Intrabronchial Instillation of Mononuclear Cells in Silicosis
The present study evaluated the safety of autologous BMDMC administration through bronchoscopy in patients with silicosis over a period of 360 days. To the best of our knowledge, this was the first study to evaluate the safety of autologous BMDMCs in patients with silicosis. The procedure was well tolerated and no adverse events were observed in the follow-up period. Even though no significant changes were reported in lung function and quality of life, autologous BMDMC transplantation seems to have led to an early increase in perfusion at the base of both lungs, which remained increased for the duration of the follow-up.
Recent studies have investigated the impact of either autologous BMDMCs or mesenchymal stem cells (MSCs) on lung diseases. Both cells present particular advantages: BMDMCs can be used in autologous transplantation on the same day of harvesting, avoiding common complications such as graft-versus-host disease, whereas MSCs have multilineage differentiation potential and immune-privileged features that enable allogenic use. So far, clinical studies have demonstrated the safety of systemic BMDMC/MSC infusion in lung diseases, with no early or late adverse effects reported. Intravenous infusion is often used in preclinical and clinical studies for the delivery of various cell types, since this route of administration provides broader biodistribution and is easy to perform. However, the administration of BMDMCs through bronchoscopy into different areas of the lungs may result in a greater number of cells at the site of injury. We administered a fixed amount of BMDMCs (2 × 10), independent of body weight, based on preclinical and clinical studies on different diseases. To evaluate the early distribution of the injected cells into the lungs, cells were labelled with 99mTc on the basis of previously published protocols.In vivo imaging and quantification of stem cells is an essential tool for stem cell tracking, although it has inherent limitations. For instance, regardless of which technique is used, cell labeling may cause cellular damage due to the labeling chemicals, and should be carefully controlled. Due to the short half-life of 99mTc (approximately 6 h), we cannot rule out that the amount of cells in the lungs may increase at later time points. Other radiopharmaceutical compounds such as indium-111 oxine would allow monitoring for up to 96 h, but have disadvantages, such as the interval of 18–24 h between infusion and imaging that is usually necessary, suboptimal photon energy, and a higher radiation burden for the cells and for the patient. We also used 99mTc-MAA perfusion scintigraphy to follow the likely pattern of distribution of the cells for up to 360 days after infusion.
No adverse events or deaths occurred among the patients treated with BMDMCs. Clinical, functional and radiological parameters were evaluated at 1-year follow-up. The clinical features of this group were stable throughout the follow-up period and no clinical signs or symptoms of bronchitis or pneumonia were observed after BMDMC administration. Even though a 1-year period is not long enough to allow definitive conclusions, it is well known that lung function deteriorates more quickly in patients with silicosis depending on continuation of exposure to silica dust, age and grade of lung lesions. The volunteers in our study were relatively young with moderate lung lesions, and exhibited clear stabilization of lung function, which could be attributable to the intervention. This hypothesis would be more clearly demonstrated if a control group with similar characteristics was added to the study. With regard to the quality of life questionnaires, no changes were seen after 360 days of follow-up. An early increase in perfusion at the base of both lungs was observed and sustained after BMDMC administration. Based on CT scan analysis, fibrosis was not prominent in the apex of the lung, but distributed across different lung segments. Therefore, the increased perfusion observed in both lung bases was likely not associated with a predominance of fibrosis in any specific segment of the lung. In line with this observation and based on our preclinical data showing that BMDMCs reduce fibrosis in a mouse model of silicosis, we may hypothesize that these cells mitigated progression of fibrosis through paracrine effects.
Since this is a safety study, analysis was only observational, and further larger-scale trials are necessary to fully examine the efficacy of BMDMCs in patients with silicosis.
Experimental studies have demonstrated the efficacy of systemic and intratracheal administration of BMDMCs in a murine model of silicosis that resembles human silicosis. BMDMC therapy (intratracheally or intravenously administered) reduced both lung inflammation and remodeling, thus improving lung mechanics, through paracrine signaling. Conversely, in the present study, no significant changes in lung function or quality of life indicators were observed over 360 days of analysis. The fact that the clinical result did not reflect the experimental data may be associated with differences in the course of the disease between animal models and humans, the number of cells administered, and the timing of analysis.
Our pilot study was limited by its small sample size; however, it was the first investigation to evaluate stem-cell therapy in silicotic patients. Further studies should be performed in a greater number of patients, with the addition of a control group, and in patients with mild and severe silicosis. Clinical trials evaluating the effects of MSC therapy in idiopathic lung fibrosis (ILF) have been published. However, this was the first study that analyzed the safety of autologous BMDMCs in patients with silicosis and, in contrast with the studies, no adverse events were observed. In this line, two clinical trials involving the endobronchial or systemic delivery of autologous adipose tissue-derived or placenta-derived mesenchymal stem cells demonstrated that these treatments are not safe in patients with IPF. In the first clinical trial, transient fever (50 % of patients), cough, dyspnea, and increased heart rate (14 % of patients) were observed following each endobronchial cell administration, and one patient experienced a change in absolute FVC of more than 10 % at 6 months, suggesting disease progression. A second phase 1b study on the use of exogenous placenta-derived MSCs in patients with IPF also observed adverse effects after therapy.
Clinical studies are required to evaluate the safety of different doses and treatment intervals of BMDMC administration and to analyze the efficacy of this approach, including pulmonary and systemic hemodynamics, lung function, hospitalizations, infections, and death. The use of a single infusion or repeated infusions also needs to be addressed, even though multiple infusions could lead to right heart overload (and pulmonary hypertension). Most patients with silicosis are not diagnosed in the early stages of the disease, but identification of these patients should be considered for a clinical trial of cell therapy. Clinical trials should include patients with different degrees of lung function impairment due to silicosis.
Discussion
The present study evaluated the safety of autologous BMDMC administration through bronchoscopy in patients with silicosis over a period of 360 days. To the best of our knowledge, this was the first study to evaluate the safety of autologous BMDMCs in patients with silicosis. The procedure was well tolerated and no adverse events were observed in the follow-up period. Even though no significant changes were reported in lung function and quality of life, autologous BMDMC transplantation seems to have led to an early increase in perfusion at the base of both lungs, which remained increased for the duration of the follow-up.
Recent studies have investigated the impact of either autologous BMDMCs or mesenchymal stem cells (MSCs) on lung diseases. Both cells present particular advantages: BMDMCs can be used in autologous transplantation on the same day of harvesting, avoiding common complications such as graft-versus-host disease, whereas MSCs have multilineage differentiation potential and immune-privileged features that enable allogenic use. So far, clinical studies have demonstrated the safety of systemic BMDMC/MSC infusion in lung diseases, with no early or late adverse effects reported. Intravenous infusion is often used in preclinical and clinical studies for the delivery of various cell types, since this route of administration provides broader biodistribution and is easy to perform. However, the administration of BMDMCs through bronchoscopy into different areas of the lungs may result in a greater number of cells at the site of injury. We administered a fixed amount of BMDMCs (2 × 10), independent of body weight, based on preclinical and clinical studies on different diseases. To evaluate the early distribution of the injected cells into the lungs, cells were labelled with 99mTc on the basis of previously published protocols.In vivo imaging and quantification of stem cells is an essential tool for stem cell tracking, although it has inherent limitations. For instance, regardless of which technique is used, cell labeling may cause cellular damage due to the labeling chemicals, and should be carefully controlled. Due to the short half-life of 99mTc (approximately 6 h), we cannot rule out that the amount of cells in the lungs may increase at later time points. Other radiopharmaceutical compounds such as indium-111 oxine would allow monitoring for up to 96 h, but have disadvantages, such as the interval of 18–24 h between infusion and imaging that is usually necessary, suboptimal photon energy, and a higher radiation burden for the cells and for the patient. We also used 99mTc-MAA perfusion scintigraphy to follow the likely pattern of distribution of the cells for up to 360 days after infusion.
No adverse events or deaths occurred among the patients treated with BMDMCs. Clinical, functional and radiological parameters were evaluated at 1-year follow-up. The clinical features of this group were stable throughout the follow-up period and no clinical signs or symptoms of bronchitis or pneumonia were observed after BMDMC administration. Even though a 1-year period is not long enough to allow definitive conclusions, it is well known that lung function deteriorates more quickly in patients with silicosis depending on continuation of exposure to silica dust, age and grade of lung lesions. The volunteers in our study were relatively young with moderate lung lesions, and exhibited clear stabilization of lung function, which could be attributable to the intervention. This hypothesis would be more clearly demonstrated if a control group with similar characteristics was added to the study. With regard to the quality of life questionnaires, no changes were seen after 360 days of follow-up. An early increase in perfusion at the base of both lungs was observed and sustained after BMDMC administration. Based on CT scan analysis, fibrosis was not prominent in the apex of the lung, but distributed across different lung segments. Therefore, the increased perfusion observed in both lung bases was likely not associated with a predominance of fibrosis in any specific segment of the lung. In line with this observation and based on our preclinical data showing that BMDMCs reduce fibrosis in a mouse model of silicosis, we may hypothesize that these cells mitigated progression of fibrosis through paracrine effects.
Since this is a safety study, analysis was only observational, and further larger-scale trials are necessary to fully examine the efficacy of BMDMCs in patients with silicosis.
Experimental studies have demonstrated the efficacy of systemic and intratracheal administration of BMDMCs in a murine model of silicosis that resembles human silicosis. BMDMC therapy (intratracheally or intravenously administered) reduced both lung inflammation and remodeling, thus improving lung mechanics, through paracrine signaling. Conversely, in the present study, no significant changes in lung function or quality of life indicators were observed over 360 days of analysis. The fact that the clinical result did not reflect the experimental data may be associated with differences in the course of the disease between animal models and humans, the number of cells administered, and the timing of analysis.
Our pilot study was limited by its small sample size; however, it was the first investigation to evaluate stem-cell therapy in silicotic patients. Further studies should be performed in a greater number of patients, with the addition of a control group, and in patients with mild and severe silicosis. Clinical trials evaluating the effects of MSC therapy in idiopathic lung fibrosis (ILF) have been published. However, this was the first study that analyzed the safety of autologous BMDMCs in patients with silicosis and, in contrast with the studies, no adverse events were observed. In this line, two clinical trials involving the endobronchial or systemic delivery of autologous adipose tissue-derived or placenta-derived mesenchymal stem cells demonstrated that these treatments are not safe in patients with IPF. In the first clinical trial, transient fever (50 % of patients), cough, dyspnea, and increased heart rate (14 % of patients) were observed following each endobronchial cell administration, and one patient experienced a change in absolute FVC of more than 10 % at 6 months, suggesting disease progression. A second phase 1b study on the use of exogenous placenta-derived MSCs in patients with IPF also observed adverse effects after therapy.
Future Perspectives
Clinical studies are required to evaluate the safety of different doses and treatment intervals of BMDMC administration and to analyze the efficacy of this approach, including pulmonary and systemic hemodynamics, lung function, hospitalizations, infections, and death. The use of a single infusion or repeated infusions also needs to be addressed, even though multiple infusions could lead to right heart overload (and pulmonary hypertension). Most patients with silicosis are not diagnosed in the early stages of the disease, but identification of these patients should be considered for a clinical trial of cell therapy. Clinical trials should include patients with different degrees of lung function impairment due to silicosis.
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