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2.
J Ethnopharmacol ; 283: 114701, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34606948

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Xuanfei Baidu Decoction (XFBD), one of the "three medicines and three prescriptions" for the clinically effective treatment of COVID-19 in China, plays an important role in the treatment of mild and/or common patients with dampness-toxin obstructing lung syndrome. AIM OF THE STUDY: The present work aims to elucidate the protective effects and the possible mechanism of XFBD against the acute inflammation and pulmonary fibrosis. METHODS: We use TGF-ß1 induced fibroblast activation model and LPS/IL-4 induced macrophage inflammation model as in vitro cell models. The mice model of lung fibrosis was induced by BLM via endotracheal drip, and then XFBD (4.6 g/kg, 9.2 g/kg) were administered orally respectively. The efficacy and molecular mechanisms in the presence or absence of XFBD were investigated. RESULTS: The results proved that XFBD can effectively inhibit fibroblast collagen deposition, down-regulate the level of α-SMA and inhibit the migration of fibroblasts. IL-4 induced macrophage polarization was also inhibited and the secretions of the inflammatory factors including IL6, iNOS were down-regulated. In vivo experiments, the results proved that XFBD improved the weight loss and survival rate of the mice. The XFBD high-dose administration group had a significant effect in inhibiting collagen deposition and the expression of α-SMA in the lungs of mice. XFBD can reduce bleomycin-induced pulmonary fibrosis by inhibiting IL-6/STAT3 activation and related macrophage infiltration. CONCLUSIONS: Xuanfei Baidu Decoction protects against macrophages induced inflammation and pulmonary fibrosis via inhibiting IL-6/STAT3 signaling pathway.


Assuntos
COVID-19/tratamento farmacológico , Medicamentos de Ervas Chinesas , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , SARS-CoV-2 , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Fitoterapia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle , Células RAW 264.7 , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
3.
Sci Total Environ ; 807(Pt 1): 150623, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-34610407

RESUMO

BACKGROUND: Epidemiological studies suggest increased risk of lung cancer associated with diesel exhaust (DE) exposure. However, DE-induced lung fibrosis may lead to cancer and needs investigation. OBJECTIVES: To study the mechanism involved in the initiation of DE- induced lung fibrosis. METHODS: C57BL/6 mice were exposed to DE for 30 min/day for 5 days/weeks for 8 weeks. Pulmonary function test was performed to measure lung function. Mice were euthanized to collect BALF, blood, and lung tissue. BALF was used for cell count and cytokine analysis. Lung tissue slides were stained to examine structural integrity. RNA from lung tissue was used for RT-PCR. Immunoblots were performed to study fibrosis and EMT pathway. RESULTS: Mice exposed to DE increase lung resistance and tissue elastance with decrease in inspiratory capacity (p < 0.05) suggesting lung function impairment. BALF showed significantly increased macrophages, neutrophils and monocytes (p < 0.01). Additionally, there was an increase in inflammation and alveolar wall thickening in lungs (p < 0.01) correlates with cellular infiltration. Macrophages had black soot deposition in lung tissue of DE exposed mice. Lung section staining revealed increase in mucus producing goblet cells for clearance of soot in lung. DE exposed lung showed increased collagen deposition and hydroxyproline residue (p < 0.01). Repetitive exposure of DE in mice lead to tissue remodeling in lung, demonstrated by fibrotic foci and smooth muscles. A significant increase in α-SMA and fibronectin (p < 0.05) in lung indicate progression of pulmonary fibrosis. TGF-ß/Smad3 signaling was activated with increase in P-smad3 expression in DE exposed mice. Decreased expression of E-cadherin and increased vimentin (p < 0.05) in lungs of DE exposed mice indicate epithelial to mesenchymal transition. CONCLUSION: DE exposure to mice induced lung injury and pulmonary fibrosis thereby remodeling tissue. The study demonstrates TGF-ß/SMAD3 pathway involvement with an activation of EMT in DE exposed mice.


