巽 浩一郎

CD40-positive dendritic cells (DCs) are stimulated with CD40 ligand (CD40L) and subsequently secrete a number of cytokines including interleukin (IL)-23, which is involved in cell-mediated immune responses. Expression of CD40 ligand (CD40L) on tumors can activate host immune systems and produce antitumor effects against the tumors. We examined a possible mechanism of the antitumor responses: tumor cells expressing CD40 can transcribe DCs-derived cytokine genes by the expressed CD40L. For the purpose, CD40-positive All and -negative P29 murine lung tumors cells, both of the same origin, were transfected with the CD40L gene (A11/CD40L and P29/CD40L). The growth rate in vitro of A11/CD40L and P29/CD40L cells was not different from that of the respective parent tumors however, the growth in vivo of A11/CD40L tumors in syngeneic mice was significantly retarded and the growth retardation of P29/CD40L tumors was marginal. Transcription of the p40 and p19 genes, IL-25 subunit genes, was up-regulated in A11/CD40L cells compared with parent All cells, whereas this up-regulation was not observed in P29/CD40L cells. Since expression of IL-23 in tumors can produce antitumor effects, the present data suggest that the CD40/CD40L interaction can activate cytokine transcripts in certain tumors and consequently contribute to antitumor responses.

Although many cases of sarcoidosis are self-limiting with spontaneous remission, uncontrolled pulmonary granulomatosis with fibrosis produces intolerable long-term respiratory symptoms in a minority of patients. Individuals with chronic pulmonary sarcoidosis require an alternative therapy to corticosteroidal treatment because of its insufficient effectiveness. Although many researchers have considered infection as the triggering factor for this disease, the mechanisms by which the candidate causative organisms induce this disorder remain unclear. We report here that extrapulmonary sensitization to Propionibacterium acnes, which is one of the candidates to date, induced pulmonary Th-1 granulomas mainly in the subpleural and peribronchovascular regions often observed in sarcoidosis. These granulomas appear to be caused by indigenous P. acnes pre-existing in the lower respiratory tract of the normal lung, which is believed to be germ-free, and by an influx of P. acnes-sensitized CD4(+) T cells from the circulation. Importantly, the eradication of indigenous P. acnes with antibiotics alleviated the granulomatous lung disease. This is the first report to present clear evidence of the contribution of an indigenous pulmonary bacterium to the formation of granulomatous lesions in the lung. We propose that treatment targeting indigenous P. acnes in the lung may be a possible remedy for pulmonary sarcoidosis.

OBJECTIVE: The Global Initiative for Obstructive Lung Disease characterizes COPD as airflow limitation caused by parenchymal destruction and/or small airway disease. This report characterizes the clinical features of these two phenotypes of COPD in Japan. METHODOLOGY: COPD was diagnosed by spirometric airflow limitation (FEV(1)/FVC < 70%), and all subjects underwent chest CT scanning. Patients with diffuse low attenuation areas (LAA) on CT scan were categorized as the emphysema-dominant phenotype; those with little LAA were categorized as the airway disease-dominant phenotype. The two groups were compared to identify significant clinical or demographic differences. RESULTS: Of the 1438 patients analysed, 1294 (90%) were classified as having an emphysema-dominant phenotype and 144 (10%) as having an airway disease-dominant phenotype. The airway disease-dominant phenotype was: more common than the emphysema-dominant phenotype in women (15%vs. 7%, P < 0.01) and in non-smokers (6%vs. 2%, P < 0.05); was more commonly complicated by asthmatic features (35%vs. 21%, P < 0.01); and had higher IgE and eosinophil levels (P < 0.05) and less lung function impairment. CONCLUSION: This analysis is the first to clinically define two phenotypes of COPD in a Japanese epidemiological survey. There appear to be striking differences as well as overlap between these two groups. Further research is warranted to determine the significance of COPD phenotypes.

The clinical presentation of respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and desquamative interstitial pneumonitis (DIP) seems to be nonspecific, although well-defined pathologic features have been described. Therefore, the clinical pictures, laboratory, radiologic and bronchoalveolar lavage fluid (BALF) findings, and prognosis of 5 patients with RB-ILD were compared with those of 7 patients with DIP. Cell differentiation in BALF could be helpful to distinguish RB-ILD and DIP. Eosinophils were observed only in DIP. The proportion of macrophages was greater in RB-ILD, whereas that of neutrophils was greater in DIP. In RB-ILD, high-resolution computed tomography (HRCT) revealed diffuse centrilobular, nodular or patchy, ground-glass opacities and peripherally distributed, irregular linear opacities. In DIP, HRCT revealed diffuse, bilateral panlobular ground-glass opacities. Clinical symptoms, abnormal radiologic and laboratory findings improved in 6 months after quitting smoking in all patients with RB-ILD. On the other hand, all patients with DIP required systemic steroid therapy, and steroid therapy was difficult to withdraw in 2 years. RB-ILD could be distinguished from DIP, which is also recognized to be a smoking-related interstitial lung disease in terms of its good prognosis, although small numbers of patients in this study limit drawing a definite conclusion, and further studies are required to determine the long-term prognosis.

