Systemic sclerosis, silica exposure and cellular therapies: The sand in the gears?

Systemic sclerosis (SSc) is a chronic orphan autoimmune disease with the highest mortality rate among rheumatic diseases. SSc-related interstitial-lung disease (ILD) remains among the leading causes of SSc-related mortality with still few therapeutic effective strategies. In patients with crystallin silica exposure, SSc is recognized as an occupational disease according to the French social security system (Table 25A of the general insurance regimen). Lympho-ablative or myeloablative immunosuppression followed by autologous hematopoietic stem-cell transplantation (aHSCT) is the only therapeutic approach with demonstrated efficacy, improved survival with disease modifying effects on SSc-fibrotic manifestations (skin disease and ILD) and quality of life. A documented past and/or present occupational silica exposure, with extensive exposure and/or silica-related ILD and/or with persistent silica content in the broncho-alveolar lavage fluid are contra-indications to aHSCT in SSc patients, due to the risk of silica-related malignancy or of SSc relapse. This article aims to discuss alternative options in SSc patients with a history of silica exposure, and how innovative cellular therapies (mesenchymal stromal cells, CAR cells) could represent new therapeutic options for these patients.

Anti-inflammatory protein TSG-6 secreted by BMSCs attenuates silica-induced acute pulmonary inflammation by inhibiting NLRP3 inflammasome signaling in macrophages.

Silicosis is a severe occupational lung disease caused by inhalation of silica particles. Unfortunately, there are currently limited treatment options available for silicosis. Recent advances have indicated that bone marrow mesenchymal stem cells (BMSCs) have a therapeutic effect on silicosis, but their efficacy and underlying mechanisms remain largely unknown. In this study, we focused on the early phase of silica-induced lung injury to investigate the therapeutic effect of BMSCs. Our findings demonstrated that BMSCs attenuated silica-induced acute pulmonary inflammation by inhibiting NLRP3 inflammasome pathways in lung macrophages. To further understand the mechanisms involved, we utilized RNA sequencing to analyze the transcriptomes of BMSCs co-cultured with silica-stimulated bone marrow-derived macrophages (BMDMs). The results clued tumor necrosis factor-stimulated gene 6 (TSG-6) might be a potentially key paracrine secretion factor released from BMSCs, which exerts a protective effect. Furthermore, the anti-inflammatory and inflammasome pathway inhibition effects of BMSCs were attenuated when TSG-6 expression was silenced, both in vivo and in vitro. Additionally, treatment with exogenous recombinant mouse TSG-6 (rmTSG-6) demonstrated similar effects to BMSCs in attenuating silica-induced inflammation. Overall, our findings suggested that BMSCs can regulate the activation of inflammasome in macrophages by secreting TSG-6, thereby protecting against silica-induced acute pulmonary inflammation both in vivo and in vitro.

Exercise training inhibits macrophage-derived IL-17A-CXCL5-CXCR2 inflammatory axis to attenuate pulmonary fibrosis in mice exposed to silica.

Exposure to crystalline silica leads to health effects beyond occupational silicosis. Exercise training's potential benefits on pulmonary diseases yield inconsistent outcomes. In this study, we utilized experimental silicotic mice subjected to exercise training and pharmacological interventions, including interleukin-17A (IL-17A) neutralizing antibody or clodronate liposome for macrophage depletion. Findings reveal exercise training's ability to mitigate silicosis progression in mice by suppressing scavenger receptor B (SRB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and Toll-like receptor 4 (TLR4) pathways. Macrophage-derived IL-17A emerges as primary source and trigger for silica-induced pulmonary inflammation and fibrosis. Exercise training effectively inhibits IL-17A-CXC motif chemokine ligand 5 (CXCL5)-Chemokine (C-X-C motif) Receptor 2 (CXCR2) axis in silicotic mice. Our study evidences exercise training's potential to reduce collagen deposition, preserve elastic fibers, slow pulmonary fibrosis advancement, and enhance pulmonary function post silica exposure by impeding macrophage-derived IL-17A-CXCL5-CXCR2 axis.

