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Biomedical subjects

Akitoshi Ishizaka

Publications and source records attributed to Akitoshi Ishizaka.

At least 19 recordsLinked to original sources
PubMed2007

TLR3-mediated synthesis and release of eotaxin-1/CCL11 from human bronchial smooth muscle cells stimulated with double-stranded RNA.

Respiratory infections with RNA viruses, such as rhinovirus or respiratory syncytial virus, are a major cause of asthma exacerbation, accompanied by enhanced neutrophilic and/or eosinophilic inflammation of the airways. We studied the effects of dsRNA synthesized during RNA virus replication, and of its receptor, TLR3, on the synthesis of eosinophilic chemokines in bronchial smooth muscle cells (BSMC). Synthetic dsRNA, polyinosinic-cystidic acid (poly(I:C)), induced the synthesis of eosinophilic chemokines, eotaxin-1/CCL11 and RANTES/CCL5, from primary cultures of human BSMC, and IL-4 increased synergistically the synthesis of poly(I:C)-induced CCL11. A robust eosinophil chemotactic activity was released from BSMC stimulated with poly(I:C) and IL-4, which was mostly inhibited by preincubation with an anti-CCL11, but not with an anti-CCL5 Ab. Although the immunoreactivity of TLR3 was detectable on the cellular surface of BSMC by flow cytometric analysis, pretreatment with an anti-TLR3-neutralizing Ab failed to block the poly(I:C)-induced synthesis of CCL11. We have determined by confocal laser-scanning microscopy that the immunoreactivity of TLR3 was aggregated intracellularly in poly(I:C)-stimulated BSMC, colocalizing with fluorescein-labeled poly(I:C). The synthesis of CCL11 was prominently inhibited by the transfection of TLR3-specific small interfering RNA or by bafilomycin A1, an endosomal acidification inhibitor, further supporting the essential role played by intracellular TLR3 in the synthesis of poly(I:C)-induced CCL11 in BSMC. In conclusion, these observations suggest that, by activating intracellular TLR3 in BSMC, respiratory RNA virus infections stimulate the production of CCL11 and enhance eosinophilic inflammation of the airways in the Th2-dominant microenvironment.

Bronchi↗
PubMed2006

New rapid detection test with a combination of polymerase chain reaction and immunochromatographic assay for Mycobacterium tuberculosis complex.

Recently, we had developed a polymerase chain reaction (PCR)-immunochromatographic assay (ICA) method for Mycobacterium tuberculosis and examined its clinical utility among 138 sputa of patients under suspicion of pulmonary tuberculosis. According to the results of fluorochrome staining of acid-fast bacillus, which were confirmed by Ziehl-Neelsen staining, these were 83 specimens (-), 7 specimens (+/-), 30 specimens (1+), 8 specimens (2+), and 10 specimens (3+). These specimens included 4 groups: group 1, 41 specimens of smear (+/-) approximately (3+) with culture-positive M. tuberculosis; group 2, 11 specimens of smear (-) with culture-positive M. tuberculosis; group 3, 12 specimens of smear (+/-) approximately (1+) with culture-positive nontuberculosis mycobacterium (NTM); and group 4, 9 specimens of smear (-) with culture-positive NTM. The positive results of PCR-ICA test and Amplicor M. tuberculosis (Amplicor MTB) test for M. tuberculosis are as follows: group 1, 40 positive by PCR-ICA and 39 positive by Amplicor MTB from 41 specimens; group 2, 1 positive by PCR-ICA and 5 positive by Amplicor MTB from 11 specimens; group 3, 0 positive by both tests from 12 specimens; and group 4, 0 positive by both tests from 9 specimens. None of NTM-positive specimens from groups 3 and 4 reacted on the PCR-ICA test for M. tuberculosis.

Bacteriological Techniques↗
PubMed2006

Pharmacokinetics of telithromycin using bronchoscopic microsampling after single and multiple oral doses.

