Safety and tolerability of pirfenidone in asbestosis: a prospective multicenter study.

BACKGROUND: Pirfenidone slows down disease progression in idiopathic pulmonary fibrosis (IPF). Recent studies suggest a treatment effect in progressive pulmonary fibrosis other than IPF. However, the safety and effectiveness of pirfenidone in asbestosis patients remain unclear. In this study, we aimed to investigate the safety, tolerability and efficacy of pirfenidone in asbestosis patients with a progressive phenotype. METHODS: This was a multicenter prospective study in asbestosis patients with progressive lung function decline. After a 12-week observational period, patients were treated with pirfenidone 801 mg three times a day. Symptoms and adverse events were evaluated weekly and patients completed online patient-reported outcomes measures. At baseline, start of therapy, 12 and 24 weeks, in hospital measurement of lung function and a 6 min walking test were performed. Additionally, patients performed daily home spirometry measurements. RESULTS: In total, 10 patients were included of whom 6 patients (66.7%) experienced any adverse events during the study period. Most frequently reported adverse events were fatigue, rash, anorexia and cough, which mostly occurred intermittently and were reported as not very bothersome. No significant changes in hospital pulmonary function (forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO), 6 min walking test or patient-reported outcomes measures before and after start of pirfenidone were found. Home spirometry demonstrated a FVC decline in 12 weeks before start of pirfenidone, while FVC did not decline during the 24 week treatment phase, but this difference was not statistically significant. CONCLUSIONS: Treatment with pirfenidone in asbestosis has an acceptable safety and tolerability profile and home spirometry data suggest this antifibrotic treatment might attenuate FVC decline in progressive asbestosis. Trial registration MEC-2018-1392; EudraCT number: 2018-001781-41.

Dibutyryl-cAMP attenuates pulmonary fibrosis by blocking myofibroblast differentiation via PKA/CREB/CBP signaling in rats with silicosis.

BACKGROUND: Myofibroblasts play a major role in the synthesis of extracellular matrix (ECM) and the stimulation of these cells is thought to play an important role in the development of silicosis. The present study was undertaken to investigate the anti-fibrotic effects of dibutyryl-cAMP (db-cAMP) on rats induced by silica. METHODS: A HOPE MED 8050 exposure control apparatus was used to create the silicosis model. Rats were randomly divided into 4 groups: 1)controls for 16 w; 2)silicosis for 16 w; 3)db-cAMP pre-treatment; 4) db-cAMP post-treatment. Rat pulmonary fibroblasts were cultured in vitro and divided into 4 groups as follows: 1) controls; 2) 10-7mol/L angiotensin II (Ang II); 3) Ang II +10-4 mol/L db-cAMP; and 4) Ang II + db-cAMP+ 10-6 mol/L H89. Hematoxylin-eosin (HE), Van Gieson staining and immunohistochemistry (IHC) were performed to observe the histomorphology of lung tissue. The levels of cAMP were detected by enzyme immunoassay. Double-labeling for α-SMA with Gαi3, protein kinase A (PKA), phosphorylated cAMP-response element-binding protein (p-CREB), and p-Smad2/3 was identified by immunofluorescence staining. Protein levels were detected by Western blot analysis. The interaction between CREB-binding protein (CBP) and Smad2/3 and p-CREB were measured by co-immunoprecipitation (Co-IP). RESULTS: Db-cAMP treatment reduced the number and size of silicosis nodules, inhibited myofibroblast differentiation, and extracellular matrix deposition in vitro and in vivo. In addition, db-cAMP regulated Gαs protein and inhibited expression of Gαi protein, which increased endogenous cAMP. Db-cAMP increased phosphorylated cAMP-response element-binding protein (p-CREB) via protein kinase A (PKA) signaling, and decreased nuclear p-Smad2/3 binding with CREB binding protein (CBP), which reduced activation of p-Smads in fibroblasts induced by Ang II. CONCLUSIONS: This study showed an anti-silicotic effect of db-cAMP that was mediated via PKA/p-CREB/CBP signaling. Furthermore, the findings offer novel insight into the potential use of cAMP signaling for therapeutic strategies to treat silicosis.

Systemic autoimmune disease in asbestosis rapidly responding to anti-interleukin-1beta antibody canakinumab: a case report.

BACKGROUND: Asbestosis is characterized by lung and pleural fibrosis and by immune system dysregulation, with autoantibody production and systemic immune-mediated disease. No specific therapies are available for asbestosis. Recently, the pivotal pathogenic role exerted by interleukin-1beta has been recently reported. CASE PRESENTATION: We treated with anti-interleukin 1 beta targeted antibody canakinumab a 67 year old man with asbestosis and long lasting systemic autoimmune features. A dramatic improvement in clinical manifestations was observed at 1 week after the first injection, with complete clinical remission at 4 months. CONCLUSION: This case suggests new perspectives for the treatment of asbestosis and its systemic features.

