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

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 beads murine model of Pseudomonas aeruginosa lung infection. Bacterial count and inflammation were evaluated in lung and other organs. Result 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 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 bacteraemia 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.

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

“…Importantly, however, note that AAT did not cause complete inhibition of LTB 4 -BLT1 engagement, and this is a further important attribute of AAT as an LTB 4 antagonist. To date, BLT1 antagonists in vivo have been limited by safety issues related to almost complete inhibition of LTB 4 (90). In light of the results of this study, AAT augmentation therapy may serve as an additional treatment strategy in management of patients with LTB 4 -driven diseases.…”

Microbiota-Driven Immune Cellular Maturation Is Essential for Antibody-Mediated Adaptive Immunity to Staphylococcus aureus Infection in the Eye

“…While this result suggests that limiting pathology by inhibiting PMN influx might be beneficial, the increased bacterial burdens and likelihood of dissemination to extraocular tissues (25) in the face of PMN deficiencies likely preclude such an approach. An analogous situation was found in humans, wherein inhibition of neutrophil influx into the lungs of cystic fibrosis (CF) patients infected with P. aeruginosa by an experimental anti-inflammatory drug, BIIL 284 (26), resulted in early termination of the clinical trial due to worse outcomes in treated patients (27).…”

Management of bronchiectasis in adults

“…Interestingly, the study reported higher airway inflammation despite reduced neutrophils and an increase in discontinuation due to infections [108]. One concern regarding anti-inflammatory drugs has been the potential that reducing neutrophil numbers could lead to uncontrolled bacterial infection, as occurred in a previous trial of a leukotriene B4 receptor antagonist in cystic fibrosis [109,110]. Statins have immunomodulatory effects and may have a role in neutrophilic inflammation.…”