OBJECTIVES: Bronchoscopic microsampling (BMS) is a new technique for repeated sampling of bronchial epithelial lining fluid (ELF) to obtain the pharmacokinetic profile of drugs. We analyzed the time versus concentration profiles of telithromycin in bronchial ELF obtained by BMS and compared these finding to those in plasma and alveolar ELF obtained by bronchoalveolar lavage (BAL). METHODS: Bronchial ELF samples were obtained from five healthy subjects using BMS probe at 0, 2, 3, 4, 6, 10 and 24h after single or multiple oral doses of 600 mg of telithromycin. Alveolar ELF was also obtained by BAL 3h after single or multiple oral doses of 600 mg of telithromycin. RESULTS: The areas under the concentration-time curve from 0 to 24h (AUC0-24) of telithromycin in plasma and bronchial ELF were 2.86+/-0.60 and 19.5+/-10.4 mg h/l after single treatment and 3.60+/-0.49 and 42.2+/-22.7 mg h/l after multiple treatments, respectively. Single and multiple oral doses of telithromycin produced significantly (p<0.05) higher AUC0-24 in bronchial ELF compared to those in plasma. While concentrations in bronchial ELF obtained by BMS were significantly lower than those in alveolar ELF obtained by BAL, they tended to be higher than those in plasma after multiple administration. The telithromycin concentrations obtained by BMS method were very consistent in bronchial ELF at different bronchi at one time point and at the same bronchus at different time points. CONCLUSIONS: Using the BMS technique, we could describe the pharmacokinetics of telithromycin in bronchial ELF. Furthermore, BMS was reasonably validated and reconfirmed to be a feasible and reliable method for measuring antimicrobial concentrations in bronchial ELF.

Administration, Oral↗
PubMed2006

Contribution of high-mobility group box-1 to the development of ventilator-induced lung injury.

RATIONALE: Proinflammatory cytokines play an important role in ventilator-induced lung injury (VILI). High-mobility group box-1 (HMGB1) is a macrophage-derived proinflammatory cytokine that can cause lung injury. OBJECTIVES: This study tested the hypothesis that HMGB1 is released in intact lungs ventilated with large Vt. A second objective was to identify the source of HMGB1. A third objective was to examine the effects of blocking HMGB1 on the subsequent development of VILI. METHODS: Bronchoalveolar lavage fluid (BALF) and lung tissues were obtained from rabbits mechanically ventilated for 4 h with a small (8 ml/kg) versus a large (30 ml/kg) Vt. BALF was also obtained from rabbits with intratracheal instillation of anti-HMGB1 antibody before the initiation of large Vt ventilation. MEASUREMENTS AND MAIN RESULTS: The concentrations of HMGB1 in BALF were fivefold higher in the large than in the small Vt group. Immunohistochemistry and immunofluorescence studies revealed expression of HMGB1 in the cytoplasm of macrophages and neutrophils in lungs ventilated with large Vt. Blocking HMGB1 improved oxygenation, limited microvascular permeability and neutrophil influx into the alveolar lumen, and decreased concentrations of tumor necrosis factor-alpha in BALF. CONCLUSIONS: These observations suggest that HMGB1 could be one of the deteriorating factors in the development of VILI.

Bronchoalveolar Lavage Fluid↗
PubMed2006

Anti-high-mobility group box chromosomal protein 1 antibodies improve survival of rats with sepsis.

BACKGROUND: High-mobility group box chromosomal protein 1 (HMGB1) has recently been shown to be an important late mediator of endotoxin shock, intraabdominal sepsis, and acute lung injury, and a promising therapeutic target of severe sepsis. We sought to investigate the effect of antibodies to HMGB1 on severe sepsis in a rat cecal ligation and puncture (CLP) model. METHODS: Adult male Sprague-Dawley rats underwent CLP and then were randomly divided into two groups: treatment with anti-HMGB1 polyclonal antibodies, and non-immune IgG-treated controls. The serum HMGB1 concentrations were measured at ten time points (preoperatively, and postoperatively at 4, 8, 20, 32, and 48 h and at 3, 4, 5, and 6 days). Hematoxylin-eosin staining, elastica-Masson staining, and immunohistochemical staining for HMGB1 were performed on the cecum and the lung to assess pathological changes 24 h after the CLP procedure. RESULTS: Treatment with anti-HMGB1 antibodies significantly increased survival [55% (anti-HMGB1) vs. 9% (controls); P< 0.01]. The serum HMGB1 concentrations at postoperative hours 20 and 32 of the anti-HMGB1 antibody-treated animals were significantly lower than those of the controls (P < 0.05). Treatment with anti-HMGB1 antibodies markedly diminished the pathological changes and the number of HMGB1-positive cells in the cecum and the lung. CONCLUSIONS: The present study demonstrates that anti-HMGB1 antibodies are effective in the treatment of severe sepsis in a rat model, thereby supporting the relevance of HMGB1 eradication therapy for severe sepsis.

Animals↗
PubMed2006

Early pulmonary resection for Mycobacterium avium complex lung disease treated with macrolides and quinolones.

