The ATP-sensitive potassium channel (K⁺_ATP) has been suggested as an important mechanism for the reactivity of vascular smooth muscle. We investigated the effects of K⁺ channel openers (lemakalim, pinacidil) on hypoxic pulmonary vasoconstriction (HPV) and angiotensin II (Ag II) induced vasoconstriction in isolated rat lungs (Sprague-Dawley rats: 300-450g). Ventilation with hypoxic gas (2% O₂, 5% CO₂) was performed for 6min after the injection of Ag II (0.1μg). Isolated lungs were perfused under constant flow (0.04ml/g/min) using 20ml of blood from donor rat. The perfusion pressure was used as the pulmonary artery pressure. Lemakalim or pinacidil was pre-administered through the reservoir. Pretreatment with pinacidil (10-⁴M) or lemakalim (10-⁵M) inhibited the pressor response to hypoxia, but did not inhibit the response to angiotensin II.
Although the effect of lemakalim on HPV was reversed by administration of glibenclamide (10-⁵M) or tolbutamide (10-³M), the effect of pinacidil on HPV was not influenced by either drug.
These results suggest that 1) K⁺ channel openers (lemakalim and pinacidil) inhibit the presser response to hypoxia, and 2) lemakalim seems to act through K⁺_ATP, whereas pinacidil may have other mechanisms of inhibition of vascular smooth muscle contraction. K⁺_ATP may play an important role in the regulation of pulmonary vascular reactivity to hypoxia.

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Electrocardiogram-gated spin-echo magnetic resonance (MR) images of the chest were obtained in five normal controls and 35 patients with pulmonary disease (11 chronic obstructive pulmonary disease, 6 pulmonary thromboembolism, 5 primary pulmonary hypertension, 4 interstitial pulmonary disease, 4 pulmonary hypertension with disturbance of portal circulation, and 5 other diseases) who underwent right cardiac catheterization. In transverse images at the level of the right main pulmonary artery (rPA) and sagittal images at the level through the midsternal line and the spinal chord, the signal intensity of blood flow in the rPA was quantitatively evaluated, and the correlations with the MR signal intensity of intravascular flow and the parameters of hemodynamics were studied. In diastole MR images of both normal controls and patients mostly showed a significant signal intensity of flowing blood, but in systole some patients demonstrated significant signals and visible flow images. In systolic MR images, the mean values of hemodynamic parameters (mean pulmonary arterial pressure (mPAP), pulmonary arteriolar resistance (PAR), and cardiac index (CI)) were abnormal in patients with significant signal intensity of flow compared with those in patients without sufficient MR signal. The signal intensity was not correlated with mPAP; however, it significantly increased as PAR increased, and it increased as CI decreased both in diastole and in systole. Especially in systole, there was good correlation between the signal intensity in transverse MR images and CI (r=-0.85, P<0.01) and between signal intensity in sagittal MR images and PAR (r=0.90, P<0.01).
These results suggest that significant flow signal in the rPA in systole has pathophysiological significance, and signal intensity is considered to be significantly affected by changes of PAR and CI. The signal intensity of blood flow in the rPA on MR images can be used as an index of the severity of right heart failure associated with pulmonary disease. MR imaging is a useful modality to evaluate pulmonary circulation disturbance because of its ability to assess blood flow in the pulmonary artery noninvasively without interference from other structures such as bone and normal lung.

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To understand the precise mechanism of bronchial hyperresponsiveness in patients with congestive heart failure, we studied the effect of mild pulmonary congestion on bronchial responsiveness to inhaled acetylcholine (ACh) in guinea pigs.
We induced mild pulmonary congestion by inflation of a balloon placed in the left atrium, and maintained the left atrial pressure (Pla) at 10mmHg for 30 minutes with continuous monitoring of lung resistance (RL) and dynamic compliance (Cdyn). Furthermore, we determined the provocative concentration of ACh producing 100% increase in RL (PC100-ACh), before and during balloon inflation.
In animals with propranolol pretreatment, but not in animals without propranolol pretreatment, mild pulmonary congestion caused slight increase in RL (N. S.) and significant decrease in Cdyn (p<0.01) and PC100-ACh (p<0.01). Cutting of bilateral vagal nerves partially inhibited the decrease of PC100-ACh, but pretreatment with either phenoxybenzamine, indomethacin, AA-861 or OKY-046 had not effect.
These results suggest that blockade of β-adrenergic receptors and the vagal reflex, but not of α-adrenergic receptors or arachidonates, contributes to bronchial hyperresponsiveness during acute pulmonary congestion.

