RESUMO
Recent progress in stem cell therapy has demonstrated the therapeutic potential of intravenous stem cell infusions for treating the life-threatening lung disease of pulmonary fibrosis (PF). However, it is confronted with limitations, such as a lack of control over cellular function and rapid clearance by the host after implantation. In this study, we developed an innovative PF therapy through tracheal administration of microfluidic-templated stem cell-laden microcapsules, which effectively reversed the progression of inflammation and fibrotic injury. Our findings highlight that hydrogel microencapsulation can enhance the persistence of donor mesenchymal stem cells (MSCs) in the host while driving MSCs to substantially augment their therapeutic functions, including immunoregulation and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling. We revealed that microencapsulation activates the MAPK signaling pathway in MSCs to increase MMP expression, thereby degrading overexpressed collagen accumulated in fibrotic lungs. Our research demonstrates the potential of hydrogel microcapsules to enhance the therapeutic efficacy of MSCs through cell-material interactions, presenting a promising yet straightforward strategy for designing advanced stem cell therapies for fibrotic diseases.
Assuntos
Cápsulas , Matriz Extracelular , Imunomodulação , Células-Tronco Mesenquimais , Fibrose Pulmonar , Animais , Matriz Extracelular/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Fibrose Pulmonar/terapia , Fibrose Pulmonar/patologia , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos Endogâmicos C57BL , Hidrogéis/química , Camundongos , MasculinoRESUMO
INTRODUCTION: Health research bodies recommend patient involvement and engagement in research and healthcare planning, although their implementation is not yet widespread. This deficiency extends to progressive pulmonary fibrosis (PPF), where crucial aspects remain unknown, including causal mechanisms, curative treatments and optimal symptom management. This study addresses these gaps by seeking stakeholders' perspectives to guide research and treatment directions. METHOD: A priority-setting partnership was established to explore stakeholders' priorities in the diagnosis, treatment, management and care of PPF, including idiopathic pulmonary fibrosis which is the archetypal PPF. Stakeholders included people living with PPF, their carers, relatives and healthcare professionals involved in their management. RESULTS: Through an online open-ended survey, 2542 responses were collected from 638 stakeholders. Thematic analysis identified 48 specific research questions, which were then cross-referenced with academic literature to pinpoint research gaps. Following the evidence check, 44 unanswered questions were shortlisted by 834 stakeholders in a second online survey. Ultimately, a top 10 priority list was established through consensus.The prioritised research questions include (1) improved diagnosis accuracy and timing, (2) development of new treatments, (3) enhanced accuracy in primary care, (4) optimal timing for drug and non-drug interventions, (5) effective cough treatment, (6) early intervention for PPF, (7) improved survival rates, (8) symptom reduction, (9) impact of interventions on life expectancy and (10) new treatments with reduced side effects. CONCLUSION: Stakeholders' priorities can be summarised into five areas: early diagnosis, drug and non-drug treatments, survival and symptom management. Ideally, these topics should guide funding bodies and health policies.
Assuntos
Progressão da Doença , Humanos , Reino Unido , Inquéritos e Questionários , Participação dos Interessados , Fibrose Pulmonar Idiopática/terapia , Fibrose Pulmonar Idiopática/diagnóstico , Pesquisa Biomédica , Masculino , Feminino , Fibrose Pulmonar/terapia , Prioridades em Saúde , PesquisaRESUMO
Pulmonary fibrosis is a complex and multifactorial condition that involves a cascade of events, including lung injury, damage of alveolar epithelial cells (AECs), generation of immune cell-driven inflammation, and activation of fibroblasts and their differentiation into myofibroblasts, resulting in the excessive production and deposition of collagen and progressive scarring and fibrosis of the lung tissue. As lung fibrosis advances, the scarring and stiffening of lung tissue can significantly hinder the exchange of oxygen and carbon dioxide, potentially leading to respiratory failure that can be life-threatening. Anti-inflammatory and immunosuppressive drugs are used to slow down the progression of the disease, manage symptoms, and enhance the patient's quality of life. However, prolonged immunosuppression could increase the susceptibility to severe bacterial, viral, or fungal pneumonia in lung-transplant recipients. Therefore, there is an urgent need for new therapeutic agents that can effectively reduce lung inflammation and fibrosis without compromising the protective immune response in patients with severe lung fibrosis. Results obtained in recently published studies demonstrated that mesenchymal stem/stromal cell-derived microRNAs (MSC-miRNAs) could attenuate detrimental immune response in injured lungs and prevent progression of lung fibrosis. Through the post-transcriptional regulation of target mRNA, MSC-miRNAs modulate protein synthesis and affect viability, proliferation, and cytokine production in AECs, fibroblasts, and lung-infiltrated immune cells. In order to delineate molecular mechanisms responsible for beneficial effects of MSC-miRNAs in the treatment of lung fibrosis, in this review article, we summarized current knowledge related to anti-fibrotic and anti-inflammatory pathways elicited in immune cells, AECs, and myofibroblasts by MSC-miRNAs.
Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Fibrose Pulmonar , Humanos , MicroRNAs/metabolismo , MicroRNAs/genética , Fibrose Pulmonar/terapia , Fibrose Pulmonar/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Transplante de Células-Tronco Mesenquimais/métodosRESUMO
BACKGROUND: Although bone marrow-derived cells with high aldehyde dehydrogenase activity (ALDHbr) have shown therapeutic potential against various diseases in animal studies, clinical trials have failed to show concurrent findings. We aimed to clarify the optimal conditions for the efficacy of ALDHbr cells by using a murine bleomycin-induced pulmonary fibrosis model. METHODS: We intravenously transferred male or female donor C57BL/6 mice-derived ALDHbr cells into recipient C57BL/6 mice under various conditions, and used mCherry-expressing mice as a donor to trace the transferred ALDHbr cells. RESULTS: Pulmonary fibrosis improved significantly when (1) female-derived, not male-derived, and (2) lineage (Lin)-negative, not lineage-positive, ALDHbr cells were transferred during the (3) fibrotic, not inflammatory, phase. Consistent with the RNA-sequencing results, female-derived Lin-/ALDHbr cells were more resistant to oxidative stress than male-derived cells in vitro, and transferred female-derived Lin-/ALDHbr cells were more viable than male-derived cells in the fibrotic lung. The mechanism underlying the antifibrotic effects of Lin-/ALDHbr cells was strongly associated with reduction of oxidative stress. CONCLUSIONS: Our results indicated that Lin-/ALDHbr cell therapy could ameliorate pulmonary fibrosis by reducing oxidative stress and suggested that their efficacy was mediated by sex-related differences. Thus, sex-awareness strategies may be important for clinical application of bone marrow ALDHbr cells as a therapeutic tool.
Assuntos
Aldeído Desidrogenase , Células da Medula Óssea , Camundongos Endogâmicos C57BL , Fibrose Pulmonar , Animais , Camundongos , Feminino , Masculino , Fibrose Pulmonar/patologia , Fibrose Pulmonar/terapia , Fibrose Pulmonar/induzido quimicamente , Células da Medula Óssea/citologia , Aldeído Desidrogenase/metabolismo , Aldeído Desidrogenase/genética , Bleomicina , Modelos Animais de Doenças , Estresse OxidativoRESUMO
Pulmonary fibrosis is a progressive disease caused by interstitial inflammation. Treatments are extremely scarce; therapeutic drugs and transplantation therapies are not widely available due to cost and a lack of donors, respectively. Recently, there has been a high interest in regenerative medicine and exponential advancements in stem cell-based therapies have occurred. However, a sensitive imaging technique for investigating the in vivo dynamics of transplanted stem cells has not yet been established and the mechanisms of stem cell-based therapy remain largely unexplored. In this study, we administered mouse adipose tissue-derived mesenchymal stem cells (mASCs) labeled with quantum dots (QDs; 8.0 nM) to a mouse model of bleomycin-induced pulmonary fibrosis in an effort to clarify the relationship between in vivo dynamics and therapeutic efficacy. These QD-labeled mASCs were injected into the trachea of C57BL/6 mice seven days after bleomycin administration to induce fibrosis in the lungs. The therapeutic effects and efficacy were evaluated via in vivo/ex vivo imaging, CT imaging, and H&E staining of lung sections. The QD-labeled mASCs remained in the lungs longer and suppressed fibrosis. The 3D imaging results showed that the transplanted cells accumulated in the peripheral and fibrotic regions of the lungs. These results indicate that mASCs may prevent fibrosis. Thus, QD labeling could be a suitable and sensitive imaging technique for evaluating in vivo kinetics in correlation with the efficacy of cell therapy.
