title: BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs.
abstract: BACKGROUND
  A clinical study to investigate the leukotriene B(4) (LTB(4))-receptor antagonist BIIL 284 in cystic fibrosis (CF) patients was prematurely terminated due to a significantly increased risk of adverse pulmonary events. We aimed to establish the effect of BIIL284 in models of Pseudomonas aeruginosa lung infection, thereby contributing to a better understanding of what could have led to adverse pulmonary events in CF patients.
  
  
  METHODS
  P. aeruginosa DNA in the blood of CF patients during and after acute pulmonary exacerbations and in stable patients with non-CF bronchiectasis (NCFB) and healthy individuals was assessed by PCR. The effect of BIIL 284 treatment was tested in an agar bead murine model of P. aeruginosa lung infection. Bacterial count and inflammation were evaluated in lung and other organs.
  
  
  RESULTS
  Most CF patients (98%) and all patients with NCFB and healthy individuals had negative P. aeruginosa DNA in their blood. Similarly, the P. aeruginosa-infected mice showed bacterial counts in the lung but not in the blood or spleen. BIIL 284 treatment decreased pulmonary neutrophils and increased P. aeruginosa numbers in mouse lungs leading to significantly higher bacteremia rates and lung inflammation compared to placebo treated animals.
  
  
  CONCLUSIONS
  Decreased airway neutrophils induced lung proliferation and severe bacteremia in a murine model of P. aeruginosa lung infection. These data suggest that caution should be taken when administering anti-inflammatory compounds to patients with bacterial infections.
authors.affiliation: Institute of Medical Microbiology and Hygiene, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Döring
authors.affiliation: Infection and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy. Electronic address: bragonzi.alessandra@hsr.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bragonzi
authors.affiliation: Infection and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Moira
authors.initials: M
authors.lastname: Paroni
authors.affiliation: Institute of Medical Microbiology and Hygiene, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Firdevs-Fatma
authors.initials: FF
authors.lastname: Aktürk
authors.affiliation: Infection and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cigana
authors.affiliation: Institute of Medical Microbiology and Hygiene, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Queen's University Belfast, Northern Ireland, UK.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Gilpin
authors.affiliation: Klinik Schillerhöhe, Robert-Bosch Krankenhaus, Gerlingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Heyder
authors.affiliation: Universitätsklinikum Frankfurt, Frankfurt, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Born
authors.affiliation: Universitätsklinikum Frankfurt, Frankfurt, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Smaczny
authors.affiliation: Klinik Schillerhöhe, Robert-Bosch Krankenhaus, Gerlingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kohlhäufl
authors.affiliation: Universitätsklinikum Frankfurt, Frankfurt, Germany.
authors.forename: Thomas O F
authors.initials: TO
authors.lastname: Wagner
authors.affiliation: Royal Brompton Hospital, London, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Loebinger
authors.affiliation: Royal Brompton Hospital, London, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Bilton
authors.affiliation: Queen's University Belfast, Northern Ireland, UK.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Tunney
authors.affiliation: Queen's University Belfast, Northern Ireland, UK.
authors.forename: J Stuart
authors.initials: JS
authors.lastname: Elborn
authors.affiliation: Division of infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Pier
authors.affiliation: Case Western Reserve University, UH Rainbow Babies & Children's Hospital, Cleveland, OH, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Konstan
authors.affiliation: Institute of Medical Microbiology and Hygiene, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Ulrich
mesh_terms: D000328:Adult; D000578:Amidines / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects; D016470:Bacteremia / Q000209:etiology*; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects; D003550:Cystic Fibrosis / Q000097:blood / Q000150:complications / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007958:Leukocyte Count; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011552:Pseudomonas Infections / Q000097:blood / Q000150:complications / Q000503:physiopathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000302:isolation & purification; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000578:Amidines; D000893:Anti-Inflammatory Agents; D002219:Carbamates; D018102:Receptors, Leukotriene B4; C424425:amelubant
keywords: Anti-inflammatory treatment; Cystic fibrosis; Pulmonary infection