BACKGROUND: The purpose of this study was to examine the postoperative outcomes of patients with Mycobacterium avium complex (MAC) lung lesions persisting despite treatment with multiple antibiotics. METHODS: Patients with localized pulmonary lesions persisting despite extensive state-of-the art antimicrobial chemotherapy became candidates for surgical resection. Twenty-two patients who were expected to retain sufficient postoperative pulmonary function were included in this study. These patients received chemotherapy for 2 to 37 months (mean, 17). Surgical procedures were lobectomy (n = 15), segmentectomy (n = 4), and partial lung resection (n = 6). Three patients underwent bilateral resections. RESULTS: Mycobacterium avium complex causing bronchiectasis or cavitary lesions was detected preoperatively in all 22 patients. There was no major operative morbidity or mortality. Postoperative chemotherapy was continued for 6 to 35 months. All patients were alive and well at follow-ups ranging from 6 to 164 months (median, 46). Both vital capacity and forced expiratory volume in 1 second after surgery were maintained at 89% and 84% of the preoperative values, respectively. Mycobacterium avium complex disappeared from sputum after surgery in all patients. In 1 patient, 4 months after resection of a cavitary lesion, MAC-positive sputum presumed to be from the contralateral lung lesion became negative during continuation of chemotherapy. CONCLUSIONS: The long-term outcomes of patients operated on for MAC resistant to antimicrobial chemotherapy were excellent. For such patients, we recommend surgery before the disease becomes exceedingly advanced and nonresectable. Additionally, in extensive disease, the excision of large cavitary bacterial foci may assist the medical management of contralateral lesions.

Adult↗
PubMed2006

Effects of diesel exhaust particles on human neutrophil activation.

Diesel exhaust particles (DEP) are associated with respiratory disease and exposure to diesel exhaust induces an inflammatory response associated with marked leukocytic infiltration in the lung. This study examined whether neutrophils are activated by the active component of DEP (methanol extract of DEP [me-DEP]). The authors demonstrated that neutrophils exposed to me-DEP had increased levels of the f-actin content, the surface expression of adhesion molecules, and the release of interleukin (IL-8) and leukotriene B4 (LTB4), superoxide, and matrix metalloproteinase (MMP-9). Thus, the author conclude that DEP exposure activates neutrophils and that these activated neutrophils could contribute to the adverse respiratory health effects associated with DEP and to the pathogenesis of chronic inflammatory lung diseases.

Actins↗
PubMed2006

Activation of a neutrophil-derived inflammatory response in the airways during cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) is believed to cause postoperative lung dysfunction. To more closely examine the inflammatory processes occurring in the airways during CPB, we serially measured inflammatory mediators, with the assistance of a new bronchoscopic microsample probe, in 11 patients undergoing repair of aortic arch aneurysms. Epithelial lining fluid (ELF) and arterial blood were sampled simultaneously after induction of anesthesia, at the time of pulmonary reperfusion, and at the end of surgery. A decrease in the PaO2/FiO2 ratio was observed at the end of surgery (P = 0.029). Although the ELF concentrations of interleukin (IL)-8, IL-6, and neutrophil elastase had increased significantly at the end of surgery (median = 23,200, 1818, and 12,900 microg/mL, respectively), they did not correlate with the degree of hypoxemia. Neutrophil elastase increased significantly at the time of pulmonary reperfusion, before IL-8 and IL-6, and independently of blood transfusions. At the end of surgery, IL-6 in ELF correlated with total blood transfusion volume (rho = 0.731, P = 0.011). These results indicate that a neutrophil-derived inflammatory response is activated in the airway in the early phase of CPB.

Aged↗
PubMed2006

[Clinical features of Pneumocystis pneumonia in patients with systemic lupus erythematosus].

Systemic lupus erythematosus (SLE) is often associated with various opportunistic infections, particularly during treatment with corticosteroids or immunosuppressants. We studied the clinical characteristics of 15 patients with SLE who underwent diagnostic bronchoalveolar lavage (BAL) and compared 6 patients with confirmed Pneumocystis pneumonia (PcP+), with 9 patients without Pneumocystis pneumonia (PcP-). The serum concentrations of beta-D-glucan and KL-6 were significantly higher in PcP+ than in PcP- patients, whereas serum LDH was similar in both groups. The serum concentrations of complement, a marker of SLE activity, and of IgG did not predict the presence of PcP. In all patients, the overall cell and lymphocyte counts were increased in the BAL fluid, without any significant difference between the PcP+ and PcP- groups. Ground-glass opacities on chest computed tomography, and oxygenation impairment (PaO2/FiO2<200Torr) were more common in PcP+ than PcP- patients. We concluded that, in patients with SLE, serum beta-D-glucan and KL-6 might be useful in the diagnosis of PcP, particularly when severe hypoxemia precludes BAL.

