• IMMUNE NETWORK
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• v.9 no.5
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• pp.192-202
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• 2009

Background: Little information is available the role of Nitric Oxide (NO) in host defenses during human tuberculosis (TB) infection. We investigated the modulating factor(s) affecting NO synthase (iNOS) induction in human macrophages. Methods: Both iNOS mRNA and protein that regulate the growth of mycobacteria were determined using reverase transcriptase-polymerase chain reaction and western blot analysis. The upstream signaling pathways were further investigated using iNOS specific inhibitors. Results: Here we show that combined treatment with 1,25-dihydroxyvitamin D3 (1,25-D3) and Interferon (IFN)-${\gamma}$ synergistically enhanced NO synthesis and iNOS expression induced by Mycobacterium tuberculosis (MTB) or by its purified protein derivatives in human monocyte-derived macrophages. Both the nuclear factor-${\kappa}B$ and MEK1-ERK1/2 pathways were indispensable in the induction of iNOS expression, as shown in toll like receptor 2 stimulation. Further, the combined treatment with 1,25-D3 and IFN-${\gamma}$ was more potent than either agent alone in the inhibition of intracellular MTB growth. Notably, this enhanced effect was not explained by increased expression of cathelicidin, a known antimycobacterial effector of 1,25-D3. Conclusion: These data support a key role of NO in host defenses against TB and identify novel modulating factors for iNOS induction in human macrophages.

• Tuberculosis and Respiratory Diseases
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• v.75 no.1
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• pp.28-31
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• 2013

Methotrexate (MTX) has been established as a standard disease-modifying anti-rheumatic drug. If adequate disease control is achieved for a reasonable period of time, tapering the MTX dosage is recommended because the chronic use of MTX can result in opportunistic infection. We present here a case of a woman with rheumatoid arthritis taking MTX, and the woman developed actively caseating endobronchial Mycobacterium intracellulare disease with pulmonary infiltrations. After discontinuing the MTX, the patient was able to tolerate 18 months of antimycobacterial treatment without flare ups of rheumatoid arthritis, and she completely recovered from nontuberculous mycobacterial respiratory disease.

• The Journal of the Korean Society for Microbiology
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• v.35 no.2
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• pp.117-127
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• 2000

The non-ELR-containing CXC chemokines Mig and IP-10 have been shown to function as chemotactic cytokines for activated T lymphocytes. In this study, we examined the potential involvement of Mig and IP-10 in antimycobacterial response of mice immunized or infected with M. bovis BCG. The accumulation of Mig and IP-10 mRNA in resident peritoneal monocytes ($RPM{\Phi}$) was slightly reduced by stimulation with vBCG, and the degree was greater for 24 hr culture even though IFN-${\gamma}$ was added. Expression of Mig, IP-10, and IFN-${\gamma}$ in 24 hr delayed-type hypersensitivity (DTH) response was stronger in vBCG-immune mice than in the non-immune. The increase of DTH measured by foot-pad thickness appears to be clearly related to the levels of chemokines Mig and IP10 messages and those of IFN-${\gamma}$ and IL-12. Stimulation with vBCG for 2 days decreased or completely dropped the levels of Mig message in non-immune or immune splenocytes, respectively, whereas IP-10 message was slightly decreased in 2 days culture. Moreover, messages for IL-12 (p40) showed similar kinetics for Mig. The levels of Mig and IP-10 mRNA during the course of infection with BCG were not readily changed in lungs, livers, and spleens from BCG-infected mice. Although there was no obvious changes of Mig and IP-10 messages in the target organs during infection process, we found that the infection progressed over the first 3 wk before being contained by the emerging immune response suggested from detectable amount of IFN-${\gamma}$ mRNA around this time. In view of selectivity of chemokines Mig and IP-10 for activated T cells, these data suggest that chemokine Mig and IP-10, especially in collaboration with IL-12 and IFN-${\gamma}$, may playa role as T cell recruiters in immune response against mycobacterial infection.

• Tuberculosis and Respiratory Diseases
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• v.68 no.4
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• pp.236-239
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• 2010

Hot tub lung is a lung disorder associated with exposure to hot tub water contaminated with Mycobacterium avium complex (MAC). Although its pathogenesis remains unclear, it may be considered hypersensitivity pneumonitis (HP) rather than an infectious disease. We report a case which fulfilled the current diagnostic criteria of hot tub lung. A patient had worked as a cleaner in the public bath for approximately one year and presented with dyspnea for over one month. The computed tomographic finding of bilateral ground glass attenuation and pathologic finding of granulomatous inflammation were consistent with HP. MAC was isolated from bronchoalveolar lavage fluid and hot tub water. After corticosteroid treatment without antimycobacterial medication, the patient improved and there has been no recurrence. The patient has since discontinued working in the public bath.

