| Budget Amount *help |
¥3,950,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
There are recently observed increasing cases of Mycobacterium avium complex (MAC) lung disease in patients with no apparent risk factors, such as upper lobe cavitary disease in the male with a history of alcohol and heavy cigarette abuse. The patients are primarily elderly women with no history of smoking, and reticulonodular infiltrates and have patchy bilateral bronchiectasis, with routine involvement of the right middle lobe and lingula. This nodular-bronchiectasis (NB) type MAC pulmonary infection is currently increasing in Japan. Although the risk factors for such MAC diseases are primarily attributable to host-side conditions, such as severe exposure to MAC pathogens in persons frequently taking shower bath and the peculiarity in the anatomical structure and physiological function of woman's lungs. At present, it is unclear whether or not there are MAC populations which preferentially cause nodular-bronchiectasis (NB) type MAC lung disease rather than causing MAC disease that mim
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ics tuberculosis (TB) with upper lobe cavitary disease frequently encountered in the male, called as TB type MAC disease. Here, we examined profiles of virulence and drug-susceptibiltiy of MAC strains isolated from Japanese patients with the NB type MAC disease (NB-MAC) and compared with the case of MAC isolates from Japanese patients with the TB type MAC disease (TB-MAC). Five each strains of NB-MAC and TB-MAC were compared with each other group for their invasiveness and the ability to intracellularly replicate in various types of cultured cells of human origin, including three macrophage cell lines and one alveolar and one bronchial epithelial cell lines. The following findings were obtained. (1) Within human macrophage cell lines, such as THP-1 and MM6 macrophages, NB-MAC strains replicated more rapidly when compared to TB-MAC strains, although such difference is insignificant. (2) There was observed no difference between NB-MAC and TB-MAC for the rate of intracellular growth within the U937 murine macrophage cell line. (3) Inside in the A549 human type II alveolar epithelial cell line, the intracellular growth of NB-MAC strains was somewhat more vigorous than TB-MAC strains. (4) Both NB-MAC and TB-MAC strains showed similar abilities to internalize into NL20 human bronchial epithelial cell line and intracellularly replicate within the NL20 cells. (5) In extracellular milieus such as those in 7HSF medium, NB-MAC grew more rapidly than TB-MAC. (6) Both NB- and TB-MAC strains induced reactive oxygen intermediate and reactive nitrogen intermediate production by THP-1 macrophages after bacterial internalization. These two types of MAC organisms showed the same efficacies in inducing macrophage generation of these antimicrobial effector molecules. (7) Drug susceptibilities of NB- and TB-MAC strains to some antimycobacterial drugs, such as rifampicin (RFP), fluoroquinolones and isoniazid (INH) were considerably different from each other, as follows. On the basis of MIC_<60>, NB-MAC was about four-times less susceptible to RFP, and fluoroquinolones (levofloxacin, gatifloxacin, sitafloxacin) than TB-MAC, while the former was two-times more susceptible to INH than the latter MAC strains. Both the two MAC showed the same levels of susceptibility to the other test drugs, including macrolides (clarithromycin, azithromycin), rifabutin, ethambutol and aminoglycosides (streptomycin, amikacin). The present findings indicate the following. First, there may be no essential difference in virulence on the basis of infectivity to host macrophages and lung epithelial cells between MAC strains isolated from NB-MAC disease and those from TB-MAC disease. Second, There may be some levels of difference in drug susceptibility for these two types of MAC isolates, especially in cases of RFP, fluoroquinolones and INH, thereby suggesting the possibility that clinical output of treatment of MAC patients using these drugs may differ from patients with NB type disease to those with TB type one. Less
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