Hiroshi Fujiwara

Keio University, Edo, Tōkyō, Japan

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Publications (12)32.33 Total impact

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    ABSTRACT: Arbekacin is a unique aminoglycoside antibiotic with anti-methicillin-resistant Staphylococcus aureus activity. The efficacy of aminoglycosides is related to their serum maximum concentration. Local concentration of antibiotics in pulmonary epithelial lining fluid, rather than its serum concentration, can help determine its clinical efficacy more precisely for treatment of respiratory infectious disease. The objective of this study was to sequentially measure arbekacin concentration in epithelial lining fluid after infusion of a single clinically available dose.
    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 06/2014;
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    ABSTRACT: RATIONALE Mild cases of Mycobacterium avium complex (MAC) lung disease are often observed without treatment; further, a consensus regarding the appropriate time to start treatment has not been established. Here, we evaluated the clinical and bacteriological characteristics of patients with MAC lung disease from whom treatment was withheld to determine if potential associations between these data are prognostic of progression and/or the need for treatment. METHODS We retrospectively reviewed the data for 56 patients with MAC lung disease from whom treatment was withheld for at least 6 months after diagnosis; patients who subsequently received treatment during the follow-up period were considered the treated group, while the remaining patients were considered the untreated group. We compared the baseline characteristics and longitudinal changes in the plain chest radiographs of the untreated and treated groups. To evaluate the radiological findings, a total lung score was calculated for each of 6 zones in the lung area using the scores for the following 4 elements: nodules, infiltration, cavity, and bronchiectasis. At diagnosis, we performed the following to examine the bacterial factors: differentiated between M. avium and M. intracellulare; identified IS1245, IS1311, and ISMav6; confirmed ISMav6 in the sequence of the cfp29 promoter; and executed a variable number tandem repeat (VNTR) analysis using M. avium tandem repeat (MATR-VNTR) and Higashi Nagoya tandem repeat (HNTR-VNTR) as the locus. RESULTS The mean follow-up period was 7.5 ± 5.8 years. Treatment was initiated in 15 cases (26.8%). M. intracellulare was observed in 7 cases (12.5%) including 3 cases of co-infection with M. avium. Although polyclonality was observed in 9 cases of M. avium (17.3%), none of these involved M. intracellulare. Of the baseline characteristics, there were significantly more women and cases of M. avium polyclonality in the treated group than in the untreated group. The lung score at diagnosis was also significantly higher in the treated group than in the untreated group. The lung scores for the elements of infiltration and bronchiectasis increased significantly from baseline in the treated group at treatment initiation; moreover, the scores were not improved after the treatment. In the untreated group, the average profile using a mixed-effects model showed that the lung score slowly but significantly increased during the observation period. CONCLUSION Radiological findings and the presence of polyclonality at diagnosis of MAC lung disease may be useful to monitor disease deterioration and predict the requirement for treatment.
    American Journal of Respiratory and Critical Care Medicine 05/2014; · 11.04 Impact Factor
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    ABSTRACT: Objective The clinical features of bacteremia due to Campylobacter jejuni (C. jejuni) have yet to be fully elucidated. Methods and Results The cases of C. jejuni bacteremia were retrospectively reviewed during a twelve-year period in a single institute. C. jejuni was identified in 7 patients through blood cultures, and disease onset occurred between June and October. Except for 2 previously healthy individuals, 5 patients had underlying diseases (chronic liver diseases, n=3; hematological malignancies, n=2). All patients were febrile, but 2 patients did not present with gastrointestinal symptoms. C. jejuni isolates were susceptible to gentamicin and macrolides, but about half of them were resistant to fluoroquinolones. Disease outcomes were favorable, and no deaths related to C. jejuni bacteremia were observed. Conclusion These results suggest that C. jejuni bacteremia could occur primarily or secondarily to gastroenteritis with a seasonal peak and that prognosis would be favorable regardless of the underlying diseases.
