{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T23:12:01Z","timestamp":1784157121389,"version":"3.55.0"},"reference-count":60,"publisher":"American Veterinary Medical Association (AVMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["ajvr"],"published-print":{"date-parts":[[2015,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n<jats:p><jats:bold>OBJECTIVE<\/jats:bold> To investigate the anti-inflammatory and immunomodulatory properties of tulathromycin in vitro and in experimental models of <jats:italic>Actinobacillus pleuropneumoniae<\/jats:italic>\u2013induced pleuropneumonia and zymosan-induced pulmonary inflammation in pigs.<\/jats:p>\n<jats:p><jats:bold>ANIMALS<\/jats:bold> 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\u2013free pigs.<\/jats:p>\n<jats:p><jats:bold>PROCEDURES<\/jats:bold> 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 <jats:italic>A pleuropneumoniae<\/jats:italic>, 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.<\/jats:p>\n<jats:p><jats:bold>RESULTS<\/jats:bold> In vitro, tulathromycin induced time- and concentration-dependent apoptosis in neutrophils, which enhanced their subsequent clearance by macrophages. In the lungs of both <jats:italic>A pleuropneumoniae<\/jats:italic>\u2013 and zymosan-challenged pigs, tulathromycin promoted leukocyte apoptosis and efferocytosis and inhibited proinflammatory leukotriene B<jats:sub>4<\/jats:sub> 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 <jats:italic>A pleuropneumoniae<\/jats:italic>\u2013inoculated pigs.<\/jats:p>\n<jats:p><jats:bold>CONCLUSIONS AND CLINICAL RELEVANCE<\/jats:bold> Tulathromycin had immunomodulatory effects in leukocytes in vitro and anti-inflammatory effects in pigs in experimental models of <jats:italic>A pleuropneumoniae<\/jats:italic> 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.<\/jats:p>","DOI":"10.2460\/ajvr.76.6.507","type":"journal-article","created":{"date-parts":[[2015,5,22]],"date-time":"2015-05-22T14:52:39Z","timestamp":1432306359000},"page":"507-519","source":"Crossref","is-referenced-by-count":14,"title":["Immunomodulatory effects of tulathromycin on apoptosis, efferocytosis, and proinflammatory leukotriene B4 production in leukocytes from Actinobacillus pleuropneumoniae\u2013or zymosan-challenged pigs"],"prefix":"10.2460","volume":"76","author":[{"given":"Stephanie C.","family":"Duquette","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie D.","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison C.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saman","family":"Sajedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Troy D.","family":"Feener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amol","family":"Bhargava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen L.","family":"Reti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory P.","family":"Muench","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas W.","family":"Morck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Allison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merlyn J.","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre G.","family":"Buret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1272","reference":[{"key":"ref1","series-title":"Pathobiology of acute pulmonary lesions in swine infected with Haemophilus (Actinobacillus) pleuropneumoniae","first-page":"574","volume":"29","author":"Bertram","year":"1988"},{"key":"ref2","series-title":"Inflammation\u2014role of the neutrophil and eosinophil","first-page":"14","volume":"15","author":"Gompertz","year":"2000"},{"key":"ref3","series-title":"Tumour necrosis factor-\u03b1 and leukotriene B4 mediate neutrophil migration in immune inflammation","first-page":"1619","volume":"134","author":"Canetti","year":"2001"},{"key":"ref4","series-title":"Leukotriene B4 is a potent and stereospecific stimulator of neutrophil chemotaxis and adherence","first-page":"658","volume":"58","author":"Palmblad","year":"1981"},{"key":"ref5","series-title":"Usefulness of lactate dehydrogenase and its isoenzymes as indicators of lung damage or inflammation","first-page":"1736","volume":"9","author":"Drent","year":"1996"},{"key":"ref6","series-title":"A blast from the past: clearance of apoptotic cells regulates immune responses","first-page":"965","volume":"2","author":"Savill","year":"2002"},{"key":"ref7","series-title":"Granulocyte apoptosis and its role in the resolution and control of lung inflammation","first-page":"S5","volume":"160","author":"Haslett","year":"1999"},{"key":"ref8","series-title":"Impairment of function in aging neutrophils is associated with apoptosis","first-page":"5124","volume":"150","author":"Whyte","year":"1993"},{"key":"ref9","series-title":"Phagocyte recognition of cells undergoing apoptosis","first-page":"131","volume":"14","author":"Savill","year":"1993"},{"key":"ref10","series-title":"Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine\/paracrine