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Activity of the respiratory muscles during natural defecation was studied in two anesthetized and two decerebrate dogs. In anesthetized dogs, excitation of the abdominal muscles and an increase in gastric pressure were observed during defecation. However, pleural pressure was little influenced by such increase in abdominal pressure, maintaining the same rhythmic changes as observed during spontaneous respiration. The rhythmic changes in pleural pressure were associated with rhythmic activity of the diaphragm. When gastric pressure increased during defecation, the diaphragmatic activity also increased during both the inspiratory and expiratory phases. In a decerebrate dog, airflow and airway pressure changed similarly to during defecation. The diaphragm was continuously active, with superimposed rhythmic augmentation. In a paralyzed and artificially ventilated dog with open-chest, the phrenic nerve similarly developed discharges. We conclude that the non-respiratory activity and rhythmic augmentation of phrenic nerve discharge during defecation is pre-programed in the command for defecation. The activity of phrenic motoneurons may be further modulated by changes in thoracic and abominal pressure. These mechanisms may act together to coordinate respiration and defecation.

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In order to clarify the features of reactive oxygen species produced by rat alveolar macrophages (AMs), the concentrations of intracellular and extracellular hydrogen peroxide were measured under various experimental conditions. Intracellular hydrogen peroxide was measured by DCFH method using a flow cytometer, while the extracellularly released fraction was measured by scopoletin method using a spectrophotometer. The concentration of intracellular hydrogen peroxide after stimulation with opsonized zymosan (10μg/ml) was significantly higher than that after stimulation with phorbol myristate acetate (PMA; 100ng/ml). On the other hand, hydrogen peroxide released extracellularly after stimulation with PMA was significantly greater that that after stimulation with opsonized zymosan.
These results indicate that the soluble membrane stimulant and the phagocytic particles have different mechanisms in activating the production of hydrogen peroxide in AMs. That is, hydrogen peroxide induced by PMA was mainly released extracellularly, while that induced by zymosan was mainly released into the intracellular environment. At rest, the concentration of intracellular hydrogen peroxide in rat AMs was high. Potassium cyanate, a known mitochondrial inhibitor, suppressed the intracellular hydrogen peroxide in AMs not only at rest but also after stimulations, indicating that most of the reactive oxygen species released into the intracellular environment in AM are produced by mitochondria. From these results, in order to gain a closer insight into the function of AMs, it is very important to distinguish the oxidative metabolites produced intracellularly which are related to bactericidal function from those of the extracellularly released fraction which give rise to lung damage.

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To study the effects of angiotensin (ANG) peptides on airway epithelial ion transport function, we evaluated the bioelectric properties of canine cultured tracheal epithelium under short-circuit conditions in vitro. Addition of ANG I, II and II dose-dependently increased short-circuit current (Isc) and transepithelial potential difference, an effect that was more pronounced with addition to the submucosal solution than to the mucosal solution, with rank order of potency of ANG II≥ANG II>>ANG I. The ANG-induced increase in Isc was not altered by the Na channel blocker amiloride, but was greatly reduced by the CI channel blocker diphenylamine-2-carboxylate and Cl-free medium. The response of Isc to ANG I was reduced by MK422, an angiotensin converting enzyme inhibitor, in a dose-dependent fashion. These results suggest that ANG II and III selectively stimulate Cl secretion across airway epithelium and that ANG I may exert its effect after its conversion to ANG II by angiotensin converting enzyme.