    Internal Medicine 01/2014; 53(17):1941-4. · 0.97 Impact Factor
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    ABSTRACT: Introduction Arbekacin is a unique aminoglycoside antibiotic with anti-methicillin-resistant Staphylococcus aureus activity. The efficacy of aminoglycosides is related to their serum maximum concentration. Local concentration of antibiotics in pulmonary epithelial lining fluid, rather than its serum concentration, can help determine its clinical efficacy more precisely for treatment of respiratory infectious disease. The objective of this study was to sequentially measure arbekacin concentration in epithelial lining fluid after infusion of a single clinically available dose. Method After the initial blood sampling, arbekacin was intravenously infused into 6 healthy volunteers over 1 h. Epithelial lining fluid and serum samples were collected by bronchoscopic microsampling 1, 1.5, 2, 2.5, 3, 4, 5, and 6 h after the start of 200 mg arbekacin infusion. Results Each probe sampled 10.1 ± 5.2 μl bronchial epithelial lining fluid. The sample dilution factor was 266.7 ± 157.1. Drug concentration was successfully measured in all but 2 of the epithelial lining fluid samples. The maximum concentration of arbekacin in epithelial lining fluid and serum was 10.4 ± 1.9 μg/ml and 26.0 ± 12.2 μg/ml, respectively. The ratio of the maximum drug concentration in the epithelial lining fluid to that in the serum was 0.47 ± 0.19. Conclusions The maximum concentration of epithelial lining fluid reached levels that would effectively treat most clinical strains of methicillin-resistant S. aureus.
    Journal of Infection and Chemotherapy. 01/2014;
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    ABSTRACT: Increasing evidence suggests that mesenchymal stem cells (MSCs) play anti-inflammatory roles during innate immune responses. However, little is known about the effect of MSCs or their secretions on the ligand response of Toll-like receptor (TLR) 7 and TLR8, receptors that recognize viral single-stranded RNA (ssRNA). Macrophages play a critical role in the innate immune response to ssRNA virus infection; therefore, we investigated the effect of MSC-conditioned medium on cytokine expression in macrophages following stimulation with TLR7/8 ligands. After stimulation with TLR7/8 ligand, bone marrow-derived macrophages cultured with MSCs or in MSC-conditioned medium expressed lower levels of tumor necrosis factor (TNF) α and interleukin (IL) 6 and higher levels of IL-10 compared to macrophages cultured without MSCs or in control medium, respectively. The modulations of cytokine expression were associated with prostaglandin E2 (PGE2) secreted by the MSCs. PGE2 enhanced extracellular signal-related kinase (ERK) signaling and suppressed nuclear factor- κ B (NF- κ B) signaling. Enhanced ERK signaling contributed to enhanced IL-10 production, and suppression of NF- κ B signaling contributed to the low production of TNF- α . Collectively, these results indicate that MSCs and MSC-conditioned medium modulate the cytokine expression profile in macrophages following TLR7/8-mediated stimulation, which suggests that MSCs play an immunomodulatory role during ssRNA virus infection.
    Mediators of Inflammation 01/2013; 2013:264260. · 3.88 Impact Factor
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    ABSTRACT: Bacillus cereus (B. cereus) is a Gram-positive rod that is widely distributed in the environment and can be a cause of food poisoning. We herein present a case of B. cereus necrotizing pneumonia in a patient with nephrotic syndrome under corticosteroid treatment after developing transient gastroenteritis symptoms. B. cereus was isolated from bronchial lavage fluid and transbronchial biopsy specimens. A multiplex polymerase chain reaction analysis of the toxin genes revealed a strain possessing enterotoxicity. The patient recovered after one week of intravenous meropenem followed by a combination of oral moxifloxacin and clindamycin. B. cereus is a pathogen that causes necrotizing pneumonia in immunocompromised hosts.
    Internal Medicine 01/2013; 52(1):101-4. · 0.97 Impact Factor
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    ABSTRACT: Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of PGD(2) and its newly found receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on the septic response. Severe sepsis is associated with the failure of neutrophil migration. To investigate whether CRTH2 influences neutrophil recruitment and the lethality during sepsis, sepsis was induced by cecal ligation and puncture (CLP) surgery in mice. CRTH2 knockout (CRTH2(-/-)) mice were highly resistant to CLP-induced sepsis, which was associated with lower bacterial load and lower production of TNF-α, IL-6, and CCL3. IL-10, an anti-inflammatory cytokine, was higher in CRTH2(-/-) mice, blunting CLP-induced lethality in CRTH2(-/-) mice. Neutrophil accumulation in the peritoneum was more pronounced after CLP in CRTH2(-/-) mice, which was associated with higher CXCR2 levels in circulating neutrophils. Furthermore, sepsis caused a decrease in the level of acetylation of histone H3, an activation mark, at the CXCR2 promoter in wild-type neutrophils, suggesting that CXCR2 expression levels are epigenetically regulated. Finally, both pharmacological depletion of neutrophils and inhibition of CXCR2 abrogated the survival benefit in CRTH2(-/-) mice. These results demonstrate that genetic ablation of CRTH2 improved impaired neutrophil migration and survival during severe sepsis, which was mechanistically associated with epigenetic-mediated CXCR2 expression. Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis.
