Role of interleukin-12 in the regulation of CD4+ T cell apoptosis in a mouse model of asthma.

Allergic asthma, a chronic inflammatory disease of the airways, is characterized by the presence of T helper 2 cells and eosinophils in sputum, bronchoalveolar lavage, and mucosal biopsy specimens. Although the T helper 1-promoting cytokine, interleukin-12, is capable of inhibiting the T helper 2-driven asthma symptoms and bronchial responsiveness, the specific mechanisms underlying these interleukin-12 actions are unclear. The anti-allergic response to interleukin-12 is only partially dependent on interferon-gamma, which induces apoptosis by enhancing expression of Fas antigen. We therefore investigated in vivo whether the anti-allergic action of interleukin-12 is mediated through induction of apoptosis. C57BL/6 mice immunized to ovalbumin by intraperitoneal injection were challenged three times with an ovalbumin aerosol every second day for 7 days. Recombinant interleukin-12 was administered intravenously after the final challenge. After the last ovalbumin challenge, mice were examined for effects of interleukin-12 on inflammatory cell infiltration and apoptosis in the lung as detected by terminal deoxynucleotidyl transferase-mediated deoxyribonucleoside triphosphate nick end-labelling. Administration of interleukin-12 reduced ovalbumin-induced pulmonary eosinophilia (P < 0.01) and CD4+ T cell infiltration (P < 0.01). Moreover, treatment with interleukin-12 shortly after ovalbumin inhalation resulted in both increased interferon-gamma production (P < 0.01) and enhanced apoptosis of CD4+ T cells in allergic airway infiltrates (P < 0.05). These results suggest that the beneficial effects of interleukin-12 in asthma may include enhancement of apoptosis of CD4+ T cells in airways.

[A case of Mycobacterium intracellulare infection complicated by immotile cilia syndrome].

A 25-year-old woman with a history of immotile cilia syndrome (ICS) was admitted to our hospital with dyspnea. Chest roentgenography revealed dense infiltrates in both lower lung fields in addition to bronchiectasis and small nodular opacities, which had been observed previously. Transbronchial lung biopsy demonstrated evidence of non-caseating epithelioid cell granuloma. Sputum specimens were examined, and isolates were identified as Mycobacterium intracellulare. The patient was given antituberculous therapy and clarithromycin, which induced clinical improvement. It is well known that bronchial mucociliary transport is severely impaired in patients with ICS. However, to our knowledge, cases of M. intracellulare infection complicated by ICS have not been reported in Japan. We must pay close attention to the concurrence of these diseases.

Heme oxygenase-1 (HO-1) protein induction in a mouse model of asthma.

BACKGROUND AND OBJECTIVE: Carbon monoxide (CO) is known to be present in measurable quantities in the exhalation of asthmatic patients. Corticosteroid treatment resulted in a decrease in exhaled CO levels in asthmatic patients, raising the possibility that an increase in exhaled CO concentration reflects inflammation of the asthmatic airway. Heme oxygenase-1 (HO-1) protein, also called HSP32, is the rate-limiting enzyme in the catabolism of heme to biliverdin, free iron and CO. However, it is unknown whether an expression of HO-1 within the lung tissue is related to allergic airway inflammation. We studied the expression of HO-1 in lung tissue and bronchoalveolar lavage cells in a mouse model of asthma. METHODS: Ovalbumin (OVA)-sensitized C57BL/6 mice were challenged with aerosolized OVA. HO-1 positive cells were identified by immunostaining in lung tissue and bronchoalveolar lavage fluid (BALF) after the challenge. RESULTS: HO-1 positive cell numbers increased in the subepithelium of the bronchi after OVA challenge. In cytospin preparations from BALF after OVA challenge, HO-1 was localized to alveolar macrophages. Inside the macrophages, HO-1 reactivity was expressed in the cytoplasm, and the perinuclear region in particular. CONCLUSION: The expression of HO-1 is increased within the lung tissue in allergic airway inflammation. Measurement of HO-1 activity may be clinically useful in the management of asthma.

[Pleural malignant mesothelioma complicated by multiple myeloma].

A 79-year-old woman was admitted because of dyspnea. Chest X-ray films and computed tomographic scans disclosed left pleural effusion and diffuse pleural thickening. A diagnosis of multiple myeloma was made on the basis of blood tests and bone marrow aspiration biopsy findings. Multiple myeloma was the suspected cause of the pleural lesions. However, a postmortem diagnosis of malignant mesothelioma of the pleura was made on the basis of histological and immunohistological studies of autopsy specimens.