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A 14-year-old girl was admitted because of cough, chest pain and hemosputum. Chest roentgenogram on admission showed a pneumothorax and a cavitary lesion with niveau formation in the right lung and cystic lesions in the bilateral lung fields. After bed rest and intravenous administration of antibiotics for two weeks, the right lung inflated well and the niveau formation disappeared, and the patient was discharged. One week later, she was readmitted with sudden-onset severe dyspnea, caused by bilateral pneumothoraces. Emergency tube thoracostomy and wedge resection of the bullous lesion was performed. Macroscopically, multiple small cystic changes were seen on the surface of the right lung. Histological examination revealed nodular proliferations of smooth muscle cells in the interstitium and vessel walls in the lung, which contained slit-like lymphatic channels. The diagnosis of pulmonary lymphangiomyomatosis was made. In this case, we could not measure receptors for estrogen and progesterone. Recently, hormonal therapy and oophorectomy have been reported as being useful. Tamoxifen (Norvadex) was therefore initiated, and the patient has remained well with slight dyspnea on exertion. There has been no recurrence of pneumothorax.
Lymphangiomyomatosis is a rare disease of unknown etiology which occurs exclusively in women, mostly in those of reproductive age. We report a 14-year-old female patient with lymphangiomyomatosis associated with repeated pneumothorax, who had been under treatment for epilepsy. We believe this case to be of importance because of the long discussed relation between pulmonary lymphangiomyomatosis and tuberous sclerosis.

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A 32-year-old female was admitted to our hospital because of abnormal pulmonary shadows and a decrease in visual acuity. Analysis of peripheral blood revealed eosinophilia, and chest roentgenogram demonstrated multiple infiltrates in the right upper lung field. Pathological examination of transbronchial lung biopsy specimens revealed necrotizing granulomatous lesions in the walls of bronchioles, and a definitive diagnosis of bronchocentric granulomatosis was made. The cause of bronchocentric granulomatosis in this patient was suggested to be an allergic reaction to Aspergillus because of positive response to skin test for Aspergillus.
Although it is reported that extrapulmonary involvement is rare in bronchocentric granulomatosis, the present case was associated with uveitis, and to our knowledge is the first reported case.

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A 65-year-old man was admitted to our hospital complaining of productive cough and dyspnea on exertion. X-ray films and CT scan of the chest disclosed diffuse reticular shadows, especially in the bilateral lower lung fields. Blood gas analysis showed severe hypoxemia. Pulmonary function test disclosed severe restrictive pattern. From these findings, the patient was thought to have pulmonary fibrosis. Right heart catheterization showed pulmonary hypertension. To evaluate the pulmonary vascular bed, we performed DSA pulmonary wedge angiography. The pulmonary capillary phase stained homogeneously in normal subjects. However, in the present case, filling of the right pulmonary A₉ was incomplete and capillary bed staining was decreased under room air condition. After breathing 5L/min oxygen for 20min., the A₉ was filled well and capillary bed staining was increased. We consider that this change was induced by inhibition of hypoxic pulmonary vasoconstriction (HPV) by oxygen. DSA pulmonary wedge angiography was useful for visual evaluation of HPV.

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We report a case of granulocyte colony-stimulating factor (G-CSF) producing lung large cell carcinoma with sarcomatous transformation. A 57-year-old man was admitted for evaluation of an abnormal shadow near the right pulmonary hilus on chest X-ray film. Brush cytology specimen from right B⁶ disclosed large cell carcinoma. His clinical stage was already IIIB (T3N3M0) on admission, so we immediately administered chemotherapy and radiation therapy. However, the patient's condition gradually deteriorated and he died of respiratory failure. Although there was no evidence of infection throughout his clinical course, his peripheral white blood cell count gradually increased and reached 47, 000/mm³ (neutrophils 96%) before death.
Histological study of the autopsy specimen revealed that the primary tumor was composed of two different elements (large cell carcinoma and spindle cell sarcomatoid element). The spindle cell sarcomatoid element appeared to have arisen from sarcomatous transformation of carcinoma cells, because the transition margin of the carcinoma to the sarcomatoid element was smooth, and special and immunohistochemical staining of both elements showed the same properties. Moreover, immunohistochemical study with monoclonal antibody to human G-CSF, 4A6 clearly demonstrated granular staining of G-CSF in the cytoplasm of tumor cells.

