Response to treatment with an analog of the luteinizing-hormone-releasing hormone in a patient with pulmonary lymphangioleiomyomatosis.

Pulmonary lymphangioleiomyomatosis is a chronic devastating disorder afflicting women of childbearing age, characterized by proliferation of atypical smooth muscle in the lung. Attempts to treat this disease have shown that a number of hormonal manipulations may be helpful but that surgical oophorectomy alone or associated with administration of progesterone is the most effective treatment. This report describes the response to treatment with an analog of luteinizing-hormone-releasing hormone, goserelin, which is able to induce a marked suppression of the secretion of ovarian sex steroid and demonstrates with pulmonary function studies, arterial blood gas determinations, and bronchoalveolar lavage parameters that this patient's disease was responsive to this agent.

Human ciliated bronchial epithelial cells: expression of the HLA-DR antigens and of the HLA-DR alpha gene, modulation of the HLA-DR antigens by gamma-interferon and antigen-presenting function in the mixed leukocyte reaction.

HLA-DR class II molecules are expressed by a variety of nonlymphoid cells, including the respiratory epithelium. However, it is not known if ciliated bronchial epithelial cells express the HLA-DR genes, if the expression of class II molecules on their surface can be modulated by immune mediators and, finally, if these cells, like other HLA-DR-positive epithelial cells, have the potential to serve as antigen-presenting cells. To answer these questions, we collected ciliated bronchial epithelial cells by brushing and by suction during fiberoptic bronchoscopy and by scraping surgically resected bronchi. The number of cells recovered by brushing or suction during fiberoptic bronchoscopy was similar (P greater than 0.2), but lower than that obtained by scraping surgically resected bronchi (P less than 0.01); however, compared with brushing, suction of ciliated bronchial epithelial cells resulted in a better viability (P less than 0.05). HLA-DR antigens on ciliated bronchial epithelial cells were detected by immunofluorescence using the PTF 29.12 and the L243 monoclonal antibodies, both recognizing HLA-DR molecules on the vast majority of ciliated bronchial epithelial cells. Cytoplasmic dot blot analysis demonstrated that ciliated bronchial epithelial cells had mRNA HLA-DR transcripts, and Northern blot hybridizations showed that the size of the HLA-DR messages was the same observed in other HLA-DR-positive cells. Interestingly, ciliated bronchial epithelial cells showed a significant decline of HLA-DR expression after 5 days in culture, but the addition of gamma-interferon to the cell cultures was associated with the persistence of the expression of class II antigens on the cell surface (P less than 0.01 with control cultures at 5 days). Finally, while ciliated bronchial epithelial cells were ineffective in stimulating allogeneic T cell proliferation in a 6-day primary mixed leukocyte reaction (MLR), the addition of phorbol myristate acetate to the MLR was able to induce a significant T cell proliferation (P less than 0.001, all comparisons). Thus, human ciliated bronchial epithelial cells express HLA-DR surface antigens and have mRNA molecules for the HLA-DR genes, and the expression of the surface class II antigens can be modulated in vitro by immune mediators.(ABSTRACT TRUNCATED AT 400 WORDS)

Characteristics and clinical significance of the lymphocytic alveolitis in interstitial lung disorders.

Although the mechanisms responsible for lung damage and respiratory function deterioration for each type of alveolitis are not entirely known, with the opportunity to study the cells present in the lower respiratory tract, their functions and the mediators released in different conditions, we will be able to better understand the link between the inflammatory process, the acute tissue damage, the progression of the disease and the pulmonary scarring. This knowledge will be helpful in a better management of patients with interstitial lung diseases modulated by immunologic mechanisms.

Human peripheral blood and pleural fluid eosinophils can be induced by immune complexes to release IgG immune complexes and aggregated IgE.

The ability of IgG and IgE immune complexes and of phorbol myristate acetate (PMA), a soluble membrane activator, to stimulate hydrogen peroxide (H2O2) release and to induce oxygen radical-mediated cytotoxic activity by human peripheral blood (PBL) eosinophils and by PBL neutrophils was evaluated in normal volunteers and patients with hypereosinophilic malignant pleural effusions due to lung cancer. PMA stimulated a significant respiratory burst. Similar results were obtained with IgG IC stimulation, although the levels of H2O2 were lower. Agg IgE induced H2O2 release only by PBL and PE eosinophils and not by neutrophils. PMA stimulation resulted in detectable cytotoxic activity. IgG IC generated both PBL and PE eosinophil and PBL neutrophil cytotoxicity. Agg IgE induced significant cellular cytotoxicity in both PBL and PE eosinophils. This study suggests that eosinophil oxidative metabolic burst and cytotoxic activity stimulated by IgG and IgE immune complexes could represent a possible mechanism of parenchymal injury in eosinophilic disorders.

