[Rapidly growing progressive massive fibrosis that was difficult to differentiate from lung cancer: report of a case].

The subject was a 79-year-old male. When he was 50-years-old, he was diagnosed to have pneumoconiosis, and his clinical course was monitored periodically during his stay at our hospital. In October 2007, chest computed tomography (CT) revealed a new shadow of a tumor mass in the right lower lobe. Lung cancer could not be ruled out by either CT or fluorodeoxyglucose-positron emission tomography (FDG-PET), and a definite diagnosis could not be established. Therefore, to make a diagnosis, we performed a partial resection of the lung and a diagnosed of progressive massive fibrosis (PMF) was obtained pathologically. Patients with pneumoconiosis have a possibility of developing new manifestations of PMF as a rapidly growing mass like a case presented in this report

Enhancement of goblet cell hyperplasia and airway hyperresponsiveness by salbutamol in a rat model of atopic asthma.

BACKGROUND: Goblet cell hyperplasia (GCH) is a prominent feature in animal models of atopic asthma produced by immunisation and following multiple challenges with antigens. The aim of this study was to examine the effect of a beta(2) agonist on the development of GCH induced by the immune response. METHODS: Brown Norway rats were immunised and challenged with an aerosol of ovalbumin for four weeks. Salbutamol (0.5 mg/kg/day) or vehicle was continuously delivered for the four weeks using a subcutaneously implanted osmotic minipump. The density of goblet cells, other morphological changes, and airway responsiveness to methacholine were evaluated 24 hours after the final challenge. RESULTS: Treatment with salbutamol induced a more than twofold increase in the mean (SE) number of goblet cells (53.7 (7.3) vs 114.5 (11.8) cells/10(3) epithelial cells, p<0.01) while it did not significantly influence airway wall thickening and eosinophilic infiltration. Airway responsiveness to methacholine expressed as the logarithmic value of the concentration of methacholine required to generate a 50% increase in airway pressure (logPC(150)Mch) was also enhanced by the beta(2) agonist (-0.56 (0. 21) vs -0.95 (0.05), p<0.05). Additional experiments revealed that the same dose of the beta(2) agonist alone did not cause GCH in non-immunised rats and that the enhancement of GCH by salbutamol was completely abolished by simultaneous treatment with methylprednisolone (0.5 mg/kg/day). CONCLUSIONS: These data suggest that salbutamol enhances goblet cell hyperplasia and airway hyperresponsiveness in this rat model of atopic asthma.

[An analysis of nutritional status and pulmonary hypertension in patients with sequela of pulmonary tuberculosis and chronic obstructive pulmonary disease].

The prognostic value of hypercapnia and/or pulmonary hypertension differs in patients with sequela of pulmonary tuberculosis (TBseq) and those with chronic obstructive pulmonary disease (COPD) who are receiving home oxygen therapy (HOT). In an attempt to identify the factors, if any, that might explain this difference, we first compared nutritional status, respiratory function test results, dyspnea indexes, and other data for hypercapnic patients (PaCO2 > or = 45 Torr) and normocapnic patients (PaCO2 < 45 Torr) receiving HOT. Second, we examined the relationship between the degree of pulmonary hypertension and several respiratory function parameters for patients in each disease category. In 44 patients with TBseq, nutritional status estimated by body mass index and serum albumin was significantly better in the hypercapnic patients than in the normocapnic patients. However, this difference was not observed in 37 patients with COPD. In 30 patients with TBseq, the degree of pulmonary hypertension correlated significantly only with PaO2; in 32 patients with COPD, however, significant correlations were observed not only with PaO2 but also with PaCO2, %VC, and FEV1. These differences distinguishing groups of patients with the 2 diseases may provide an explanatory basis for the difference in prognostic value of hypercapnia and/or pulmonary hypertension in patients receiving HOT.

Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway.

