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The clearance of apoptotic neutrophils, inhibition of proinflammatory signaling, and production of proresolving lipids (including lipoxins, such as lipoxin A<jats:sub>4<\/jats:sub>[LXA<jats:sub>4<\/jats:sub>]) 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<jats:italic>in vitro<\/jats:italic>and in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mannheimia haemolytica<\/jats:named-content>-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<jats:italic>in vivo<\/jats:italic>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 LTB<jats:sub>4<\/jats:sub>and prostaglandin E<jats:sub>2<\/jats:sub>(PGE<jats:sub>2<\/jats:sub>). In calcium ionophore (A23187)-stimulated bovine neutrophils, TUL inhibited phospholipase D (PLD), cytosolic phospholipase A<jats:sub>2<\/jats:sub>(PLA<jats:sub>2<\/jats:sub>) activity, and the release of LTB<jats:sub>4<\/jats:sub>. In contrast, TUL promoted the secretion of LXA<jats:sub>4<\/jats:sub>in resting and A23187-stimulated neutrophils, while levels of its precursor, 15(<jats:italic>S<\/jats:italic>)-hydroxyeicosatetraenoic acid [15(<jats:italic>S<\/jats:italic>)-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.<\/jats:p>","DOI":"10.1128\/aac.02813-14","type":"journal-article","created":{"date-parts":[[2014,5,13]],"date-time":"2014-05-13T08:07:32Z","timestamp":1399968452000},"page":"4298-4307","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":16,"title":["Tulathromycin Exerts Proresolving Effects in Bovine Neutrophils by Inhibiting Phospholipases and Altering Leukotriene B<sub>4<\/sub>, Prostaglandin E<sub>2<\/sub>, and Lipoxin A<sub>4<\/sub>Production"],"prefix":"10.1128","volume":"58","author":[{"given":"Carrie D.","family":"Fischer","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie C.","family":"Duquette","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernard S.","family":"Renaux","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Troy D.","family":"Feener","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas W.","family":"Morck","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morley D.","family":"Hollenberg","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Merlyn J.","family":"Lucas","sequence":"additional","affiliation":[{"name":"Veterinary Medicine Research and Development, Zoetis, Kalamazoo, Michigan, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andre G.","family":"Buret","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"27","article-title":"Role of prostaglandins in microcirculatory function","volume":"13","author":"Kaley G","year":"1985","unstructured":"KaleyGHintzeTHPanzenbeckMMessinaEJ. 1985. 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