Irinotecan is an active cytotoxic agent for various cancers, and is converted to SN-38, its most active metabolite, by carboxylesterase converting enzyme (CCE) in vivo. Although the primary metabolic site is in the liver, ex vivo studies have proven that irinotecan is also converted to SN-38 in intestines, plasma and tumor tissues. The present study attempted to elucidate the in vitro conversion efficiency in human plasma, and to examine possible inter-individual variability and its clinical significance. Plasma samples were taken from 57 patients with lung cancer, 3 patients with benign pulmonary diseases and 9 healthy volunteers. After addition of 157 mM irinotecan to plasma, time courses of SN-38 concentration, measured by high-performance liquid chromatography (HPLC), were investigated. All subjects showed linear increase in SN-38 concentration during the first 60-min period, followed by a plateau. Mean and standard deviation of the conversion rate in the first 60 min were 515.9 +/- 50.1 pmol/ml/h (n = 69), with a coefficient of variation of 0.097. Although most of the subjects showed comparable conversion rates, 3 subjects had significantly higher conversion rates. In conclusion, the results of this study suggest that the enzyme activity of CCE in human plasma may show inter-individual variability.

We used a PCR and sequence procedure to analyze the Ig V(H) gene and the mutations in the 5' regulatory regions of BCL-6 genes in pulmonary lymphoproliferative disorders (mucosa-associated lymphoid tissue (MALT) lymphoma, HIV-related, EBV-related, and virus-negative lymphocytic interstitial pneumonia (LIP)). Eight of 20 (40%) pulmonary MALT lymphoma and 10 of 20 LIP (5 of 5 (100%) HIV-related, 2 of 5 (40%) EBV-related, and 3 of 10 (30%) virus-negative LIP) cases showed BCL-6 gene mutations. Intraclonal heterogeneity of the BCL-6 mutations was observed only in pulmonary MALT lymphoma cases whose Ig V(H) genes also showed intraclonal heterogeneity. Ongoing BCL-6 mutations might reflect re-entry into a germinal center pathway to further mutations. BCL-6 mutations in pulmonary MALT lymphoma and HIV-negative LIP showed some features (high transition to transversion ratio, standard polarity, and RGYW/WRCY bias) of Ig V(H) gene hypermutation, leading to the view that pulmonary MALT lymphomas and HIV-negative LIP are under the influence of germinal center hypermutation mechanisms. Because BCL-6 mutations in HIV-related LIP cases did not demonstrate features of Ig V(H) gene hypermutation, immunological reactions in HIV-related LIP are the result of a process different from that found in HIV-negative pulmonary lymphoproliferative disorders.

OBJECTIVE: Decreased expression of prostacyclin synthase (PGIS) is observed in the lung vasculature of patients with pulmonary arterial hypertension and the biosynthesis of prostacyclin (PGI2) may be impaired in chronic thromboembolic pulmonary hypertension (CTEPH). Whether it is genetically determined or develops as the disease progresses is unclear. A variable-number tandem repeat (VNTR) polymorphism has been detected in the 5'-upstream promoter region of the PGIS gene. It has been demonstrated that the alleles vary in size from three to seven repeats of nine base pairs, and transcriptional activity increased with the number of repeats. The purpose of the present study was to elucidate the association between the VNTR polymorphisms of the PGIS gene and CTEPH in Japanese subjects. METHODOLOGY: Ninety patients with CTEPH and 144 control subjects were investigated for the presence of VNTR polymorphisms. Sixty-two blood samples were obtained from CTEPH patients and the plasma concentrations of prostacyclin and thromboxane A2 metabolites were measured. RESULTS: VNTR polymorphisms in the prostacyclin synthase gene were grouped into L alleles (five, six and seven repeats) and S alleles (three and four repeats). The overall distribution of the alleles and genotypes were not significantly different between CTEPH patients and the control subjects. The patients with the LL genotype had higher plasma concentrations of 6-keto-prostaglandin F1alpha than patients with the LS and SS genotypes. CONCLUSIONS: Our results suggested that the specific VNTR polymorphism in the 5'-upstream promoter region of the PGIS gene regulated prostacyclin production, but did not seem to be associated with the development of CTEPH in this patient population.

Gliotoxin, one of the mycotoxins produced by Aspergillus fumigatus, has various, potent bioactivities. However, it has not been considered to be a toxic (or virulence) factor because of its slow production. The aim of the present study was to investigate the effects of aeration on the cytotoxicity of A. fumigatus culture filtrate, and to determine the optimal condition for the rapid production of gliotoxin from this fungus. Fungal culture filtrates were made in three different containers under various conditions of aeration and O2 concentration. These filtrates were compared in terms of their cytotoxicity on murine macrophages and analyzed by gas chromatography. The culture filtrate showed high cytotoxicity when it was made under highly aerated conditions, but it was significantly less cytotoxic when prepared under non-aerated conditions. The cytotoxic activity became evident within 15 h of culture at 20% O2, when the fungus had already started producing gliotoxin. The culture filtrates also contained some other as yet unidentified substances that might also to some extent contribute to the cytotoxicity. In light of these results, the authors propose that a highly aerated condition is responsible for the rapid production of gliotoxin, and that gliotoxin might play an important role in the respiratory infection by A. fumigatus, with other toxic substances acting additively or synergistically.

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease characterized by hamartomatous proliferation of abnormal smooth muscle cells in the lungs. Recently, severe LAM has been listed as an indicated disease for lung transplantation. A 34-yr-old woman with severe pulmonary cystic changes in a chest CT scan was diagnosed as having an isolated form of pulmonary LAM without genetic disorders. Despite intensive progesterone treatment, her pulmonary functions deteriorated rapidly. In January 2001, a left single-lung transplantation was performed from a cadaveric donor. The total operating time was 8 hours and 47 minutes. Total ischemic time was 5 hours and 59 minutes, which was within the permitted time limit. Except for right pneumothorax, the postoperative course was fairly good without any sign of rejection or infection in the allograft. For about two months after transplantation, bronchostenosis occurred in the left lower lobe bronchus, and necessitated a stent placement. During the following three months, stenosis of the bronchi in the anastomotic and peripheral sites occurred repeatedly, which also necessitated stent placement or balloon dilations on each occasion. Despite all the intensive treatment, the bronchostenosis of the peripheral sites still remains and improvement of her pulmonary functions has been poor. Moreover, a recent chest CT scan revealed a progression of the disease in the native lung. Consequently, we registered her as a candidate for transplantation of the right lung. Bronchostenosis should be kept in mind as a complication of lung transplantation.