Assuntos
Bleomicina , Modelos Animais de Doenças , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , Fibrose Pulmonar , Animais , Bleomicina/efeitos adversos , Bleomicina/toxicidade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/terapia , Fibrose Pulmonar/patologia , Camundongos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Pontos Quânticos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Tomografia Computadorizada por Raios X , Tecido Adiposo/citologia , Tecido Adiposo/diagnóstico por imagemRESUMO
Idiopathic pulmonary fibrosis is a major cause of death with few treatment options. Here, we demonstrate the therapeutic efficacy for lung fibrosis of adult lung cell transplantation using a single-cell suspension of the entire lung in two distinct mouse systems: bleomycin treatment and mice lacking telomeric repeat-binding factor 1 expression in alveolar type 2 (AT2) cells (SPC-Cre TRF1fl/fl), spontaneously developing fibrosis. In both models, the progression of fibrosis was associated with reduced levels of host lung progenitors, enabling engraftment of donor progenitors without any additional conditioning, in contrast to our previous studies. Two months after transplantation, engrafted progenitors expanded to form numerous donor-derived patches comprising AT1 and AT2 alveolar cells, as well as donor-derived mesenchymal and endothelial cells. This lung chimerism was associated with attenuation of fibrosis, as demonstrated histologically, biochemically, by computed tomography imaging, and by lung function measurements. Our study provides a strong rationale for the treatment of lung fibrosis using lung cell transplantation.
Assuntos
Modelos Animais de Doenças , Animais , Camundongos , Bleomicina , Fibrose Pulmonar/terapia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/metabolismo , Pulmão/patologia , Pulmão/metabolismo , Fibrose Pulmonar Idiopática/terapia , Fibrose Pulmonar Idiopática/patologia , Transplante de Pulmão/efeitos adversosRESUMO
Idiopathic pulmonary fibrosis (IPF) is characterised by lung scarring and stiffening, for which there is no effective cure. Based on the immunomodulatory and anti-fibrotic effects of induced pluripotent stem cell (iPSC) and mesenchymoangioblast-derived mesenchymal stem cells (iPSCs-MSCs), this study evaluated the therapeutic effects of iPSCs-MSCs in a bleomycin (BLM)-induced model of pulmonary fibrosis. Adult male C57BL/6 mice received a double administration of BLM (0.15â¯mg/day) 7-days apart and were then maintained for a further 28-days (until day-35), whilst control mice were administered saline 7-days apart and maintained for the same time-period. Sub-groups of BLM-injured mice were intravenously-injected with 1×106 iPSC-MSCs on day-21 alone or on day-21 and day-28 and left until day-35 post-injury. Measures of lung inflammation, fibrosis and compliance were then evaluated. BLM-injured mice presented with lung inflammation characterised by increased immune cell infiltration and increased pro-inflammatory cytokine expression, epithelial damage, lung transforming growth factor (TGF)-ß1 activity, myofibroblast differentiation, interstitial collagen fibre deposition and topology (fibrosis), in conjunction with reduced matrix metalloproteinase (MMP)-to-tissue inhibitor of metalloproteinase (TIMP) ratios and dynamic lung compliance. All these measures were ameliorated by a single or once-weekly intravenous-administration of iPSC-MSCs, with the latter reducing dendritic cell infiltration and lung epithelial damage, whilst promoting anti-inflammatory interleukin (IL)-10 levels to a greater extent. Proteomic profiling of the conditioned media of cultured iPSC-MSCs that were stimulated with TNF-α and IFN-γ, revealed that these stem cells secreted protein levels of immunosuppressive factors that contributed to the anti-fibrotic and therapeutic potential of iPSCs-MSCs as a novel treatment option for IPF.
