title: Immunomodulatory effects of tulathromycin on apoptosis, efferocytosis, and proinflammatory leukotriene B4 production in leukocytes from Actinobacillus pleuropneumoniae-or zymosan-challenged pigs.
abstract: OBJECTIVE
  To investigate the anti-inflammatory and immunomodulatory properties of tulathromycin in vitro and in experimental models of Actinobacillus pleuropneumoniae-induced pleuropneumonia and zymosan-induced pulmonary inflammation in pigs.
  
  
  METHODS
  Blood samples from six 8- to 30-week-old healthy male pigs for the in vitro experiment and sixty-five 3-week-old specific pathogen-free pigs.
  
  
  METHODS
  Neutrophils and monocyte-derived macrophages were isolated from blood samples. Isolated cells were exposed to tulathromycin (0.02 to 2.0 mg/mL) for various durations and assessed for markers of apoptosis and efferocytosis. For in vivo experiments, pigs were inoculated intratracheally with A pleuropneumoniae, zymosan, or PBS solution (control group) with or without tulathromycin pretreatment (2.5 mg/kg, IM). Bronchoalveolar lavage fluid was collected 3 and 24 hours after inoculation and analyzed for proinflammatory mediators, leukocyte apoptosis, and efferocytosis.
  
  
  RESULTS
  In vitro, tulathromycin induced time- and concentration-dependent apoptosis in neutrophils, which enhanced their subsequent clearance by macrophages. In the lungs of both A pleuropneumoniae- and zymosan-challenged pigs, tulathromycin promoted leukocyte apoptosis and efferocytosis and inhibited proinflammatory leukotriene B4 production, with a concurrent reduction in leukocyte necrosis relative to that of control pigs. Tulathromycin also attenuated the degree of lung damage and lesion progression in A pleuropneumoniae-inoculated pigs.
  
  
  CONCLUSIONS
  Tulathromycin had immunomodulatory effects in leukocytes in vitro and anti-inflammatory effects in pigs in experimental models of A pleuropneumoniae infection and nonmicrobial-induced pulmonary inflammation. These data suggested that in addition to its antimicrobial properties, tulathromycin may dampen severe proinflammatory responses and drive resolution of inflammation in pigs with microbial pulmonary infections.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Duquette
authors.forename: Carrie D
authors.initials: CD
authors.lastname: Fischer
authors.forename: Alison C
authors.initials: AC
authors.lastname: Williams
authors.forename: Saman
authors.initials: S
authors.lastname: Sajedy
authors.forename: Troy D
authors.initials: TD
authors.lastname: Feener
authors.forename: Amol
authors.initials: A
authors.lastname: Bhargava
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Reti
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Muench
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Morck
authors.forename: Jim
authors.initials: J
authors.lastname: Allison
authors.forename: Merlyn J
authors.initials: MJ
authors.lastname: Lucas
authors.forename: Andre G
authors.initials: AG
authors.lastname: Buret
mesh_terms: D000189:Actinobacillus Infections / Q000276:immunology / Q000662:veterinary*; D016977:Actinobacillus pleuropneumoniae; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004187:Disaccharides / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D010587:Phagocytosis / Q000187:drug effects; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000662:veterinary*; D013047:Specific Pathogen-Free Organisms; D013552:Swine; D013553:Swine Diseases / Q000188:drug therapy / Q000276:immunology*; D015054:Zymosan / Q000494:pharmacology; D018942:Macrolides
chemical_list: D000893:Anti-Inflammatory Agents; D004187:Disaccharides; D006571:Heterocyclic Compounds; D007975:Leukotriene B4; D015054:Zymosan; C485204:tulathromycin; D018942:Macrolides