Background. In multiple system atrophy (MSA) patients, a variety of sleep-related respiratory disturbances, including sleep apnea-hypopnea, are frequently manifested. Both nasal continuous positive airway pressure (CPAP) therapy and tracheostomy have been shown to be effective to treat sleep-related breathing disorders in patients with MSA. Case. A 62-year-old man with MSA accompanied by sleep apnea-hypopnea syndrome and marked obesity was admitted because of gradual worsening daytime sleepiness, fatigue and snoring. Arterial blood gas analysis showed hypoxemia and hypercapnia. Laryngoscopy revealed vocal cord abductor paralysis. He was first treated by CPAP therapy. Next, tracheostomy was performed to avoid sudden death due to vocal cord abductor paralysis. Conclusion. CPAP therapy and subsequent tracheostomy gradually improved daytime hypoxia and hypercapnia as well as sleep desaturation, suggesting that oxygen desaturation due to sleep disordered breathing and obesity may partly contribute to the pathogenesis of alveolar hypoventilation in the present case.

<p>慢性閉塞性肺疾患（COPD）は一つの疾患単位というよりは異質な病態の集合体であるため，治療は一様には行えない．特に，喘息病態合併の有無は治療反応性に影響しうる．COPDに喘息病態の合併があるときには，吸入ステロイド薬の使用を積極的に施行すべきである．COPDおよび気管支喘息の病態・治療は，慢性安定期と急性増悪時において異なる．病名治療でなく，病態および薬剤の特性を理解して，治療にあたる必要がある．</p>

Gliotoxin, one of the mycotoxins produced by Aspergillus fumigatus, has various, potent bioactivities. However, it has not been considered to be a toxic (or virulence) factor because of its slow production. The aim of the present study was to investigate the effects of aeration on the cytotoxicity of A. fumigatus culture filtrate, and to determine the optimal condition for the rapid production of gliotoxin from this fungus. Fungal culture filtrates were made in three different containers under various conditions of aeration and O2 concentration. These filtrates were compared in terms of their cytotoxicity on murine macrophages and analyzed by gas chromatography. The culture filtrate showed high cytotoxicity when it was made under highly aerated conditions, but it was significantly less cytotoxic when prepared under non-aerated conditions. The cytotoxic activity became evident within 15 h of culture at 20% O2, when the fungus had already started producing gliotoxin. The culture filtrates also contained some other as yet unidentified substances that might also to some extent contribute to the cytotoxicity. In light of these results, the authors propose that a highly aerated condition is responsible for the rapid production of gliotoxin, and that gliotoxin might play an important role in the respiratory infection by A. fumigatus, with other toxic substances acting additively or synergistically.

Substantial variation among countries has been reported regarding mortality data for COPD in industrialized countries. Differences in COPD death rates among countries have attracted considerable attention, with multiple suggested hypothesis, including smoking behaviors, air pollution, respiratory infections and genetic factors. However, the lack of standardization of death certification as well as differences among countries in diagnostic standards of COPD, could limit the interpretation of the data. No meaningful international comparisons of COPD prevalence can be possible until a GOLD initiative bring information about COPD to public health officials, the medical community, and the public throughout the world. No comparable data regarding the COPD epidemiology such as Nippon COPD Epidemiology(NICE) study, has been available in other countries than Japan. NICE study indicated that most of COPD cases(90%) are undiagnosed, and a significant attention will be required to raise awareness of COPD.

STUDY OBJECTIVES: Orexin and orexin receptors are present in the CNS. The effects of orexin peptides have been uniformly reported as excitatory, and the posterior hypothalamus containing orexin neurons has been implicated in arousal state control. Therefore, it is probable that the orexin system may have a neuromodulatory effect on arousal states. The aim of the present study was to investigate the relationship between plasma orexin-A levels and arousals from sleep in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). DESIGN: An analysis was conducted in 30 male patients with OSAHS, which had been diagnosed by polysomnography by the presence of an apnea-hypopnea index (AHI) of > 5, and 20 male age-matched and body mass index (BMI)-matched control subjects. RESULTS: Plasma orexin-A levels were higher in patients with OSAHS compared with those in control subjects (p < 0.05). Plasma orexin-A levels correlated positively, but weakly, with the arousal index (r = 0.51; p < 0.05) and the AHI (r = 0.52; p < 0.05). However, plasma orexin-A levels did not relate to age, BMI, Epworth sleepiness scale, PaO(2), PaCO(2), minimum arterial oxygen saturation (SaO(2)) during sleep, or mean SaO(2) during sleep. Plasma orexin-A levels can be a measure of both AHI and arousal index. CONCLUSION: These results suggested that the orexin system may be involved in arousal mechanisms in patients with OSAHS.

COPDの主なリスクファクターは,喫煙である.しかし喫煙者の一部にのみCOPDは発症し,遺伝的因子および環境因子の双方がその発症に関与している多因子疾患と考えられる. COPDの疾患感受性候補遺伝子は数多く挙げられているが,しばしば異なる結果が報告されており,その解釈は慎重におこなう必要がある.オランダ仮説,アデノウイルスの潜伏感染,アポトーシスなどもCOPDの発症に関与している可能性もある.