Assuntos
Fibrose Pulmonar , Animais , Transição Epitelial-Mesenquimal , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Transdução de Sinais , Fator de Crescimento Transformador beta , Emissões de Veículos/toxicidade
4.
Cells ; 10(12)2021 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-34943963

RESUMO

Cellular senescence is the arrest of normal cell division and is commonly associated with aging. The interest in the role of cellular senescence in lung diseases derives from the observation of markers of senescence in chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (IPF), and pulmonary hypertension (PH). Accumulation of senescent cells and the senescence-associated secretory phenotype in the lung of aged patients may lead to mild persistent inflammation, which results in tissue damage. Oxidative stress due to environmental exposures such as cigarette smoke also promotes cellular senescence, together with additional forms of cellular stress such as mitochondrial dysfunction and endoplasmic reticulum stress. Growing recent evidence indicate that senescent cell phenotypes are observed in pulmonary artery smooth muscle cells and endothelial cells of patients with PH, contributing to pulmonary artery remodeling and PH development. In this review, we analyze the role of different senescence cell phenotypes contributing to the pulmonary artery remodeling process in different PH clinical entities. Different molecular pathway activation and cellular functions derived from senescence activation will be analyzed and discussed as promising targets to develop future senotherapies as promising treatments to attenuate pulmonary artery remodeling in PH.


Assuntos
Senescência Celular/genética , Hipertensão Pulmonar/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fibrose Pulmonar/genética , Envelhecimento/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Hipertensão Pulmonar/patologia , Inflamação/genética , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Estresse Oxidativo/genética , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Fibrose Pulmonar/patologia
5.
Pan Afr Med J ; 40: 169, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34970411

RESUMO

Twenty months into the COVID-19 pandemic, we are still learning about the various long-term consequences of COVID-19 infection. While many patients do recover with minimal long-term consequences, some patients develop irreversible parenchymal and interstitial lung damage leading to diffuse pulmonary fibrosis. Unfortunately, these are some of the consequences of post-SARS-CoV-2 infection which thousands more people around the world will experience and which will outlast the pandemic for a long time to come. It is now being observed at various leading medical centres around the world that lung transplantation may be the only meaningful treatment available to a select group of patients experiencing serious lung damage and non-resolving COVID-19-associated respiratory failure, resulting from the triad of coronavirus infection, a hyper-inflammatory immune response to it and the inability of the human body to repair that injury.


Assuntos
COVID-19 , Transplante de Pulmão , Fibrose Pulmonar , Humanos , Incidência , Pulmão/patologia , Pandemias , Fibrose Pulmonar/epidemiologia , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , SARS-CoV-2
6.
Sci Rep ; 11(1): 19979, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620968

RESUMO

COVID-19 pandemic led to a worldwide increase of hospitalizations for interstitial pneumonia with thrombosis complications, endothelial injury and multiorgan disease. Common CT findings include lung bilateral infiltrates, bilateral ground-glass opacities and/or consolidation whilst no current laboratory parameter consents rapidly evaluation of COVID-19 risk and disease severity. In the present work we investigated the association of sFLT-1 and CA 15.3 with endothelial damage and pulmonary fibrosis. Serum sFlt-1 has been associated with endothelial injury and sepsis severity, CA 15.3 seems an alternative marker for KL-6 for fibrotic lung diseases and pulmonary interstitial damage. We analysed 262 SARS-CoV-2 patients with differing levels of clinical severity; we found an association of serum sFlt-1 (ROC AUC 0.902, decision threshold > 90.3 pg/mL, p < 0.001 Sens. 83.9% and Spec. 86.7%) with presence, extent and severity of the disease. Moreover, CA 15.3 appeared significantly increased in COVID-19 severe lung fibrosis (ICU vs NON-ICU patients 42.6 ± 3.3 vs 25.7 ± 1.5 U/mL, p < 0.0001) and was associated with lung damage severity grade (ROC AUC 0.958, decision threshold > 24.8 U/mL, p < 0.0001, Sens. 88.4% and Spec. 91.8%). In conclusion, serum levels of sFlt-1 and CA 15.3 appeared useful tools for categorizing COVID-19 clinical stage and may represent a valid aid for clinicians to better personalise treatment.