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles alleviated silica induced lung inflammation and fibrosis in mice via circPWWP2A/miR-223-3p/NLRP3 axis.

Silicosis is a progressive inflammatory disease with poorly defined mechanisms and limited therapeutic options. Recent studies found that microRNAs (miRNAs) and circular RNAs (circRNAs) were involved in the development of respiratory diseases; however, the function of non-coding RNAs in silicosis was still needed to be further explored. We found that miR-223-3p was significantly decreased in macrophages and lung tissues of mice after silica treatment, which were consistent with the results of GEO database microarray analysis. Notably, NLRP3 is a target gene downstream of miR-223-3p. And circular RNA PWWP2A (circPWWP2A) was significantly elevated after silica stimulation. To elucidate the role of these RNAs in silica-induced inflammation in macrophages and lung tissues, we investigated the upstream molecular mechanisms of circPWWP2A on the inflammatory response. The inhibitory effect of miR-223-3p on its target NLRP3 was suppressed by circPWWP2A, which led to lung fibrosis. Our study found that circPWWP2A could adsorb miR-223-3p to regulate NLRP3 after silica stimulation in pulmonary fibrosis. And our results revealed that the circPWWP2A-miR-223-3p-NLRP3 axis was potentially instrumental in managing silica-induced inflammation and fibrosis. Previous studies have demonstrated that human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EVs) exhibit anti-inflammatory and anti-fibrotic effects in multiple organs. However, the potential effectiveness of hucMSC-EVs against silicosis or the underlying mechanisms of their biological outcomes remains unclear. Therefore, we used 3D culture technology to extract hucMSC-EVs and observed their effects in macrophages and lung tissues, respectively. According to the EVmiRNA database, miR-223-3p was abundant in MSC-EVs. In addition, hucMSC-EVs may modulate lung function, reduce the secretion of inflammatory factors (NLRP3, IL-1ß, IL-18 and cleaved Caspase-1) and attenuate the deposition of fibrosis-related factors (Collagen Ⅰ, Collagen Ⅲ, fibronectin and α-SMA). In vitro results evinced that hucMSC-EVs reduced the inflammatory response of macrophages and restricted the activation and proliferation of fibroblasts. Moreover, our study showed that hucMSCs-EVs acted as a mediator to transfer miR-223-3p to suppress circPWWP2A, thereby alleviating pulmonary fibrosis through the NLRP3 signaling pathway. These data may provide potentially novel strategies for investigating the pathogenesis of silicosis and developing novel treatments for this disease.

Adenoviral Transduction of Dickkopf-1 Alleviates Silica-Induced Silicosis Development in Lungs of Mice.

Silicosis is an occupational disease caused by inhalation of silica dust, which is hallmarked by progressive pulmonary fibrosis associated with poor prognosis. Wnt/ß-catenin signaling is implicated in the development of fibrosis and is a therapeutic target for fibrotic diseases. Previous clinical studies of patients with pneumoconiosis, including silicosis, revealed an increased concentration of circulating WNT3A and DKK1 proteins and inflammatory cells in bronchoalveolar lavage compared with healthy subjects. The present study evaluated the effects of adenovirus-mediated transduction of Dickkopf-1 (Dkk1), a Wnt/ß-catenin signaling inhibitor, on the development of pulmonary silicosis in mice. Consistent with previous human clinical studies, our experimental studies in mice demonstrated an aberrant Wnt/ß-catenin signaling activity coinciding with increased Wnt3a and Dkk1 proteins and inflammation in lungs of silica-induced silicosis mice compared with controls. Intratracheal delivery of adenovirus expressing murine Dkk1 (AdDkk1) inhibited Wnt/ß-catenin activity in mouse lungs. The adenovirus-mediated Dkk1 gene transduction demonstrated the potential to prevent silicosis development and ameliorate silica-induced lung fibrogenesis in mice, accompanied by the reduced expression of epithelia--mesenchymal transition markers and deposition of extracellular matrix proteins compared with mice treated with "null" adenoviral vector. Mechanistically, AdDkk1 is able to attenuate the lung silicosis by inhibiting a silica-induced spike in TGF-ß/Smad signaling. In addition, the forced expression of Dkk1 suppressed silica-induced epithelial cell proliferation in polarized human bronchial epithelial cells. This study provides insight into the underlying role of Wnt/ß-catenin signaling in promoting the pathogenesis of silicosis and is proof-of-concept that targeting Wnt/ß-catenin signaling by Dkk1 gene transduction may be an alternative approach in the prevention and treatment of silicosis lung disease.

Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment.

Glycolytic reprogramming is an important metabolic feature in the development of pulmonary fibrosis. However, the specific mechanism of glycolysis in silicosis is still not clear. In this study, silicotic models and silica-induced macrophage were used to elucidate the mechanism of glycolysis induced by silica. Expression levels of the key enzymes in glycolysis and macrophage activation indicators were analyzed by Western blot, qRT-PCR, IHC, and IF analyses, and by using a lactate assay kit. We found that silica promotes the expression of the key glycolysis enzymes HK2, PKM2, LDHA, and macrophage activation factors iNOS, TNF-α, Arg-1, IL-10, and MCP1 in silicotic rats and silica-induced NR8383 macrophages. The enhancement of glycolysis and macrophage activation induced by silica was reduced by Ac-SDKP or siRNA-Ldha treatment. This study suggests that Ac-SDKP treatment can inhibit glycolytic reprogramming in silica-induced lung macrophages and silicosis.

Exosomes derived from three-dimensional cultured human umbilical cord mesenchymal stem cells ameliorate pulmonary fibrosis in a mouse silicosis model.

BACKGROUND: Silicosis is an occupational respiratory disease caused by long-term excessive silica inhalation, which is most commonly encountered in industrial settings. Unfortunately, there is no effective therapy to delay and cure the progress of silicosis. In the recent years, stem cell therapy has emerged as an attractive tool against pulmonary fibrosis (PF) owing to its unique biological characteristics. However, the direct use of stem cells remains limitation by many risk factors for therapeutic purposes. The exclusive utility of exosomes secreted from stem cells, rather than cells, has been considered a promising alternative to overcome the limitations of cell-based therapy while maintaining its advantages. METHODS AND RESULTS: In this study, we first employed a three-dimensional (3D) dynamic system to culture human umbilical cord mesenchymal stem cell (hucMSC) spheroids in a microcarrier suspension to yield exosomes from serum-free media. Experimental silicosis was induced in C57BL/6J mice by intratracheal instillation of a silica suspension, with/without exosomes derived from hucMSC (hucMSC-Exos), injection via the tail vein afterwards. The results showed that the gene expression of collagen I (COL1A1) and fibronectin (FN) was upregulated in the silica group as compared to that in the control group; however, this change decreased with hucMSC-Exo treatment. The value of FEV0.1 decreased in the silica group as compared to that in the control group, and this change diminished with hucMSC-Exo treatment. These findings suggested that hucMSC-Exos could inhibit silica-induced PF and regulate pulmonary function. We also performed in vitro experiments to confirm these findings; the results revealed that hucMSC-Exos decreased collagen deposition in NIH-3T3 cells exposed to silica. CONCLUSIONS: Taken together, these studies support a potential role for hucMSC-Exos in ameliorating pulmonary fibrosis and provide new evidence for improving clinical treatment induced by silica.

Magnetic targeting increases mesenchymal stromal cell retention in lungs and enhances beneficial effects on pulmonary damage in experimental silicosis.

Silicosis is a pneumoconiosis caused by inhaled crystalline silica microparticles, which trigger inflammatory responses and granuloma formation in pulmonary parenchyma, thus affecting lung function. Although systemic administration of mesenchymal stromal cells (MSCs) ameliorates lung inflammation and attenuates fibrosis in experimental silicosis, it does not reverse collagen deposition and granuloma formation. In an attempt to improve the beneficial effects of MSCs, magnetic targeting (MT) has arisen as a potential means of prolonging MSC retention in the lungs. In this study, MSCs were incubated with magnetic nanoparticles and magnets were used for in vitro guidance of these magnetized MSCs and to enhance their retention in the lungs in vivo. In vitro assays indicated that MT improved MSC transmigration and expression of chemokine receptors. In vivo, animals implanted with magnets for 48 hours had significantly more magnetized MSCs in the lungs, suggesting improved MSC retention. Seven days after magnet removal, silicotic animals treated with magnetized MSCs and magnets showed significant reductions in static lung elastance, resistive pressure, and granuloma area. In conclusion, MT is a viable technique to prolong MSC retention in the lungs, enhancing their beneficial effects on experimentally induced silicosis. MT may be a promising strategy for enhancing MSC therapies for chronic lung diseases.

[Progress in study on intervention of silica-induced pulmonary fibrosis with the exosomes released from mesenchymal stem cells].

Pneumoconiosis is an occupational disease which seriously endangers the health of workers exposed to dust. Silica is regarded as the most serious cause of pneumoconiosis because it can cause diffuse pulmonary fibrosis in workers' lung tissue. Mesenchymal stem cells (MSCs) are adult stem cells with multiple differentiation potential. As member of extracellular vesicles family, exosomes can be secreted from MSCs to regulate and intervene tumorigenesis, cardiovascular disease, immune system disorder and tissue damage disease. This article reviews the experimental results in the field of intervention of MSCs and its exosomes in silicosis research in recent years, which plays an important role in indicating direction in the future research on the mechanism and function of MSCs exosomes in the therapy of silica-induced pulmonary fibrosis.

Asbestosis and silicosis hospitalizations in Italy (2001-2015): results from the National Hospital Discharge Registry.

BACKGROUND: This work is aimed at evaluating the quality of Italian hospitalizations data about asbestosis and silicosis, assessing the impact of these diseases on the national health system and providing advice related to public health. METHODS: Italian hospital discharge data (2001-15) with diagnosis of asbestosis or silicosis were analysed by the multiple correspondence analysis and diseases epidemics were evaluated through hospitalization rates. RESULTS: Hospitalizations were concentrated in the northwestern area, referred mainly to males and oldest people, the most treated tumors were lung cancer and mesothelioma (for asbestosis) and cares were aimed at reducing symptoms and increasing blood oxygenation. Overall adjusted Italian hospitalization rates of asbestosis and silicosis were, respectively, 25.2 and 74.9 per 1 000 000 residents. With respect to asbestosis, hospitalizations treating silicosis reported doubled mortality (10.5 vs. 5.7%), longer stays (10.4 vs. 8.6 mean days) and older patients (77 vs. 72 years on average). Diseases rates reduced over time (with a steeper slope for silicosis) and in both fibroses increased hospital mortality (92.1% in asbestoses, 59.5% in silicoses) and percentage of urgent hospitalizations (116.0% in asbestoses, 56.6% in silicoses). CONCLUSION: Hospitalizations data regarding asbestosis and silicosis are consistent. Silicosis had a higher impact than asbestosis on the Italian health system. Although data show decreasing incidence of both fibroses, multiple correspondence analysis highlights that levels of illness severity were higher in silicosis and increased over time in both diseases. Further studies investigating the effectiveness of the current health surveillance programs concerning these diseases are suggested.

Inhibition of MARCO ameliorates silica-induced pulmonary fibrosis by regulating epithelial-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) is linked to fibrosis following exposure to silica. The scavenger receptor, macrophage receptor with collagenous structure (MARCO) plays an important role in silica-induced inflammation, however, the effect of MARCO on silica-induced fibrosis has not been identified. We hypothesized that MARCO would regulate EMT and be involved in the development of silicosis. Herein, we found that MARCO was highly expressed in lung tissue after exposure to silica and a MARCO inhibitor PolyG could alleviate pulmonary fibrosis in vivo. Our results confirmed that the expression of epithelial marker such as E-cadherin decreased, while the expression of mesenchymal markers, including vimentin and α-SMA increased after silica treatment. Furthermore, PolyG administration efficiently blocked the mRNA and protein expression of EMT markers and decreased the level of fibrosis-related transcription factors and proteins, such as Col1a1, Col3a1, Collagen I and Collagen III in the lungs of silica-exposed rats. The findings demonstrate that the macrophage membrane receptor MARCO controls the fibrotic response through regulating EMT in experimental silicosis and suggest a novel target for preventive intervention.

Therapeutic effects of adipose-tissue-derived mesenchymal stromal cells and their extracellular vesicles in experimental silicosis.

BACKGROUND: Silicosis is an occupational disease that affects workers who inhale silica particles, leading to extensive lung fibrosis and ultimately causing respiratory failure. Mesenchymal stromal cells (MSCs) have been shown to exert therapeutic effects in lung diseases and represent an alternative treatment for silicosis. Recently, it has been suggested that similar effects can be achieved by the therapeutic use of extracellular vesicles (EVs) obtained from MSCs. The aim of this study was to investigate the effects of adipose-tissue-derived MSCs (AD-MSCs) or their EVs in a model of silicosis. METHODS: Silicosis was induced by intratracheal instillation of silica in C57BL/6 mice. After the onset of disease, animals received saline, AD-MSCs, or EVs, intratracheally. RESULTS: At day 30, AD-MSCs and EVs led to a reduction in collagen fiber content, size of granuloma, and in the number of macrophages inside granuloma and in the alveolar septa. In addition, the expression levels of interleukin 1ß and transforming growth factor beta in the lungs were decreased. Higher dose of EVs also reduced lung static elastance when compared with the untreated silicosis group. CONCLUSIONS: Both AD-MSCs and EVs, locally delivered, ameliorated fibrosis and inflammation, but dose-enhanced EVs yielded better therapeutic outcomes in this model of silicosis.

Transplantation of adipose-derived mesenchymal stem cells attenuates pulmonary fibrosis of silicosis via anti-inflammatory and anti-apoptosis effects in rats.

BACKGROUND: Silicosis has been topping the list of high-incidence occupational diseases in developing countries and cannot be completely cured. Recent advances in stem cell research have made possible the treatment of various diseases including lung fibrosis. The application of stem cell therapy in occupational diseases, in particular the use of adipose-derived mesenchymal stem cells (AD-MSCs) in treatment of silicosis, has not yet been reported. The aim of the study is to explore the intervening effect of silica-induced lung fibrosis in rats. METHODS: In this study, we investigated the anti-pulmonary fibrosis effects of the transplantation of AD-MSCs in rats in which lung fibrosis was induced by oral tracheal intubation with silica suspension. Twenty rats were divided into four groups: control group (n = 5), exposure group (n = 5), vehicle group (n = 5) and treatment group (n = 5). AD-MSCs were given to rats after exposure to silica for 24 h. Twenty-eight days after AD-MSC transplantation, we examined the organ coefficient, inflammatory cytokines, apoptosis, pathological and fibrotic changes in lung tissue. RESULTS: Results showed that exposure to silica for 28 days induced an increase of the lung coefficient with significant pulmonary fibrosis. Treatment with AD-MSC transplantation led to a remissive effect on pulmonary fibrosis. We found that after AD-MSC transplantation the inflammatory response decreased and Caspase-3 protein expression significantly decreased with a significant increase of the Bcl-2/Bax ratio. CONCLUSIONS: Anti-inflammatory and anti-apoptosis of AD-MSCs may play important roles in their anti-pulmonary fibrosis effect. Our data suggest that transplantation of AD-MSCs holds promise for potential interference in the formation of silicosis through regulating inflammatory and apoptotic processes.

Occupational lung diseases in Australia.