STUDY OBJECTIVES: Vascular endothelial growth factor (VEGF) signaling may be required for maintenance of the alveolar structures, and alveolar septal cell apoptosis could contribute to the pathogenesis of COPD presenting emphysematous changes; however, the common mutation at position 936 in the 3' untranslated region of the VEGF gene, a C to T substitution (the C allele was denoted as 1, and the T allele as 2), VEGF936*2, has been reported to be associated with significantly lower VEGF plasma levels. Based on these concepts, we hypothesized that VEGF936*1/2 polymorphism may be linked to the development of COPD. DESIGN: The differences in VEGF936*1/2 allele frequency were examined in 113 patients with smoking-related COPD and two control groups (101 smoker/ex-smoker control subjects and 102 population control subjects) using the polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: VEGF936*1/2 allele frequencies did not differ among the groups: 0.792/0.208 in COPD patients, 0.822/0.178 in smoker/ex-smoker control subjects, and 0.842/0.152 in population control subjects. CONCLUSION: The 936 C/T polymorphism of the VEGF gene (including both homozygous and heterozygous) was not associated with the development of COPD (odds ratio, 1.23; 95% confidence interval, 0.760 to 1.995).

An experimental model, in which exogenous gene expression in the lung is achieved, has been established. A fibroblast cell line was transfected with the lacZ gene and was administered to syngeneic mice by either intravenous or intratracheal injection. Enzyme-linked immunosorbent assay and histochemical detection of beta-galactosidase revealed efficient gene delivery to the lung by either route. Kinetic studies demonstrated that the expression peaked immediately after the injection, and this high level was maintained for 7 days by intratracheal and for 14 days by intravenous administration. This system may have potential relevance for certain experimental models requiring specific gene delivery to the lung.

OBJECTIVE: The onset of sarcoidosis may be triggered by any hereditary and/or environmental factor. Among these factors, psychosocial stress may play a critical role in the onset of sarcoidosis. The aim of the present study was to evaluate the influence of stressful life events on the onset of sarcoidosis. METHODOLOGY: The social and/or life events experienced prior to diagnosis in 55 patients with sarcoidosis, were evaluated quantitatively using the Social Readjustment Rating Scale (SRRS), the most authoritative method to quantify the magnitude of the events requiring changes in lifestyle. In addition, personality with respect to stress-reactivity was simultaneously evaluated using the Minnesota Multiphasic Personality Inventory (MMPI) alexithymia scale. Both the degree of stress, evaluated by SRRS, and stress-reactivity, evaluated by MMPI scale, of sarcoidosis patients were compared with those of 92 healthy controls. RESULTS: The magnitude of stressful life events was significantly higher in patients with sarcoidosis compared with healthy controls. In addition, capacity for coping with stress was found to be inferior in sarcoidosis patients compared with that in the control groups. CONCLUSION: These results indicated that psychosocial stress assessed on the basis of alexithymic characteristics of the self perception of stress may be partly implicated in the development of sarcoidosis.

CD40/CD40 ligand (CD40L) interaction plays an essential role in cell-mediated immune responses. We examined whether expression of CD40L in murine lung carcinoma (A11) cells could produce antitumor effects. The proliferation rate in vitro of A11 cells transfected with the murine CD40L gene (A11/CD40L) was not different from that of parent cells; however, half of the immunocompetent mice inoculated with A11/CD40L cells did not form tumors and the growth of A11/CD40L tumors developed in the rest of mice was significantly retarded compared with that of parent tumors. Protective immunity was also induced in the mice that had rejected A11/CD40L cells. In T-cell-defective nude mice, these antitumor effects were not observed. Bone-marrow-derived dendritic cells (DCs), when cultured with A11/CD40L cells, formed clusters with the tumors and showed upregulated CD86 expression. Expression of the interleukin-23 (IL-23) p19, IL-12p35, IL-18, interferon-gamma (IFN-gamma) and Mig (monokine induced by IFN-gamma) genes was induced in the DCs that were cultured with A11/CD40L but not with A11 cells, and P40, the subunit of both IL-12 and IL-23, was secreted from the cocultured DCs. These data directly showed that the expression of CD40L in tumors facilitated the interaction between DCs and the tumors, enhanced the maturation of DCs, induced secretion of cytokines, and consequently produced T-cell-dependent systemic immunity.

We studied the quality of life of obesity hypoventilation syndrome (OHS) by comparing it with age- and body mass index-matched patients without hypoventilation and age-matched obstructive sleep apnea (OSA) patients with body mass index (BMI) under 30, and the efficacy of nasal continuous positive airway pressure (CPAP) therapy for 3 to 6 months on the quality of life in these patients. Prospectively recruited patients from six sleep laboratories in Japan were administered assessments of the general health status by the Short-Form 36 Health Survey (SF-36) and subjective sleepiness by the Epworth Sleepiness Scale (ESS). Compared with matched healthy subjects, OHS and OSA patients not yet treated had worse results on the ESS scores and the SF-36 subscales for physical functioning, role limitations due to physical problems, general health perception, energy/vitality, role limitations due to emotional problems, and social functioning. The ESS scores of OHS patients were worse than those of the OSA groups including the age- and BMI-matched OSA patients. In the SF-36 subscales of OHS patients, only the subscale of social functioning showed worse results compared with that of BMI-matched OSA patients. After 3 to 6 months of treatment, ESS scores and these SF-36 subscales in all three patient groups improved to the normal level. These results suggested that the quality of life of OHS before nasal CPAP was significantly impaired and that nasal CPAP for OHS improved the quality of life associated with the improvement of daytime sleepiness to the level of the other OSA patients.

