The feasibility of prostate-specific membrane antigen positron emission tomography(PSMA PET/CT)-guided radiotherapy in oligometastatic prostate cancer patients

Background. To investigate the efficacy and toxicity of 68Ga-PSMA-HBED-CC (68Ga-PSMA) PET-CT-guided RT in the treatment of oligometastatic prostate cancer retrospectively. Methods. A total of 23 prostate cancer patients with biochemical relapse, of which 13 were castration sensitive (CS) and 10 castration resistant (CR), were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤3 metastases detected by 68Ga PSMA PET-CT. Androgen deprivation therapy was continued in CR patients. Results. A total of 38 metastases were treated. The involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), paraaortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.1 ng/mL (range 0.1-29.0 ng/mL). A median dose of 43.5 Gy (range 30-64 Gy) was delivered by IMRT-IGRT in 12-27 fractions. At a median follow-up of 7 months (range 2-17 months), 19 patients (83%) were in remission. Four patients (17%) developed distant recurrences. The actuarial 1-year LC, PFS and OS rates were 100, 51 (95% CI 8-83%) and 100%. Univariate analysis demonstrated a statistically significantly better PFS in CS patients as compared to CR patients (1-year PFS 67 vs. 0%, p < 0.01). One patient experienced grade 2 acute gastrointestinal toxicity. Grade 3 or more toxicity events were not observed. Conclusions. By providing optimal LC, low toxicity and a promising PFS in CS patients, the current retrospective study illustrated that 68Ga PSMA PET-CT-guided RT may be an attractive treatment strategy in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited (AU)

No disponible

The feasibility of prostate-specific membrane antigen positron emission tomography(PSMA PET/CT)-guided radiotherapy in oligometastatic prostate cancer patients.

BACKGROUND: To investigate the efficacy and toxicity of 68Ga-PSMA-HBED-CC (68Ga-PSMA) PET-CT-guided RT in the treatment of oligometastatic prostate cancer retrospectively. METHODS: A total of 23 prostate cancer patients with biochemical relapse, of which 13 were castration sensitive (CS) and 10 castration resistant (CR), were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤3 metastases detected by 68Ga PSMA PET-CT. Androgen deprivation therapy was continued in CR patients. RESULTS: A total of 38 metastases were treated. The involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), paraaortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.1 ng/mL (range 0.1-29.0 ng/mL). A median dose of 43.5 Gy (range 30-64 Gy) was delivered by IMRT-IGRT in 12-27 fractions. At a median follow-up of 7 months (range 2-17 months), 19 patients (83%) were in remission. Four patients (17%) developed distant recurrences. The actuarial 1-year LC, PFS and OS rates were 100, 51 (95% CI 8-83%) and 100%. Univariate analysis demonstrated a statistically significantly better PFS in CS patients as compared to CR patients (1-year PFS 67 vs. 0%, p < 0.01). One patient experienced grade 2 acute gastrointestinal toxicity. Grade 3 or more toxicity events were not observed. CONCLUSIONS: By providing optimal LC, low toxicity and a promising PFS in CS patients, the current retrospective study illustrated that 68Ga PSMA PET-CT-guided RT may be an attractive treatment strategy in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited.

Self-management reduces both short- and long-term hospitalisation in COPD.

The aim of the present study was to assess the long-term impact on hospitalisation of a self-management programme for chronic obstructive pulmonary disease (COPD) patients. A multicentre, randomised clinical trial was carried out involving 191 COPD patients from seven hospitals. Patients who had one or more hospitalisations in the year preceding study enrolment were assigned to a self-management programme "Living Well with COPD(TM)" or to standard care. Hospitalisations from all causes were the primary outcome and were documented from the provincial hospitalisation database; emergency visits were recorded from the provincial health insurance database. Most patients were elderly, not highly educated, had advanced COPD (reflected by a mean forced expiratory volume in one second of 1 L), and almost half reported a dyspnoea score of 5/5 (modified Medical Research Council). At 2 years, there was a statistically significant and clinically relevant reduction in all-cause hospitalisations of 26.9% and in all-cause emergency visits of 21.1% in the intervention group as compared to the standard-care group. After adjustment for the self-management intervention effect, the predictive factors for reduced hospitalisations included younger age, sex (female), higher education, increased health status and exercise capacity. In conclusion, in this study, patients with chronic obstructive pulmonary disease who received educational intervention with supervision and support based on disease-specific self-management maintained a significant reduction in hospitalisations after a 2-year period.

