VEGF regulates the proliferation of acid-exposed alveolar lining epithelial cells.

BACKGROUND: Acid induced pneumonitis resulting in acute respiratory distress syndrome (ARDS) is characterised by increased alveolar permeability and accumulation of neutrophils. It is hypothesised that vascular endothelial growth factor (VEGF) is involved in the development of lung oedema. Furthermore, lower levels of VEGF are detected in bronchoalveolar lavage fluid from patients with ARDS than from non-ARDS patients. We hypothesised that VEGF acts cytoprotectively and have investigated this possibility in vitro with A549 cells. METHODS: A549 cells were incubated in 24 well culture dishes 24 hours before exposure to acid, then incubated with serum free medium containing various concentrations of HCl for 30 minutes at 37 degrees C in 5% CO(2). The acidified medium was changed to normal complete medium; at specified incubation periods the supernatants were collected and the VEGF concentration measured and the number of adherent cells counted. RESULTS: Proliferation of A549 cells and VEGF production were suppressed for at least 48 hours in HCl at a concentration of 50 mM. Restoration of cellular proliferation occurred following exogenous administration of VEGF (concentration of 1-250 ng/ml) and was inhibited by co-incubation with neutralising anti-VEGF antibody, indicating an interaction between VEGF molecules and A549 cells. Control cells were not influenced by administration of exogenous VEGF or anti-VEGF antibody. Treatment with neutralising anti-VEGF receptor (VEGFR) antibodies against VEGFR-1 and VEGFR-2 suppressed proliferation of acid exposed A549 cells but had no effect on control cells. CONCLUSIONS: Exogenous VEGF interacts with VEGFR-1 and VEGFR-2 on the surface and regulates the proliferation of injured alveolar lining epithelial cells in an autocrine or paracrine fashion.

[Evaluation of spontaneous pneumothorax in patients with pulmonary lymphangioleiomyomatosis].

We retrospectively evaluated the development of spontaneous pneumothorax in patients with pulmonary lymphangioleiomyomatosis (LAM). Fifteen patients with LAM, whose diagnosis was confirmed histopathologically, were enrolled. All were women, and had a mean age at diagnosis of 31.6 +/- 7.3 years. They were divided into two groups according to the presence or absence of pneumothorax at the time of onset, Group A consisting of nine patients with pneumothorax, and Group B, of six without pneumothorax. Spontaneous pneumothorax developed in 15 out of a total of 18 hemithoraces in Group A patients in whom 13 hemithoraces were surgically treated for pneumothorax (eight open thoracotomies and five video-assisted thoracoscopic surgeries). Bullectomy with either parietal pleurectomy, pleural abrasion, or instillation of chemical irritants to prevent the recurrence of pneumothorax offered better outcomes than bullectomy alone in terms of the postoperative recurrence rate of pneumothorax (p < 0.05). On the other hand, three of the five Group B cases developed pneumothorax during the course of LAM, but none was operated because of severely impaired lung function. The other patient in Group B was not only free of pneumothorax at onset, but also did not develop pneumothorax or suffer from impaired lung function. There were no deaths due to pneumothorax recorded among Group A patients, but two patients in group B died. A better survival rate was noted in Group A than in Group B by Kaplan-Meier analysis, suggesting that these two groups may represent the broad clinical spectrum of LAM.

[A case of chondrosarcoma originating from the rib and presenting as a posterior mediastinal tumor-like shadow].

A 66-year-old man was admitted to our hospital because of induction therapy of interferon for chronic hepatitis due to hepatitis C virus. On routine investigation, a mass-like lesion was detected at the level of the hilum of the left lung on the chest plain radiograph. On the thoracic CT, the heterogeneous tumor, including calcification, was 6 cm in diameter in the posterior mediastinal area, and the rib and vertebra had been damaged by it. The tumor extended to the descending aorta and the left main bronchus. A small nodule in the left S1 + 2 was noted on another slice section of this thoracic CT. The possible diagnoses, based on these radiological findings, for this tumor were primary lung cancer, posterior mediastinal tumor and malignant tumor originating from the chest wall. The diagnosis of chondrosarcoma was made based on the histological findings of the specimen obtained from the tumor. This tumor could not be resected in this case, because it had extensively damaged the rib and vertebra, and the nodular lesion in the left S1 + 2 was regarded as a metastasis from it. Although reports of chondrosarcoma originating from a rib and presenting as a posterior mediastinal tumor-like shadow are rare, chondrosarcoma should be considered as a possible diagnosis for such tumors-posterior mediastinal masses with characteristic findings such as a large tumor in contact with the chest wall, and containing calcification, with destruction of bone and dissection of the rib as shown in our CT findings.