Bronchoalveolar lavage during fiberoptic bronchoscopy: what has it brought to pulmonary medicine?

In the last 13 years, bronchoalveolar lavage has been widely used to study the mechanisms involved in the defense of the lower respiratory tract and in the pathogenesis of a variety of lung disorders. This technique, which is a relatively safe and simple extension of fiberoptic bronchoscopy, has been proved to be a powerful investigative tool with enormous potential since it has enhanced our knowledge on a variety of disorders, including interstitial lung diseases, lung destruction associated to cigarette smoking and, recently, bronchial asthma. In addition, bronchoalveolar lavage has also been utilized as an interesting test to help in the diagnostic procedures and in the management of patients with a variety of pulmonary diseases. Its actual importance in clinical respiratory medicine, however, is still under debate and the value of some suggested applications remains to be established.

Changes in pulmonary surfactant composition following MACC chemotherapy for lung carcinoma.

Many antineoplastic drugs can derange lung structures, cause necrosis of type I pneumocytes, abnormal proliferation of type II alveolar epithelial cells, and, occasionally, accumulation of inflammatory and immune effector cells. Since type II cells secrete lung surfactant, treatment may alter surfactant composition. In 8 patients with nonresectable lung cancer, we performed bronchoalveolar lavage before and after MACC polychemotherapy (methotrexate, doxorubicin HCl, cyclophosphamide and lomustine). Before treatment, cellular composition and the phospholipid and fatty acid constituents of lavage surfactant were similar to those found in control subjects. After MACC polychemotherapy there was, in all patients, a mild decrease in the number of immune effector cells, without changes in the relative proportion of cell types. In addition, MACC therapy resulted in a significant decrease of phosphatidylcholine levels, and increased levels of phosphatidylglycerol, whereas the levels of palmitic lavage surfactant were decreased. These MACC treatment abnormalities of the phospholipid and fatty acid composition of lung surfactant may reflect preclinical pulmonary toxicity. The decrease in the numbers of bronchoalveolar cells suggests that the changes in surfactant composition may be chemically induced rather than immune mediated.

Symptomatic treatment of recurrent malignant pleural effusions with intrapleurally administered Corynebacterium parvum. Clinical response is not associated with evidence of enhancement of local cellular-mediated immunity.

Intrapleural injection of Corynebacterium parvum (CBP) has been recently proposed as a useful symptomatic treatment of recurrent malignant effusions. Although the result is often a fibrotic thickening of the pleura, CBP is thought to stimulate the effector cells present in the effusion and, possibly, to activate the antitumor cytotoxic activity of the pleural fluid mononuclear cells. To test this hypothesis, we studied 7 patients with recurrent malignant pleural effusions caused by lung cancer and evaluated the cellular composition, the proportions of lymphocyte subpopulations, and the cytotoxic activity of mononuclear cells in the pleural fluid before and 7 days after injection of CBP in the pleural space. The CBP treatment induced a marked decrease in the rate of accumulation of pleural fluid (p less than 0.01) and in the concentration of immune effector cells in the pleural exudate (p less than 0.001). These changes were associated with a decrease in the percentages of pleural fluid monocytes and lymphocytes present (p less than 0.01, each comparison) and to a marked increase in the percentages of pleural fluid neutrophils (p less than 0.001). No significant changes in the proportions of T- and B-lymphocytes or in the proportions of helper/inducer and suppressor/cytotoxic T-cells or of natural killer cells were observed in the pleural exudate after CBP treatment (p greater than 0.2, each comparison). In addition, the cytotoxic activity of pleural fluid mononuclear cells was similar before and after CBP treatment (p greater than 0.2), and the levels of interferon, as a marker of immunoactivation of mononuclear cells, were not changed after treatment (p greater than 0.2).(ABSTRACT TRUNCATED AT 250 WORDS)

Helper T-lymphocytes in pulmonary sarcoidosis. Functional analysis of a lung T-cell subpopulation in patients with active disease.

Pulmonary sarcoidosis is a disease characterized by increased numbers of T-lymphocytes in the alveolar structures, which through the production of lymphokines modulate granuloma formation and polyclonally activate B cells to secrete immunoglobulins. The T-lymphocyte alveolitis is associated with a different expansion of various T-cell subpopulations identified by different monoclonal antibodies. Patients with active disease have increased numbers of helper T cells in the lungs, recognized by the OKT4 monoclonal antibody and decreased numbers of suppressor OKT8-positive lung T cells, whereas patients with inactive disease have increased numbers of OKT8-positive T cells and decreased numbers of OKT4-positive T cells in the lungs. Using the IgG fraction of a monoclonal antibody called 5/9, which reacts in normal subjects with approximately 30% of the OKT4-positive T-lymphocytes, it has been shown that the 5/9-positive T cells appear preferentially expanded in pulmonary sarcoidosis at sites of disease activity. To evaluate the functions of the T-cell subpopulation identified by the 5/9 monoclonal antibody in pulmonary sarcoidosis, we studied the unfractionated T-lymphocytes and the 5/9-positive and the 5/9-negative T-cell fractions in bronchoalveolar lavage of 12 patients with active lung disease. On T-cell suspensions, the spontaneous release of monocyte chemotactic factor and the polyclonal activation of autologous peripheral blood lymphocytes were determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Different expansions of T lymphocyte subpopulations in the lung and corticosteroid-induced changes in patients with active pulmonary sarcoidosis.

