BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs

Gerd Döring, Alessandra Bragonzi, Moira Paroni, Firdevs Fatma Aktürk, Cristina Cigana, Annika Schmidt, Deirdre Gilpin, Susanne Heyder, Torsten Born, Christina Smaczny, Martin Kohlhäufl, Thomas O F Wagner, Michael R. Loebinger, Diana Bilton, Michael M. Tunney, J. Stuart Elborn, Gerald B. Pier, Michael W. Konstan, Martina Ulrich

Research output: Contribution to journalArticle

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Abstract

Background: A clinical study to investigate the leukotriene B4 (LTB4)-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.

Original languageEnglish
Pages (from-to)156-163
Number of pages8
JournalJournal of Cystic Fibrosis
Volume13
Issue number2
DOIs
Publication statusPublished - Mar 2014

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Bacteremia
Neutrophils
Inflammation
Lung
Pseudomonas aeruginosa
Cystic Fibrosis
Bronchiectasis
Bacterial Load
amelubant
Leukotriene B4 Receptors
Infection
Leukotriene Antagonists
DNA
Bacterial Infections
Agar
Pneumonia
Fibrosis
Anti-Inflammatory Agents
Spleen
Placebos

Keywords

  • Anti-inflammatory treatment
  • Cystic fibrosis
  • Pulmonary infection

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Pediatrics, Perinatology, and Child Health
  • Medicine(all)

Cite this

BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs. / Döring, Gerd; Bragonzi, Alessandra; Paroni, Moira; Aktürk, Firdevs Fatma; Cigana, Cristina; Schmidt, Annika; Gilpin, Deirdre; Heyder, Susanne; Born, Torsten; Smaczny, Christina; Kohlhäufl, Martin; Wagner, Thomas O F; Loebinger, Michael R.; Bilton, Diana; Tunney, Michael M.; Elborn, J. Stuart; Pier, Gerald B.; Konstan, Michael W.; Ulrich, Martina.

In: Journal of Cystic Fibrosis, Vol. 13, No. 2, 03.2014, p. 156-163.

Research output: Contribution to journalArticle

Döring, G, Bragonzi, A, Paroni, M, Aktürk, FF, Cigana, C, Schmidt, A, Gilpin, D, Heyder, S, Born, T, Smaczny, C, Kohlhäufl, M, Wagner, TOF, Loebinger, MR, Bilton, D, Tunney, MM, Elborn, JS, Pier, GB, Konstan, MW & Ulrich, M 2014, 'BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs', Journal of Cystic Fibrosis, vol. 13, no. 2, pp. 156-163. https://doi.org/10.1016/j.jcf.2013.10.007
Döring, Gerd ; Bragonzi, Alessandra ; Paroni, Moira ; Aktürk, Firdevs Fatma ; Cigana, Cristina ; Schmidt, Annika ; Gilpin, Deirdre ; Heyder, Susanne ; Born, Torsten ; Smaczny, Christina ; Kohlhäufl, Martin ; Wagner, Thomas O F ; Loebinger, Michael R. ; Bilton, Diana ; Tunney, Michael M. ; Elborn, J. Stuart ; Pier, Gerald B. ; Konstan, Michael W. ; Ulrich, Martina. / BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs. In: Journal of Cystic Fibrosis. 2014 ; Vol. 13, No. 2. pp. 156-163.
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abstract = "Background: A clinical study to investigate the leukotriene B4 (LTB4)-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.",
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T1 - BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs

AU - Döring, Gerd

AU - Bragonzi, Alessandra

AU - Paroni, Moira

AU - Aktürk, Firdevs Fatma

AU - Cigana, Cristina

AU - Schmidt, Annika

AU - Gilpin, Deirdre

AU - Heyder, Susanne

AU - Born, Torsten

AU - Smaczny, Christina

AU - Kohlhäufl, Martin

AU - Wagner, Thomas O F

AU - Loebinger, Michael R.

AU - Bilton, Diana

AU - Tunney, Michael M.

AU - Elborn, J. Stuart

AU - Pier, Gerald B.

AU - Konstan, Michael W.

AU - Ulrich, Martina

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N2 - Background: A clinical study to investigate the leukotriene B4 (LTB4)-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.

AB - Background: A clinical study to investigate the leukotriene B4 (LTB4)-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.

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KW - Cystic fibrosis

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