Inflammasome and IL-1beta-mediated disorders.

The NLRP3 inflammasome is an intracellular complex that regulates the release of proinflammatory cytokines such as interleukin-1beta in response to exogenous pathogens and endogenous danger signals. Evidence from studies involving human genetics, human ex vivo mononuclear cell responses, and in vivo and in vitro murine models confirms the importance of the inflammasome and interleukin-1beta in the pathogenesis of several inherited and complex diseases. The availability of several effective interleukin-1beta targeted therapies has allowed for successful proof-of-concept studies in several of these disorders. However, many other diseases are likely to be mediated by the inflammasome and interleukin-1beta, providing additional targets in the future.

Silico-asbestosis that responded to steroid therapy.

A 73-year-old man with silico-asbestosis responded to steroid therapy. Chest CT scans showed diffuse micronodular opacities and ground glass opacities bilaterally throughout the entire lung fields, as well as progressive massive fibrosis in the bilateral upper lung fields. Diagnostic thoracoscopic biopsy revealed mixed dust pneumoconiosis with silicotic nodules, as well as fibrosis similar to that of Usual Interstitial Pneumonia (UIP) with many fibroblastic foci and alveolitis. Many asbestos bodies were also detected by iron staining.

Peritoneal mesothelioma after environmental asbestos exposure.

Mesothelioma are primary malignant neoplasms of the serous membranes. They usually involve the pleura and rarely the pericardium, the peritoneum and the tunica vaginalis testis. About 90% are associated with exposure to asbestos. The exposure is generally occupational, an environmental inhalation of asbestos and asbestiform fibers in areas in Turkey has been observed and presents a major health problem. This report of a patient from Anatolia with peritoneal mesothelioma after environmental exposure outlines the importance of considering this pathology in the differential diagnosis of a Turkish patient presenting with ascites.

Mechanisms of colchicine effect in the treatment of asbestosis and idiopathic pulmonary fibrosis.

The objective of this study was to evaluate the mechanisms of colchicine action in pulmonary fibrosis. The study included 10 patients with pulmonary fibrosis (idiopathic pulmonary fibrosis 5, asbestosis 4, and scleroderma 1) who had been admitted to Bellevue Hospital Center, a tertiary care public hospital in New York City. We administered colchicine 0.6 mg orally for 12 weeks to patients with pulmonary fibrosis. Symptoms, high resolution CT scans, pulmonary function tests, and bronchoalveolar lavage parameters were compared prior to and after treatment. Results showed declines in dyspnea index, selective improvement in several CT scans, but no statistically significant change in BAL cells, cytokines, fibronectin, or hydroxyproline. However, there was a decline in hydroxyproline in the BAL fluid in 8/10 patients. We concluded that colchicine has a mild antifibrotic effect which may be in inhibiting collagen formation since there was no effect on the inflammation that accompanies fibrosis.

Asbestos-induced injury to cultured human pulmonary epithelial-like cells: role of neutrophil elastase.

The mechanisms responsible for asbestos-induced pulmonary epithelial cell cytotoxicity, especially oxidant-independent mechanisms, are not established. We determined whether human polymorphonuclear leukocyte (PMN) proteases contribute to asbestos-induced damage to human pulmonary epithelial-like cells (PECs) assessed using an in vitro chromium-51 release assay. Serine antiproteases, phenylmethylsulfonyl fluoride and alpha 1-antitrypsin, each ameliorated PEC injury induced by amosite asbestos and PMNs. A role for a specific proteinase, human neutrophil elastase (HNE), is supported by the facts that (1) asbestos increased HNE release assessed by an enzyme-linked immunosorbent assay technique (1.7 +/- 0.5 vs. 2.8 +/- 0.5 micrograms/ml; P < .025), (2) purified HNE or porcine pancreatic elastase (PPE) each alone caused PEC detachment, (3) asbestos plus either HNE or PPE caused PEC lysis similar to that mediated by asbestos and PMNs, and (4) cationic agents released from PMNs were unlikely to be involved because polyanions did not ameliorate injury resulting from asbestos and PMNs. Compared to elastase, cathepsin G caused less PEC detachment and negligible augmentation in asbestos-induced PEC lysis. Asbestos increased the association of 125I-labeled elastase with PECs nearly 50-fold compared with PPE alone (14.4% vs. 0.3%, respectively; P < .01) and nearly 10-fold compared with another particle, opsonized zymosan. We conclude that PMN-derived proteases, especially elastase, may contribute to asbestos-induced lung damage by augmenting pulmonary epithelial cell injury.

Biphasic lung diffusing capacity: detection of early asbestos induced changes in lung function.