    The Journal of Immunology 04/2012; 188(11):5655-64. · 5.52 Impact Factor
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    ABSTRACT: With the recent increasing use of nanoparticles, there is concern that they may become an environmental risk factor as airborne particles. However, the impact of these particles on susceptible subjects with predisposing lung disease have not been sufficiently elucidated. In the present study, we investigated the effects of nanoparticles on pulmonary inflammatory and fibrotic changes induced by intratracheal bleomycin (BLM) challenge in mice. Mice were intratracheally administered either vehicle, 14-nm carbon black nanoparticles (CBNPs), BLM or BLM plus CBNP. First, we assessed lung collagen content, lung compliance and fibrotic changes in histopathology on day 21 after instillation. Then, to elucidate how CBNP contributes to the development of BLM-induced fibrosis, we collected bronchoalveolar lavage (BAL) fluid on days 2, 7, 14 and 21 and determined the total and differential cell counts and concentrations of two proinflammatory cytokines (keratinocyte chemoattractant [KC] and interleukin [IL]-6) and two fibrogenic mediators (CC chemokine ligand 2 [CCL2] and transforming growth factor-β(1) [TGF-β(1)]). Expression of nitrotyrosine, an indicator of oxidant injury, was also evaluated on days 7 and 21. CBNP, when combined with BLM, significantly enhanced BLM-induced increase in lung collagen content, decrease in lung compliance, and fibrotic changes in histopathology. CBNP significantly augmented BLM-induced increase in the numbers of inflammatory cells in BAL fluid on days 2 and 7 and levels of KC and IL-6 on day 2. In addition, CBNP administered in combination with BLM significantly elevated the levels of CCL2 on days 2, 7 and 14, and TGF-β(1) on day 14 in BAL fluid as compared with BLM alone. Nitrotyrosine expression was also increased by BLM plus CBNP compared with BLM alone. In contrast, CBNP did not exert any significant effect on these parameters by itself. These results indicate that CBNP can exaggerate BLM-induced inflammatory and fibrotic changes in the lung, suggesting the potential impact of nanoparticles on lung inflammation and fibrosis.
    Experimental Biology and Medicine 03/2011; 236(3):315-24. · 2.80 Impact Factor
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    ABSTRACT: The clinical features of PCP differ according to the factors responsible for the predisposing immunosuppression. Although the diagnosis of PCP often requires BAL, the profiles of the inflammatory mediators in the BAL fluid are not thoroughly documented. The aim of the current study was to characterize the profiles of inflammatory mediators in BAL fluid during PCP in patients with underlying autoimmune diseases, malignancies, or AIDS. The medical records of 14 patients with autoimmune diseases, 10 with malignancies, and 8 with AIDS, all of whom had been diagnosed with PCP by microscopic examination of BAL fluid, were reviewed. The concentrations of TNF-alpha, MCP-1, HMGB1, IL-8, IL-6, IL-10, and IFN-gamma in the BAL fluid that had been obtained for the diagnosis of PCP were measured. The concentrations of MCP-1, IL-8, and IL-6 differed according to the underlying disease, tending to be higher in patients with autoimmune diseases and lower in those with AIDS. The concentrations of HMGB1, IL-8, and IL-6 were positively correlated with the proportion of neutrophils in BAL fluid and inversely with the oxygenation index. Although the serum concentrations of CRP and LDH were positively correlated with those of IL-8 and MCP-1, none of the mediators in BAL fluid was correlated with the serum beta-D-glucan concentration. The production of inflammatory mediators in the lung differed between the patient groups with different underlying disorders. The modest upregulation of IL-8 and IL-6 might be associated with the milder clinical manifestations of PCP in AIDS patients.