Longitudinal follow-up study of 11 patients with pulmonary lymphangioleiomyomatosis: diverse clinical courses of LAM allow some patients to be treated without anti-hormone therapy.

OBJECTIVE: The purpose of this study is to clarify the existing issues on the clinical diversity, natural history, and mode of disease progression of pulmonary lymphangioleiomyomatosis (LAM). METHODOLOGY: Eleven patients with LAM were reviewed retrospectively with special reference to serial changes in pulmonary function and radiological findings during the course of their disease, treatment, and outcome. All patients were female with a mean age of 33.8 years at presentation and the observation period ranged from 2.1 to 20.8 years (mean 7.4 years). RESULTS: Four of six patients, treated with anti-hormone therapy, presented with exertional dyspnoea, marked airflow limitation (forced expiratory volume in 1 s/forced vital capacity, 23-38%), and severely impaired diffusing capacity (%DLCO, 21.4-36% of the predicted). The remaining two patients showed only a decreased diffusing capacity (70.6% and 59.4% of the predicted) which rapidly deteriorated with subsequent development of airflow limitation. Repeated chest computed tomographic (CT) examinations revealed increasing numbers of cysts with simultaneous loss of normal lung parenchyma in these two patients. In contrast, the five patients who received no anti-hormone therapy had no respiratory symptoms aside from pneumothorax at onset. Remarkable differences were noted, with pulmonary function being well maintained and slow progression of cystic changes on CT being observed in the latter group. CONCLUSIONS: Diverse clinical courses observed in patients with pulmonary LAM can be well delineated and assessed by periodic examinations including pulmonary function tests and chest CT imaging. Anti-hormone therapy is not always necessary for a certain group of LAM patients and they appear to have a stable course and favourable outcomes without anti-hormone treatment.

[A study of the difficulty of identifying normal intrathoracic structures on CRT images: a search for the optimal luminescence ratio].

This study was concerned with 2 issues: whether there are any normal intrathoracic anatomical structures that are relatively more difficult to identify on CRT (cathode-ray tube) monitor images, and if so, what their features are. Four physicians examined 7 intrathoracic anatomical structures on 50 chest roentgenograms that were displayed on CRT monitors and as conventional X-ray films on a light box. They categorized the visibility of each structure into 5 grades. The 7 structures were the spinal process behind the trachea, right margin of trachea, right main bronchus, left main bronchus, vascular shadow behind right diaphragm, vascular shadow behind cardiac shadow, and right margin of descending aorta. Luminescence ratios were calculated as the ratio of the density of a given viewpoint relative to adjacent areas on the images. We also examined the correlations between luminescence ratio and degree of difficulty in interpreting CRT images at a variety of selected luminescence ratios. Although the spinal process and trachea were easy to identify on CRT images as well as conventional films, other structures were difficult to recognize on CRT images. The luminescence ratio of each structure was higher on conventional film, and relatively low for those structures that were difficult to identify on CRT images. Each structure became gradually easier to identify with increasing luminescence ratios, up to a value of 1.07 maximum. However, this improvement in visibility leveled off beyond 1.07. We concluded that the luminescence ratio should be maintained at more than 1.07 to facilitate optimal identification of overlapping anatomical structures on CRT images.

[Idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia and pleural effusion].

A 56-year-old man was admitted for further evaluation of mediastinal lymphadenopathy and left pleural effusion. A blood test revealed polyclonal hypergammaglobulinemia with an elevated erythrocyte sedimentation rate and level of C-reactive protein. Chest computed tomography disclosed bilateral hilar and multiple mediastinal lymph-node swelling and bilateral pleural thickening accompanied by a moderate amount of left pleural effusion. Biopsy specimens from mediastinal lymph nodes and the right pleura were obtained under video-assisted thoracoscopy. Histology on microscopic examination demonstrated mature plasma cells and lymphocyte infiltration in the conserved lymph-node structure and the pleura, suggesting a diagnosis of idiopathic plasmacytic lymphadenopathy (IPL) with polyclonal hyperimmunoglobulinemia. Interestingly, IL-6 was elevated in the pleural effusion but normal in serum. This was a rare and instructive case of IPL accompanied by pleural effusion that was considered to be an important determinant of the clinical spectrum of the disease.

