Intrapulmonary concentrations of inflammatory cytokines in a mouse model of chronic respiratory infection caused by Pseudomonas aeruginosa.
We investigated the role of inflammatory cytokines in a mouse model of chronic Pseudomonas aeruginosa infection mimicking diffuse panbronchiolitis (DPB), and determined the effects of clarithromycin therapy on the production of these cytokines. The concentrations of IL-1beta, IL-2, IL-4, IL-5, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) were measured serially in the lungs of mice with experimentally induced chronic respiratory P. aeruginosa infection until 60 days after inoculation. The concentrations of these cytokines during the course of the disease were significantly higher than baseline (before inoculation, P<0.01 for all cytokines). Clarithromycin significantly inhibited the production of IL-1beta and TNF-alpha in the lung (P<0.01). The same treatment also reduced the levels of other cytokines, albeit insignificantly. Treatment with anti-TNF-alpha antibody significantly reduced the number of pulmonary lymphocytes and concentration of IL-1beta in the lung (P<0.01), but did not change the number of viable bacteria. Our findings resemble those detected in bronchoalveolar lavage fluid of patients with DPB and indicate that inflammatory cytokines play an important role in chronic P. aeruginosa lung infection. Our results also show that macrolides modulated the production of these cytokines, ultimately reducing lymphocyte accumulation in the lung. Our data suggest that anti-TNF-alpha antibody might be a useful new strategy for the treatment of chronic respiratory P. aeruginosa infection.
Yanagihara
K
K
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. kyana-ngs@umin.ac.jp
Tomono
K
K
Kuroki
M
M
Kaneko
Y
Y
Sawai
T
T
Ohno
H
H
Miyazaki
Y
Y
Higashiyama
Y
Y
Maesaki
S
S
Kadota
J
J
Kohno
S
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001988:Bronchiolitis / Q000276:immunology*; D017291:Clarithromycin / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000276:immunology*; D008297:Male; D051379:Mice; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000276:immunology; D014020:Tissue Extracts; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000900:Anti-Bacterial Agents; D016207:Cytokines; D007375:Interleukin-1; D007376:Interleukin-2; D015848:Interleukin-5; D014020:Tissue Extracts; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D017291:Clarithromycin