Dexamethasone impairs pulmonary defence against Pseudomonas aeruginosa through suppressing iNOS gene expression and peroxynitrite production in mice.
To elucidate the in vivo mechanisms involved in the impairment in pulmonary defence as the result of treatment with glucocorticoids, we established fatal pneumonia with bacteraemia in dexamethasone (DEX)-treated mice by means of an intratracheal challenge of Pseudomonas aeruginosa. An increased neutrophil influx was observed in bronchoalveolar lavage (BAL) fluids from both untreated and DEX-treated mice. The complete suppression of an inducible isoform of nitric oxide synthase (iNOS) mRNA expression and tumour necrosis factor alpha (TNF-alpha) production during the early phase of pneumonia, but not CXC chemokine production, were found in the case of the DEX-treated mice. An immunohistochemical study with a specific antibody also revealed negative staining for nitrotyrosine in the lung tissue of DEX-treated mice, while the formation of nitrotyrosine, which indirectly indicates the generation of peroxynitrite with a potent bactericidal activity, was detected clearly in the bronchial epithelium as well as alveolar phagocytic cells of lung tissue from untreated mice. Furthermore, an intraperitoneal administration of S-methyl-isothiourea (SMT), a potent inhibitor of NOS, significantly decreased the survival and increased bacterial density in the case of untreated mice. In contrast, no significant effects on the survival and bacterial density in the lung and blood were found as the result of treatment with SMT in DEX-treated mice. Collectively, a complete repression of iNOS gene expression and a lack of the generation of peroxynitrite as well as an inhibition of TNF-alpha production in the lung appeared to be responsible for the progression of the fatal pneumonia due to P. aeruginosa in DEX-treated mice.
Satoh
S
S
Department of Internal Medicine, Institute of Tropical Medicine, Nagasaki University, Japan.
Oishi
K
K
Iwagaki
A
A
Senba
M
M
Akaike
T
T
Akiyama
M
M
Mukaida
N
N
Atsushima
K M
KM
Nagatake
T
T
D000818:Animals; D019743:Chemokines, CXC / Q000096:biosynthesis; D015169:Colony Count, Microbial; D003907:Dexamethasone / Q000633:toxicity*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000633:toxicity*; D008168:Lung / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008808:Mice, Inbred CBA; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000096:biosynthesis*; D018410:Pneumonia, Bacterial / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000472:pathogenicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D019743:Chemokines, CXC; D005938:Glucocorticoids; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D030421:Peroxynitrous Acid; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse