We defined “intractable asthma” at the 3rd Asia-Pacific Congress on Diseases of the Chest (1973), Symposium [Bronchial Asthma] as follows:
1) Attacks develop easily and frequently with little correlation to provocation and seasonal factors.
2) Attacks respond poorly to treatment and show a tendency to develop status asthmaticus.
3) Steroid dependence is remarkable.
The purpose of this study was to clarify the characteristics of intractable asthma, and then to find rational and effective treatments.
1) Administration of β-stimulants is known to cause remission of bronchospasm by increasing cAMP content in bronchial smooth muscles. However, the effect of β-stimulants is usually weakened by the following factors. 1) aging, 2) occurence of attacks throughout the year, 3) chronic atopic type, 4) complications of chronic sinusitis paranasalis and, 5) chronic pulmonary emphysema, 6) continuous administration of β-stimulants.
2) Repetition of both sensitizations and anaphylactic attacks by allergen inhalations induced a β-blocking condition in the airways. Thus it is reasonable that the effects of catecholamine secreted during both exercise and the attacks are diminished in asthmatic patients. Therefore this β-blocking mechanism has been recognized as one of the new factors causing intractable asthma.
3) We examined the effect of airway narrowing and impairment of mucociliary transport on mucous plug formation in airways using chicken tracheas. It was found that mucous plug formation was accelerated by airway narrowing, excessive volume of mucous and ciliary dysfunction. It was also observed that once a mucous plug was formed, it was often retained even when airway narrowing was almost completely relieved.
4) Using frog palates, we studied the effects of pharmacologic agents on mucociliary transport and mucous production. Since isoproterenol increased mucous production to the same degree as acetylcholine, isoproterenol, an effective β-stimulant, might form mucus plugs when slight narrowing of airways remains.
5) A series of studies suggested that the β-blocking condition in the airway is involved in the development of intractable asthma. Therefore, unlike Ca-antagonists, the application of forskolin, a direct activator of adenylate cyclase, and cGMP-related substances such as nitroprusside and 8Br-cGMP are hopeful new treatments for intractable asthma.

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The inflammatory process consists of an exudative phase where fluid and cells leave the circulation and accumulate in the tissue, and a proliferative or repair phase where connective tissue is deposited to form a scar. When this process occurs in mucus membranes, it is associated with a shedding of epithelial cells and an increase in the amount of mucus that is produced. An inflammatory process in the small airways can show all of the changes that occur as part of this general pattern. For example, in asthma there is marked epithelial shedding leading to increased epithelial cell turnover and thickening of the basement membrane associated with a thick mucus exudate which can occlude the airways. While the smooth muscle in the airway wall tends to proliferate, there is relatively little deposition of collagen in the airway wall and no organization of the exudate in the airway lumen. This contrasts sharply with situations where more severe tissue injury is followed by organization of the exudate in the airway lumen with marked collagen deposition leading to the airway obliteration. Between these two extremes the histological appearance of the inflammatory process can be quite varied and includes epithelial changes such as goblet cell and squamous cell metaplasia, an infiltration of inflammatory cells into the airway wall, hypertrophy and hyperplasia of the airway muscle and less prominent deposition of collagen in the airway wall and lumen. The rather stereotyped nature of this response makes it extremely difficult to associate specific stimuli with a typical response so that a diagnosis of small airways disease may be too non-specific to be helpful. However, it seems likely that a better understanding of the nature of the inflammatory process in the peripheral airways will lead to a clearer concept of the pathogenesis of several obstructive lung diseases.

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Genetic and familial factors determining pathogenesis and pathophysiology were examined in patients with chronic bronchitis, bronchial asthma, sarcoidosis, and lung cancer and their healthy relatives.
Sons of bronchitics has smaller than average lung volumes though they were within normal limits, high permeability for CO, low airflow in the small airways, and lower leukocyte chemotaxis to C_5a, while daughters did not show such trends. Mucociliary clearance in the hilar region was slower than controls in sons of bronchitics. In 35% of healthy siblings of asthmatics, airway reactivity to inhaled acetylcholine was increased. Hilar mucociliary clearance was also reduced in these siblings.
HLA DRw 52 was predominant (83.3%, p<0.002) and DRw 53 was infrequent (41.7%, p<0.007) in patients with sarcoidosis, occurrences in the controls being 50.9 and 71.9%, respectively.
In patients with lung cancer as well as their sons and daughters, serum selenium concentration was low compared to controls with no family history for cancer in first and second degree relatives; families of adenocarcinoma patietns having the lowest selenium among the families. Serum vitamin E level was also low in families of adenocarcinoma patiets. Occurrence of benzopyrene-induced sister chromatid exchange in peripheral lymphocytes was more frequent in families of lung cancer patients than families of non-cancer patients.

