title: Tulathromycin exerts proresolving effects in bovine neutrophils by inhibiting phospholipases and altering leukotriene B4, prostaglandin E2, and lipoxin A4 production.
abstract: The accumulation of neutrophils and proinflammatory mediators, such as leukotriene B4 (LTB4), is a classic marker of inflammatory disease. The clearance of apoptotic neutrophils, inhibition of proinflammatory signaling, and production of proresolving lipids (including lipoxins, such as lipoxin A4 [LXA4]) are imperative for resolving inflammation. Tulathromycin (TUL), a macrolide used to treat bovine respiratory disease, confers immunomodulatory benefits via mechanisms that remain unclear. We recently reported the anti-inflammatory properties of TUL in bovine phagocytes in vitro and in Mannheimia haemolytica-challenged calves. The findings demonstrated that this system offers a powerful model for investigating novel mechanisms of pharmacological immunomodulation. In the present study, we examined the effects of TUL in a nonbacterial model of pulmonary inflammation in vivo and characterized its effects on lipid signaling. In bronchoalveolar lavage (BAL) fluid samples from calves challenged with zymosan particles (50 mg), treatment with TUL (2.5 mg/kg of body weight) significantly reduced pulmonary levels of LTB4 and prostaglandin E2 (PGE2). In calcium ionophore (A23187)-stimulated bovine neutrophils, TUL inhibited phospholipase D (PLD), cytosolic phospholipase A2 (PLA2) activity, and the release of LTB4. In contrast, TUL promoted the secretion of LXA4 in resting and A23187-stimulated neutrophils, while levels of its precursor, 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], were significantly lower. These findings indicate that TUL directly modulates lipid signaling by inhibiting the production of proinflammatory eicosanoids and promoting the production of proresolving lipoxins.
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Carrie D
authors.initials: CD
authors.lastname: Fischer
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Duquette
authors.affiliation: Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Renaux
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Troy D
authors.initials: TD
authors.lastname: Feener
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Morck
authors.affiliation: Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
authors.affiliation: Veterinary Medicine Research and Development, Zoetis, Kalamazoo, Michigan, USA.
authors.forename: Merlyn J
authors.initials: MJ
authors.lastname: Lucas
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada aburet@ucalgary.ca.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Buret
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D000001:Calcimycin / Q000494:pharmacology; D002417:Cattle; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004187:Disaccharides / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D044045:Lipoxins / Q000819:agonists* / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052638:Particulate Matter; D054467:Phospholipases A2 / Q000378:metabolism*; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D015054:Zymosan; D018942:Macrolides
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000001:Calcimycin; D015232:Dinoprostone; D004187:Disaccharides; D006571:Heterocyclic Compounds; D006893:Hydroxyeicosatetraenoic Acids; D007975:Leukotriene B4; D044045:Lipoxins; D052638:Particulate Matter; D054467:Phospholipases A2; D015054:Zymosan; C040527:lipoxin A4; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C485204:tulathromycin; D018942:Macrolides