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A 23-year-old female was admitted with dyspnea, dry cough, and rhonchi. No abnormalities were detected on chest roentgenogram. Fiberbronchoscopy revealed a polypoid lesion with necrotic material occluding the left main bronchus. The pathological diagnosis of the biopsied material was low grade mucoepidermoid carcinoma. Following tumor reduction by Nd-YAG laser, it was clear that the primary lesion originated from the left upper bronchus. Sleeve lobectomy was performed, and the tumor was proved to be early lung cancer of hilar type with extension limited to the bronchial wall.

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A 60-year-old female was admitted to our hospital because of respiratory failure. She was diagnosed as having systemic lupus erythematosus (SLE) in 1971 and had been treated with low-dose oral corticosteroids for 13 years. She developed cough, fever and anemia several days after oral corticosteroids were tapered. Initially, she had no complications such as congestive heart failure, renal failure or bleeding tendency. Respiratory failure progressed without any response to antibiotic therapy. Chest roentgenogram showed bilateral diffuse infiltrates and airbronchograms. There was no improvement even with steroid pulse therapy, and she died of multiple organ failure. Autopsy revealed massive intra-alveolar hemorrhage and interstitial pneumonitis. Deposition of immunoglobulins in the lung was not seen. To our knowledge, this is the 11th reported case of SLE associated with pulmonary hemorrhage in Japan.

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A 58-year-old man was refered for the evaluation of a lung nodule on chest X-ray. On admission, chest X-ray showed a solitary nodule with cavitation in the left lung field. Histological examination revealed epithelioid cell granulomas and the diagnosis of pulmonary tuberculosis was made. He was treated with INH, ethambutol (EB), and rifampicin (RFP). On the 16th day of treatment, he developed dry cough and high fever. On the 20th day, dyspnea developed and PaO₂ was decreased to 38.2Torr. Chest X-ray showed new widespread infiltrates in both lung fields and bilateral pleural effusions. The size of the cavitary lesion was decreased. Transbronchial biopsy specimen showed slight interstitial thickening, lymphocyte infiltration, and multiple granulomas. Drug lymphocyte stimulation test was positive only with INH (230%). INH-induced pneumonitis was highly suspected. All drugs was discontinued and hydrocortisone 2400mg daily was started. He soon became afebrile, and dyspnea and dry cough resolved. Chest X-ray film showed resolution of infiltrative shadows. He was subsequently successfully treated with streptomycin, EB, and RFP without any adverse effects. To our knowledge, this is the sixth reported case of INH-induced pneumonitis.

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We report a case of adult primary varicella pneumonia. A 34-year-old man was admitted to our hospital with fever, dry cough and eruptions. He had no history of chicken pox and his sons had contracted varicella 2 weeks before the onset of his symptoms. Chest X-ray showed diffuse nodular shadows in both lungs. The diagnosis of primary varicella pneumonia was made based on family history, typical eruptions and high titer of antibody against Varicella zoster virus. An electron micrograph indicated this case to be primary varicella pneumonia with fibrosis and edema of interstitial spaces and the presence of virus-like particles in cells. The patient was treated with antibiotics, an antiviral agent and immunoglobulin. The clinical symptoms and diffuse nodular shadows resolved with this treatment.