Asbestos related changes in the single breath carbon monoxide diffusing capacity (DLCO) were longitudinally analysed in 14 subjects exposed predominantly to chrysotile asbestos in an asbestos cement factory. These subjects were examined annually over the past nine years; their lung function was initially characterised with increased DLCO as the sole functional abnormality and they had normal chest radiographs. The radiological examination included a chest x ray film and, in the past two years, high resolution computed tomography (HRCT). A biphasic DLCO change was found: an initial increase followed by a relative decrease. The increase in DLCO was mainly caused by an increase in the membrane component (Dm). Indomethacin treatment applied after the sixth annual follow up significantly reduced DLCO and Dm. The decrease in DLCO correlated well with the parenchymal abnormalities found on HRCT, whereas the chest x ray film profusion score for small opacities (ILO classification) was unchanged. In conclusion, the data suggested that, as well as the absolute values of pulmonary function tests, the measurement of progression of functional parameters is essential in the assessment of pleural and parenchymal disease of the lung related to exposure to asbestos. High resolution computed tomography is suggested as the radiological method of choice in subjects with an isolated decrease in DLCO. Exposure to asbestos can be associated not only with a reduction in DLCO, but also with a temporary increase in DLCO caused by a subclinical inflammatory reaction.

[Pathological observation of experimental asbestosis treated by hydroxy piperquin phosphate in dogs].

The paper presents experimental asbestosis treated with hydroxy piperquin phosphate (HPQP) in dogs. Results showed that the total cell number of bronchoalveolar lavage fluid, the viability of alveolar macrophages and the enzyme activities of lactate dehydrogenase, acid phosphatase and beta-glucuronidase of alveolar macrophages in treated dogs were higher than those in exposed dogs, asbestos fibers contents in the lungs and the mean scores of lung lesions in the treated dogs were markedly less than those in the exposed dogs. These findings support that HPQP may play a role in protecting alveolar macrophages from damage and inhibiting the progression of lung fibrosis, and that the clinical application of HPQP is somehow evidenced by this study.

[The effect of oral N-acetylcysteine on glutathione concentration in bronchoalveolar lavage of patients with fibrosing lung diseases]. / Der Effekt von oralem N-Acetylcystein auf die Glutathion-Konzentration in der bronchoalveolären Lavage von Patienten mit fibrosierenden Lungenerkrankungen.

Glutathione (GSH) is an important constituent in protecting the cellular elements within the lower respiratory tract against oxydants. We measured GSH in bronchoalveolar lavage fluid (BAL) in twelve patients with lung fibrosis and compared the data to eight healthy controls. GSH in BAL was 0.71 +/- 0.34 mumol/l in patients with lung fibrosis and 0.88 +/- 0.35 mumol/l in the controls (p greater than 0.05). After relating GSH on the volume of the epithelial lining fluid (ELF), determined by the urea method, GSH/ELF was 93 +/- 71 mumol/l in lung fibrosis and significantly different (p less than 0.005) from 387 +/- 240 mumol/l in the controls. In seven patients (four lung fibrosis, one desquamative pneumonitis, two asbestosis) GSH in BAL was determined before and after seven days of medication with 1800 mg N-acetylcysteine/day. We observed a significant increase of GSH in BAL from 0.93 +/- 0.46 to 1.56 +/- 0.92 mumol/l. Our observations confirm that in patients with lung fibrosis the protective ability against oxydants is diminished and that one parameter of the antioxydative capacity (GSH) can be increased in BAL by oral administration of N-acetylcysteine. Further studies are necessary to investigate the clinical and therapeutic implications of our findings.

Effects of cyclophosphamide treatment in experimental asbestosis.

The potential role of immunosuppressive therapy in asbestosis was evaluated in the sheep model of experimental asbestosis. A diffuse peribronchiolar alveolar and interstitial fibrosing alveolitis was developed in 10 animals following 2 years of exposure consisting of slow intratracheal infusion of 100 mg Canadian chrysotile in 100 ml saline every 2 weeks. A control group of 10 sheep concomitantly receiving only 100 ml saline intratracheally was also enrolled in the study. One group of 5 control sheep and one group of 5 asbestosis sheep received 1 mg/kg cyclophosphamide in 10 ml saline iv every 2 weeks, the other 10 sheep receiving only saline. One year after beginning of therapy, survival rates were comparable in the 2 control groups and the asbestosis group without therapy at 80%, whereas it was significantly reduced at 20% in the asbestosis group with therapy. Deaths in the latter were associated with significant increase in peripheral blood and lung lavage neutrophils, increased intensity of fibrosing alveolitis, worsening of lung functions, and worsening in the radiographic diffuse lung opacities. This was documented on histopathology to be associated with more intense fibrotic disease and bacterial pneumonia in the group of sheep with asbestosis receiving the immunosuppressor drug. We conclude that cyclophosphamide therapy in experimental asbestosis accelerated the fibrotic process and reduced significantly the survival rate of the animals.