mechanisms involving TGF-\u03b2, PGE2, and PAF","first-page":"890","volume":"101","author":"Fadok","year":"1998"},{"key":"ref11","series-title":"Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages","first-page":"865","volume":"83","author":"Savill","year":"1989"},{"key":"ref12","series-title":"How dying cells alert the immune system to danger","first-page":"279","volume":"8","author":"Kono","year":"2008"},{"key":"ref13","series-title":"Actinobacillus species and their role in animal disease","first-page":"18","volume":"159","author":"Rycroft","year":"2000"},{"key":"ref14","series-title":"Haemophilus pleuropneumoniae infection in swine: a review","first-page":"1331","volume":"182","author":"Sebunya","year":"1983"},{"key":"ref15","series-title":"Comparative virulence of NAD-dependent and NAD-independent Actinobacillus pleuropneumoniae strains","first-page":"303","volume":"39","author":"Dom","year":"1992"},{"key":"ref16","series-title":"Actinobacillus pleuropneumoniae disease and serology","first-page":"161","volume":"7","author":"Marsteller","year":"1999"},{"key":"ref17","series-title":"Effects of oral administration of tilmicosin on pulmonary inflammation in piglets experimentally infected with Actinobacillus pleuropneumoniae","first-page":"100","volume":"66","author":"Nerland","year":"2005"},{"key":"ref18","series-title":"Understanding the pharmacokinetics of tulathromycin: a pulmonary perspective","first-page":"211","volume":"37","author":"Villarino","year":"2014"},{"key":"ref19","series-title":"Effects of erythromycin on experimental extrinsic allergic alveolitis","first-page":"253","volume":"29","author":"Miyajima","year":"1999"},{"key":"ref20","series-title":"Antiasthmatic activity of macrolide antibiotic, roxithromycin: analysis of possible mechanisms in vitro and in vivo","first-page":"308","volume":"105","author":"Konno","year":"1994"},{"key":"ref21","series-title":"Significance of IL-1\u03b2 and IL-1 receptor antagonist (IL-1Ra) in bronchoalveolar lavage fluid (BALF) in patients with diffuse panbrochiolitis (DPB)","first-page":"461","volume":"103","author":"Kadota","year":"1996"},{"key":"ref22","series-title":"Effect of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6, IL-8 and sICAM-1 by cultured human bronchial epithelial cells","first-page":"1451","volume":"8","author":"Khair","year":"1995"},{"key":"ref23","series-title":"Role of interleukin-8 (IL-8) and an inhibitory effect of erythromycin on IL-8 release in the airways of patients in chronic airway diseases","first-page":"4145","volume":"62","author":"Oishi","year":"1994"},{"key":"ref24","series-title":"Inhibitory effect of erythromycin on interleukin 8 production by 1 alpha,25-dihydroxyvitamin D3-stimulated THP-1 cells","first-page":"1548","volume":"40","author":"Fujii","year":"1996"},{"key":"ref25","series-title":"Effect of antibiotics on the generation of reactive oxygen species","first-page":"449","volume":"86","author":"Miyachi","year":"1986"},{"key":"ref26","series-title":"Antibiotic inhibition of the respiratory burst response in human polymorphonuclear leukocytes","first-page":"863","volume":"34","author":"Hand","year":"1990"},{"key":"ref27","series-title":"Erythromycin shortens neutrophil survival by accelerating apoptosis","first-page":"872","volume":"39","author":"Aoshiba","year":"1995"},{"key":"ref28","series-title":"Immuno-modulation and anti-inflammatory benefits of antibiotics: the example of tilmicosin","first-page":"1","volume":"74","author":"Buret","year":"2010"},{"key":"ref29","series-title":"Anti-inflammatory benefits of tilmicosin in calves with Pasteurella haemolytica\u2013infected lungs","first-page":"765","volume":"59","author":"Chin","year":"1998"},{"key":"ref30","series-title":"Tilmicosin induces apoptosis in bovine neutrophils in the presence of in the absence of Pasteurella haemolytica and promotes neutrophil phagocytosis by macrophages","first-page":"2465","volume":"44","author":"Chin","year":"2000"},{"key":"ref31","series-title":"Anti-inflammatory benefits of antibiotic-induced neutrophil apoptosis: tulathromycin induces caspase-3-dependent neutrophil programmed cell death and inhibits NF-\u03baPB signaling and CXCL8 transcription","first-page":"338","volume":"55","author":"Fischer","year":"2011"},{"key":"ref32","series-title":"Tulathromycin: an overview of a new tiamilide antibiotic for livestock respiratory disease","first-page":"83","volume":"6","author":"Evans","year":"2005"},{"key":"ref33","series-title":"Cellular uptake of the triamilide tulathromycin by bovine and porcine phagocytic cells in vitro","first-page":"186","volume":"82","author":"Siegel","year":"2004"},{"key":"ref34","series-title":"Direct and indirect anti-inflammatory effects of tulathromycin in bovine macrophages: inhibition of CXCL-8 secretion, induction of apoptosis, and promotion of