title: A Randomized Placebo Controlled Trial of Ibuprofen for Respiratory Syncytial Virus Infection in a Bovine Model.
abstract: BACKGROUND
  Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and hospital admission in infants. An analogous disease occurs in cattle and costs US agriculture a billion dollars a year. RSV causes much of its morbidity indirectly via adverse effects of the host response to the virus. RSV is accompanied by elevated prostaglandin E2 (PGE2) which is followed by neutrophil led inflammation in the lung. Ibuprofen is a prototypical non-steroidal anti-inflammatory drug that decreases PGE2 levels by inhibiting cyclooxygenase.
  
  
  OBJECTIVE
  We hypothesized that treatment of RSV with ibuprofen would decrease PGE2 levels, modulate the immune response, decrease clinical illness, and decrease the histopathological lung changes in a bovine model of RSV. We further hypothesized that viral replication would be unaffected.
  
  
  METHODS
  We performed a randomized placebo controlled trial of ibuprofen in 16 outbred Holstein calves that we infected with RSV. We measured clinical scores, cyclooxygenase, lipoxygenase and endocannabinoid products in plasma and mediastinal lymph nodes and interleukin (Il)-4, Il-13, Il-17 and interferon-γ in mediastinal lymph nodes. RSV shedding was measured daily and nasal Il-6, Il-8 and Il-17 every other day. The calves were necropsied on Day 10 post inoculation and histology performed.
  
  
  RESULTS
  One calf in the ibuprofen group required euthanasia on Day 8 of infection for respiratory distress. Clinical scores (p<0.01) and weight gain (p = 0.08) seemed better in the ibuprofen group. Ibuprofen decreased cyclooxygenase, lipoxygenase, and cytochrome P450 products, and increased monoacylglycerols in lung lymph nodes. Ibuprofen modulated the immune response as measured by narrowed range of observed Il-13, Il-17 and IFN-γ gene expression in mediastinal lymph nodes. Lung histology was not different between groups, and viral shedding was increased in calves randomized to ibuprofen.
  
  
  CONCLUSIONS
  Ibuprofen decreased PGE2, modulated the immune response, and improved clinical outcomes. However lung histopathology was not affected and viral shedding was increased.
authors.affiliation: Department of Emergency Medicine, Division of Pediatric Emergency Medicine, Sutter Medical Center Sacramento, Sacramento, California, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Walsh
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, 1 Shields Ave, Davis, California, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Behrens
authors.affiliation: California Animal Health and Food Safety Laboratory, San Bernardino branch, 105 W Central Ave, San Bernardino, California, United States of America.
authors.forename: Francisco R
authors.initials: FR
authors.lastname: Carvallo Chaigneau
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, 1 Shields Ave, Davis, California, United States of America.
authors.forename: Heather
authors.initials: H
authors.lastname: McEligot
authors.affiliation: Department of Nutrition, University of California Davis, Davis, 95616 California, United States of America.|NIH West Coast Metabolomics Center, University of California Davis, Davis, California, United States of America.
authors.forename: Karan
authors.initials: K
authors.lastname: Agrawal
authors.affiliation: Obesity and Metabolism Research Unit, United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, California, United States of America.|Department of Nutrition, University of California Davis, Davis, 95616 California, United States of America.|NIH West Coast Metabolomics Center, University of California Davis, Davis, California, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Newman
authors.affiliation: California Animal Health and Food Safety Laboratory, 620 W. Health Sciences Drive, Davis, California, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Anderson
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, 1 Shields Ave, Davis, California, United States of America.
authors.forename: Laurel J
authors.initials: LJ
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002417:Cattle; D002418:Cattle Diseases / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007052:Ibuprofen / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D008297:Male; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D018112:Respiratory Syncytial Virus, Bovine / Q000187:drug effects*; D019562:Viral Load / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007052:Ibuprofen