[A senile case of acute necrotizing myopathy presenting prolonged severe muscle paralysis due to high dose glucocorticoid and muscle relaxant].

An 82-year old man was admitted with dyspnea, productive cough and wheezing. In addition to antibiotics (meropenem trihydrate 0.5 g/day), glucocorticoids (hydrocortisone 1.250 mg, methylpredonisolone 4.250 mg) were administered for the severe bronchospasms. Since his respiratory condition deteriorated, he underwent mechanical ventilation using a muscle relaxant (vecuronium bromide, total dose 776 mg) in combination with high dose glucocorticoid. As his pneumonia improved on the 10th hospital day, we started weaning him from the ventilator. However, we were unable to complete weaning from the ventilator because of prolonged quadriplegia and paralysis of the respiratory muscles. A few days later, myoglobinuria appeared. Electrophysiological examinations suggested the involvement of both neuromuscular junctions and muscles. Muscle biopsy showed rhabdomyolysis. Acute necrotizing myopathy was diagnosed due to high doses of glucocorticoid, muscle relaxant, or both. He required about 3 months to be weaned from the mechanical ventilation, and another 3 months to leave the hospital. Based on our experience, we should consider acute myopathy as an adverse effect of glucocorticoids, muscle relaxants or both in elderly patients who require mechanical ventilation.

[Microscopic polyangitis with pleuritis as the only pulmonary complication].

A 75-year-old woman was admitted to our hospital because of high fever and appetite loss. A chest roentgenogram and computed tomographic scans revealed pleural effusion without obvious infitrative or interstitial shadows in both lung fields. Laboratory data showed microhematuria, proteinuria, and telescoped sediment with a moderate increase in C-reactive protein, suggestive of acute glomerulonephritis. Because infectious pleuritis, was initially suspected, the patient was treated with antibiotics. However, her general condition deteriorated, and the right pleural effusion increased. Levels of myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA) in serum and pleural effusion were markedly elevated, yielding a conclusive diagnosis of MPO-ANCA-related vasculitis, especially microscopic polyangitis (MPA). The Patient was immediately treated treated with prednisolone, cyclophosphamide, and plasma exchange. Several weeks later, her general condition dramatically improved, and the level of MPO-ANCA in serum markedly decreased. In addition, the pleural effusion completely disappeared. Unfortunately, the patient eventually died of opportunistic infections (MRSA-pneumonia and Aspergillus-pneumonia) 6 months after admission. This was a unique case of MPA associated with pleuritis without interstitial pneumonia or alveolar hemorrhage.

[Nontuberculous mycobacterial infection followed for 12 years].

A 67-year-old woman presented in September 1985 with productive cough, bloody sputum, and dyspnea on exertion. Productive cough and bloody sputum had developed when the patient was 55 years old. Sputum culture and radiologic findings yielded a diagnosis of nontuberculous mycobacteriosis (NTM). Antituberculous therapy with INH, RFP, and EB was initiated in November 1987 because of the development of a cavity in the right upper lobe, and led to resolution of the lesion and clinical symptoms. Despite progression of bronchiectatic changes in both lungs and a relapse of her clinical symptoms during the following 10 years, the patient retained enough pulmonary function to be able to maintain an active daily life until she died of advanced gastric cancer at the age of 79. Autopsy revealed cystic bronchiectasis accompanied by bronchial wall thickening in both lungs, with some granuloma and acid-fast-bacteria observed in lung tissue. In this report, we concluded that patients with NTM usually experience a gradual progression of symptoms and radiographic changes during their clinical course, and that their pulmonary function may be conserved well enough to maintain an active daily life.

[A case of elderly onset sarcoidosis].