Chronic airway inflammation, one of the pathophysiologic features of bronchial asthma, is suspected to be responsible for irreversible pathological changes of airways, called airway remodeling. To examine the mechanisms of airway remodeling in asthma, we investigated the expression of epidermal growth factor (EGF) and its receptor immunohistochemically in asthmatic human airways. Airway specimens from seven patients with asthma were obtained from autopsied and surgically resected lungs. Control specimens were obtained from lungs of eight subjects without asthma and other pulmonary complications at autopsy. We stained those specimens by the avidin-biotin-peroxidase complex (ABC) method with anti-human polyclonal EGF antibody and monoclonal EGF receptor antibodies. Three different portions of airways-large bronchi (about 1 cm in diameter), small bronchi (about 3 mm in diameter), and peripheral airways (less than 2 mm in diameter)-were examined. The thickness of the bronchial smooth muscle and basement membrane was significantly greater in the asthmatic airways than in controls. Clear immunoreactivities of EGF were widely observed on bronchial epithelium, glands, and smooth muscle in asthmatic airways. In the controls, the bronchial epithelium and the bronchial glands partially expressed faint EGF immunoreactivity. For the EGF receptor, clear immunoreactivities were also observed on bronchial epithelium, glands, smooth muscle, and basement membrane in asthmatic airways. In control airways, only part of the bronchial epithelium and smooth muscle weakly expressed EGF receptor immunoreactivity. These results suggest a possible contribution of EGF to the pathophysiology of bronchial asthma, including airway remodeling.

A case of sarcoidosis that developed three years after the onset of hard metal asthma.

A 23-year-old man who worked at a hard metal factory from 1988 had developed bronchial asthma in 1990. He was diagnosed as having bronchial asthma by inhalation challenge with cobalt. He never developed a severe attack after that by avoiding inhalation of cobalt. In 1993, he developed iridocyclitis, and his chest radiograph showed bilateral hilar lymph node swelling. He was diagnosed as having sarcoidosis with pathological certainty and an increased serum angiotensin-converting enzyme (ACE) level. On second admission, an inhalational challenge with cobalt resulted in no significant decrease of FEV1. Cobalt is well known to cause occupational asthma and other interstitial lung diseases. Although we could not get clear evidence suggesting an association between the sarcoidosis and his history of cobalt exposure, there is a possibility that changes in the immune reaction to cobalt might explain the improvement of asthma followed by sarcoidosis in this case.

[Evaluation on the clinical background on early death in patients with pulmonary tuberculosis during the past five years].

We evaluated the clinical background of early death (within 3 months after admission to our hospital) in patients with active pulmonary tuberculosis during the past five years (1992-1996). Among 65 active pulmonary tuberculosis patients who died during the past five years, 32 (49%) died directly of tuberculosis. Thirteen (41%) of those 32 patients died of acute respiratory failure and 9 patients (28%) died in emacitation state. Twenty two patients (69%) died within 3 months after admission to our hospital (the early death group) and 10 patients (31%) died after 3 months (the late death group). Thirteen patients (59%) in the early death group died of acute respiratory failure. On the other hand, none in the late death group died of acute respiratory failure but 4 patients died of chronic heart and/or respiratory failure and 4 patients died in emarciation state. Compared to the patients in the late death group, more patients in the early death group had long total delays (patient's and doctor's delays), had coexisiting diseases, had fallen into acute respiratory failure, and were under malnutrition. We evaluated the nutritional condition of patients using the Onodera's PNI (Prognostic Nutritional Index; 10 x serum almumin concentration + 0.005 x peripheral lymphocyte count) and the PNI value was lower among the patients in the early death group than among those in the late death group. To prevent death due to tuberculosis, we emphasize that it is important to start anti-tuberculosis therapy before patients fall into acute respiratory failure and/or malnutrition.

Mechanisms of epidermal growth factor-induced contraction of guinea pig airways.