Assuntos
COVID-19/sangue , Mucina-1/sangue , Fibrose Pulmonar/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Idoso , Biomarcadores/sangue , COVID-19/complicações , COVID-19/patologia , Feminino , Humanos , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/complicações , Fibrose Pulmonar/patologia , SARS-CoV-2/isolamento & purificação
7.
Adv Respir Med ; 89(5): 477-483, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34612504

RESUMO

INTRODUCTION: COVID-19-associated pulmonary sequalae have been increasingly reported after recovery from acute infection. Therefore, we aim to explore the charactersitics of persistent lung parenchymal abnormalities in patients with COVID-19. MATERIAL AND METHODS: An observational study was conducted in patients with post-COVID lung parenchymal abnormalities from April till September 2020. Patients ≥18 years of age with COVID-19 who were diagnosed as post-COVID lung parenchymal abnormality based on respiratory symptoms and HRCT chest imaging after the recovery of acute infection. Data was recorded on a structured pro forma, and descriptive analysis was performed using Stata version 12.1. RESULTS: A total of 30 patients with post-COVID lung parenchymal abnormalities were identified. The mean age of patients was 59.1 (SD 12.6), and 27 (90.0%) were males. Four HRCT patterns of lung parenchymal abnormalities were seen; organizing pneumonia in 10 (33.3%), nonspecific interstitial pneumonitis in 17 (56.7%), usual interstitial pneumonitis in 12 (40.0%) and probable usual interstitial pneumonitis in 14 (46.7%). Diffuse involvement was found in 15 (50.0%) patients, while peripheral predominance in 15 (50.0%), and other significant findings were seen in 8 (26.7%) patients. All individuals were treated with corticosteroids. The case fatality rate was 16.7%. Amongst the survivors, 32.0% recovered completely, 36.0% improved, while 32.0% of the patients had static or progressive disease. CONCLUSION: This is the first study from Southeast Asia that identified post-COVID lung parenchymal abnormalities in patients who had no pre-existing lung disease highlighting the importance of timely recognition and treatment of this entity that might lead to fatal outcome.


Assuntos
COVID-19/diagnóstico por imagem , COVID-19/patologia , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/patologia , Adulto , COVID-19/complicações , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , SARS-CoV-2/isolamento & purificação , Tomografia Computadorizada por Raios X
8.
Front Immunol ; 12: 687397, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34671341

RESUMO

Severe COVID-19 is characterized by acute respiratory distress syndrome (ARDS)-like hyperinflammation and endothelial dysfunction, that can lead to respiratory and multi organ failure and death. Interstitial lung diseases (ILD) and pulmonary fibrosis confer an increased risk for severe disease, while a subset of COVID-19-related ARDS surviving patients will develop a fibroproliferative response that can persist post hospitalization. Autotaxin (ATX) is a secreted lysophospholipase D, largely responsible for the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling lysophospholipid with multiple effects in pulmonary and immune cells. In this review, we discuss the similarities of COVID-19, ARDS and ILDs, and suggest ATX as a possible pathologic link and a potential common therapeutic target.


Assuntos
COVID-19/patologia , Diester Fosfórico Hidrolases/metabolismo , Fibrose Pulmonar/patologia , Síndrome do Desconforto Respiratório/patologia , Anti-Inflamatórios/uso terapêutico , COVID-19/sangue , Dexametasona/uso terapêutico , Humanos , Pulmão/patologia , Lisofosfolipídeos/metabolismo , Diester Fosfórico Hidrolases/sangue , Fibrose Pulmonar/sangue , Síndrome do Desconforto Respiratório/sangue , SARS-CoV-2 , Transdução de Sinais/imunologia
9.
Front Immunol ; 12: 735922, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34671353

