title: The Regulation of Proresolving Lipid Mediator Profiles in Baboon Pneumonia by Inhaled Carbon Monoxide.
abstract: Strategies for the treatment of bacterial pneumonia beyond traditional antimicrobial therapy have been limited. The recently discovered novel genus of lipid mediators, coined "specialized proresolving mediators" (SPMs), which orchestrate clearance of recruited leukocytes and restore epithelial barrier integrity, have offered new insight into the resolution of inflammation. We performed lipid mediator (LM) metabololipidomic profiling and identification of LMs on peripheral blood leukocytes and plasma from a baboon model of Streptococcus pneumoniae pneumonia. Leukocytes and plasma were isolated from whole blood of S. pneumoniae-infected (n = 5-6 per time point) and control, uninfected baboons (n = 4 per time point) at 0, 24, 48, and 168 hours. In a subset of baboons with pneumonia (n = 3), we administered inhaled carbon monoxide (CO) at 48 hours (200-300 ppm for 60-90 min). Unstimulated leukocytes from control animals produced a proresolving LM signature with elevated resolvins and lipoxins. In contrast, serum-treated, zymosan-stimulated leukocytes and leukocytes from baboons with S. pneumoniae pneumonia produced a proinflammatory LM signature profile with elevated leukotriene B4 and prostaglandins. Plasma from baboons with S. pneumoniae pneumonia also displayed significantly reduced LM-SPM levels, including eicosapentaenoic acid-derived E-series resolvins (RvE) and lipoxins. CO inhalation increased levels of plasma RvE and lipoxins relative to preexposure levels. These results establish the leukocyte and plasma LM profiles biosynthesized during S. pneumoniae pneumonia in baboons and provide evidence for pneumonia-induced dysregulation of these proresolution programs. Moreover, these SPM profiles are partially restored with inhaled low-dose CO and SPM, which may shorten the time to pneumonia resolution.
authors.affiliation: 1 Department of Anesthesiology, Perioperative and Pain Medicine, and.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: 2 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Kraft
authors.affiliation: 1 Department of Anesthesiology, Perioperative and Pain Medicine, and.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.affiliation: 1 Department of Anesthesiology, Perioperative and Pain Medicine, and.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: 3 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Fredenburgh
authors.affiliation: 4 Departments of Respiratory Care and Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; and.
authors.forename: Dean R
authors.initials: DR
authors.lastname: Hess
authors.affiliation: 1 Department of Anesthesiology, Perioperative and Pain Medicine, and.
authors.forename: Nan
authors.initials: N
authors.lastname: Chiang
authors.affiliation: 2 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Karen
authors.initials: K
authors.lastname: Welty-Wolf
authors.affiliation: 5 Division of Pulmonary and Critical Care Medicine, Weill Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Augustine M
authors.initials: AM
authors.lastname: Choi
authors.affiliation: 2 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
authors.affiliation: 1 Department of Anesthesiology, Perioperative and Pain Medicine, and.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage*; D004353:Drug Evaluation, Preclinical; D007155:Immunologic Factors / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D007975:Leukotriene B4 / Q000097:blood; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood*; D008297:Male; D055442:Metabolome; D010215:Papio; D011018:Pneumonia, Pneumococcal / Q000097:blood* / Q000188:drug therapy / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000276:immunology
chemical_list: D007155:Immunologic Factors; D008055:Lipids; D007975:Leukotriene B4; D002248:Carbon Monoxide
keywords: bacterial; inflammation resolution; pneumonia; therapeutic carbon monoxide