Assuntos
Bleomicina , Células-Tronco Pluripotentes Induzidas , Pulmão , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , Fibrose Pulmonar , Animais , Masculino , Células-Tronco Mesenquimais/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fibrose Pulmonar/terapia , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Fator de Crescimento Transformador beta1/metabolismoRESUMO
PURPOSE OF REVIEW: Pulmonary fibrosis (PF) negatively influences health-related quality of life (HRQOL). Patients living with PF have voiced the desire for a focus on symptoms and HRQOL in both disease monitoring and treatment decisions. RECENT FINDINGS: Currently available disease modifying treatments do little to impact HRQOL. Newer studies evaluating pharmacologic and nonpharmacologic therapies targeting symptoms and HRQOL in PF have been conducted with some promising results. There is increasing recognition of the importance of incorporating HRQOL as a higher tier endpoint in clinical trials. Disease-specific measure of HRQOL have been developed for those living with PF, and there is ongoing work to better understand the validity and reliability characteristics of these tools. In addition to research, there is recognition of the potential benefits of measuring HRQOL and symptoms in clinical practice in facilitate integrating patient perspective into care and allow for more personalized treatment approaches. SUMMARY: There is increased momentum to discover treatments that impact HRQOL in PF. More work is desperately needed to identify better treatment targets, and to incorporate HRQOL and symptoms as higher tier endpoints in clinical trials. Further work is also needed to address the practicalities of integrating HRQOL measurement into clinical care.
Assuntos
Fibrose Pulmonar , Qualidade de Vida , Humanos , Fibrose Pulmonar/terapia , Fibrose Pulmonar/psicologia , Reprodutibilidade dos TestesRESUMO
PURPOSE OF REVIEW: Updated clinical practice guidelines for pulmonary fibrosis recommend early integrated palliative care using a primary palliative approach. Clinicians need to be aware of the various palliative interventions in order to implement guidelines' recommendations. This review provides an update on evidence-based palliative therapies. RECENT FINDINGS: Literature review indicates early integration of palliative care in pulmonary fibrosis is feasible and meets patient needs. Key components of a primary palliative approach include comprehensive symptoms and needs screening, systematic symptom management using nonpharmacologic interventions, supplemental oxygen and opioids for dyspnea and cough. Patient-centered communication is essential for successful integration of palliative care. Early, iterative advance care planning in clinic to understand patient goals, values and preferences for current and future care, improves patient care and satisfaction. Prioritizing caregiver inclusion in clinics can address their needs. Collaborating with a multidisciplinary allied team facilitates integration of palliative care and supports patients throughout the disease course. Different models of palliative care delivery exist and can be adapted for local use. The use of artificial intelligence algorithms and tools may improve care and continuity. SUMMARY: Clinicians must develop competency in palliative care. Organizational and policy support is essential to enable seamless integration of palliative care throughout the care continuum.
Assuntos
Cuidados Paliativos , Fibrose Pulmonar , Humanos , Cuidados Paliativos/métodos , Fibrose Pulmonar/terapia , Planejamento Antecipado de Cuidados , Guias de Prática Clínica como Assunto , Assistência Centrada no PacienteRESUMO
Pulmonary fibrosis is a kind of fibrotic interstitial pneumonia with poor prognosis. Aging, environmental pollution, and coronavirus disease 2019 are considered as independent risk factors for pulmonary fibrogenesis. Consequently, the morbidity and mortality striking continues to rise in recent years. However, the clinical therapeutic efficacy is very limited and unsatisfactory. So it is necessary to develop a new effective therapeutic approach for pulmonary fibrosis. Human umbilical cord mesenchymal stem cells (hucMSCs) are considered as a promising treatment for various diseases because of their multiple differentiation and immunomodulatory function. The key bottleneck in the clinical application of hucMSCs therapy is the high-quality and large-scale production. This study used FloTrix miniSpin bioreactor, a three-dimensional (3D) cell culture system, for large-scale expansion of hucMSCs in vitro, and proved 3D cultured hucMSCs inhibited the differentiation of fibroblasts into myofibroblasts and myofibroblasts proliferation and migration, leading to slow down the development of pulmonary fibrosis. Further mechanistic studies clarified that hucMSCs reduced the amount of binding between circELP2 and miR-630, resulting in blocking YAP/TAZ translocation from cytoplasm to nucleus. This condition inhibited mitochondrial fusion and promoted mitochondrial fission, and ultimately improved fusion/fission balance and cellular homeostasis. To sum up, this work clarified the anti-fibrosis and mechanism of hucMSCs cultured from the 3D FloTrix miniSpin bioreactor. We hope to provide new ideas and new methods for the clinical transformation and industrialization of hucMSCs therapy.