BACKGROUND: Small cell lung carcinoma (SCLC) has the propensity to grow rapidly and metastasize extensively. Detection of micro-dissemination of SCLC may have clinical relevance. For its detection, tumor-specific gene expressions were examined in peripheral blood and bone marrow aspirate from patients with SCLC. METHODS: Expression of prepro-gastrin-releasing peptide (preproGRP), neuromedin B receptor (NMB-R) and gastrin-releasing peptide receptor (GRP-R) were examined by reverse transcriptase polymerase chain reaction (RT-PCR) in peripheral blood and bone marrow aspirate from 40 untreated patients with SCLC. Control samples consisted of peripheral blood samples from 5 patients with nonsmall cell lung cancer (NSCLC) and 20 healthy volunteers. RESULTS: Positive rates of preproGRP, NMB-R, and GRP-R in bone marrow aspirate of patients with SCLC were 23% (9/40), 8% (3/40), and 10% (4/40), respectively. Those rates in peripheral blood were 11% (4/38), 5% (2/38), and 29% (11/38), respectively. Although GRP-R expression was detected in patients with NSCLC and in healthy volunteers, preproGRP and NMB-R expressions were not detected in patients with NSCLC and in healthy volunteers. All three gene expressions in bone marrow were more frequently observed in patients with bone marrow metastasis, accessed by biopsy, than in patients without. PreproGRP gene expression in bone marrow was also more frequent in patients with bone metastasis, accessed by bone scintigram, than in patients without, and was related to poorer survival. CONCLUSIONS: Micro-dissemination of SCLC was detectable by RT-PCR of preproGRP and NMB-R, both specific for SCLC. These gene expressions in bone marrow may be related to disease extent and prognosis.

The interaction between Fas and Fas ligand (FasL) is involved in the apoptotic death of a number of cells including lymphocytes. Forced expression of FasL in tumors can induce apoptosis of infiltrating Fas-positive T cells; accordingly, tumors can survive in the milieu of systemic immune responses. However, FasL-expressing murine lung carcinoma (A11) and melanoma (B16) cells did not develop subcutaneous tumors and FasL-expressing A11 (A11/FasL) cells produced few spontaneous lung metastatic foci in syngeneic mice. The mice that rejected A11/FasL cells were resistant to subsequent challenge of parent A11 but not irrelevant B16 cells. Vaccination of mice with UV-treated A11/FasL, but not UV-treated A11 cells, however, augmented the growth rate of A11 but not B16 tumors, both of which were subsequently inoculated. The number of lung metastatic foci of A11 cells was also increased in the mice that received UV-treated A11/FasL but not UV-treated A11 cells. Intraperitoneal injection of UV-treated A11/FasL cells resulted in the production of larger amounts of immunosuppressive TGF-beta in peritoneal exudate than that of UV-treated A11 cells. Expression of the CD80 costimulatory molecule in tissues where UV-treated A11/FasL cells were inoculated was lower than the expression at an untreated A11/FasL-injected site. Our results indicated that apoptotic FasL-expressing tumor cells could impair host immune responses against the tumors, in contrast to potent antitumor immunity generated by viable FasL-expressing tumors.

Cancer chemotherapy for haemodialysis patients has never been established. To elucidate the feasibility of cisplatin-based combination chemotherapy for haemodialysis patients with lung cancer, a dose escalation study was conducted. Five haemodialysis patients with lung cancer were treated with cisplatin and etoposide. A starting dose of 40 mg m-2 of cisplatin on day 1 and 50 mg m-2 of etoposide on days 1, 3 and 5 were administered as the first course for the first patient. Membrane haemodialysis was regularly performed three times a week and soon after the completion of therapy. By monitoring toxicity and pharmacokinetics data, the dose was escalated course by course and patient by patient. Dose escalation was completed for the first two patients resulting in full-dose chemotherapy consisting of 80 mg m-2 of cisplatin on day 1 and 100 mg m-2 of etoposide on days 1, 3 and 5. Multiple courses of the full-dose chemotherapy were administered to the other three patients. Toxicity was manageable and tolerable for all. Pharmacokinetics data were comparable to those from patients with normal renal function, except for potential long-lasting higher levels of free platinum in the renal insufficiency group. In conclusion, this standard-dose combination chemotherapy was feasible even for haemodialysis patients. © 2003 Cancer Research UK.

Background. Placement of a silicon tracheobronchial prosthesis in emergency situations has become an established therapeutic option to relieve airway stenosis due to malignant diseases. However, the alternative use of a metallic stent has never been fully evaluated. Purpose. To elucidate the clinical relevance of placing metallic stents in patients with critical airway stenosis due to malignant diseases. Patients and Methods. Thirteen patients with critical airway stenosis treated by placing metallic stents and meeting some defined conditions were retrospectively reviewed in terms of usefulness and adverse events. The stents were placed by flexible bronchoscopes under topical anesthesia in all cases. Results. Metallic stent placement was easy, quick and successful in every patient, and airway stenosis was quickly relieved after the procedure in all patients. Accordingly, dyspnea as assessed by a scoring system was improved from I day to I month after the placement. Performance status was not improved significantly by the procedure. Adverse events of serious nature were observed in 6 of the 13 patients. Conclusion. Metallic tracheobronchial stents for patients with airway stenosis and critical conditions seemed to have advantages in relieving dyspnea. Considering the adverse events, however, the choice of this option should be restricted to patients with limited expected survival.

