title: Anti-inflammatory effects of retinoids and carotenoid derivatives on caspase-3-dependent apoptosis and efferocytosis of bovine neutrophils.
abstract: 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.
  
  
  METHODS
  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.
  
  
  METHODS
  In vitro, neutrophils and monocyte-derived macrophages isolated from blood of healthy Angus heifers were treated with all-trans retinoic acid (1 μM) 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
  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.
authors.affiliation: Department of Biological Science, the Inflammation Research Network, Faculty of Science, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Duquette
authors.forename: Carrie D
authors.initials: CD
authors.lastname: Fischer
authors.forename: Troy D
authors.initials: TD
authors.lastname: Feener
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Muench
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Morck
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Barreda
authors.forename: James G
authors.initials: JG
authors.lastname: Nickerson
authors.forename: Andre G
authors.initials: AG
authors.lastname: Buret
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid; D002338:Carotenoids / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism*; D002417:Cattle; D005260:Female; D007962:Leukocytes; D007975:Leukotriene B4; D008264:Macrophages / Q000276:immunology; D008297:Male; D016978:Mannheimia haemolytica / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects*; D016871:Pasteurellaceae Infections / Q000276:immunology / Q000382:microbiology / Q000662:veterinary; D010587:Phagocytosis / Q000187:drug effects; D012176:Retinoids / Q000494:pharmacology*; D015054:Zymosan / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D012176:Retinoids; D007975:Leukotriene B4; D002338:Carotenoids; D015054:Zymosan; D053148:Caspase 3