Although sarcoidosis is generally considered a disease of young and middle aged adults, there have been a certain number of cases among elderly. However it is unknown whether sarcoidosis in the elderly is recurrence of prior disease or initial onset at old ages. We present a 77-year-old woman with sarcoidosis the onset of which was considered to be in the last 6 months prior to the initial diagnosis. The patient was admitted to our hospital for further evaluation of bilateral hilar and mediastinal lymphadenopathy (BHL) and uveitis. BHL was not present in a chest radiograph taken 6 months prior to the admission. A clinical diagnosis of sarcoidosis was made by elevated serum angiotensin converting enzyme (ACE) and lysozyme (24.9 IU/L and 18.2 micrograms/ml, respectively), negative tuberculin skin test, concomitant presence of uveitis, and a high proportion of lymphocytes (33.2%) in bronchoalveolar lavage fluid with an elevated CD4/CD8 ratio (24.5). This is a noteworthy case of sarcoidosis in which we could confirm elderly onset of the disease.

Repeated ultrasonically guided needle biopsy of small subpleural nodules.

STUDY OBJECTIVE: To detect the significance of repeated ultrasonically guided needle biopsy (UGNB) for the diagnosis of nodular lesions

[Intralobar pulmonary sequestration presenting increased serum CEA, CA 19-9, and CA 125, and associated with asymptomatic pulmonary aspergillosis].

A 44-year-old woman was admitted to our hospital for further evaluation of a consolidated shadow in the left lower lobe and the evaluation of serum tumor markers (CEA 46.3 ng/ml, CA 19-9 1911 U/ml, and CA 125 103 U/ml). Chest computed tomography revealed an irregular shaped, low density mass shadow in the left S10 region, suggesting the diagnosis of pulmonary sequestration or bronchial atresia. However digital subtraction angiography failed to demonstrate an anomalous feeding artery. We could not rule out the possibility that a malignant lesion was included in the consolidated shadow. A left thoracotomy revealed an intralobar pulmonary sequestration of the left lower lobe. Hyphae of aspergillus were found in the lumen of the cystic bronchus of the resected lung. Immunohistochemical studies showed strong expression of CEA, CA 19-9, and CA 125 by bronchial epithelia in the pulmonary sequenstration. The serum values of tumor markers returned to their normal ranges after surgery.

[Summer-type hypersensitivity pneumonitis with remarkable obstructive impairment of pulmonary function].

A 57-year-old-man was admitted because of persistent cough and progressive dyspnea over a period of 2 months. Examination revealed wheezing in both lungs, severe hypoxemia, and marked obstructive impairment of pulmonary function. A chest CT scan showed diffuse small nodular lesions with patchy air space opacifications. The patient was initially given a diagnosis of bronchiolitis of unknown cause. He showed marked improvement after treatment with oral prednisolone, but developed fever and dyspnea after returning home. This episode indicated hypersensitivity pneumonitis, a diagnosis supported by findings of increased CD 8 positive T-lymphocytes in bronchoalveolar lavage fluid, and a high titer of serum anti-Trichosporon antibody. Lung biopsy samples obtained under video-assisted thoracoscopy disclosed noncaseating granulomas in terminal and respiratory bronchioles, which resulted in marked narrowing of the lumen. The pathologic changes seemed to be consistent with obstructive impairment of pulmonary function in this patient.

Progressive interstitial pneumonia associated with myelodysplastic syndrome: implication of superoxide hyperproduction by neutrophils.

Interstitial pneumonia and aseptic neutrophilic infiltration in the lung are rare pulmonary manifestations of myelodysplastic syndrome (MDS). We report a patient with progressive interstitial pneumonia associated with MDS. Histological examination of the lung revealed infiltration of atypical haematopoietic cells associated with MDS and diffuse alveolitis with honeycombing. Neutrophils obtained from the patient showed superoxide hyperproduction after stimulation with phagocytosis and phorbol myristate acetate, which might be attributed to the pathogenesis of interstitial pneumonia.

[Pulmonary cavernous hemangioma--identification of its endothelial cell origin by immunohistological staining].

A 45-year-old woman was referred to our hospital because of a tumorous shadow in the S10 segment of the left lung. A chest computed tomography (CT) scan showed a nodular lesion with a slightly irregular margin and no contrast enhancement. CT-guided aspiration biopsy was tried but did not result in a histological diagnosis. The tumor was excised during video-assisted thoracoscopic surgery. Histological examination of the specimen revealed cavernous hemangioma. Most cells lining the lumen of the cavernous structure stained positively for von Willebrand factor antibody and negatively for anti-epithelial membrane antigen antibody, which suggests that the tumor was associated with endothelium. To the best of our knowledge, this is the first report of a case in which the diagnosis of pulmonary cavernous hemangioma was confirmed with an immunohistological study.