Renin-angiotensin system component gene polymorphism in Japanese bronchial asthma patients.

The influence of renin-angiotensin system (RAS) component gene polymorphism in the pathogenesis of bronchial asthma was investigated in an association study involving 119 bronchial asthma patients and 208 control subjects. The selected RAS polymorphisms were angiotensinogen (Agt) T235/M235 and angiotensin I-converting enzyme (ACE) insertion/deletion (I/D). The control allelic frequencies of the Agt T235/M235 (0.84/0.16) and ACE I/D (0.63/0.37) in this study were similar to the previous reports in Japanese normal population. The allelic frequencies of the Agt T235/M235 (0.84/0.16) and ACE I/D (0.65/ 0.35) among the asthma patients were not significantly different from those among the control subjects. There was no association between severity of bronchial asthma and the selected RAS component gene polymorphism. From these data, we conclude that in the Japanese population, the RAS component gene polymorphism is not associated with increased risk for bronchial asthma.

[Nedaplatin and etoposide combination chemotherapy in a patient with small cell carcinoma undergoing hemodialysis].

A 61-year-old man with chronic renal failure caused by polycystic kidney disease requiring hemodialysis three times weekly developed small cell carcinoma of the lung. The patient received combination chemotherapy with nedaplatin (50 mg) and etoposide (50 mg). Blood levels were monitored, showing that nedaplatin was more dialyzable than cisplatin. The patient achieved a complete response. These results suggest that nedaplatin-etoposide combination chemotherapy may be safer than cisplatin-containing regimen for patients with chronic renal failure hemodialysis and that a satisfactory response can be expected.

Kinetics of apoptosis in the lung of mice with allergic airway inflammation.

BACKGROUND: Apoptosis has been suggested as a means to facilitate the resolution of eosinophilic inflammation in bronchial asthma. However, the natural course of apoptosis has not been elucidated in vivo, and there is no direct evidence for eosinophilic apoptosis within lung tissue. OBJECTIVE: The purpose of this study is to clarify whether the apoptosis occurs within the lung tissue, and to define the time-course of change in apoptosis ratio during the resolution of pulmonary eosinophilic inflammation. METHODS: Ovalbumin (OVA)-sensitized Balb/c mice were challenged with aerosolized OVA. We studied apoptotic cells in the lung of OVA-sensitized mice at 1, 3, 7 and 14 days after OVA challenge by in situ detection of DNA fragmentation with deoxynucleotidyl transferase deoxyuridyl triphosphatase nick endlabelling (TUNEL) technique. Apoptotic cells also were identified by electron microscopic analysis in the lung 7 days after OVA challenge. RESULTS: The TUNEL-method revealed that eosinophils localized in the subepithelium of bronchi undergo apoptosis following OVA challenge. Electron microscopy confirmed the presence of apoptotic cells, apoptotic bodies, and macrophages ingesting apoptotic bodies within the lung tissue. The number of apoptotic cells increased concomitantly with the increase in eosinophilic infiltration for 3 days post-challenge. However, both the apoptotic cell counts and the apoptotic ratio continued to increase even after the eosinophil count peaked, indicating rather late induction of apoptosis in the lung. In addition, TUNEL-positive cells were localized in the lung for 14 days post-challenge, indicating prolonged induction of apoptosis after the OVA challenge. CONCLUSION: Our findings constitute direct evidence of eosinophilic apoptosis in situ, and display the kinetics of apoptosis in the lung of the allergic inflammation.

Two cases of eosinophilic gastroenteritis associated with analgesic-induced bronchial asthma.

Two patients (one male and one female) with bronchial asthma were diagnosed as having eosinophilic gastroenteritis (EG). The condition was revealed by biopsies through fibrescopic endoscopy. According to the Klein classification, they had mucosal disease. The symptoms were abdominal pain and nausea. The symptoms subsided with corticosteroid administration in one patient and with palliative treatment in the other patient. It was suggested that fibrescopic endoscopy biopsy is needed to identify coexisting EG if a bronchial asthma patient complains of severe gastrointestinal symptoms.

[Large-cell carcinoma presenting as diffuse thickening of the pleura and resembling malignant mesothelioma].