Adult↗
PubMed2006

[Small cell lung cancer with Sjögren's syndrome and Lambert-Eaton myasthenic syndrome].

A 72-year-old man was admitted to our hospital with complaints of dry mouth, muscle weakness of the lower limbs and gait disturbance. The patient had dry mouth, dry eyes, positive anti-SS-B antibody and salivary gland inflammation. Sjögren's syndrome was diagnosed. Since muscle weakness of the lower limbs and gait disturbance were not compatible with Sjögren's syndrome, we considered the possibility of paraneoplastic syndrome. Serum levels of CEA, NSE and ProGRP were elevated. Chest roentgenogram and CT showed a nodular lesion in the right upper lobe of the lung and swollen lymph nodes in the hilum and mediastinum. Small cell lung cancer was diagnosed by bronchoscopy. Anti-P/Q-type Ca2+ channel antibody was positive. Electromyogram showed a reduction in the amplitude of the evoked muscle action potential response after slow repetitive stimulation and did not show a reduction after rapid repetitive stimulation. Based on these findings, we made a diagnosis of Lambert-Eaton myasthenic syndrome (LEMS). Concurrent chemoradiotherapy induced an improvement of muscle weakness of the lower limbs. LEMS is frequently associated with a malignant tumor and an autoimmune disorder. We thought that in this patient, the presentation of LEMS was apparent because he had both Sjögren's syndrome and small cell lung cancer.

Aged↗
PubMed2005

Various adhesion molecules impair microvascular leukocyte kinetics in ventilator-induced lung injury.

Although the endothelial expression of various adhesion molecules substantially differs between pulmonary microvessels, their importance for neutrophil and lymphocyte sequestration in ventilator-induced lung injury (VILI) has not been systematically analyzed. We investigated the kinetics of polymorphonuclear cells (PMN) and mononuclear cells (MN) in the acinar microcirculation of the isolated rat lung with VILI by real-time confocal laser fluorescence microscopy, with or without inhibition of ICAM-1, VCAM-1, or P-selectin by monoclonal antibodies (MAb). Adhesion molecules in each microvessel were estimated by intravital fluorescence microscopy or immunohistochemical staining. In high tidal volume-ventilated lungs, 1) ICAM-1, VCAM-1, and P-selectin were differently upregulated in venules, arterioles, and capillaries; 2) venular PMN rolling was improved by inhibition of ICAM-1, VCAM-1, or P-selectin, whereas arteriolar PMN rolling was improved by ICAM-1 or VCAM-1 inhibition; 3) capillary PMN entrapment was ameliorated only by anti-ICAM-1 MAb; and 4) MN rolling in venules and arterioles and MN entrapment in capillaries were improved by ICAM-1 and VCAM-1 inhibition. In conclusion, the contribution of endothelial adhesion molecules to abnormal leukocyte behavior in VILI-injured microcirculation is microvessel and leukocyte specific. ICAM-1- and VCAM-1-dependent, but P-selectin-independent, arteriolar PMN rolling, which is expected to reflect the initial stage of tissue injury, should be taken as a phenomenon unique to ventilator-associated lung injury.

Animals↗
PubMed2005

High mobility group box 1 protein interacts with multiple Toll-like receptors.

High mobility group box 1 (HMGB1), originally described as a DNA-binding protein, can also be released extracellularly and functions as a late mediator of inflammatory responses. Although recent reports have indicated that the receptor for advanced glycation end products (RAGE) as well as Toll-like receptor (TLR)2 and TLR4 are involved in cellular activation by HMGB1, there has been little evidence of direct association between HMGB1 and these receptors. To examine this issue, we used fluorescence resonance energy transfer (FRET) and immunoprecipitation to directly investigate cell surface interactions of HMGB1 with TLR2, TLR4, and RAGE. FRET images in RAW264.7 macrophages demonstrated association of HMGB1 with TLR2 and TLR4 but not RAGE. Transient transfections into human embryonic kidney-293 cells showed that HMGB1 induced cellular activation and NF-kappaB-dependent transcription through TLR2 or TLR4 but not RAGE. Coimmunoprecipitation also found interaction between HMGB1 and TLR2 as well as TLR4, but not with RAGE. These studies provide the first direct evidence that HMGB1 can interact with both TLR2 and TLR4 and also supply an explanation for the ability of HMGB1 to induce cellular activation and generate inflammatory responses that are similar to those initiated by LPS.