• Tuberculosis and Respiratory Diseases
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• v.64 no.6
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• pp.422-426
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• 2008

Background: Mycobacterium abscessus is the most pathogenic and drug-resistant rapid-growing mycobacterium. Clarithromycin or azithromycin are the only regular oral antimycobacterial agents that have an effect on M. abscessus. We tried to detect the clarithromycin-resistant strains from the clinical isolates of M. abscessus. Methods: We tried to isolate the clarithromycin-resistant strains from 220 clinical isolates of M. abscessus by performing using reverse hybridization assay (RHA) and the broth microdilution test (BMT). Results: Seven resistant strains (3.2%) from all the tested clinical isolates were detected by BMT. Three of these resistant strains were also detected by RHA and it was confirmed that they had point mutants. Conclusion: These results showed that clarithromycin resistance in M. abscessus clinical isolates is related to a point mutation and other unknown mechanisms.

• Archives of Pharmacal Research
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• v.29 no.1
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• pp.26-33
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• 2006

Some new derivatives of 1,2,4-triazolo[2,3-a]benzimidazoles were synthesized through the reaction of 1,2-diaminobenzimidazole with carbon disulfide. The resulting 1,2,4-triazolo-[2,3a]benzimidazole-2-thione intermediate was reacted with one equivalent of alkyl halides to give the corresponding 2-alkylthio derivatives, which were further alkylated through the reaction with another one equivalent of different alkyl halides to afford the target compounds; 1-alkyl-2alkylthio-1,2,4-traizolo[2,3-a]benzimidazoles. On the other hand, the 1,2-disubstituted derivatives with two identical alkyl substituents were prepared by the reaction of 1,2,4-triazolo[2,3-a]benzimidazole-2-thione with two equivalents of the alkyl halides. The structures of the new compounds were assigned by spectral and elemental methods of analyses. The synthesized compounds were tested for their antibacterial and antifungal activities. Most of the tested compounds proved comparable results with those of ampicillin and fluconazole reference drugs. The study indicated that, the antibacterial as well as the antifungal activities of the test compounds were improved with increase in the bulkiness of the introduced alkyl groups. Also, some active antibacterial compounds were tested for their antimycobacterial activity. All the test compounds showed equipotent antitubercular activity as that of INH as a reference drug.

• Tuberculosis and Respiratory Diseases
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• v.53 no.2
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• pp.173-182
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• 2002

Background : Nontuberculous mycobacteria (NTM) have usually been considered to be contaminants of colonizers when isolated from respiratory specimens in Korea, where there is a high prevalence of tuberculosis and a low rate of HIV infections. Therefore, there has been few studies on the clinical significance of NTM species in immunocompetent patients were investigated. Methods : Thirty-five NTM isolates, for which species identification was requested by the treating physicians during 1999 at the Asan Medical Center, were retrospectively analyzed. They were identified to the species level by mycolic acid analysis using high-performance liquid chromatography. The medical records of the patients with the NTM isolates were reviewed to identify those patients who met the American Thoracic Society (ATS)'s criteria for mycobacterial pulmonary infection. Their antimicrobial susceptibility data were compared with the clinical outcomes. Results : The NTM were identified as M. intracellulare (6 isolates), M. avium (5), M. abscessus (5), M. gordonae (5), M. terrae complex (4), M. szulgai (2), M. kansasii (2), M. fortuitum (2), M. peregrinum (1), M. mucogenicum (1), M. celatum (1), and M. chelonae (1). All 35 patients showed clinical symptoms and signs of chronic lung disease, but none had a HIV infections; 16 (45.7%) patients were found to be compatible with a NTM pulmonary infection according to the ATS criteria, 5 and 4 cases were affected with M. intracellulare and M. abscessus, respectively; 8 patients had a history of pulmonary tuberculosis. 13 patients received antimycobacterial therapy for an average of 21 months and 9 patients were treated with second-line drugs. Only 4 patients had improved radiologically. Conclusion : A NTM should be considered a potential pathogen of pulmonary infections in immunocompetent patients with chronic pulmonary diseases. Most NTM infections were left untreated for a prolonged period and showed a poor outcome as a result, M. intracellulare and M. abscessus were the two most frequent causes of NTM pulmonary infections in this study. Species identification and antimycobacterial susceptibility tests based on the species are needed for the optimum management of a NTM pulmonary infection in patients.