Assuntos
Células-Tronco Mesenquimais , Dinâmica Mitocondrial , Fibrose Pulmonar , Cordão Umbilical , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Cordão Umbilical/citologia , Fibrose Pulmonar/terapia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Animais , Diferenciação Celular , Técnicas de Cultura de Células em Três Dimensões/métodos , Células Cultivadas , Proliferação de CélulasRESUMO
INTRODUCTION: Progressive pulmonary fibrosis (PPF) is a manifestation of a heterogenous group of underlying interstitial lung disease (ILD) diagnoses, defined as non-idiopathic pulmonary fibrosis (IPF) progressive fibrotic ILD meeting at least two of the following criteria in the previous 12 months: worsening respiratory symptoms, absolute decline in forced vital capacity (FVC) more than or equal to 5% and/or absolute decline in diffusing capacity for carbon monoxide (DLCO) more than or equal to 10% and/or radiological progression. AREAS COVERED: The authors subjectively reviewed a synthesis of literature from PubMed to identify recent advances in the diagnosis and characterisation of PPF, treatment recommendations, and management challenges. This review provides a comprehensive summary of recent advances and highlights future directions for the diagnosis, management, and treatment of PPF. EXPERT OPINION: Recent advances in defining the criteria for PPF diagnosis and licensing of treatment are likely to support further characterisation of the PPF patient population and improve our understanding of prevalence. The diagnosis of PPF remains challenging with the need for a specialised ILD multidisciplinary team (MDT) approach. The evidence base supports the use of immunomodulatory therapy to treat inflammatory ILDs and antifibrotic therapy where PPF develops. Treatment needs to be tailored to the specific underlying disease and determined on a case-by-case basis.
Assuntos
Antifibróticos , Progressão da Doença , Fibrose Pulmonar , Humanos , Fibrose Pulmonar/fisiopatologia , Fibrose Pulmonar/terapia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/diagnóstico , Antifibróticos/uso terapêutico , Capacidade Vital , Doenças Pulmonares Intersticiais/fisiopatologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/terapia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Pulmonary fibrosis is a pathological hallmark of lung injury. It is an aggressive disease that replaces normal lung parenchyma by fibrotic tissue. The transforming growth factor-beta-mothers against decapentaplegic homolog 3 (TGF-ß1-Smad3) signaling pathway plays a key role in regulating lung fibrosis. Decorin (DCN), a small leucine-rich proteoglycan, has a modulatory effect on the immune system by reversibly binding with TGF-ß and reducing its bioavailability. Mesenchymal stem cell (MSC) therapy is a new strategy that has an immune-modulatory capacity. OBJECTIVE: The aim of this study was to introduce a new therapeutic approach to harness remodeling in injured lung. MATERIAL AND METHODS: Bone marrow MSCs were isolated and transduced by decorin gene. Lung injury was induced by bleomycin and mice were treated with MSCs, MSCs-decorin, and decorin. Then, oxidative stress biomarkers, remodeling biomarkers, bronchoalveolar lavage cells, and histopathology study were conducted. RESULTS: Reduced catalase and superoxide dismutase increased due to treatments. Elevated malondialdehyde, hydroxyproline, TGF-ß levels, and polymorphonuclear cells count decreased in the treated groups. Additionally, the histopathology of lung tissues showed controlled inflammation and fibrosis. CONCLUSION: Transfected decorin gene to MSCs and used cell therapy could control remodeling and bleomycin-induced lung injury.
Assuntos
Bleomicina , Decorina , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Fibrose Pulmonar , Decorina/genética , Decorina/metabolismo , Animais , Camundongos , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/terapia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/terapia , Lesão Pulmonar/imunologia , Lesão Pulmonar/genética , Transdução Genética , Estresse Oxidativo , Células Cultivadas , Modelos Animais de Doenças , Masculino , HumanosRESUMO
BACKGROUND: Pulmonary fibrosis is a progressive disease with high incidence and poor prognosis. It is urgent to explore new therapeutic methods for pulmonary fibrosis. As a new treatment method, gene therapy has attracted more and more attention. CCDC59 is a transcriptional coactivator of SP-B and SP-C. Our study mainly aims to explore the effect of overexpression of CCDC59 gene in pulmonary fibrosis of mice. METHODS: CCDC59 overexpressing lentivirus was constructed and then concentrated. RT-qPCR, Western blotting, and immunofluorescence assays were used to detect the expression of CCDC59, SP-B and SP-C protein in cell line and lung tissues after infected with lentivirus. Immunohistochemical staining and hematoxylin-eosin staining assays were used to assess the degree of fibrosis and ELISA assay was used to detect the concentrations of inflammatory factors, SP-B, and SP-C in bronchoalveolar lavage fluid of mice. Dynamic changes of mice lung function at various time points were assessed by lung function test assay. HIPPO pathway and proliferation capacity of alveolar type II epithelial cells were evaluated by immunofluorescence staining and Western blotting. RESULTS: Results showed that endotracheal instillation of CCDC59 overexpressed lentivirus significantly alleviated bleomycin-induced inflammation and pulmonary fibrosis in mice. Overexpression of CCDC59 protein in type II alveolar epithelial cells can enhance the expression of SP-B and SP-C. Overexpression of CCDC59 protein significantly protected against pulmonary inflammatory response and improved lung function of mice. Overexpression of CCDC59 protein significantly alleviated the hyperactivation of HIPPO pathway and increased the proliferative capacity of type II alveolar epithelial cells in lung. CONCLUSION: CCDC59 can alleviate inflammation and pulmonary fibrosis in mice by upregulating the expression of SP-B and SP-C in type II alveolar epithelial cells and alleviating the hyperactivation of HIPPO pathway. Our study offers a new potential treatment for pulmonary fibrosis.
Assuntos
Fibrose Pulmonar , Proteína C Associada a Surfactante Pulmonar , Animais , Humanos , Masculino , Camundongos , Bleomicina , Modelos Animais de Doenças , Lentivirus/genética , Pulmão/patologia , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Pneumonia/genética , Pneumonia/terapia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/terapia , Proteína C Associada a Surfactante Pulmonar/genética , Proteína C Associada a Surfactante Pulmonar/metabolismoRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung interstitial lesions with the disease pathophysiology incompletely understood, which is a serious and fatal disorder with limited treatment options. Mesenchymal stem cells (MSCs) have exhibited promising therapeutic capability for IPF. While most types of MSCs are obtained invasively, urine-derived stem cells (USCs) can be gained in a safe, noninvasive, and inexpensive procedure, which are readily available and reported to exhibit no risk of teratoma formation or oncogenic potential in vivo, sounding alternative to other MSCs. This study aims to investigate the therapeutic effect and mechanism of USCs on IPF, using a bleomycin (BLM)-induced IPF model in mice. METHODS: Cell surface marker examination by flow cytometry analysis and cell differentiation culture were used to characterize USCs obtained from healthy individuals. BLM was instilled endotracheally in adult C57BL/6 mice, followed by USCs or human bone marrow-derived mesenchymal stem cells (BMSCs) treatment by tail vein injection on day 14. Mice were euthanized on day 14 before administration or day 21 for the evaluation of pulmonary histopathology and hydroxyproline (HYP) content. Inflammatory factors of the lung, including transforming growth factor (TGF)-ß1, TNF-α, IL-6, MMP2 were analyzed by quantitative real-time PCR (qRT-PCR). Additionally, immunohistochemistry (IHC) and western blotting (WB) were applied to evaluate the expression of α-SMA and activation of TGF-ß1-Smad2/3 in lung. RESULTS: USCs highly expressed CD29 and CD90, showing negative expression of hematopoietic stem cell markers (CD45, CD34) and could differentiate into, at least, bone and fat in vitro. In mice challenged with BLM, septal thickening and prominent fibrosis were observed on day 14, with higher HYP content and mRNA levels of TGF-ß1, TNF-α and IL-6 exhibited, compared to untreated mice. USCs could migrate to lung and accumulate there in mouse model after intravenous injection. Transplantation of USCs into BLM-induced mice improved their pulmonary histopathology, decreasing Ashcroft score, Szapiel score, HYP content and mRNA levels of TGF-ß1 and MMP2 of lung, similar to the effects of BMSCs. IHC and WB further revealed that USCs could inhibit activation of the TGFß1-Smad2/3 pathway of lung in vivo. CONCLUSIONS: Transplantation of USCs effectively reverses pulmonary fibrotic phenotype in an experimental IPF model, inhibiting the TGF-ß1-Smad2/3 pathway, a key driver of fibrosis. These results suggest the therapeutic application of USCs for IPF, instead of other types of MSCs obtained invasively.