Diffuse progressive pulmonary interstitial and intra-alveolar cholesterol granulomas in childhood.

We describe an 18 year old male with pulmonary interstitial and intra-alveolar cholesterol granulomas (PICG), which developed to severe respiratory failure over 15 yrs. The histological diagnosis was made on the basis of open lung biopsy findings at the age of 3 yrs and autopsy at 18 yrs of age. Although the pathological features of the lung were similar to that of paediatric patients with lipoid pneumonia coexisting with pulmonary alveolar proteinosis (PAP), gastro-oesophageal reflux (GOR) and a diverse group of severe primary diseases, the patient lacked evidence for any of these. We believe the present case provides a new example of a diffuse-type of lipoid pneumonia coexisting with pulmonary alveolar proteinosis, which we call cholesterol granulomas.

[Pulmonary eosinophilic granuloma with relatively rapid progression and remission].

A 53-year-old woman with a smoking history of 20 pack-years was admitted to the hospital because of dry coughing and exertional dyspnea that had progressed over the previous 3 months. A chest X-ray film taken one month before the onset of symptoms was almost normal. Diffuse small nodular shadows with infiltration were evident one month after the onset of symptoms, and increased rapidly until admission to the hospital. Eosinophilic granuloma was diagnosed histologically after thoracoscopy. The symptoms, chest X-ray findings and pulmonary-function data improved spontaneously after admission to the hospital and the nodular shadows had a almost completely disappeared by 5 months later; the patient continued to smoke. The present case is unique and valuable because it shows the natural course of eosinophilic granuloma from the onset of symptoms to remission.

Prognostic value of Ia+ T lymphocytes in bronchoalveolar lavage fluid in pulmonary sarcoidosis.

We investigated the value of the la+ T-lymphocyte (CD3+ HLA-DR+) ratio in bronchoalveolar lavage fluid (BALF) for predicting the outcome of pulmonary sarcoidosis. Analysis of the BALF la+ T% in 166 patients with pulmonary sarcoidosis by dual-color flow cytometry revealed a wide range of values, of from 0.5 to 85.3%. Although the majority of patients had less than 40% la+ T cells in their BALF, a minor peak was observed at 50 to 60%. The BALF la+ T% value was not influenced by smoking, sex, or age, thus differing from other BALF activation markers. Fifty patients could be followed up precisely for 3 yr after their initial bronchoalveolar lavage (BAL) to evaluate outcome with respect to chest X-ray findings, clinical symptoms, serum angiotensin converting enzyme (ACE) activity, and extrapulmonary involvement. The 50 patients were divided into two groups, with a BALF la+ T% < 40% (n = 34) and > or = 40% (n = 16), respectively. Serum ACE activity returned to normal within 1 yr in the < 40% group, but remained high for the entire follow-up period in the > or = 40% group. The significant difference was observed in the persistence of pulmonary involvement between the two groups except for four patients who showed Stage 0 disease (p < 0.02). Thirteen of 31 patients in the < 40% group showed normalization of chest X-ray findings after three years, whereas only one out of 15 patients in the > or = 40% group showed resolution of pulmonary involvement. Our results suggest that the BALF la+ T% may be a novel marker for predicting the long-term prognosis in pulmonary sarcoidosis.

Disintegration of the 'waterfall phenomenon' in the inferior vena cava due to right heart failure.

The concept of the waterfall phenomenon in Zone 2 in the pulmonary vasculature is well known from West's lung model. It is believed that the flow through this zone is determined by the pressure difference between the pulmonary artery and alveoli, and the left atrial pressure is not transmissible to the alveolar capillaries. However, it is impossible to see whether alveolar capillaries are really displaying the waterfall phenomenon or not. In this review, the interrelation between the flow and geometry of the alveolar capillaries in the waterfall phenomenon is analyzed based on physiological studies using a model system and isolated lung lobe experiments. Further, extending the concept to the analysis of ventilatory changes of the inferior vena cava (IVC) configuration, it is ascertained that the waterfall phenomenon normally occurs in the IVC during inspiration just before it enters the thorax and the waterfall phenomenon in the IVC disintegrates with elevation of the central venous pressure. Because these configurations of the IVC in normal and abnormal conditions are visible with ultrasonography, the technique is very useful as a noninvasive approach to diagnose right heart failure.