We investigated the functional effects of epidermal growth factor (EGF) on guinea pig airways in vitro. EGF (3 ng/ml to 1 microgram/ml) induced a concentration-dependent contraction in epithelium-denuded strips. The average maximal contraction was 0.64 +/- 0.1 g (mean +/- S.E., for n = 27), which was 72.0 +/- 9.5% of the 100 mM KCl-induced contraction. The EC50 was 12.3 +/- 1.6 ng/ml. The presence of the epithelium significantly suppressed the EGF-induced contraction (P < 0.01). EGF-induced contraction was abolished by cyclooxygenase inhibitors (indomethacin and ibuprofen) and a 5-lipoxygenase inhibitor, 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-1,4-benz oqu inone (AA-861). It was also inhibited by a leukotriene-receptor antagonist, 8-[p-(4-phenylbutyloxy)benzoyl]amino-2-(tetrazol-5-yl)-4-oxo -4H-1-benzopyran hemihydrate (ONO-1078) but not affected by a thromboxane A2-synthetase inhibitor, (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid (OKY-046) or a thromboxane A2-receptor antagonist, 9,11-epithio-11,12-methano-thromboxane A2 (ONO-3708). A phospholipase A2 inhibitor (mepacrine) inhibited the EGF-induced contraction but a diacylglycerol-lipase inhibitor, 1,6-di-(O-(carbamoyl)cyclohexanone oxime)hexane (U-57908) and a phospholipase D inhibitor (wortmannin) did not affect it. A tyrosine kinase inhibitor (genistein) abolished it. Measurement of prostanoids showed that EGF (300 ng/ml) did not increase the prostaglandin F2 alpha level in either epithelium-intact or epithelium-denuded strips. In epithelium-intact strips, EGF significantly increased the prostaglandin E2 concentration (P < 0.01). These results suggest that EGF causes contraction of guinea pig airway smooth muscle by activating tyrosine kinase followed by phospholipase A2 activation, and that arachidonic acid metabolites, especially leukotrienes, may have important roles in this contraction.

Smoking promotes insidious and chronic farmer's lung disease, and deteriorates the clinical outcome.

Although the prevalence of serum precipitating antibodies for farmer's lung disease (FLD) is lower in smokers than in nonsmokers and FLD predominates in nonsmokers, the affects of smoking on the clinical course of the disease is not known. We compared the clinical findings and the prognosis between 12 smokers (SM-FLD) and 31 non-smokers with FLD (NS-FLD). There was no difference in age, sex, working years on farm, clinical symptoms, laboratory findings, radiographic findings, between the two groups. However, for the type of onset on the first visit for FLD, "acute single episode" type was less common, and "recurrent" and "insidious onset" types were more common in SM-FLD than in NS-FLD (8.3 vs 58.1, 91.7 vs 41.9%, respectively, p < 0.05). Although working status and mask wearing status were not significantly different between the two groups after the diagnosis of FLD, patients with symptoms and/or radiographic abnormalities of FLD of more than 6 months were found more frequently in SM-FLD than in NS-FLD (66.7 vs 19.4%, p < 0.005). And also SM-FLD had more recurrences of FLD than NS-FLD after the initial diagnosis of FLD (1.58 +/- 1.56 vs 0.47 +/- 1.07, p < 0.05). SM-FLD tended to have lower % VC than NS-FLD (73.6 +/- 7.4 vs 88.5 +/- 3.9%, respectively, p = 0.06). Regarding the prognosis, the 10-year survival rates were 70.7% in SM-FLD, and 91.5% in NS-FLD (p < 0.05). These results suggest that smoking may make FLD insidious and chronic, and deteriorates the clinical outcome.

Three cases of idiopathic interstitial pneumonia with bullae seen in schoolteachers.

We encountered three patients with chronic interstitial pneumonia with many bullae in the lower lung fields whose lifetime occupation was teaching school. Pathological examination of autopsy lungs of these patients revealed interstitial pneumonia and multiple bullae throughout the lungs, including the lower lobe. Since blackboard chalk has been used as a popular writing material among teachers in Japan, the mineral contents in the lungs of two of the three cases and four control cases with idiopathic interstitial pneumonia (IIP) (whose occupations were not teaching) were analyzed. The amount of deposition of total dust, inorganic dust, non-SiO2 inorganic dust, and calcium was significantly higher in the lungs of two schoolteachers compared with those of the control lungs. The amount of free silica in case 1 and alpha-quartz in case 3 were also significantly higher than in the controls. Two thirds of the chalk produced in Japan is still made from gypsum and involves small amounts of silica and other minerals, in addition to calcium. These findings indicated the deposition of chalk in the lungs of these patients with interstitial pneumonia and multiple bullae.

[Factors influencing patterns of airway response after allergen challenge in patients with bronchial asthma].

