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.
Subject(s)
Amidines , Bacteremia/etiology , Carbamates , Cystic Fibrosis , Inflammation/drug therapy , Neutrophils , Pseudomonas aeruginosa , Adult , Amidines/administration & dosage , Amidines/adverse effects , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/adverse effects , Carbamates/administration & dosage , Carbamates/adverse effects , Cystic Fibrosis/blood , Cystic Fibrosis/complications , Cystic Fibrosis/physiopathology , Disease Models, Animal , Female , Humans , Inflammation/metabolism , Inflammation/physiopathology , Leukocyte Count , Lung/microbiology , Lung/pathology , Male , Mice , Neutrophils/drug effects , Neutrophils/metabolism , Pseudomonas Infections/blood , Pseudomonas Infections/complications , Pseudomonas Infections/physiopathology , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/isolation & purification , Receptors, Leukotriene B4/antagonists & inhibitors , Treatment OutcomeABSTRACT
The currently available immunosuppressive agents applied in human transplantation medicine are highly potent in the protection from acute allograft rejection. However, long-term allograft survival is still poor as these drugs fail to sufficiently prevent chronic allograft rejection. Naturally occurring regulatory T cells have been postulated as the key players to establish long-lasting transplantation tolerance. Thus, the development of immunosuppressive regimens which shift the pathological balance of cytopathic versus regulatory T cells of human allograft recipients towards a protective T-cell composition is a promising approach to overcome limitations of current transplantation medicine. Thirty-three patients that received rapamycin (RPM) or calcineurin inhibitor treatment following lung transplantation were included and their T-cell compartments analysed. Twelve healthy volunteers without history of lung disease served as controls. In this article, we show that treatment of human lung transplant recipients with RPM is associated with an increased frequency of regulatory T cells, as compared with treatment with calcineurin inhibitors or to healthy controls. Moreover, regulatory T cells during treatment with RPM were CD62Lhigh, a phenotype that displayed an enhanced immunosuppressive capacity ex vivo. Our data support the use of RPM in human lung transplant recipients and undertaking of further prospective studies evaluating its impact on allograft and patient survival.