that GH treatment should start early, and that measurements of microarchitecture should be considered in the management of GHD.Item Open Access Studies of the cell surface of pasteurella haemolytica-A1 and adhesion in bovine pneumonic pasteurellosis(1991) Morck, Douglas W.; Costerton, J. William F.