• Biomedical Science Letters
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• v.11 no.4
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• pp.465-471
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• 2005

Ofloxacin has antimycobacterial activity that possibly contributes a pivotal role in the second-line drug regimens that are used for the treatment of multidrug-resistant tuberculosis. However, in some communities, the resistance rate of Mycobacterium tuberculosis to this agent is surging. Therefore, a rapid and accurate method that can be used to determine the resistance of M tuberculosis to the ofloxacin can be very useful for effective treatment of the patients. As an effort to develop such a method, this study was set up to reveal general types of mutations that are related to ofloxacin resistance of M tuberculosis. From previous studies, it has been well known that ofloxacin resistance is associated with mutations in a gene encoding the gyrase A subunit protein. In this study, we obtained 43 ofloxacin-resistant and 50 ofloxacin-susceptible M tuberculosis clinical isolates from Masan National TB Hospital, and sequences of DNA fragment of 320 bp, region of gyrA corresponding to the ofloxacin resistance-determining region were analyzed. In brief, the results showed that a total of seven mutation types were found at gyrA. Theses mutations were all clustered within nucleotides 2574 to 2586 of the gyrA gene (codons 88 to 94). Codon 94 was the most frequently substituted site. Twenty-four of the 43 isolates had mutations at this position resulting in a total of five different types of amino acid changes $(Asp{\to}Ala,\;Asp{\to}Gly,\;Asp{\to}His,\;Asp{\to}Tyr,\;and\;Asp{\to}Asn)$. Five isolates contained a mutation at codon 90 resulting $Ala{\to}Val$ change. Four isolates had mutations at codon 91 causing a $Ser{\to}Pro$ change at this site. Two isolates contained a mutation at codon 88 and each of them resulted in different types of amino acid changes $(Gly{\to}Cys,\;Gly{\to}Ala)$. On the other hand, polymorphic site at codon 95 was found in both ofloxacin-resistant and ofloxacin-susceptible isolates. From these results, we concluded that the rate of mutations present in gyrA among ofloxacin-resistant M. tuberculosis in Korea is similar to the general rates of mutations found throughout the world. Subsequently, an oligonucleotide probe was designed based on the results of sequence analysis and was used to develop a dot blot hybridization assay system to determine ofloxacin-resistance of M tuberculosis. To evaluate this probe, dot-blot hybridization was carried out using other 57 clinical isolates, and the results showed that the dot-blot hybridization assay is good for detecting sequence alterations atgyrA gene.

• Biomedical Science Letters
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• v.16 no.2
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• pp.119-122
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• 2010

Interleukin-1${\beta}$ $(IL-1{\beta})$ is one of the key proinflammatory cytokines and it plays an important role for the antimycobacterial host defense mechanisms. In this study, we examined Mycobacterium tuberculosis (MTB)-stimulated induction of IL-1${\beta}$ and evaluated the associated signal transduction pathways. In PMA-differentiated THP-1 cells, MTB infection increased mRNA expression of IL-$1{\beta}$ in a dose-dependent manner. The expression of IL-1${\beta}$ mRNA began to be induced at 1.5 h after infection, and induced expression of IL-1${\beta}$ was retained for 48 h after MTB infection. The increase in expression of IL-1${\beta}$ caused by MTB was reduced in cells treated with Ro-31-8425 (an inhibitor of PK$C{\alpha}$, ${\beta}I$, ${\beta}II$, ${\gamma}$, ${\varepsilon}$) or PD98059 (an inhibitor of MEK1), meanwhile, pre-treatment with $G\ddot{o}6976$ (an inhibitor of $Ca^{2+}$ dependent PK$C{\alpha}$ and PK$C{\beta}I$) or Rottlerin (an inhibitor of PK$C{\delta}$) has no effect on MTB-induced expression of $IL-1{\beta}$ mRNA. These results show that the expression of $IL-1{\beta}$ mRNA caused by MTB may be mediated via MEK1 and PKC isoforms including PK$C{\beta}II$, $PKC{\gamma}$, or $PKC{\varepsilon}$. Further studies are required to determine whether other PKC isoforms $(PKC {\eta},\;{\theta},\;{\varepsilon},\;and\;{\lambda}/{\iota})$, except $PKC{\delta}$, $PKC{\alpha}$, and $PKC{\beta}I$, are also involved in $IL-1{\beta}$ mRNA expression after mycobacterial infection.

• Tuberculosis and Respiratory Diseases
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• v.66 no.1
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• pp.37-41
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• 2009

Hot tub lung has been described as a pulmonary illness associated with exposure to nontuberculous mycobacteria,mainly hot bathtub water contaminated with Mycobacterium avium complex (MAC) and hence the name. Although not entirely clear, its etiology has been thought to involve either an infection or a hypersensitivity pneumonitis secondary to MAC. Herein, we describe 2 female patients (60 and 53 years old) admitted to our hospital with hot tub lung, and both of whom worked in a public bath. Both women were initially admitted following several months of exertional dyspnea and cough. The patients had been working as body-scrubbers in a public bath for several years. Their chest CT scans showed bilateral diffuse ground-glass opacities with multifocal air-trappings and poorly defined centrilobular nodules in both lungs. Pathological findings from lung specimens revealed small non-necrotizing granuloma in the lung parenchyme with relatively normal-looking adjacent alveoli. Discontinuation of working in the public bath led to an improvement in symptoms and radiographic abnormalities, without antimycobacterial therapy.