Randomised trial of ambulatory oxygen in oxygen-dependent COPD.

Long-term oxygen therapy may limit a patient's ability to remain active and may be detrimental to the rehabilitation process. This study aimed to determine the effect of ambulatory oxygen on quality of life and exercise capacity in patients with chronic obstructive pulmonary disease fulfilling the usual criteria of long-term oxygen therapy. In a 1-yr, randomised, three-period, crossover trial, 24 patients (mean age 68 yrs; mean arterial partial pressure of oxygen at rest 7.1 kPa (53 mmHg)) were allocated to one of the six possible sequences generated by three interventions: 1) standard therapy (home oxygen therapy with an oxygen concentrator only); 2) standard therapy plus as-needed ambulatory oxygen; and 3) standard therapy plus ambulatory compressed air. The comparison of ambulatory oxygen versus ambulatory compressed air was double blind. The main outcomes were quality of life (Chronic Respiratory Questionnaire), exercise tolerance (6-min walk test) and daily duration of exposure to oxygen therapy. The trial was stopped prematurely after an interim analysis. On average, the patients used few ambulatory cylinders (7.5 oxygen cylinders versus 7.4 compressed air cylinders over a 3-month study period). Ambulatory oxygen had no effect on any of the outcomes. In conclusion, the current results do not support the widespread provision of ambulatory oxygen to patients with oxygen-dependent chronic obstructive pulmonary disease.

Mineralogy of lung tissue in dental laboratory technicians' pneumoconiosis.

This article reports on a case of pneumoconiosis in a dental laboratory technician with a history of respiratory exposure to dental materials. Special attention is paid to the mineralogical analysis of the lung biopsy. The abundance of chromium, cobalt, and silica particles suggests that the dental technician's pneumoconiosis is the result of the combined effects of hard metal dusts and silica particles generated during finishing dental frameworks. Adequate technical protection such as a local ventilation system should be considered in dental laboratories to prevent respiratory exposure of dental technicians to airborne contaminants.

[Asbestos exposure and pleuropulmonary cancer]. / Exposition à l'amiante et cancers pleuro-broncho-pulmonaires.

Pleuropulmonary cancers are recognized asbestos-related diseases. Mesothelioma occurs almost uniquely in individuals exposed to asbestos whereas lung cancer is strongly associated with smoking. If the asbestos exposure is sufficient however, the incidence of lung cancer is higher than would be expected from the smoking effect alone. For lung cancer in asbestos workers, asbestosis is not a prerequisite for recognition as an occupation related disease. The intensity and duration of exposure to asbestos are factors associated with higher risk of lung cancer. These factors can be estimated on the basis of the work history or, when necessary, by analyzing mineral dust from available lung tissues.

Clearance of man made mineral fibres from the lungs of sheep.