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We report two cases of Churg-Strauss syndrome. The first case was a 25-year-old woman with a one year history of bronchial asthma, who developed fever, skin eruptions, abdominal pain and mononeuritis multiplex. During treatment with prednisolone 40mg per day, chest X-ray films showed bilateral wide-spread infiltrates. When the dosage of prednisolone was increased to 80mg per day, these infiltrates disappeared. Skin and lung biopsy specimens demonstrated allergic vasculitis and eosinophilic pneumonia. There was no response to high-dose methylprednisolone pulse therapy for persistent severe abdominal pain and mononeuritis multiplex. Pericardial and pleural effusions with eosinophilia recurred eight months later.
The second case was a 31-year-old man with a six year history of bronchial asthma, who developed fever, skin eruptions, myalgia and mononeuritis multiplex. One year later, during treatment with prednisolone 15mg per day, bronchial asthma with eosinophilia relapsed and chest X-ray films showed bilateral patchy infiltrates. Skin biopsy specimens demonstrated eosinophilic infiltrates and necrotizing vasculitis, while lung biopsy specimens demonstrated eosinophilic infiltrates and small granulomas. With additional administration of cyclophosphamide, he has had no evidence of active disease for six years.
In both cases, the neurological symptoms persisted despite treatment with high doses of steroids, and during tapering of prednisolone, vasculitis syndrome relapsed. Therefore, long-term careful surveillance is necessary in this disease.

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A 67-year-old female was admitted to our hospital with status asthmaticus. Serum alkaline phosphatase (ALP) level was elevated and ALP-linked immunoglobulins (ALP-Igs) were detected by ALP isozyme analysis. Treatment with predonisolone resulted in improvement of her asthmatic symptoms and serum ALP level. Thereafter, elevations of serum ALP and ALP-Igs levels were seen whenever she had an asthmatic attack. She had no manifestations of autoimmune diseases. Changes in ALP-Igs levels in association with asthmatic activity suggested that ALP-Igs were related to the pathogenesis of bronchial asthma in this case.

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We report a case of Pneumonitis and hepatic injury caused by Sho-saiko-to. A 56-year-old man was admitted to our hospital because of hepatic disorder. The levels of serum transaminases returned to normal within two months without specific treatment and he was discharged. Four weeks later, he was readmitted because of severe pneumonitis and mild hepatic disorder. Under the suspicion of drug-induced pneumonitis, all medications were discontinued and high-dose glucocorticoid including “pulse therapy” was given. Consequently, pneumonitis and hepatic function markedly improved. Careful history taking revealed the ingestion of Sho-saiko-to before both admissions. Lymphocyte stimulation test against Sho-saiko-to was positive. Challenge test using Sho-saiko-to resulted in decrease of PaO₂ and elevation of serum transaminases. Based on these findings, the diagnosis of pneumonitis and hepatic injury induced by Sho-saiko-to was established.

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A 34-year-old male patient was admitted to our hospital because of progressive exertional dyspnea and weight loss (8kg in one year). Twelve years previously, he had had an episode of uveitis accompanied with bilateral hilar lymphadenopathy. Scalene node biopsy at that time revealed non-caseating epithelioid granulomas. Four years later, a follow-up chest radiograph showed bilateral fine nodular lesions. The bilateral parenchymal lesions gradually increased in density, and eventually, formed a confluent air-space consolidation containing multi-locular cavities.
On physical examination, the patient was emaciated (Ht 165cm, Wt 40kg). Nodular cutaneous lesions were present on his face and elbows. Hypoxemia with hypercapnea (PaO₂ 56Torr, PaCO₂ 51Torr) was noted. Repeated sputum cultures yielded negative results for acid-fast bacilli, fungi, and other pathological organisms. A transbronchial lung biopsy specimen obtained from near the cavitary lesion revealed non-caseating granulomas compatible with sarcoidosis. Skin lesion biopsy showed similar findings. The cavitation, was therefore considered to be due to ischemic necrosis of confluent sarcoid granulomas. Prednisolone (40mg daily) was given with a prompt improvement of symptoms including dyspnea, as well as the radiographic abnormalities.
We conclude that uncomplicated pulmonary sarcoidosis may rarely develop into an aggressive parenchymal disease with cavitation. It is of importance to differentiate such cases from infectious diseases (tuberculosis, mycosis etc.) because of the need for corticosteroid treatment.

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