A 65-year-old man had a right-sided pleural effusion. A thoracic CT scan revealed diffuse pleural thickening resembling malignant mesothelioma. Repeated needle biopsies did not yield a definitive diagnosis. At autopsy, diffuse pleural thickening was found, and examination of a specimen of lung tissue showed large-cell carcinoma. Hyalinized fibrous tissue with malignant cell infiltration was seen in the thickened pleural tissue and metastatic pleuritis was diagnosed. Large-cell carcinoma of the lung should be considered in the differential diagnosis of pleural thickening.

[Long-term follow-up and autopsy of a Japanese patient who had emphysema associated with alpha 1-antitrypsin deficiency].

A 49-year-old woman was found to have emphysema associated with alpha 1-antitrypsin deficiency in February 1975. She was followed until her death in October, 1994. The Pi phenotype was M null and the genotype was M malton. She had been on home oxygen therapy since 1987. An autopsy revealed the typical bullous lungs with panacinar emphysema. We know of no previous case in Japan of emphysema associated with alpha 1-antitrypsin deficiency.

Role of eosinophils and cell adhesion molecules in the allergen-induced asthmatic response of rats.

To evaluate the airway infiltration of eosinophils in the asthmatic responses of Brown-Norway rats, which were sensitized with ovalbumin, the time course of eosinophil infiltration and respiratory resistance (Rrs) after ovalbumin challenge was measured. The effect of treatment with monoclonal antibody against ICAM-1 and CD18 was studied. Finally, the expression of ICAM-1 and CD18 in the airway was investigated. All rats showed Rrs increase 6-7 hours after ovalbumin challenge, indicating a late asthmatic response (LAR). Animals with LAR had higher eosinophil counts than those with an immediate asthmatic response (IAR) and in the sensitized but nonchallenged animals. Rats treated with the antibodies showed significantly smaller increases in Rrs and lower eosinophil counts than the control animals. Immunohistochemical staining in airway was performed. ICAM-1 immunoreactivity was positive on both the epithelium and the vascular endothelium of a trachea section, and on the pulmonary vascular endothelium. ICAM-1 expression was upregulated after challenge. The number of CD18-positive cells in sections of trachea and lung increased after challenge. Our results show that eosinophil infiltration is important in LAR development and the treatment with antagonists of ICAM-1 and CD18 may provide a therapeutic approach to reducing asthmatic symptoms.

Prostate cancer-induced oncogenic hypophosphatemic osteomalacia.

A 65-year-old male with prostate carcinoma showed mild hypocalcemia of 7.9 mg/dl, marked hypophosphatemia of 1.7 mg/dl, hyperphosphaturia (tubular reabsorption of phosphorus 43% and tubular threshold for phosphorus of 0.6 mg/dl), low serum 1,25 (OH)2D level of less than 5 pg/ml and osteomalacia indicated by a marked increase of relative osteoid volume and fractional formation rate in the undecalcified section. Oncogenic osteomalacia due to prostatic carcinoma with suppression of 1,25 (OH)2D production and phosphaturia was suggested.

[Regional pulmonary function test--pulmonary nuclear medicine].

Pulmonary nuclear medicine has been dominated by techniques that depict the distribution of pulmonary ventilation and perfusion. At present, there are three commercially available methods of performing a ventilation study. One of the methods utilizes xenon-gas 133Xe, one utilizes radioactive krypton gas, 81mKr, and the last is performed with a radioactive aerosol, usually the radio aerosol of 99Tc human serum albumin (HSA). Ventilation studies with 133Xe usually consist of an image taken after inhalation of a single breath, which can be followed by a serial image. After a rebreathing period of 3 to 5 minutes, the tracer (133Xe) is washed out of the lungs. The washout portion of the 133Xe study is the most reliable and sensitive to detect of the slow compartments. Krypton-81m has a very short physical half-life of 13 seconds. Thus, ventilation scans can be obtained in desired projections, and the rapid disappearance of the tracer from lungs will allow ventilation studies to be performed before and after medications and exercise. Radioaerosols also provide a means for investigating regional ventilation. Radioaerosols are small particles, rather than gases, and are deposited in the lung by impaction, sedimentation and random contact. With the recent development of new radiopharmaceuticals and refinement of current imaging techniques, especially quantitative techniques and single-photon emission computed tomography of the lung, pulmonary nuclear medicine has expanded its horizons.