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ABSTRACT: 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.
Clinical & Experimental Immunology 12/2001; 126(2):266-73. · 3.36 Impact Factor
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ABSTRACT: Hepatocyte growth factor (HGF) is postulated to play an important role in the repair of pulmonary epithelium in acute lung injury. To evaluate the role of HGF in bacterial pneumonia, the kinetics of HGF production and the cellular sources of HGF have been examined in the lungs of mice that had been intratracheally challenged with Pseudomonas aeruginosa. Neutrophil accumulation in the airway occurred immediately, reached a peak at 36 h, and then progressively declined by 14 d after infection. We found a biphasic pattern of HGF messenger RNA expression and protein synthesis in the lung after bacterial infection. The first peak for HGF production was found at 6 h after infection, and the primary source of HGF was shown to be bronchial epithelial cells. Interestingly, the second peak for HGF production, which was found around 48 to 72 h after infection, was closely associated with the increase in the percentage of alveolar macrophages (AMs) that became positive for myeloperoxidase, indicating phagocytosis of apoptotic neutrophils. The cellular source of the second peak was found to be AMs. Further, murine AMs which phagocytosed apoptotic neutrophils induced higher levels of HGF production in vitro. These results strongly indicate a novel mechanism of HGF production by AMs, which are phagocytosing apoptotic neutrophils, and the pivotal role of AMs in the healing and repair of damaged pulmonary epithelium through the production of HGF.
American Journal of Respiratory Cell and Molecular Biology 06/2001; 24(5):608-15. · 5.13 Impact Factor
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ABSTRACT: In order to investigate the role of the cytokine-induced neutrophil chemoattractant (CINC) in chronic bronchopulmonary infection, we developed a rat model of bronchopulmonary infection with Pseudomonas aeruginosa by using the agar bead method, and determined the kinetics of bacterial and cell number, as well as the concentrations of CINC-1, CINC-2, and CINC-3 in bronchoalveolar lavage (BAL) fluids in this model. The bacterial number in the lung rapidly increased from days 1 to 4, and declined 14 days after challenge. Neutrophil number in BAL fluid increased up to one day after challenge, and then slowly decreased during 14 days post-challenge. Among the CINCs, the local production of CINC-2 alpha sharply increased at day 1 and then decreased until day 4 post-challenge, while the local production of CINC-1 slightly increased at day 1 post-challenge. Neither CINC-2 beta nor CINC-3 were detected during the entire course of the infection. Increased CINC-2 mRNA expression in the lung tissue after challenge was associated with CINC-2 alpha production in BAL fluid. Moreover, an immunohistochemical study demonstrated the localization of CINC-1 and CINC-2 alpha primarily in alveolar macrophages and, to a much lesser extent, in bronchial epithelium of infected lung tissues, whereas CINC-2 beta and CINC-3 were not detected. When anti-CINC-1 or anti-CINC-2 alpha polyclonal antibodies were used for neutralizing neutrophil chemotactic activities in BAL fluids, the anti-CINC-2 alpha antibody inhibited 70% of the chemotactic activity in BAL fluids from infected rats at day 1 after challenge. No inhibition was observed by anti-CINC-1 antibody. These data indicate that CINC-2 alpha, which is produced by alveolar macrophages and bronchial epithelial cells, plays a pivotal role in neutrophil accumulation in the airway of a rat model of chronic bronchopulmonary infection with P. aeruginosa.
Cytokine 12/2000; 12(11):1662-8. · 3.02 Impact Factor
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ABSTRACT: To elucidate the mechanism of the high incidence of lower respiratory tract infections in patients with diabetes mellitus, we investigated the kinetics of production of macrophage inflammatory protein 2 (MIP-2), an important mediator of lung neutrophil recruitment, using mice with streptozotocin-induced diabetes. Intratracheal challenge with 1 mg of lipopolysaccharide (LPS), an endotoxin, per kg of body weight resulted in a time-dependent increase in the levels of MIP-2 protein in bronchoalveolar lavage (BAL) fluid, with the peak concentration (49.4 +/- 13 ng/ml) occurring at 3 h and significant neutrophil accumulation becoming apparent by 3 h in normal mice. In diabetic mice, the peak level of MIP-2 protein in BAL fluid did not occur until 6 h and was reduced to 21.9 +/- 10 ng/ml. Immunohistochemical studies using anti-MIP-2 antibody confirmed that the main cellular source of MIP-2 in the lung after LPS challenge was alveolar macrophages (AMs) in normal mice. The lungs in diabetic mice, however, showed no AMs staining for MIP-2 within 3 h after LPS challenge. PCR analysis using whole-lung RNA showed a time-dependent increase in MIP-2 mRNA levels after LPS instillation. The level of MIP-2 mRNA in diabetic mice was markedly decreased compared to that in normal mice. Our results indicate that impairment of MIP-2 mRNA expression in the AMs in diabetic mice resulted in delayed neutrophil recruitment in the lungs, and this may explain the development and progression of pulmonary infection in diabetes mellitus.
Infection and Immunity 06/2000; 68(5):2925-9. · 4.16 Impact Factor
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ABSTRACT: A 41-year-old male received acupuncture in the right shoulder for the sake of arthralgia. Three days after acupuncture he was admitted due to severe epigastralgia. Erythematous change and swelling were observed around the right shoulder. A study by magnetic resonance showed an increased signal intensity in a portion of the right subscapular muscle. Four hours after admission he became hypotensive. The erythematous and necrotic change in the right shoulder skin rapidly spread. Excisional debridement in the right lateral chest wall was immediately done. However, the patient died one day after admission despite administration of a high-dose ampicillin and other supportive therapies. Bacteriological and histological examinations confirmed severe streptococcal myositis. This is a case report of toxic shock-like syndrome probably caused by acupuncture.
Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 08/1998; 72(7):776-80.