OBJECTIVES: To compare the clearance rate, the related pathology, and the chemical and morphological changes of three man made mineral fibres (MMMFs) in the sheep model of pneumoconiosis. METHODS: Fibrous particles were extracted from lung parenchyma and analysed by transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). RESULTS: The concentration of MMMF11, MMMF21, refractory ceramic fibre (RCF-1), and crocidolite asbestos fibres decreased with time according to a slow and a fast kinetic component. There was a statistical difference in the four regression lines as a function of time and the type of fibres (p < 0.001). The diameter of MMMFs decreased during the course of the time, whereas the crocidolite fibres did not seem to show any change. There was a statistical difference in the four regression lines as a function of time (p = 0.037) and type of fibres (p < 0.001). Ferruginous bodies were counted in the 40 sheep for which the latency period was 2 years. No typical ferruginous bodies were found in the groups exposed to MMMFs. The geometric mean concentration of asbestos bodies in the group exposed to crocidolite was 2421 bodies/g lung tissue (95% CI 385 to 15260). CONCLUSIONS: The number of initially retained fibres decreased with time according to a slow and a fast kinetic component. MMMF11 and MMMF21 have similar clearance, faster than RCF-1 and crocidolite. The geometric mean diameter and length of MMMF decreased with time, but crocidolite did not. After 2 years in the sheep tracheal lobe, ferruginous bodies were not found in all three MMMF groups but were substantial in the crocidolite group. Clearance is thought to proceed through dissolution and macrophage translocation.

Tentative explanatory variable of lung dust concentration in gold miners exposed to crystalline silica.

INTRODUCTION: The first objective of the study was to investigate the relationships between quantitative lung mineral dust burdens, dust exposure history, and pathological fibrosis grading in silicotic workers. The second objective was to evaluate the association between particle size parameters, concentration of retained silica particles and the severity of the silicosis. Sixty-seven paraffin-embedded lung tissue samples of silicotic patients were analyzed. The cases of silicosis included 39 non-lung cancer patients and 28 patients with lung cancer. All of the cases were gold miners in the Province of Ontario, Canada. MATERIAL AND METHODS: Particles, both angular and fibrous, were extracted from lung parenchyma by a bleach digestion method, mounted on copper microscopic grids by a carbon replica technique, and analyzed by transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). Quartz concentration was also determined by X-ray diffraction (XRD) on a silver membrane filter after the extraction from the lung parenchyma. RESULTS: Total particles, silica, clay, and quartz also increase in concentration with increased age at death, although the trends are not statistically significant. Quartz concentration has a statistically significant correlation with the silicosis severity score (r = +0.45, p < 0.001), with the geometric mean concentration increasing from 2.24 micrograms/mg in the group having silicosis severity score less than 1 to 4.80 micrograms/mg in group with highest score. Quartz concentration is the only significant explanatory variable of the silicosis severity with a regression coefficient of +0.41 (p < 0.001). CONCLUSION: Among several dust exposure variables extracted from the work history of the miners, the calendar year of first exposure was the primary significant determinant of lung retained total particles, silica, and clay minerals, except for quartz. A statistically significant linear relationship between lung quartz concentration and silicosis severity in the gold miners was observed (p < 0.001). Among the several types of lung particles detected, quartz was the only significant determinant of the silicosis severity in the gold miners in this study and vice versa, although it explained only 20% of the variation in the severity. This study suggested no significant linear relationship between the duration of dust exposure and the lung burden of any particle types in the gold miners.

Angular and fibrous particles in lung in relation to silica-induced diseases.

INTRODUCTION: The lung concentration of angular and fibrous particles was measured in cases of lung fibrosis only, in cases of lung fibrosis and lung cancer, and in cases of lung cancer only. These patients worked in different trades (mining, foundries, construction and were not a homogeneous group of exposed workers. MATERIAL AND METHODS: Particles, both angular and fibrous, were extracted from lung parenchyma by a bleach digestion method, mounted on copper microscopic grids by a carbon replica technique, and analyzed by transmission electron microscopy (TEM) and energy-dispersive spectroscopy (EDS). The quartz concentration was also determined by X-ray diffraction (XRD) on a silver membrane filter after extraction from the lung parenchyma. RESULTS: (1) Lung cancer and lung fibrosis cases retained more metal-rich particles (P = 0.02) and more angular particles of all sorts (P = 0.009) than did lung fibrosis cases only, and the differences were statistically significant. (2) However, more quartz was retained in the lungs in lung fibrosis cases than in lung fibrosis or lung cancer cases, but the difference in the concentrations was not statistically significant. (3) More ferruginous bodies were retained in the lungs in lung cancer and lung fibrosis cases than in cases of lung fibrosis only, and the difference in the concentrations was statistically significant (P = 0.02). CONCLUSION: Results obtained from lung tissue must always be interpreted cautiously. However, these results are consistent with the hypothesis that workers in some trades such as foundries were exposed not only to quartz but also to asbestos, ceramic fibers, metal-rich non fibrous particles, and other likely carcinogenic chemicals. The wide range of particle types identified in the lungs of these workers illustrates the complexity of trying to determine disease origins in these work environments. Epidemiology studies have to control for the exposure to these carcinogens as well as for smoking habits.