Arterial oxygenation during sleep in Sherpa highlanders has been relatively unexplored. This study was designed to investigate arterial oxygen saturation (Sa(O(2))) and pulse rate (PR) during sleep in 61 Sherpa (29 men, 32 women) who had lived at 3,450-3,850 m in Nepal, from adolescence through old age, and to estimate the relative effects of aging on arterial oxygenation during sleep. The mean Sa(O(2)) during sleep (mSa(O(2))) was found to decrease with age, and to negatively correlate with the mean PR during sleep. About one-third of subjects (n=19) exhibited a periodical fluctuation of Sa(O(2)) during sleep. The subjects who exhibited a periodical fluctuation of Sa(O(2)) during sleep were older and their mSa(O(2)) were lower compared with those who did not exhibit a periodical fluctuation of Sa(O(2)), and the cycle of periodical fluctuation got longer with advancing years. These findings indicated that sleep desaturation occurs in high altitude residents with advancing years.

Fas ligand (FasL)-expressing tumor cells are found to effectively mediate rejection of the coinoculated FasL negative parental cells while having no effect on the growth of histologically distinct tumor cells. These observations indicate that FasL induces a specific immune response against Ag derived from FasL-bearing tumors and suggest a possible role for FasL in tumor Ag presentation. Indeed, tumor cells expressing FasL can efficiently interact with dendritic cells (DCs) and this interaction requires the expression of membrane-bound FasL on tumors and Fas on DCs. Moreover, DCs cocultured with FasL-expressing tumors are able to elicit a tumor-specific immune response in vivo, suggesting that DCs acquire tumor Ag during the Fas/FasL-mediated DC-tumor contact. These results identify a novel role for FasL in augmenting tumor-DC interactions and subsequent tumor Ag acquisition by DCs, and suggest that FasL-expressing tumor cells could be used to generate tumor-specific DC vaccines.

Endobronchial ultrasonography (US) with 4.5-F small-caliber US probes, combined with bronchoalveolar lavage technique, was evaluated in autopsied lungs and 22 patients with various pulmonary interstitial or alveolar diseases. Several different echoic patterns were found that may reflect changes due to pathologic alteration of lung parenchyma. This technique may have potential for evaluation and diagnosis of peripheral lung diseases.

A case of lung adenocarcinoma and extensive deep vein thrombosis in a patient with Peutz-Jeghers syndrome (PJS) is presented. A 31-year-old Chinese man complained of shoulder pain and swelling of the right arm. A series of diagnostic procedures revealed a primary adenocarcinoma in the left upper lobe with cervical and supraclavicular lymph node metastases accompanied by deep vein thrombosis in the superior vena cava and right jugular vein. In addition, typical pigmentation of the lips and oral mucosa and multiple hamartomas in the stomach, duodenum and colon led to the diagnosis of PJS. PJS is known to be associated with increased risk of malignancies, especially in the gastrointestinal tract, breast, genitals and pancreas. As bronchoscopic examination showed no hamartomatous lesions in the bronchi, the development of primary lung cancer in this young patient might be independent of any hamartomatous lesion and might be associated with some genetic factors relating to PJS.

A novel gene transcript that is downregulated by HPV16 E6 protein was identified in mouse cells using differential hybridization and designated E6DG1. The cloned cDNA of E6DG1 was 1.3 kb in length and contained a small ORF potentially encoding a polypeptide of 45 amino acids. In vitro transcription and translation of E6DG1 cDNA resulted in a product of approximately 7 kDa and Western blot analysis using antibodies for E6DG1 peptide detected 7 and 14 kDa proteins. Downregulation of E6DG1 mRNA levels in cells expressing HPV16 E6 protein was observed at subconfluent cell densities, but not in confluent cells. Repression of E6DG1 protein enhanced the anchorage-independent growth and weakened the cell adhesion in Panc1 cells. Immunofluorescence analysis revealed the localization of E6DG1 within the nucleus. These results indicate that the E6DG1 protein may function in a signaling pathway related to anchorage-independent growth and adhesion control.

STUDY OBJECTIVES: Alveolar septal cell apoptosis may contribute to the pathogenesis of emphysema. Because tumor necrosis factor (TNF)-alpha is assumed to play an important role in the induction of apoptosis, and allele 2 of the polymorphism at position--308 in the promoter of the TNF-alpha gene has been associated with alteration of TNF-alpha secretion in vitro, we hypothesized that genotypes containing this allele would show more destructive emphysematous changes of the lung. DESIGN: The percentage ratio of the low attenuation area to the corresponding lung area was evaluated using a visual scoring system for CT findings in patients with COPD (n = 84), and these patients were classified into two groups: those with a visual score < 11 and those with a visual score > or = 11. A polymerase chain reaction-based assay was developed to determine the TNF-alpha genotype (TNF-alpha-308*1/2) between subjects with high and low visual scores on chest CT scans. RESULTS: The TNF-alpha-308*1/2 allele frequency tended to differ between patients with a visual score < 11 (0.90/0.10) and those with a visual score > or = 11 (0.81/0.19) [odds ratio, 2.15; 95% confidence interval, 0.87 to 5.30; p = 0.09]. CONCLUSION: These results indicate that the TNF-alpha-308 allele 2 may be partly associated with the extent of emphysematous changes in patients with COPD.