We examined patterns of airway response of thirty nine asthma patients who had positive responses on allergen inhalation tests. Six types of inhaled allergens were used: house dust mite, animal, pollen, plant, mold, and others. Three patterns of responses were found: isolated immediate asthmatic response (IAR), immediate and late response (Dual), and isolated late asthmatic response (LAR). No relationship was found between the pattern of response and pulmonary function, airway sensitivity, IgE RIST titers, numbers of eosinophils, or concentration of inhaled antigens. Animal antigens tended to cause a dual response, and molds did only rarely. Ten of 39 challenged patients had an isolated LAR, half of which were caused by mold antigen inhalation. RAST scores were lower in isolated LAR than in other responses. Changes in the number and proportion of peripheral leukocytes during the challenge tests were also studied. Total leukocyte count had increased significantly in the isolated LAR group by 24 hours after the inhalation. These results suggest that the pattern of airway response after inhalation depended in part on the type of inhaled antigen, and that non-IgE mediated immune reactions have some role in the isolated LAR.

Dairy farmers have increased methacholine bronchial responsiveness independent of sensitization to mold antigens.

Patients with farmer's lung disease (FLD) and dairy farmers have nonspecific bronchial hyperresponsiveness. To examine the factors determining bronchial hyperresponsiveness among dairy farmers, we studied airway functions, airway responses to inhaled methacholine, serum total IgE levels, and antigen-specific IgE levels in 37 dairy farmers and 11 local control subjects. The 37 dairy farmers consisted of three groups; 12 farmers with episodes of FLD (FLD group), 13 farmers with serum antibody to Micropolyspora faeni (MF) and/or Thermoactinomyces vulgaris (TV) but without episodes of FLD (Ab(+) group), and 12 farmers without serum antibodies to MF and TV and without episodes of FLD (Ab(-) group). Pulmonary function tests showed small airways disorders among farmers (each of the three groups versus control subjects; p < 0.05). Methacholine provocation test, utilizing PD35Grs (a cumulative dose of methacholine that induces 35% reduction in respiratory conductance [Grs]), showed bronchial hyperresponsiveness in each group of dairy farmers compared with that in control subjects (Log PD35Grs, mean +/- SEM: 1.22 +/- 0.18, 1.00 +/- 0.17, and 1.20 +/- 0.20, respectively, versus 2.10 +/- 0.09; p < 0.001). However, there was no statistically significant difference in bronchial responsiveness among the three groups of dairy farmers. In addition, there was no significant difference in serum total IgE levels and specific IgE antibodies among the four groups. These results suggest that the bronchial hyperresponsiveness to methacholine among dairy farmers is not due to past episodes of FLD or sensitization to MF and/or TV, but is possibly due to the occupational environment of dairy farming.

In vivo, in vitro correlation of acetylcholine airway responsiveness in sensitized guinea pigs. The role of modified epithelial functions.

Many attempts have failed to correlate in vivo airway responsiveness with in vitro airway smooth muscle functions. We have reexamined this relation by taking account of airway epithelial functions in guinea pigs sensitized with inhaled ovalbumin (OA). In vivo responses were assessed by the provocative concentration of acetylcholine (ACh) required to double the airway opening pressure (PC200) under mechanical ventilation. In vitro responses were measured in a perfused whole-tracheal preparation. The negative logarithm of the molar concentration of ACh required to produce a 10% reduction in diameter was calculated both for epithelial-side stimulation (PC10(in)) and for serosal-side stimulation (PC10(out)). OA-sensitized guinea pigs showed significantly smaller log PC200 than control animals (0.51 +/- 0.07 and 0.81 +/- 0.10, respectively, p < 0.01). In in vitro study, there were variable differences in PC10(in) and PC10(out) in each animal. The difference in sensitivity between epithelial- and serosal-side stimulation (PC10(in-out)) showed a significant correlation in PC10(in) (r = 0.82, n = 9, p < 0.01) but not to PC10(out) (r = 0.39, p > 0.1), indicating that the variation in PC10(in-out) resulted from the changes in PC10(in). For in vivo-in vitro correlation, log PC200 correlated significantly with PC10(in) (r = 0.68, n = 9, p < 0.05) but not with PC10(out) (r = 0.18, p > 0.1). These results indicate that the sensitization by inhalation of OA produces increased airway responsiveness to ACh in vivo and that this airway responsiveness may be related, at least in part, to the altered airway epithelial functions.