Assuntos
Bleomicina , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Transdução de Sinais , Proteína Smad2 , Proteína Smad3 , Fator de Crescimento Transformador beta1 , Animais , Camundongos , Fator de Crescimento Transformador beta1/metabolismo , Proteína Smad2/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Proteína Smad3/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/terapia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Diferenciação Celular/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Masculino , Fibrose Pulmonar Idiopática/terapia , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologiaRESUMO
PURPOSE OF REVIEW: To review the current understanding of the impact, mechanisms and treatments for cough in patients with interstitial lung disease (ILD). Evidence suggests that cough is a prevalent symptom in patients with ILD and has a significant impact on patients. RECENT FINDINGS: There is increasing interest in the role of cough hypersensitivity as seen in chronic refractory cough in patients with ILD, and encouraging recent results suggest that ILD-associated cough responds to opiate therapy. SUMMARY: Understanding the aetiology of cough in patients with ILD is crucial to continue to develop therapies which might be effective in reducing cough and increasing quality of life.
Assuntos
Tosse , Doenças Pulmonares Intersticiais , Qualidade de Vida , Humanos , Tosse/etiologia , Tosse/terapia , Doenças Pulmonares Intersticiais/terapia , Doenças Pulmonares Intersticiais/complicações , Fibrose Pulmonar/complicações , Fibrose Pulmonar/terapia , Doença CrônicaRESUMO
COVID-19 is caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and manifests primarily as acute lung injury with diffuse interstitial lung disease evident in imaging. Patients often present with clinical features similar to those of autoimmune diseases and share imaging, treatment and serological similarities with autoimmune-related interstitial lung diseases. The association between autoimmune abnormalities and post-COVID-19 pulmonary fibrosis is also recognized. This article provided a comprehensive review of the pathogenic mechanisms, clinical manifestations, and therapeutic interventions associated with autoimmune abnormalities induced by SARS-CoV-2 infection.
Assuntos
Doenças Autoimunes , COVID-19 , Doenças Pulmonares Intersticiais , SARS-CoV-2 , Humanos , COVID-19/complicações , COVID-19/imunologia , COVID-19/terapia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/terapia , Doenças Autoimunes/terapia , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/terapiaRESUMO
BACKGROUND: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders, a subset of which develop progressive pulmonary fibrosis (PPF). There is little information on the epidemiology and treatment of PPFs in Japan. This retrospective cohort study estimated the incidence probability of progression to PPFs in patients with fibrosing ILDs other than idiopathic pulmonary fibrosis in a real-world Japanese setting. Management procedures and treatment patterns were also quantified. METHODS: Data were extracted from the Medical Data Vision database from 01-Jan-2012 to 28-May-2020, comprising a 6.91-year patient identification period, 1-year pre-index period, and post-index period. The primary outcome was the cumulative incidence probability of progression to PPF up to 24 months. Subgroup analyses were performed by the presence/absence of connective tissue disease-ILD and by pre-specified ILD clinical diagnosis. RESULTS: Of the 34,960 eligible patients (mean age: 71.1 years, males: 52.5%), 14,580 (41.7%) progressed to PPF. The 24-month incidence probability of progression to PPF was 39.5%. A relatively comparable percentage of patients progressed across all ILD subtypes. Oral corticosteroids and tacrolimus were the most common therapies during the pre- and post-index periods. Treatment rates were very low in the post-index period. CONCLUSIONS: This is the first claims database study to estimate the incidence probability of progression to PPF in Japan. Progression appeared common in patients with chronic fibrosing ILDs, with comparable percentages of patients across all subtypes developing PPF at 2 years. Future studies should assess the impact of regular monitoring and early intervention on treating fibrotic ILDs and preventing progression.