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The respiratory muscles form a pump just as vital as the heart. Compared to the heart, the respiratory muscles are characterized by not only anatomically complex geometry and functional interactions between muscles, but voluntary as well as involuntary under-control.
Recently it has become apparent that the inspiratory muscles fail in much the same manner as the heart fails. Since then respiratory muscle fatigue has become a clinical entity and inspiratory muscle fatigue has been known to lead to respiratory failure.
Diagnosis of inspiratory muscle fatigue can be done by magnetometry as originally described by Konno and Mead and by a frequency spectrum analysis of the EMG.
The grade of the inspiratory muscle fatigue can be detected by a tension-time index for the diaphragm.
New therapeutical approaches have been made. Pharmacological application of Coenzyme Q₁₀ was introduced. Human technological instruments, 1) Ventilator-Speaking System 2) Postural Intermittent PEEP Bed 3) CFRP-Portable Ventilator and 4) Portable O₂ Enricher have been developed.

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Airway narrowing occurs not only in the central airways but also in the peripheral airways in asthmatic patients. However, little is known about the morphological change in the respiratory bronchioles and alveolar ducts, which are the conductive portion of lung parenchyma.
Recently, it was proved that multiple ring-shadows observed in selective alveolo-bronchography (SAB) films represent alveolar ducts by correlating roentgenographic and histologic observation using resected human lung.
In order to investigate the morphological change in the conductive portion of lung parenchyma in asthmatic patients and its relationship with clinical background, we measured the diameter of ring-shadows on the SAB films and correlated them with the various clinical features.
Magnified SAB films of 37 patients with asthma, 14 normal subjects and 10 patients with chronic pulmonary emphysema were selected from the SAB film library and the diameters of ring-shadows were measured using a viewer and calipers. The real diameters of ring-shadows were calculated by dividing the measured diameter by magnifying rate. Results were as follows:
1) The average diameter of ring-shadows in the asthmatic group, normal group and emphysema group were 342±69μm, 523±75μm and 904±97μm respectively, and the differences between any 2 of the 3 groups were statistically significant. The average diameter in asthmatics was slightly smaller than in the normal group. The average diameter in the emphysema group was much larger than in the normal or asthma group.
2) The diameter of ring-shadows of asthmatics correlated well with the clinical type of asthma. Asthmatic patients of mixed or infectious type showed a larger diameter than those of atopic type. Among patients of either mixed or infectious type, steroid-dependent patients seem to have larger diameter than non-dependent patients. No relationship was observed between the diameter and age or duration of asthma.
3) There was no relationship between bronchoconstrictive findings of central airways and the diameter of ring-shadows.
4) These results suggest that in asthma, airway narrowing occurs even in the conductive portion of lung parenchyma, probably due to constriction of airway smooth muscle, and in asthma, central aieways narrowing does not produce the dilation of the conductive portion of lung parenchyma, which is thought to be an initial stage of pulmonary emphysema.

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Localization of tissue angiotensin-converting enzyme (ACE) and its activity were studied by ACE substrate film method in the normal lung and lung with granulomas induced by Freund's complete adjuvant in rabbit. The tissue ACE activity in the normal lung was seen in bronchus-associated lymphoid tissues and lymphoepithelium, but not seen in other lung components such as alveolar septa, vessels, bronchia and interstitial connective tissues. The normal alveolar macrophages showed no or little ACE activity. In the lungs with granulomas induced 2 weeks preiously by Freund's complete adjuvant, the tissue ACE activity developed in the granulomas but was not seen in the other lung components. Most of the alveolar macrophages in this stage showed apparent ACE activity. In the lungs with induced for a period of 4 week, the ACE activity was increased in the granulomas and was also recognized in the alveolar spaces along the thickened alveolar septa and vessels near the granulomas. The alveolar macrophages showed marked ACE activity.
These results suggest that the localization of the tissue ACE activity coincides with the distribution of macrophage series cells, but the ACE activity of normal macrophages is too low to be detected on the substrate film. On the other hand, the macrophages activated by Freund's complete adnuvant induced high ACE activity.

