Browsing by Author "Fischer, Carrie D."

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    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.
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    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.
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    Novel anti-inflammatory and pro-resolving mechanisms of antibiotics: leukocyte apoptosis, inhibition of nf-kb, and modulation of lipid signaling by tulathromycin
    (2012) Fischer, Carrie D.; Buret, Andre G.
    The accumulation of neutrophils and inflammatory mediators, such as interleukin- 8 (CXCL-8) and leukotriene B4 (LTB4), are classic markers of inflammatory disease. Clearance of apoptotic neutrophil, inhibition of pro-inflammatory signaling, and production of pro-resolving mediators, including lipoxins (LXA4), are imperative for resolving inflammation. Findings indicate that immunomodulation by macrolide antibiotics generate anti-inflammatory benefits via mechanisms that remain obscure. Tulathromycin, a new antimicrobial macrolide for bovine respiratory disease (BRD), offers superior clinical efficacy for reasons not fully understood. The pathogenesis of BRD is due, at least in part, to the severe host inflammatory response to invading pathogens, such as Mannheirnia haernolytica. The aim of this study was to identify immunomodulating actions of tulathromycin and, in the process, establish tulathromycin as a new model for characterizing novel anti-inflammatory properties of antibiotics. To investigate the effects of tulathromycin in vivo, calves were challenged intra­tracheally with live M. haemolytica or zymosan, and treated with vehicle or tulathromycin. Bronchoalveolar lavage samples collected 3 and 24 h post-challenge indicated that tulathromycin promoted neutrophil apoptosis and clearance of these cells by alveolar macrophages. In addition, tulathromycin reduced pulmonary levels of LTB4 and prostaglandin E2 (PGE2); however, there was no effect of tulathromycin on neutrophil trafficking to the lungs. In vitro, tulathromycin cell-selectively and dose­dependently induced apoptosis in bovine neutrophils and macrophages. The pro-apoptotic effects of tulathromycin were caspase-dependent, and occurred in the presence and absence of live M. haemolytica. Tulathromycin increased surface expression of phosphatidylserine on neutrophils, which were readily phagocytosed by bovine macrophages. There was no apparent effect of tulathromycin on oxidative burst in neutrophils. Furthermore, tulathromycin blocked NF-KB signaling and production of CXCL-8 in LPS-stimulated neutrophils and macrophages. Tulathromycin inhibited activity of anti-apoptotic and pro-inflammatory phospholipase D (PLD) and cytosolic PLA2, the latter blocking, at least in part, the production of LTB4 in neutrophils. In contrast, tulathrornycin promoted the secretion of the pro-resolving lipid mediator, lipoxin A4, in neutrophils. Lastly, tulathromycin promoted the intracellular accumulation of phospholipids in neutrophils. Collectively, the findings illustrate novel mechanisms through which tulathromycin confers anti-inflammatory benefits, and in turn, shed light on promising avenues for the development of novel, improved, therapeutics.