[Asbestos exposure and pleuropulmonary cancer]. / Exposition à l'amiante et cancers pleuro-broncho-pulmonaires.

Pleuropulmonary cancers are recognized asbestos-related diseases. Mesothelioma occurs almost uniquely in individuals exposed to asbestos whereas lung cancer is strongly associated with smoking. If the asbestos exposure is sufficient however, the incidence of lung cancer is higher than would be expected from the smoking effect alone. For lung cancer in asbestos workers, asbestosis is not a prerequisite for recognition as an occupation-related disease. The intensity and duration of exposure to asbestos are factors associated with higher risk of lung cancer. These factors can be estimated on the basis of the work history or, when necessary, by analyzing mineral dust from available lung tissues.

[Quebec spirometry reference values]. / Valeurs de références spirométriques québécoises.

Lung volumes forced expiratory flow rates and carbon monoxide diffusing capacity (apnea) were measured in 397 non-smoking, nonatopic, asymptomatic subjects (219 women, 178 men). The equipments and methods for measurements met the ATS criteria. The linear regression of the different variables according to age and height allowed the elaboration of a new set of predictive equations (Quebec). When comparing the different reference values used in North America and Europe, it is found that those of Miller and associates as well as those recommended by the CECA provide the best description of the Quebec situation. However, we would eventually prefer the reference values of Miller and associates over those of the CECA, because they better fit the current ATS criteria and also provide references for smokers. Lung volumes and forced expiratory flow rates of 97 non-smoking, nonatopic, asymptomatic manual workers were measured in the same conditions and submitted to the same comparisons. Quebec predictive values as well as those of Miller and associates isolated the same individuals in the so called abnormal zone. We therefore conclude that Quebec's standards should be preferred in the Province of Quebec pulmonary function laboratories.

Angular and fibrous particles in lung are markers of job categories.

INTRODUCTION: The lung concentration of angular and fibrous particles has been measured when cases are stratified into their job categories; 21 miners (metallic mines such as gold, zinc and copper), 18 iron foundrymen, 22 non-iron foundrymen, four welders, three sand-blast workers, four construction workers, three technicians and professionals, seven workers in other trades excluding welding. Twelve asbestos miners representing a positive exposure to asbestos and 20 people representing a background population were added to the previous groups. MATERIAL AND METHODS: Particles, both angular and fibrous, were extracted from lung parenchyma by a bleach digestion method, mounted on copper microscopic grids by a carbon replica technique and analyzed by transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). Quartz concentration was also determined by X-ray diffraction (XRD) on a silver membrane filter after the extraction from the lung parenchyma. RESULTS: (1) The highest concentrations of quartz were found in mines (metallic mines), iron foundrymen and sand-blast workers. Notable amounts quartz were found in welders and professionals. (2) The highest concentrations of short fibres were found in non-iron foundrymen, asbestos miners and construction workers. (3) The highest concentrations of long fibres were found in non-iron foundry men and asbestos miners. (4) The highest concentrations of ferruginous bodies were found in non-iron foundrymen and asbestos miners. (5) The non-iron foundrymen were exposed to ceramic fibres and asbestos fibres. CONCLUSION: The results of the study may not be representative of the broad spectrum of workers in the industrial activities in which they have been involved. However, the detailed composition of the retained particles of our workers is explained both qualitatively and quantitatively by their work histories. Finally, the broad range of particle types identified in the lungs of these workers illustrate the complexity or trying to determine disease origins in these occupational settings.

