Inhaled fluticasone propionate impairs pulmonary clearance of Klebsiella pneumoniae in mice.
BACKGROUND
Recent trials demonstrate increased pneumonia risk in chronic obstructive pulmonary disease patients treated with the inhaled corticosteroid (ICS) fluticasone propionate (FP). There is limited work describing FP effects on host defenses against bacterial pneumonia.


METHODS
C57BL/6 mice received daily, nose-only exposure to nebulized FP or vehicle for 8 days, followed by pulmonary challenge with Klebsiella pneumoniae. Bacterial burden, phagocytosis, leukocyte recruitment, cytokine expression, nitric oxide release, and survival were measured.


RESULTS
Inhaled FP increased bacterial burden in lungs and blood 48 h after infection but affected neither in vivo phagocytosis of bacteria by alveolar macrophages (AM) nor alveolar neutrophil recruitment. AM from FP-treated mice showed impaired expression of infection induced TNF-alpha, IP-10 (CXCL-10), and interleukin 6 (IL-6), and AM also showed a trend towards impaired intracellular pathogen control following in vivo infection. In vitro FP treatment resulted in a dose-dependent impairment of cytokine expression by AM. Furthermore, infection-induced nitric oxide (but not hydrogen peroxide) production was impaired by FP in vivo and in vitro. FP decreased survival in this model.


CONCLUSIONS
Exposure to inhaled FP impairs pulmonary clearance of K. pneumoniae in mice, an effect associated with greater systemic bacteremia and death. Decreased AM cytokine and nitric oxide expression parallel the failure to control infection. These results support the study of ICS effects on human pulmonary host defenses.
Department of Medicine, Section of Pulmonary and Critical Care Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Craig M
CM
Patterson
Richard L
RL
Morrison
Alain
A
D'Souza
Xu S
XS
Teng
Kyle I
KI
Happel
D000280:Administration, Inhalation; D000730:Androstadienes / Q000008:administration & dosage* / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D000068298:Fluticasone; D007710:Klebsiella Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D007711:Klebsiella pneumoniae / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018410:Pneumonia, Bacterial / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology
D000730:Androstadienes; D000068298:Fluticasone