Chronic hypoxemia has been suggested as the cause of weight loss in malnourished patients with chronic obstructive pulmonary disease. Insulin-like growth factor I (IGF-I) is believed to improve nitrogen balance and have anabolic effects, and it has been proposed as one of the mediators of vascular smooth muscle proliferation. The aim of this study was to assess the effects of IGF-I administration on the nutritional status and pulmonary vasculature in normoxic and chronic hypoxic rats. Twenty rats were randomly assigned to the normoxic (n = 10) and chronic hypoxic groups (n = 10). They received daily subcutaneous injections of either 3.2 mg/kg of recombinant human IGF-I (rhIGF-I) or isotonic saline (control group) for 3 weeks. Body weight was greater in IGF-I-treated rats compared with vehicle-treated rats, especially during the early and late stages of chronic hypoxic exposure, whereas similar weight gain was observed between IGF-I- and vehicle-treated normoxic rats. In addition, IGF-I treatment increased serum total protein and albumin at the end of hypoxic exposure. However, IGF-I had no additive effects on the degree of pulmonary hypertension. These results indicated that IGF-I promoted anabolism under chronic exposure to hypoxia, whereas no adverse effect was observed in the development of pulmonary hypertension.

Ku70 protein, cooperating with Ku80 and DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs), is involved in DNA double-strand break (DNA DSB) repair and V(D)J recombination. Recent studies have revealed increased ionizing radiosensitivity in Ku70-deficient cells. The presented study, using a human squamous cell lung carcinoma cell line, demonstrated that introduction of an antisense Ku70 nucleic acid made the cells more radio- and chemosensitive than the parental cells. Ku70 protein expression was suppressed in the cells with antisense Ku70 construct when compared to the wild-type cells. A relatively small but statistically significant increase in radiosensitivity of the cells was achieved by the introduction of the antisense Ku70. The increased radiosensitivity in vitro was accompanied by an approximately two-fold increase in alpha and alpha/beta values in a linear-quadratic model. The antisense Ku70 increased the chemosensitivity of the cells to some DNA-damaging agents such as bleomycin and methyl methanesulfonate, but not to cisplatin, mitomycin C, and paclitaxel. This system provides us with partial suppression of Ku70, and will be a useful experimental model for investigating the physiological roles of the DNA DSB repair gene.

Interaction between Fas and Fas ligand (FasL) induces apoptotic cell death of Fas-positive cells. Expression of FasL on tumors therefore possibly kills activated Fas-positive cytotoxic T cells that infiltrated into the tumors and consequently the tumors can evade from systemic immune responses. Previous studies however showed that forced expression of FasL in tumors induced neutrophil-mediated inflammatory reactions and accordingly produced T cell independent antitumor effects in the inoculated animals. We then analyzed the FasL-mediated antitumor responses with genetically mutated mice. Murine lung carcinoma (A11) cells transfected with the FasL gene (A11/FasL), which was able to kill Fas-positive B cells, did not form subcutaneous tumors and produced few lung spontaneous metastatic foci in immunocompetent mice. The mice that rejected A11/FasL cells developed tumor-specific protective immunity. A11/FasL cells were also rejected in T cell-defective nude mice and in CD18-deficient mice which showed impaired neutrophil functions, but not in Fas-defective (lpr/lpr) mutant mice. Antitumor activities on A11 cells were dependent on the number of co-injected A11/FasL cells but those on irrelevant B16 murine melanoma cells were not produced even with a large number of co-injected A11/FasL cells. In contrast to previous reports, the present study implies that T cells can also be effectors of FasL-mediated antitumor responses and neutrophils are not absolutely required for the responses.

We used a denaturing gradient gel electrophoresis (DGGE) procedure with 40-nucleotide guanine- and cytosine-rich sequences in the polymerase chain reaction (PCR) and sequencing analysis to analyze the T cell antigen receptor (TCR)-Vgamma gene repertoire of infiltrating T lymphocytes in pulmonary lymphoproliferative disorders. Six of 15 low-grade mucosa-associated lymphoid tissue (MALT) lymphomas and 8 of 15 cases of lymphocytic interstitial pneumonia (LIP) showed some oligoclonal bands for TCR-Vgamma genes on DGGE. Sequencing analysis demonstrated plural oligoclonal TCR-Vgamma clones among the oligoclonal PCR products on DGGE, leading to the conclusion that conventional antigen-specific oligoclonal expansions may play some role in the pathogenesis of pulmonary lymphoproliferative disorders. The frequency of oligoclonal infiltrating T cell expansions in human immunodeficiency virus (HIV)-related LIP (100%) was significantly higher than in low-grade pulmonary MALT lymphomas (40%) or in HIV-negative LIP (30%). Because recent evidence demonstrates that the V3 loop in the proviral amino acid sequences of mononuclear cells from bronchoalveolar lavage is more homogeneous than those from peripheral blood, this homogeneity might result in oligoclonal expansions of infiltrating T lymphocytes as a consequence of ongoing reactions against lung-specific viral strains.

The Medical Research Council (MRC) and Nocturnal Oxygen Therapy Trial (NOTT) studies performed in the late 1970s regarding effects of long-term oxygen therapy (LTOT) have revealed that LTOT improved the prognosis in patients with hypoxemic COPD and established the basis of prescription of LTOT. However, whether LTOT improved HRQoL as a secondary end point has not been clarified. Therefore we prospectively examined the effects of LTOT on HRQoL, evaluated by SF-36 and SGQR, in 43 patients with chronic lung diseases who were prescribed LTOT. HRQoL was assessed before LTOT and short- and long-term after prescription of LTOT. In this study it was demonstrated that LTOT ameliorated some physical and mental functions in patients with chronic lung diseases.