efferocytosis","first-page":"1385","volume":"57","author":"Fischer","year":"2013"},{"key":"ref35","series-title":"Tulathromycin exerts pro-resolving effects in bovine neutrophils by inhibiting phospholipases and altering leukotriene B4, prostaglandin E2, and lipoxin A4 production","first-page":"4298","volume":"58","author":"Fischer","year":"2014"},{"key":"ref36","series-title":"An automated myeloperoxidase assay","first-page":"158","volume":"36","author":"Krueger","year":"1990"},{"key":"ref37","series-title":"Tilmicosin-induced bovine neutrophil apoptosis is cell-specific and downregulates spontaneous LTB4 synthesis without increasing Fas expression","first-page":"213","volume":"35","author":"Lee","year":"2004"},{"key":"ref38","series-title":"Standards and policies","year":"2015"},{"key":"ref39","series-title":"Nuclear staining with alum hematoxylin","first-page":"159","volume":"84","author":"Llewellyn","year":"2009"},{"key":"ref40","series-title":"American Registry of Pathology manual of histologic staining methods of the Armed Forces Institute of Pathology","first-page":"122","author":"Luna","year":"1960"},{"key":"ref41","series-title":"Clinical implications of the immunomodulatory effects of macrolides","first-page":"5S","volume":"117","author":"Tamaoki","year":"2004"},{"key":"ref42","series-title":"Virulence factors of Actinobacillus pleuropneumoniae involved in colonization, persistence and induction of lesions in its porcine host","first-page":"65","volume":"41","author":"Chiers","year":"2010"},{"key":"ref43","series-title":"Endobronchial inoculation with Apx toxins of Actinobacillus pleuropneumoniae leads to pleuropneumonia in pigs","first-page":"4350","volume":"65","author":"Kamp","year":"1997"},{"key":"ref44","series-title":"Apoptosis, oxidative metabolism and interleukin-8 production in human neutrophils exposed to azithromycin: effects of Streptococcus pneumoniae","first-page":"19","volume":"46","author":"Koch","year":"2000"},{"key":"ref45","series-title":"Macrolide antibiotics induce apoptosis of human peripheral lymphocytes in vitro","first-page":"247","volume":"24","author":"Ishimatsu","year":"2004"},{"key":"ref46","series-title":"Anti-inflammatory capabilities of macrolides","first-page":"451","volume":"44","author":"Zalewska-Kaszubska","year":"2001"},{"key":"ref47","series-title":"Erythromycin inhibits transcriptional activation of NF-\u03baPB, but not NFAT, through calcineurin-independent signaling in T cells","first-page":"2678","volume":"43","author":"Aoki","year":"1999"},{"key":"ref48","series-title":"Telithromycin inhibits the production of proinflammatory mediators and the activation of NF-\u03baPB in in vitro-stimulated murine cells","first-page":"343","volume":"53","author":"Leiva","year":"2008"},{"key":"ref49","series-title":"Macrolides attenuate mucus hypersecretion in rat airways through inactivation of NF-\u03baPB","first-page":"63","volume":"13","author":"Ou","year":"2008"},{"key":"ref50","series-title":"Resolution of inflammation: the beginning programs the end","first-page":"1191","volume":"6","author":"Serhan","year":"2005"},{"key":"ref51","series-title":"Inflammatory resolution: new opportunities for drug discovery","first-page":"401","volume":"3","author":"Gilroy","year":"2004"},{"key":"ref52","series-title":"Apoptosis of neutrophils","first-page":"56","volume":"111","author":"Maianski","year":"2004"},{"key":"ref53","series-title":"Early events in spontaneous neutrophil apoptosis","first-page":"461","volume":"32","author":"Scheel-Toellner","year":"2004"},{"key":"ref54","series-title":"Effect of apoptosis of phagocytosis, respiratory burst and CD18 adhesion receptor expression of bovine neutrophils","first-page":"37","volume":"22","author":"Van Oostveldt","year":"2002"},{"key":"ref55","series-title":"Recognition and phagocytosis of cells undergoing apoptosis","first-page":"491","volume":"53","author":"Savill","year":"1997"},{"key":"ref56","series-title":"Phosphatidylserine externalization is a downstream event of interleukin-1-\u03b2-converting enzyme family protease activation during apoptosis","first-page":"2060","volume":"89","author":"Naito","year":"1997"},{"key":"ref57","series-title":"Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways","first-page":"445","volume":"35","author":"Ravichandran","year":"2011"},{"key":"ref58","series-title":"Phagocytosis of apoptotic cells","first-page":"280","volume":"44","author":"Hart","year":"2008"},{"key":"ref59","series-title":"Secondary necrosis: the natural outcome of the complete apoptotic program","first-page":"4491","volume":"584","author":"Silva","year":"2010"},{"key":"ref60","series-title":"Efficacy of tulathromycin in the treatment of respiratory disease in pigs caused by Actinobacillus pleuropneumoniae","first-page":"433","volume":"158","author":"Hart","year":"2006"}],"container-title":["American Journal of Veterinary 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