Immunohistochemical localization of transforming growth factor beta isoforms in asbestos-related diseases.

Transforming growth factor beta (TGF-beta), a multifunctional cytokine and growth factor, plays a key role in scarring and fibrotic processes because of its ability to induce extracellular matrix proteins and modulate the growth and immune function of many cell types. These effects are important in inflammatory disorders with fibrosis and cancer. The asbestos-related diseases are characterized by fibrosis in the lower respiratory tract and pleura and increased occurrence of lung cancer and mesothelioma. We performed immunohistochemistry with isoform-specific antibodies to the three TGF-beta isoforms on 16 autopsy lungs from Quebec, Canada, asbestos miners and millers. There was increased immunolocalization of all three TGF-beta isoforms in the fibrotic lesions of asbestosis and pleural fibrosis. The hyperplastic type II pneumocytes contained all three isoforms. By contrast, there was differential spatial immunostaining for the TGF-beta isoforms in malignant mesothelioma, with TGF-beta 1 in the stroma but TGF-beta 2 in the tumor cells. These data are consistent with an important role for TGF-beta in accumulation of extracellular matrix and cell proliferation in asbestos-related diseases.

Transforming growth factor-beta1 is a potent inhibitor of glutathione synthesis in the lung epithelial cell line A549: transcriptional effect on the GSH rate-limiting enzyme gamma-glutamylcysteine synthetase.

Glutathione (GSH) is an essential antioxidant tripeptide that protects mammalian cells against oxidants and xenobiotics. Patients with fibrotic lung disorders have very low levels of GSH in their alveolar epithelial lining fluid (ELF), whereas transforming growth factor (TGF)-beta is overexpressed in their alveolar epithelial cells. We observed that TGF-beta1 increased susceptibility of the human alveolar epithelial cell line A549 to H2O2-mediated cytotoxicity (P < 0.05), decreased the activities of the antioxidant enzymes glutathione reductase and catalase by 31%, and markedly decreased GSH content in A549 cells (P < 0.01). GSH depletion was associated with an equivalent decrease in the activity of the rate-limiting enzyme in GSH synthesis, gamma-glutamylcysteine synthetase (gamma-GCS) (P < 0.01). Western blot analysis confirmed that the loss of gamma-GCS activity was associated with a marked decrease in gamma-GCS heavy subunit (gamma-GCShs) protein. TGF-beta1 suppressed the steady-state level of messenger RNA (mRNA) for the gamma-GCShs gene, with a maximal effect at 24 h. The half-life of gamma-GCShs mRNA was not affected by TGF-beta1, but transcription of the gene was downregulated as determined with nuclear run-on assays. Our findings indicate for the first time that TGF-beta1 is a potent inhibitor of GSH synthesis in human lung epithelial cells, and that the inhibition is mediated, at least in part, by a transcriptional effect on the gene encoding gamma-GCShs. Regulation of gamma-GCShs gene expression by TGF-beta1 is likely to play an important role in lower respiratory tract GSH homeostasis, and may represent a novel target for therapeutic efforts in lung fibrosis.

Immunohistochemical localization of transforming growth factor-beta and insulin-like growth factor-I in asbestosis in the sheep model.