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Immediate-type I hypersensitivity reactions are characterized by the immunologically-induced release of histamine, SRS-A, serotonin and prostaglandins. Recently, SRS-A was identified as the mixture of substances derived from arachidonic acid and named leukotrienes C₄ (LTC₄), LTD₄ and LTE₄. The present investigation was conducted to explore the effect of various drugs on antigen-induced contractile responses in actively sensitized guinea pig tracheal and lung parenchymal strips.
Sixty Hartley strain guinea pigs, weighing 300-350g, were sacrificed. Guinea pig tracheal and lung parenchymal strips were removed and suspended in bioassay glass jackets and superfused with Krebs-Henseleit solution at 37°C, saturated with oxygen and carbon dioxide. Contraction of tissues was detected by an isotonic transducer and displayed on a polyrecorder.
1) Antigen-induced contractile responses in guinea pig tracheal strips were attenuated significantly by pretreatment with mepyramine or AA-861, and the attenuation became more marked by combining the two drugs.
2) In the same way, contractile responses in guinea pig lung parenchymal strips were attenuated significantly by pretreatment with mepyramine or AA-861.
3) The contractile responses in guinea pig tracheal strips showed an attenuating tendency following pretreatment with methysergide.
4) The contractile responses in guinea pig lung parenchymal strips were attenuated significantly by pretreatment with methysergide or AA-861.
5) The contractile responses in guinea pig lung parenchymal strips were attenuated significantly by pretreatment with AA-861, methysergide and mepyramine. The attenuation became more marked by adding indomethacin.
The above results may suggest that mainly leukotrienes and histamine are released from guinea pig tracheal tissue, while mainly leukotrienes, serotonin and histamine are released from lung parenchymal tissues by antigen challenge.

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The purpose of this study was to investigate the usefulness of bronchoalveolar lavage (BAL) for the diagnosis of pulmonary sarcoidosis in uveitis patients without any radiological intrathoracic involvement.
The BAL studies revealed that 6 of 11 patients with uveitis showed normal findings similar to nonsmoking healthy controls (n=11). Five patients, however, showed increased proportions of lymphocytes or changes of T-cell subsets in BAL fluid, such as increased proportion of OKT4⁺ cells, decreased proportion of OKT8⁺ cells, or increased ratio of OKT4⁺ cells/OKT8⁺ cells.
Transbronchial lung biopsy was performed to obtain a definitive histological diagnosis in 5 patients with abnormal findings of BAL fluid described above. Noncaseating epithelioid cell granuloma was demonstrated in 2 patients with a higher ratio of OKT4⁺ cells/OKT8⁺ cells and one patient with a high proportion of lymphocytes in BAL fluid.
An immunohistochemical study of biopsied lung specimens demonstrated that many Leu 1-, Leu 3- and Leu 4- positive lymphocytes were found in granulomata, although there were very few Leu-2a positive cells in tissue.
T-cell subsets or ACE levels in peripheral blood were within normal limits in all cases. Thus, these parameters were poor markers for suggesting pulmonary sarcoidosis in the present series of patients.
These results suggest that analysis of BAL lymphocytes is useful for the diagnosis of pulmonary sarcoidosis in uveitis patients with normal chest X-ray films.

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A case of interstitial pneumonia with autoimmune hemolytic anemia, succumbing due to cytomegalovirus pneumonia, is reported. A 55 year-old man was admitted because of dyspnea. He had suffered from autoimmune hemolytic anemia and had been treated with corticosteroid for 8 years. Bilateral interstitial shadows on chest X-ray film, mild hypoxemia and decreased diffusion capacity were recognized and a diagnosis of interstitial pneumonia was made by transbronchial lung biopsy. The interstitial pneumonia was progressive and treatment with prednisolone and azathioprine was unsuccessful. Bronchoalveolar lavage fluid showed increased proportions of lymphocyte and OKT4+ cells in T lymphocyte subsets. The titer of CMV antibody was 1:32. Pulse therapy with methylprednisolone followed by combination of prednisolone and cyclophosphamide was unsatisfactory. High fever and severe respiratory failure developed and the patient died 9 months after admission. At autopsy, marked interstitial pneumonia and cytomegalic inclusion bodies suggestive of recent cytomegolovirus infection were seen in the lungs.

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A 31 year-old carpenter who had kept a rabbit in his living room for about 18 months was admitted because of recurrent asthmatic attacks. Laboratory findings revealed peripheral eosinophilia, markedly elevated serum IgE and positive serum precipitating antibody to rabbit hair. Skin tests confirmed that he was allergic to rabbit hair. Allergen inhalation provocation test was positive with a typical dual asthmatic response. Furthermore environmental exposure induced diffuse parenchymal shadows in his chest X-ray film which suggested PIE with asthma. We considered this case as an example of transition between bronchial asthma with late asthmatic response and PIE with asthma.