Occupational exposures are an important determinant of respiratory health. International estimates note that about 15% of adult-onset asthma, 15% of chronic obstructive pulmonary disease and 10-30% of lung cancer may be attributable to hazardous occupational exposures. One-quarter of working asthmatics either have had their asthma caused by work or adversely affected by workplace conditions. Recently, cases of historical occupational lung diseases have been noted to occur with new exposures, such as cases of silicosis in workers fabricating kitchen benchtops from artificial stone products. Identification of an occupational cause of a lung disease can be difficult and requires maintaining a high index of suspicion. When an occupational lung disease is identified, this may facilitate a cure and help to protect coworkers. Currently, very little information is collected regarding actual cases of occupational lung diseases in Australia. Most assumptions about many occupational lung diseases are based on extrapolation from overseas data. This lack of information is a major impediment to development of targeted interventions and timely identification of new hazardous exposures. All employers, governments and health care providers in Australia have a responsibility to ensure that the highest possible standards are in place to protect workers' respiratory health.

Blocking the 4-1BB Pathway Ameliorates Crystalline Silica-induced Lung Inflammation and Fibrosis in Mice.

Long term pulmonary exposure to crystalline silica leads to silicosis that manifests progressive interstitial fibrosis, eventually leading to respiratory failure and death. Despite efforts to eliminate silicosis, clinical cases continue to occur in both developing and developed countries. The exact mechanisms of crystalline silica-induced pulmonary fibrosis remain elusive. Herein, we find that 4-1BB is induced in response to crystalline silica injury in lungs and that it is highly expressed during development of experimental silicosis. Therefore, we explore the role of 4-1BB pathway during crystalline silica-induced lung injury and find that a specific inhibitor blocking the pathway could effectively alleviate crystalline silica-induced lung inflammation and subsequent pulmonary fibrosis in vivo. Compared to controls, the treated mice exhibited reduced Th1 and Th17 responses. The concentrations of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF), including tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-17A following crystalline silica challenge were also reduced in inhibitor-treated mice. Although there was no significant alteration in Th2 cytokines of IL-4 and IL-13, another type of pro-fibrogenic cell, regulatory T cell (Treg) was significantly affected. In addition, one of the major participants in fibrogenesis, fibrocyte recruited less due to the blockade. Furthermore, we demonstrated the decreased fibrocyte recruitment was associated with chemokine reductions in lung. Our study discovers the 4-1BB pathway signaling enhances inflammatory response and promotes pulmonary fibrosis induced by crystalline silica. The findings here provide novel insights into the molecular events that control crystalline silica-induced lung inflammation and fibrosis through regulating Th responses and the recruitment of fibrocytes in crystalline silica-exposed lung.

Recurrent secondary spontaneous pneumothorax in silicosis: a case report.

Silicosis is an occupational lung disease which is caused by inhalation and accumulation of crystalline silica particles in the lung. It commonly occurs in workers involved in quarrying, mining, sandblasting, tunneling, foundry work, and ceramics. Pneumothorax is one of the complications of silicosis with pleural involvement. The occurrence of pneumothorax in a patient with silicosis is a rare event, but it may be fatal. The rate of pneumothorax recurrence in silicosis is usually low. We report a case of recurrent secondary spontaneous pneumothorax in silicosis.

Treatment of silicosis with hepatocyte growth factor-modified autologous bone marrow stromal cells: a non-randomized study with follow-up.

Pulmonary silicosis is an irreversible and untreatable disease that is characterized by interstitial lesions and perpetual fibrosis in the lungs. This study was performed to determine whether mesenchymal stem cells (MSCs) and hepatocyte growth factor (HGF) could exhibit therapeutic effects on human silicosis. This non-randomized uncontrolled trial comprised four patients with pulmonary silicosis who had developed lung fibrosis and received autologous bone marrow MSCs previously transfected by a vector containing human HGF cDNA (MSCs/HGF). MSCs/HGF were intravenously administered weekly for three consecutive weeks at a dose of 2 x 10(6) cells/kg. Pulmonary function, high kilo-voltage chest X-ray radiography, computed tomography (CT) scan, and peripheral blood lymphocyte subset and serum IgG concentrations were evaluated after cell therapy. The treatment was found to be generally safe. Symptoms such as cough and chest distress gradually ameliorated at six months post-therapy, accompanied by the significant improvement of pulmonary function. The ratios of the peripheral CD4- and CD8- positive cell concentrations were increased (P < 0.05). Furthermore, the serum IgG levels in these patients were decreased and reached the normal range (P < 0.05). CT scans showed partial absorption of the nodular and reticulonodular lesions in the lungs during follow-up of at least 12 months. The effectiveness of this novel regimen observed in these patients suggests that a placebo-controlled clinical trial needs to be developed. This study carries trial registration No. NCT01977131 (ClinicalTrials.gov).