Interaction of Fas and Fas ligand (FasL) in immunocompetent cells plays a crucial role(s) in their effector functions and in the regulation of host immune responses. Expression of FasL in tumors possibly counteracts Fas-positive effector T cells that infiltrate into tumors and consequently the Fas/FasL interaction can contribute to the escape of tumor cells from systemic immune systems. However, forced expression of FasL in tumors unexpectedly induced migration of neutrophils into the tumors and the FasL-expressing tumors were rejected due to the inflammatory reaction. Since FasL is released from the cell surface, we examined whether soluble or membranebound FdsL molecules produced such antitumor effects. Faspositive B cells were effectively killed by membrane-bound but not soluble FasL in which the leader sequence of interleukin-4 was ligated with the extracytoplasmic portion of FasL. Mice inoculated with All murine lung cancer cells expressing membrane-bound FasL did not develop tumors and had few spontaneous lung metastatic foci. In contrast, mice injected with A11 cells secreting soluble FasL developed tumors the growth of the tumors and the number of lung metastatic foci from subcutaneous tumors were not different from those of parent tumors. The chemotactic activity of FasL, tested by intraperitoneal injection of parent and the FasL-expressing A11 cells, showed that the level of neutrophil migration by All cells secreting soluble FasL was greater than that by parent cells but was not as significant as that by All cells expressing membranebound FasL. The antitumor activity induced by expressed FasL seems to be correlated with the apoptosis-inducing activity through the Fas/FasL interaction but not directly with the chemotactic activity for neutrophils.

慢性閉塞性肺疾患(COPD)の初期には自覚症状は認めないため,その正確な疫学は不明であるが,非可逆釣な疾患であることより,今後の一つの方向性として,早期のCOPD・発症リスクのある症例の把握が必要になる.予後に影響を及ぼす因子としては,血液ガスの値,小児期・青年期の呼吸機能の発達の程度,喫煙状況,呼吸困難の程度,栄養状態,気道閉塞の可逆性,組織低酸素の程度,肺循環障害の程度などが挙げられる.さらには,発症年齢,性差,治療の影響(吸入ステロイド・非侵襲的人工呼吸)なども考えられる.

Tumor necrosis factor α (TNF-α), a potent proinflammatory cytokine, may be involved in the development of chronic obstructive pulmonary disease (COPD). The production of TNF-α is elevated in the airways of these patients. A polymorphism at position -308 of the TNF-α gene promoter (TNF-α-308*1/2) is known to be associated with alteration of TNF-α secretion in vitro. In this study we examined the differences in TNF-α-308*1/2 allele frequency to investigate the association of this polymorphism with the presence of smoking-related COPD. TNF-α-308*1/2 allele frequency in 106 patients (73 men and 33 women) was compared with 110 asymptomatic smoker/ex-smoker control subjects matched for sex and age and population control subjects consisting of 129 blood donors. Genotype was analyzed by the polymerase chain reaction-restriction fragment length polymorphism technique on genomic DNA isolated from peripheral blood lymphocytes. TNF-α-308*1/2 allele frequencies were significantly different among the groups: 0.835/0.165 in patients with COPD, 0.918/0.082 in smoker/ex-smoker control subjects, and 0.922/0.078 in population control subjects. These results indicate that TNF-α-308*1/2 alleles are significantly associated with the presence of smoking-related COPD.

Inhaled PGI2 has been reported to elicit pulmonary vasodilation, but whether it is also effective in treating chronic hypoxic pulmonary hypertension is still uncertain. We designed this study to address the in vivo effectiveness of inhaled Beraprost, a stable PGI2 analogue, on pulmonary vascular tone during hypoxic exposure in normoxic (N) and chronically hypoxic (CH) rats. Pulmonary vasodilation was observed by low-dose inhaled Beraprost in N rats, but not in CH rats. It was not until higher doses of Beraprost were given that pulmonary vasodilation was obtained in CH rats. When the agent was continuously administered by an intravascular route at the inhaled dose, it elicited no vasodilation in N rats. On the contrary, it elicited profound vasodilation in CH rats, although a concomitant systemic hypotension was observed. The PGI2 receptor mRNA expression was unchanged in the lungs of CH rats compared with that of N rats. We conclude that low doses of aerosolized Beraprost may reduce pulmonary vascular tone in rats without preexisting lung diseases. In contrast, when hypoxic pulmonary hypertension is present, the threshold of Beraprost inhalation was elevated to provoke pulmonary vasodilation.

Objective. To define the clinico-epidemiological features of pulmonary histiocytosis X in Japan. Methods. A nationwide survey was carried out in 1997 using two questionnaires. Results. The first questionnaire, which attempted to determine the number of patients during 1996, revealed that the number of patients treated at hospitals with 200 or more beds during the one-year period was estimated to be 160 (95% confidence interval: 140-180). The estimated crude prevalence among those aged 16 to 70 years was calculated as 0.27 and 0.07 per 100,000 population in males and females, respectively. The second questionnaire was concerned with the clinico-epidemiological features of the disease. Seventy-three histologically diagnosed patients were evaluated. It primarily afflicted younger adults, between the ages of 20 and 50, and showed a male predominance. Over 90% of the patients were smokers or ex-smokers and over 50% started smoking before 20 years of age, suggesting a strong association with cigarette smoking. Steroid therapy was applicable to 34% of the patients. In the patients who received steroid therapy, regression and stabilization were observed in 28% and deterioration in 36%. As for the patients for whom steroids were not required, remission occurred in 63% and progression in 10%. The ratio of remissions plus stabilization was higher in the patients who were not treated with steroids compared with those who required steroid therapy (p&lt 0.05). Conclusion. In patients with pulmonary histiocytosis X therapeutic results obtained with steroids seemed not to be encouraging, although steroids are thought to be the most plausible treatment.