Animals↗
PubMed2005

Differences in pulmonary function before vs. 1 year after hypofractionated stereotactic radiotherapy for small peripheral lung tumors.

PURPOSE: To evaluate long-term pulmonary toxicity of stereotactic radiotherapy (SRT) by pulmonary function tests (PFTs) performed before and after SRT for small peripheral lung tumors. METHODS AND MATERIALS: A total of 17 lesions in 15 patients with small peripheral lung tumors, who underwent SRT between February 2000 and April 2003, were included in this study. Twelve patients had primary lung cancer, and 3 patients had metastatic lung cancer. Primary lung cancer was T1-2N0M0 in all cases. Smoking history was assessed by the Brinkman index (number of cigarettes smoked per day multiplied by number of years of smoking). Prescribed radiation doses at the 80% isodose line were 40-60 Gy in 5-8 fractions. PFTs were performed immediately before SRT and 1 year after SRT. Test parameters included total lung capacity (TLC), vital capacity (VC), forced expiratory volume in 1 s (FEV1.0), and diffusing capacity of lung for carbon monoxide (DLCO). PFT changes were evaluated in relation to patient- and treatment-related factors, including age, the Brinkman index, internal target volume, the percentages of lung volume irradiated with >15, 20, 25, and 30 Gy (V15, V20, V25, and V30, respectively), and mean lung dose. RESULTS: There were no significant changes in TLC, VC, or FEV1.0 before vs. after SRT. The mean percent change from baseline in DLCO was significantly increased by 128.2%. Univariate and multivariate analyses revealed a correlation between DLCO and the Brinkman index. CONCLUSIONS: One year after SRT as compared with before SRT, there were no declines in TLC, VC, and FEV1.0. DLCO improved in patients who had been heavy smokers before SRT, suggesting a correlation between DLCO and smoking cessation. SRT seems to be tolerable in view of long-term lung function.

Aged↗
PubMed2005

Role of Rho-kinase in reexpansion pulmonary edema in rabbits.

Reexpansion of a collapsed lung increases the microvascular permeability and causes reexpansion pulmonary edema. Neutrophils and their products have been implicated in the development of this phenomenon. The small GTP-binding proteins Rho and its target Rho-kinase (ROCK) regulate endothelial permeability, although their roles in reexpansion pulmonary edema remain unclear. We studied the contribution of ROCK to pulmonary endothelial and epithelial permeability in a rabbit model of this disorder. Endothelial and epithelial permeability was assessed by measuring the tissue-to-plasma (T/P) and bronchoalveolar lavage (BAL) fluid-to-plasma (B/P) ratios with (125)I-labeled albumin. After intratracheal instillation of (125)I-albumin, epithelial permeability was also assessed from the plasma leak (PL) index, the ratio of (125)I-albumin in plasma/total amount of instilled (125)I-albumin. T/P, B/P, and PL index were significantly increased in the reexpanded lung. These increases were attenuated by pretreatment with Y-27632, a specific ROCK inhibitor. However, neutrophil influx, neutrophil elastase activity, and malondialdehyde concentrations in BAL fluid collected from the reexpanded lung were not changed by Y-27632. In endothelial monolayers, Y-27632 significantly attenuated the H(2)O(2)-induced increase in permeability and mitigated the morphological changes in the actin microfilament cytoskeleton of endothelial cells. These in vivo and in vitro observations suggest that the Rho/ROCK pathway contributes to the increase in alveolar barrier permeability associated with reexpansion pulmonary edema.

Actin Cytoskeleton↗
PubMed2005

Tacrolimus (FK506) has protective actions against murine bleomycin-induced acute lung injuries.

The effects of tacrolimus on murine acute lung injury were tested, especially in comparison to dexamethasone. Acute lung injury was induced by intratracheal instillation of bleomycin. Oral tacrolimus significantly improved survival rates of bleomycin-exposed mice, while cyclosporin A or dexamethasone did not. After instillation of bleomycin (day 0), a migration of neutrophils into alveolar spaces peaked on day 3, with concomitant increases of chemokines. On day 6, marked morphological changes in the lungs were observed. All these changes were significantly inhibited by tacrolimus. Furthermore, DNA ladder and immunohistochemical analyses of lungs showed that apoptosis of lung cells appeared on day 6 and was abolished only by the treatment of tacrolimus. These results suggest that both anti-inflammatory and anti-apoptotic action of tacrolimus contribute to improvement of bleomycin-induced acute lung injury.

Acute Disease↗