Pulmonary sarcoidosis is a disease characterized by increased numbers of T lymphocytes within the alveolar structures and the consequent spontaneous release of a variety of mediators relevant to the pathogenesis of this disorder. This phenomenon is associated with a different expansion of the T cell subpopulations present in the lung. Using monoclonal antibodies specific for T cell subsets with helper functions, we have evaluated the different T lymphocyte subpopulations present in patients with active and inactive pulmonary sarcoidosis. The small fraction of helper T cells recognized by the 5/9 monoclonal antibody appear to be preferentially expanded in the lung of patients with active disease. The functions of the 5/9+ lung T cells in pulmonary sarcoidosis were evaluated by considering the spontaneous release of monocyte chemotactic factor, the help in immunoglobulin production, and the spontaneous production of interleukin-2 by the 5/9+ lung T cells from patients with active disease. These T cell functions appeared to be restricted to the 5/9+ T cell subset. The sensitivity of the 5/9+ lung T cells to corticosteroid treatment in pulmonary sarcoidosis was studied by performing bronchoalveolar lavage in patients with active disease before and after oral prednisone therapy. Evaluation of lymphocyte subsets after 3 months of therapy showed a marked reduction of 5/9+ T cell percentages even though the overall proportion of lavage cells that were T lymphocytes was still elevated. Thus the 5/9 monoclonal antibody may be considered a good marker in gauging the activity of the alveolitis in pulmonary sarcoidosis because it recognizes the T cell subsets responsible for many activities relevant to the pathogenesis of this disorder. In addition, analysis of the proportions of 5/9+ lung T cells may result in a useful means to evaluate the early response to therapy.

Alveolar macrophage stimulation of T-cell proliferation in autologous mixed lymphocyte reactions. Role of HLA-DR antigens.

Alveolar macrophages act as accessory cells in lymphocyte response to mitogens or alloantigens. Because the autologous mixed lymphocyte reaction (MLR), in which HLA-DR-positive non-T cells stimulate the proliferation of autologous T lymphocytes, represents a good model to study macrophage-T cell interaction, we examined and compared the ability of human alveolar macrophages and peripheral blood-derived monocytes to induce T-cell proliferation in autologous MLR. Maximal T lymphocyte proliferation was observed in both alveolar-macrophage- and blood-monocyte-stimulated autologous MLR at a T cell to alveolar macrophage or blood monocyte ratio of 4:1, but the ability to stimulate T-cell proliferation was lower for alveolar macrophages than for blood monocytes (p less than 0.01). Because HLA-DR antigens modulate monocyte-T cell interaction, we quantified the proportions of HLA-DR-positive cells in alveolar macrophage and blood monocyte suspensions and determined the inhibitory effects on T-cell proliferation of masking HLA-DR antigens on stimulator cells with monoclonal antibodies. The proportions of HLA-DR-positive cells were higher in alveolar macrophage than in blood suspensions (p less than 0.01); interestingly, however, the preincubation of the stimulator cells with anti-HLA-DR monoclonal antibodies inhibited to a similar extent both alveolar-macrophage- and blood-monocyte-stimulated autologous MLR (p greater than 0.2). These studies indicate that alveolar macrophages are less effective than blood monocytes are as stimulator cells in autologous MLR and that, although the masking of HLA-DR molecules results in inhibition of autologous MLR, T-cell proliferation is not dependent on the numbers of stimulator cells bearing HLA-DR antigens. The autologous MLR may represent a good model to study the functions of alveolar macrophages during their interaction with autologous T cells in health and disease.

Acute myelomonocytic leukemia. Demonstration of pulmonary involvement by bronchoalveolar lavage.

Massive pulmonary infiltration by leukemic cells resulting in respiratory symptoms is a rare complication of acute leukemia. We report the findings in a patient with acute myelomonocytic leukemia presenting with acute onset of fever, dyspnea, and nonproductive cough, in whom the diagnosis of pulmonary invasion by leukemic cells was made by cytochemical analysis of bronchoalveolar cells recovered by lavage.

Lung inflammation in sarcoidosis: analysis of immunoglobulin levels in bronchoalveolar lavage fluid in active and inactive disease.