    Microbiology and Immunology 07/2010; 54(7):425-33. · 1.55 Impact Factor
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    ABSTRACT: Acute exacerbation of interstitial pneumonia (IP-AE) can occasionally occur and has a poor prognosis. Direct hemoperfusion with a polymyxin B immobilized fiber column (PMX-DHP) has been shown to have a beneficial effect on acute respiratory distress syndrome, which has similar pathological features to that of IP-AE. This study was aimed to investigate the effects of PMX-DHP on IP-AE and serum indicators for epithelial damage. Nine patients with a clinical diagnosis of interstitial pneumonia, who developed acute exacerbation, were included in this study. Five patients had been given a diagnosis of idiopathic pulmonary fibrosis (IPF) and 3 cases were diagnosed as collagen vascular disease-associated interstitial pneumonia (CVD-IP). On days 30 and 60, 6 and 4 patients were surviving, respectively. On day 60, all 3 patients with CVD-IP were alive, while 4 of 5 patients with IPF had died. In 4 patients who survived for 60 days or longer, serum levels of LDH, CRP, and SP-D were significantly decreased after PMX-DHP, whereas KL-6 level was unchanged. In 5 patients, who died by day 60, no significant changes in the serum markers were observed. These data suggest that serum levels of LDH, CRP, and SP-D might be predictive of successful PMX-DHP treatment in cases of IP-AE.
    Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 11/2009; 47(11):978-84.
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    ABSTRACT: Bacterial genome is characterized by frequent unmethylated cytosine-phosphate-guanine (CpG) motifs. Deleterious effects can occur when synthetic oligodeoxynucleotides (ODN) with unmethylated CpG dinucleotides (CpG-ODN) are administered in a systemic fashion. We aimed to evaluate the effect of intratracheal CpG-ODN on lung inflammation and systemic inflammatory response. C57BL/6J mice received intratracheal administration of CpG-ODN (0.01, 0.1, 1.0, 10, or 100 microM) or control ODN without CpG motif. Bronchoalveolar lavage (BAL) fluid was obtained 3 or 6 h or 1, 2, 7, or 14 days after the instillation and subjected to a differential cell count and cytokine measurement. Lung permeability was evaluated as the BAL fluid-to-plasma ratio of the concentration of human serum albumin that was injected 1 h before euthanasia. Nuclear factor (NF)-kappaB DNA binding activity was also evaluated in lung homogenates. Intratracheal administration of 10 microM or higher concentration of CpG-ODN induced significant inflammatory cell accumulation into the airspace. The peak accumulation of neutrophils and lymphocytes occurred 1 and 2 days after the CpG-ODN administration, respectively. Lung permeability was increased 1 day after the 10 microM CpG-ODN challenge. CpG-ODN also induced nuclear translocation of NF-kappaB and upregulation of various inflammatory cytokines in BAL fluid and plasma. Histopathology of the lungs and liver revealed acute lung injury and liver damage with necrosis, respectively. Control ODN without CpG motif did not induce any inflammatory change. Since intratracheal CpG-ODN induced acute lung injury as well as systemic inflammatory response, therapeutic strategies to neutralize bacterial DNA that is released after administration of bactericidal agents should be considered.
    Respiratory research 09/2009; 10:84. · 3.64 Impact Factor
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    ABSTRACT: Patients with Mycobacterium avium-intracellulare complex (MAC) pulmonary disease often suffer from weight loss. Adipokines are factors secreted by adipocytes, including leptin and adiponectin, as well as some inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6). Body mass index (BMI) is known to be inversely correlated with adiponectin and positively with leptin, TNF-alpha, and IL-6. We aimed to evaluate the levels of serum adipokines, including adiponectin, leptin, TNF-alpha, and IL-6 in patients with MAC pulmonary disease. Forty consecutive patients with MAC pulmonary disease (8 males; median age 62 years; median BMI 18.1) were examined. Serum levels of adiponectin, leptin, TNF-alpha, and IL-6 were measured with ELISA. Age-, sex- and BMI-matched healthy subjects served as controls. Serum adiponectin was significantly elevated in patients with MAC pulmonary disease compared with the controls (p < 0.01). In both the patients and controls, serum adiponectin levels were inversely correlated with BMI (p < 0.05). No significant correlation was observed between serum adiponectin levels and C-reactive protein or lung function. Serum leptin levels, which were positively correlated with BMI, did not differ between patients and controls. Serum levels of TNF-alpha and IL-6 were significantly greater in patients with MAC pulmonary disease than in controls. The levels of TNF-alpha and IL-6 were not correlated with BMI and other adipokines examined. The results of the present study indicate that, in patients with MAC pulmonary disease, adiponectin is inappropriately secreted and may play a role in the pathophysiology of the disease.
    Respiration 07/2009; 79(5):383-7. · 2.92 Impact Factor