Pilot safety study of intrabronchial instillation of bone marrow-derived mononuclear cells in patients with silicosis.

BACKGROUND: Silicosis is an occupational disease for which no effective treatment is currently known. Systemic administration of bone marrow-derived mononuclear cells (BMDMCs) has shown to be safe in lung diseases. However, so far, no studies have analyzed whether bronchoscopic instillation of autologous BMDMCs is a safe route of administration in patients with silicosis. METHODS: We conducted a prospective, non-randomized, single-center longitudinal study in five patients. Inclusion criteria were age 18-50 years, chronic and accelerated silicosis, forced expiratory volume in 1 s <60 % and >40 %, forced vital capacity ≥60 % and arterial oxygen saturation >90 %. The exclusion criteria were smoking, active tuberculosis, neoplasms, autoimmune disorders, heart, liver or renal diseases, or inability to undergo bronchoscopy. BMDMCs were administered through bronchoscopy (2 × 10(7) cells) into both lungs. Physical examination, laboratory evaluations, quality of life questionnaires, computed tomography of the chest, lung function tests, and perfusion scans were performed before the start of treatment and up to 360 days after BMDMC therapy. Additionally, whole-body and planar scans were evaluated 2 and 24 h after instillation. RESULTS: No adverse events were observed during and after BMDMC administration. Lung function, quality of life and radiologic features remained stable throughout follow-up. Furthermore, an early increase of perfusion in the base of both lungs was observed and sustained after BMDMC administration. CONCLUSION: Administration of BMDMCs through bronchoscopy appears to be feasible and safe in accelerated and chronic silicosis. This pilot study provides a basis for prospective randomized trials to assess the efficacy of this treatment approach. CLINICAL TRIALS. GOV IDENTIFIER: NCT01239862 Date of Registration: November 10, 2010.

Exercise training for asbestos-related and other dust-related respiratory diseases: a randomised controlled trial.

BACKGROUND: The study aimed to determine the short and long-term effects of exercise training on exercise capacity and health-related quality of life (HRQoL) compared to usual care in people with dust-related pleural and interstitial respiratory diseases. No previous studies have specifically evaluated exercise training in this patient population. METHODS: Participants with a diagnosis of a dust-related respiratory disease including asbestosis and asbestos related pleural disease were recruited and randomised to an eight-week exercise training group (EG) or a control group (CG) of usual care. Six-minute walk distance (6MWD), St George's Respiratory Questionnaire (SGRQ) and Chronic Respiratory Disease Questionnaire (CRQ) were measured at baseline, eight weeks and 26 weeks by an assessor blinded to group allocation. RESULTS: Thirty-three of 35 male participants completed the study. Sixty-nine percent of participants had asbestos related pleural disease. At eight weeks, compared to the CG, the EG showed a significantly increased 6MWD (mean difference (95%CI)) 53 metres (32 to 74), improved SGRQ total score, -7 points (-13 to -1) and increased CRQ total score, 6.4 points (2.1 to 10.7). At 26 weeks significant between-group differences were maintained in 6MWD, 45 metres (17 to 73) and CRQ total score, 13.1 points (5.2 to 20.9). CONCLUSION: Exercise training improved short and long-term exercise capacity and HRQoL in people with dust-related pleural and interstitial respiratory diseases. CLINICAL TRIAL REGISTRATION NUMBER: ANZCTR12608000147381. Date trial registered: 27.03.2008.