Cellular and biochemical analyses of bronchoalveolar lavage (BAL) were performed in 8 normal subjects and in 18 patients with pulmonary sarcoidosis. The patients were divided into two groups, according to the intensity of the alveolitis as assessed by lung T-lymphocyte percentage and by 67Ga lung scan. High-intensity alveolitis (HIA) patients had an increased ratio of OKT4-positive: OKT8-positive T cells in their lungs, but not in their blood, compared to low-intensity alveolitis (LIA) patients and to controls. Biochemical analyses of BAL showed that HIA patients had increased albumin and IgG concentrations compared to LIA patients and to controls. IgA concentrations were more elevated in sarcoid patients than in controls, with no difference between the two groups of patients. No differences were detected in IgM concentrations between the three groups of subjects. The levels of different Ig classes were then calculated as a ratio with respect to albumin in order to determine whether their presence in BAL fluid was due to increased alveolar-capillary 'leak'. The IgG:albumin ratio was significantly higher in HIA patients compared to LIA patients and to controls, whereas comparison of the IGA: albumin and IgM: albumin ratios showed no significant differences between the three groups of subjects. These findings suggest that alveolar-capillary permeability is increased in pulmonary sarcoidosis and provide evidence that local IgG production is enhanced in active states of this disease.

Low-dose cisplatin and etoposide in advanced non-small cell lung carcinoma.

Twenty-seven consecutive patients with locally advanced or metastatic non-small cell lung carcinoma were treated with low-dose cisplatin and etoposide. Out of 25 evaluable patients, 8% had a partial response, 56% had stable disease and 36% had disease progression. The overall median survival was 4 months. The survival of the two responding patients was 5 and 6.5 months. The patients showing stable disease or progression had a median survival of 6 and 3 months, respectively. Toxicity including myelosuppression, nephrotoxicity and gastrointestinal side effects was generally mild. In this trial the combination of low-dose cisplatin and etoposide did not yield the same positive results observed by other authors. The different selection of patients and criteria of response evaluation could represent the main reason for this disagreement in results.

Pulmonary sarcoidosis: excess of helper T lymphocytes and T cell subset imbalance at sites of disease activity.

Different lymphocyte subpopulations have been evaluated in bronchoalveolar fluid and blood obtained from six patients with active and six with inactive pulmonary sarcoidosis and from six normal subjects by means of two recently described monoclonal antibodies, 5/9 and MLR4. The percentages of OKT4 positive (helper) and OKT8 positive (suppressor) T cells were also determined. Patients with active sarcoidosis had significantly higher proportions of 5/9 positive T cells in the bronchoalveolar fluid than patients with inactive disease (p less than 0.01) or normal subjects (p less than 0.001). In contrast, the proportions of 5/9 positive blood T cells were similar in the three groups studied. Patients with active sarcoidosis had also a greater proportion proportion of MLR4 positive T lymphocytes in bronchoalveolar fluid than patients with inactive disease or normal subjects (p less than 0.01 for each comparison), but similar proportions of MLR4 positive blood T cells were found in each group. The ratio of 5/9 positive to MLR4 positive T cells was higher in the bronchoalveolar fluid (but not in the blood) in patients with either active or inactive sarcoidosis than in normal subjects. These observations suggest that the MLR4 negative fraction rather than the MLR4 positive fraction of the 5/9 positive T cells is preferentially expanded in the lungs of patients with pulmonary sarcoidosis and may indicate a secondary role for the MLR4 positive T cells in producing lung injury in this disorder. Comparisons of the OKT4 positive and 5/9 positive T cells showed that in patients with active disease most of the lung T lymphocytes expressed both the OKT4 and the 5/9 surface antigens, so the 5/9 monoclonal antibody may be considered a good marker of activity in this disorder. Pulmonary sarcoidosis may be characterised by the preferential expansion of helper T cell subsets at sites of disease activity.

Intrapleural Corynebacterium parvum for malignant pleural effusions.

A pilot study of topical (intrapleural) treatment with Corynebacterium parvum was carried out in 10 patients with malignant pleural effusions complicating primary or secondary neoplasms and necessitating frequent thoracocentesis for symptomatic relief. The method was aspiration of all intrapleural fluid except a small portion left for dilution, and then injection of 7 mg of a preparation of Corynebacterium parvum suspended in 20 ml of normal saline solution. The treatment was repeated in each case as clinical conditions called for further thoracocentesis. In eight of these 10 patients the treatment resulted in prompt reduction of the rate of accumulation of pleural fluid and a striking change of cell sediment composition, with appreciable reduction in or complete disappearance of malignant cells and a rise in lymphocyte and neutrophil polymorph counts. The best responders were patients with primary pleural mesothelioma. Clinical improvement was evident in all responders.