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We reported two cases of piperacillin-induced pneumonitis. The first case, a 64-year-old man, had been treated with cefbuperazone because of acute pneumonia; however his condition deteriorated. On February 25, 1982, cefbuperazone was changed to piperacillin, kanamycin, and venilon. The patient improved. Twenty-two days after this, he developed chills, remittent fever, with abnormal findings on his chest X-ray. On physical examination, crepitant rales were heard at the base of the right lung. Piperacillin therapy was discontinued, subsequently, he showed a rapid resolution of symptoms accompanied by marked regression of the pulmonary infiltrates on his chest X-ray. The second case, a 79-year old man, developed acute pneumonia on December 21, 1983 and was treated with piperacillin. Eleven days after, he developed an intermittent fever and showed abnormal shadows on his chest X-ray. Once piperacillin was changed to cefmenoxime, he demonstrated a rapid improvement. The results of lymphocyte stimulation tests were positive to piperacillin in both cases. These in-vitro tests were carried out in accordance with the clinical diagnosis of drug allergy in both cases.
To our knowledge, there has been no previous case report of pulmonary hypersensitivity to piperacillin. Clinicians should be alerted to the possibility of the occurence of such a complication in patients being treated with piperacillin.

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Intrathoracic lipomas are rare tumors. Those in a subpleural position without an extrathoracic component represent only a small fraction of the entire group. A case of benign subpleural lipoma was presented.
The patient was a 45 year-old asymptomatic female in whom a routine roentgenogram revealed an abnormal mass shadow in August 1980. The chest X-ray showed a well-defined extrapleural mass density in the right third intercostal space. Computed tomography through the middle part of thorax showed a homogenous density adjacent to the rib with a CT value of -140. Intrathoracic lipoma was suspected preoperatively. At thoracotomy, a solid encapsulated yellow mass found sub-pleurally at the level of 4th rib. The base was loosely attached to the periosteum of the IVth rib and intercostal muscle fascia. The entire mass was excised. Microscopically multiple sections revealed mature adipose tissue with a capsular surface.
The use of computed tomographic scan in evaluating intrathoracic abnormalities, particularly fat-containing masses, is recommended to obtain diagnostic clues in such cases.

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We performed bronchofiberscopy in five immunosuppressed patients (1 case of lung cancer, 3 cases of hematologic malignancy, 1 case of sarcoidosis treated with corticoid) on supplemental oxygen. In all patients, hypoxemia and diffuse pulmonary infiltrates were present, and Pneumocystis carinii was found by bronchoalveolar lavage. Two were diagnosed by both bronchoalveolar lavage and transbronchial lung biopsy. The lavage procedure was completed within five minutes in all patients. Two patients had a transient increase in temperature after the lavage, but no serious complications were seen. Bronchoalveolar lavage is an easy, safe, and valuable procedure for diagnosis of Pneumocystis carinii pneumonia. In addition, we believe that bronchoalveolar lavage is useful for evaluation of pulmonary complications in immunosuppressed patients, especially those with diffuse pulmonary infiltrates.

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The first case of urinothorax in Japan was reported.
A 67 year old man was admitted to our hospital because of hemoptysis and was diagnosed as having metastatic lung cancer from pancreas cancer.
Fifty days after admission, he complained of flank tenderness and lateral chest wall swelling in only the left side. The fluid collection in the left pleural cavity was found on chest X-ray film and BUN and serum creatinine level also were elevated at this time. Thoracentesis yielded a large amount of yellow fluid with a creatinine concenration of 10.1mg/dl, urea nitrogen of 123mg/dl and total protein 0.3g/dl with concomitant serum level 9.2mg/dl, 115mg/dl and 6.8g/dl, respectively. The central venous pressure did not elevate. Although some questions remained, we diagnosed acute renal failure with pleural effusion at this stage.
Abdominal CT scan showed urinoma in the left retroperitoneal space and multiple renal cysts of bilateral kidneys. A left percutaneous nephrostomy catheter was put in place. A nephrostogram performed through the catheter demonstrated extravasation of contrast material from the renal pelvis and confirmed the abdominal urinoma.
After drainage, the serum creatinine and BUN levels immediately fell and left pleural effusion diminished. At the same time, swelling of left lateral chest wall and left flank pain disappeared.
Thirty days after drainage, he suddenly died because of aspiration. Pancreas cancer, lymphangitis carcinomatosa, multiple renal cysts were revealed and left ureteral obstruction caused by cancer invasion were proved at autopsy.
We therefore conclude that his pleural fluid was urinothorax secondary to the urinoma.
When pleural fluid shows higher level of creatinine than that of serum, we should consider the possibility of urinothorax.

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A 39-year-old male was admitted to our hospital because of cough and dyspnea. The chest x-ray revealed consolidation in the bilateral middle-lower lung fields. The diagnosis of pulmonary cryptococcosis was made by transbronchial lung biopsy of the right lung, and symptoms and cosolidation were improved transiently by treatment with anti-fungal agents. We could not find any underlying diseases despite of intensive examination during the treatment. However pulmonary involvement became larger suddenly, he died of respiratory failure. Post-mortem examination revealed malignant lymphoma invading both lungs diffusely and pulmonary cryptococcosis.

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