Gamma-interferon modifies guinea pig airway functions in vitro.

Cytokines produced by T-lymphocytes may have significant roles in the airway inflammation seen in bronchial asthma. Gamma interferon (IFN-gamma), a T-cell derived cytokine, is known to modify functions of both immune and non-immune cells. In this study, we investigated whether IFN-gamma can modify guinea pig airway functions in vitro. The isometric tension of guinea pig airway strips was measured in a tissue bath filled with Krebs-Henseleit solution. Contracting responses to carbachol and KCl, and the relaxing response to isoproterenol (ISO) were examined. Effects of IFN-gamma were examined by comparing responses of the strips incubated with or without IFN-gamma (1000 U.ml-1; 25,000 U.ml-1). Contracting responses to carbachol and KCl were not affected by the incubation with IFN-gamma other than slight increased in maximum contraction by carbachol after 5 hours incubation with 25,000 U.ml-1 of IFN-gamma. Both 1 and 5 h incubation of strips with 25,000 U.ml-1 IFN-gamma significantly increased the sensitivity to ISO (p < 0.01 and p < 0.05, respectively) without affecting maximum relaxation. The effect of IFN-gamma on ISO relaxation was abolished by the denudation of airway epithelium from strips, indomethacin (2 microM), and cycloheximide (70 microM) but not by N omega-nitro-L-arginine methyl ester (30 microM). In addition, heat-inactivated IFN-gamma and bacterial endotoxin (LPS, 0.625 pg.ml-1) had no effect on ISO relaxation. These results suggest that IFN-gamma is able to modify airway smooth muscle response to beta-adrenergic agonist by inducing release of prostanoids from airway epithelium.

[Bronchial asthma--airway inflammation and asthma--role of airway epithelium].

The importance of airway inflammation in the pathophysiology of bronchial asthma has been recognized recently. This inflammation is organized by the interaction between inflammatory cells and the cells which compose airway structures. We studied the role of airway epithelium in airway hyperresponsiveness and airway inflammation, which are the major characteristics of bronchial asthma, and demonstrated a close relationship between them. On the bases of these data and the data reported by many other researchers, and from the point of view of airway inflammation, we discussed the possible roles of airway epithelium in bronchial asthma.

[A case of chronic hepatitis C complicated by ischemia-like changes seen on the electrocardiogram during interferon treatment].

A 53-year-old woman was admitted to the hospital for chest pain with headache, nausea and vomiting, two and a half hours after an intramuscular injection of 6 x 10(6) units of IFN (interferon) alpha 2a, in the 11th week of IFN treatment for chronic hepatitis C. The electrocardiogram (ECG) showed ST depression and T inversion in leads II, III, aVF and V3-V6, as commonly seen in myocardial ischemia. However, emergency coronary angiography (CAG) did not show stenosis or spasms clearly, serum CPK was always within the normal limits, Tc-99m PYP scintigraphy and T1-201 scintigraphy did not show any abnormal uptake or defect, and the echocardiogram did not show any abnormality. She recovered from chest pain and the ischemia-like changes seen on the ECG, after IFN treatment was stopped, and she rested for 7 days from this treatment and other treatment using nitrites and a calcium-antagonist. After recovery, the ECG during exercise and hyperventilation showed changes similar to those seen on admission. From these findings, this case was considered to be precipitated by spasms of coronary microvessels, which were not noticeable in CAG. The cause was thought to be complicated by IFN treatment, because this episode appeared after IFN injection, and improved after stopping IFN treatment.

[Immunohistochemical and electromicroscopic study of a case of primary nodular pulmonary amyloidosis].

A 41-year-old man was hospitalized for further evaluation of an abnormal chest films which revealed a nodular shadow in the right middle lung field, which remarkably enlarged during one year. As no diagnostic procedures ruled out lung carcinoma of right S6, a right lower lobectomy was performed. Pathologically the nodules were composed of amorphous and eosionphilic materials which were diagnosed as amyloid by Congo-red stain and electron microscopic examination. Since there were no deposits in other organs and there was no abnormality of serologic and urinary protein analysis, a diagnosis of primary nodular pulmonary amyloidosis was established.