Asbestosis is characterized by increased collagen deposition along the walls of terminal respiratory bronchioles that extends into the alveolar ducts and septae. Alveolar macrophages are activated and release growth factors that stimulate mesenchymal cell proliferation and enhanced formation of extracellular matrix. Both insulin-like growth factor-I (IGF-I), and transforming growth factor beta (TGF-beta) regulate cellular growth and promote matrix accumulation and are hypothesized to play important roles in asbestosis. We performed immunohistochemistry using polyclonal antibodies to specific synthetic peptides of the three mammalian isoforms of TGF-beta (TGF-beta 1, -beta 2, -beta 3) and to IGF-I on lungs of sheep treated intratracheally with chrysotile asbestos. All three TGF-beta isoforms were found in bronchial and bronchiolar epithelium, macrophages, and bronchial and vascular smooth muscle in control lungs. The distribution of TGF-beta was increased in these lung constituents as fibrotic lesions developed. Fibrotic lesions additionally demonstrated intense immunostaining of all three TGF-beta isoforms that localized to the extracellular matrix zones with little staining of interstitial cells. In the control sheep lungs, IGF-I staining was detected in bronchial and bronchiolar epithelium, bronchial glands, bronchial and vascular smooth muscle, endothelium, and macrophages. IGF-I immunostaining was detected in macrophages in peribronchial fibrosis and in fibroblasts along the periphery of and within lesions, but not in the extracellular matrix. Metaplastic proliferating epithelium and macrophages were strongly immunoreactive for IGF-I in advanced lesions. Our data demonstrate different immunostaining patterns for IGF-I and TGF-beta in asbestosis, with IGF-I in the cellular periphery and TGF-beta in the extracellular matrix consistent with a complementary role in stimulating interstitial fibroblast proliferation and new collagen deposition in areas of active fibrosis.

Retention of asbestos fibres in lungs of workers with asbestosis, asbestosis and lung cancer, and mesothelioma in Asbestos township.

OBJECTIVE: To conduct a mineralogical study on the particles retained in the necropsied lungs of a homogenous group of asbestos miners and millers from Asbestos township (and a local reference population) and to consider the hypothesis that there is a difference in size between fibres retained in the lungs of patients with asbestosis with and without lung cancer. METHODS: Samples of lung tissue were obtained from 38 patients with asbestosis without lung cancer, 25 with asbestosis and lung cancer, and 12 with mesothelioma, from necropsied Quebec chrysotile miners and millers from Asbestos township. Fibre concentrations in the lungs of these patients were compared with those in tissue from necropsies carried out on a local reference population: men who had died of either accidental death or acute myocardial infarction between 1990 and 1992. 23 were born before 1940 and 26 after 1940. RESULTS: Geometric mean (GM) concentrations were higher in cases than in the controls for chrysotile fibres 5 to 10 microns long in patients with asbestosis with or without lung cancer; for tremolite fibres 5 to 10 microns long in all patients; for crocidolite, talc, or anthophyllite fibres 5 to 10 microns long in patients with mesothelioma; for chrysotile and tremolite fibres > or = 10 microns long in patients with asbestosis; and crocidolite, talc, or anthophyllite fibres > or = 10 microns long in patients with mesothelioma. However, median concentrations of each type of fibre in the lungs did not show any significant differences between the three disease groups. Average length to diameter ratios of the fibres were calculated to be larger in patients with asbestosis and lung cancer than in those without lung cancer for crocidolite fibres > or = 10 microns long, for chrysotile, amosite, and tremolite fibres 5 to 10 microns long, and for chrysotile and crocidolite fibres < 5 microns long. However, there was no statistical difference in the median length to diameter ratios for any type of fibres across the disease groups when they were calculated in each patient. Cumulative smoking index (pack-years) was higher in the group with asbestosis and lung cancer but was not statistically different from the two other disease groups. CONCLUSION: Lung cancers occurred in workers with asbestosis from Asbestos township who had an equal concentration of retained fibres but a tendency to a higher length to diameter ratio of amphiboles. These workers had a 29% higher average cumulative smoking index.

Transforming growth factor-beta (TGF-beta) in silicosis.