Assuntos
Bases de Dados Factuais , Progressão da Doença , Fibrose Pulmonar , Humanos , Japão/epidemiologia , Idoso , Masculino , Incidência , Feminino , Fibrose Pulmonar/epidemiologia , Fibrose Pulmonar/terapia , Estudos Retrospectivos , Pessoa de Meia-Idade , Tacrolimo/administração & dosagem , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/terapia , Estudos de Coortes , Idoso de 80 Anos ou maisRESUMO
Pulmonary Fibrosis (PF) describes a group of lung diseases characterised by progressive scarring (fibrosis). Symptoms worsen over time and include breathlessness, tiredness, and cough, giving rise to psychological distress. Significant morbidity accompanies PF, so ensuring patients' care needs are well defined and provided for, represents an important treatment strategy. The purpose of this systematic review was to synthesise what is currently known about the psychosocial morbidity, illness experience and needs of people with pulmonary fibrosis and their informal caregivers. Eight databases (MEDLINE, EMBASE, PUBMED, Cochrane database of Systematic reviews (CDSR), Web of Science Social Sciences Citation Index, PsycINFO, PsycARTICLES and CINAHL) were used to identify studies exploring the supportive needs of adults with PF and/or their caregivers. Methodological quality was assessed using the Mixed Methods Appraisal Tool. 53 studies were included, the majority using qualitative methodology (79 %, 42/53), 6 as part of mixed methodological studies. Supportive care needs were mapped to eight domains using an a priori framework analysis. Findings highlight a lack of psychological support throughout the course of the illness, misconceptions about and barriers to, the provision of palliative care despite its potential positive impacts. Patients and caregivers express a desire for greater disease specific education and information provision throughout the illness. Trials of complex interventions are needed to address the unique set of challenges for patients and carers living with PF.
Assuntos
Cuidadores , Fibrose Pulmonar , Humanos , Cuidadores/psicologia , Fibrose Pulmonar/psicologia , Fibrose Pulmonar/terapia , Cuidados Paliativos/psicologia , Apoio Social , Adulto , Masculino , Feminino , Qualidade de VidaRESUMO
Interstitial lung diseases (ILDs) in adults and children (chILD) are a heterogeneous group of lung disorders leading to inflammation, abnormal tissue repair and scarring of the lung parenchyma often resulting in respiratory failure and death. Inherited factors directly cause, or contribute significantly to the risk of developing ILD, so called familial pulmonary fibrosis (FPF), and monogenic forms may have a poor prognosis and respond poorly to current treatments. Specific, variant-targeted or precision treatments are lacking. Clinical trials of repurposed drugs, anti-fibrotic medications and specific treatments are emerging but for many patients no interventions exist. We convened an expert working group to develop an overarching framework to address the existing research gaps in basic, translational, and clinical research and identified areas for future development of preclinical models, candidate medications and innovative clinical trials. In this Position Paper, we summarise working group discussions, recommendations, and unresolved questions concerning precision treatments for FPF.
Assuntos
Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Animais , Gerenciamento Clínico , Fibrose Pulmonar/terapia , Fibrose Pulmonar/genética , Fibrose Pulmonar/etiologia , Ensaios Clínicos como AssuntoRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown origin with limited treatment options and poor prognosis. The encouraging findings from preclinical investigations utilizing mesenchymal stem cells (MSCs) indicated that they could serve as a promising therapeutic alternative for managing chronic lung conditions, such as IPF. The objective of this study was to compare the efficiency of bone marrow-derived MSCs (BM-MSCs) versus prednisolone, the standard anti-inflammatory medication, in rats with bleomycin (BLM)-induced lung fibrosis. Four groups were created: a control group, a BLM group, a prednisolone-treated group, and a BM-MSCs-treated group. To induce lung fibrosis, 5â mg/kg of BLM was administered intratracheally. BLM significantly increased serum levels of pro-inflammatory cytokines and oxidative stress markers. The disturbed lung structure was also revealed by light and transmission electron microscopic studies. Upregulation in the immune expression of alpha-smooth muscle actin, transforming growth factor beta-1, and Bax was demonstrated. Interestingly, all findings significantly regressed on treatment with prednisolone and BM-MSCs. However, treatment with BM-MSCs showed better results than with prednisolone. In conclusion, BM-MSCs could be a promising approach for managing lung fibrosis.