Silicosis is characterized by fibrosing nodular lesions that may eventually develop into progressive massive fibrosis (PMF). Cytokines (interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNF-alpha] and growth factors insulin-like growth factor-1 [IGF-1] platelet-derived growth factor [PDGF]) have been implicated in the formation of these lesions. TGF-beta promotes extracellular matrix accumulation by upregulating collagen and fibronectin gene expression, and inhibits matrix degradation by decreasing secretion of proteases and increasing secretion of protease inhibitors. We hypothesized that TGF-beta is associated with matrix deposition and fibrosis in silicosis. To test this hypothesis we studied early and late nodular lesions and PMF (11 cases and two controls) with immunohistochemistry, using rabbit polyclonal antibody to the purified whole molecule of TGF-beta in Bouin's fixed lung tissue. This antibody is reactive with both intra- and extracellular forms of TGF-beta. In the control lungs, small amounts of TGF-beta were present in the bronchial epithelium, macrophages, bronchial and vascular smooth muscle, and bronchial glands. There was minimal to moderate staining in the early silicotic peribronchiolar lesions. In the nodular lesions of silicosis, central hyalinized areas contained the maximum staining for TGF-beta. Fibroblasts in the periphery of the nodular lesions were also positive. In acute silicosis, there was marked staining of hyperplastic alveolar epithelium. Macrophages were markedly positive. In the PMF lesions, large areas of scar tissue contained TGF-beta. These data suggest a major role for TGF-beta in silicosis, particularly in the formation of silicotic nodules and the development of PMF.

Effect of exposure to silica on human alveolar macrophages in supporting growth activity in type II epithelial cells.

BACKGROUND: The proliferative response of type II cells is an important event following silica-induced lung injury. Alveolar macrophages, when activated by fibrogenic agents, secrete various biological mediators which affect cell growth. METHODS: Human alveolar macrophages from normal volunteers were incubated in serum-free medium or in the presence of increasing concentrations of silica. Alveolar macrophage conditioned media were diluted and added to type II cell cultures for proliferation studies. Purified type II pneumocytes were isolated from fetal rat lungs for bioassays. Growth factor activities were partially characterised by size exclusion chromatography. Each fractionated mitogenic peak was preincubated with monoclonal antibody against platelet derived growth factor (PDGF) or antisera against insulin-like growth factor 1 (IGF-1) or fibroblast derived growth factor (FGF) in order to study the nature of each activity. RESULTS: Conditioned media from alveolar macrophages exposed to silica induced an increase in type II cell DNA synthesis and cell number over that seen when type II cells were incubated with unstimulated alveolar macrophage supernatants. Size exclusion of alveolar macrophage supernatants exposed to silica showed four peaks of type II cell stimulating activity with apparent molecular weights of 38, 22, 16, and 8 kDa. Anti-PDGF antibody significantly reduced the activity of the first and second peaks, antiserum against IGF-1 partially reduced the activity of the first and fourth peaks, and antiserum against FGF reduced only the third peak of activity. CONCLUSIONS: Human alveolar macrophages exposed to silica in vitro release mitogens for type II pneumocytes including PDGF-like, IGF-1-like, and FGF-like molecules. These agents are likely to be involved in the epithelial repair and type II cell hyperplasia observed in silicosis.

Inorganic particles in the lungs of five aluminum smelter workers with pleuro-pulmonary cancer.

This paper reports on the inorganic particles in the lungs of four workers who died from lung cancer and one who died from mesothelioma. All five workers were involved in different operations and activities in aluminum reduction plants. Retained fibrous and nonfibrous particles were evaluated by transmission electron microscopy and energy dispersive spectroscopy after lung digestion. Asbestos fibers, fragments of silicates, and metal-rich nonfibrous particles of chromium-cobalt and aluminum were detected. Conclusions drawn from the evaluation of the particles retained in the lungs of only five workers must be cautious. However, these results are consistent with the hypothesis that carcinogenic polycyclic aromatic hydrocarbons may not be the only contaminants that could explain excess mortality from malignant lung neoplasm in aluminum smelter workers.