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 is considered an airway/multi-systemic disease, and demise has been associated with an uncontrolled immune response and a cytokine storm in response to the virus. However, the lung pathology, immune response, and tissue damage associated with COVID-19 demise are poorly described and understood due to safety concerns. Using post-mortem lung tissues from uninfected and COVID-19 deadly cases as well as an unbiased combined analysis of histology, multi-viral and host markers staining, correlative microscopy, confocal, and image analysis, we identified three distinct phenotypes of COVID-19-induced lung damage. First, a COVID-19-induced hemorrhage characterized by minimal immune infiltration and large thrombus; Second, a COVID-19-induced immune infiltration with excessive immune cell infiltration but no hemorrhagic events. The third phenotype correspond to the combination of the two previous ones. We observed the loss of alveolar wall integrity, detachment of lung tissue pieces, fibroblast proliferation, and extensive fibrosis in all three phenotypes. Although lung tissues studied were from lethal COVID-19, a strong immune response was observed in all cases analyzed with significant B cell and poor T cell infiltrations, suggesting an exhausted or compromised immune cellular response in these patients. Overall, our data show that SARS-CoV-2-induced lung damage is highly heterogeneous. These individual differences need to be considered to understand the acute and long-term COVID-19 consequences.


Assuntos
COVID-19/mortalidade , COVID-19/patologia , Lesão Pulmonar/patologia , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Linfócitos T CD8-Positivos/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/patologia , Células Epiteliais/patologia , Feminino , Hemorragia/patologia , Humanos , Inflamação/patologia , Pulmão/patologia , Lesão Pulmonar/virologia , Linfopenia/patologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/patologia , Neutrófilos/imunologia , SARS-CoV-2 , Trombose/patologia
10.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502019

RESUMO

The lungs play a very important role in the human respiratory system. However, many factors can destroy the structure of the lung, causing several lung diseases and, often, serious damage to people's health. Nerve growth factor (NGF) is a polypeptide which is widely expressed in lung tissues. Under different microenvironments, NGF participates in the occurrence and development of lung diseases by changing protein expression levels and mediating cell function. In this review, we summarize the functions of NGF as well as some potential underlying mechanisms in pulmonary fibrosis (PF), coronavirus disease 2019 (COVID-19), pulmonary hypertension (PH), asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. Furthermore, we highlight that anti-NGF may be used in future therapeutic strategies.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Pulmão/patologia , Fator de Crescimento Neural/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Asma/tratamento farmacológico , Asma/patologia , COVID-19/tratamento farmacológico , COVID-19/patologia , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/patologia , Pulmão/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular/métodos , Fator de Crescimento Neural/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/patologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia
11.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502194

RESUMO

Aging and smoking are associated with the progressive development of three main pulmonary diseases: chronic obstructive pulmonary disease (COPD), interstitial lung abnormalities (ILAs), and idiopathic pulmonary fibrosis (IPF). All three manifest mainly after the age of 60 years, but with different natural histories and prevalence: COPD prevalence increases with age to >40%, ILA prevalence is 8%, and IPF, a rare disease, is 0.0005-0.002%. While COPD and ILAs may be associated with gradual progression and mortality, the natural history of IPF remains obscure, with a worse prognosis and life expectancy of 2-5 years from diagnosis. Acute exacerbations are significant events in both COPD and IPF, with a much worse prognosis in IPF. This perspective discusses the paradox of the striking pathological and pathophysiologic responses on the background of the same main risk factors, aging and smoking, suggesting two distinct pathophysiologic processes for COPD and ILAs on one side and IPF on the other side. Pathologically, COPD is characterized by small airways fibrosis and remodeling, with the destruction of the lung parenchyma. By contrast, IPF almost exclusively affects the lung parenchyma and interstitium. ILAs are a heterogenous group of diseases, a minority of which present with the alveolar and interstitial abnormalities of interstitial lung disease.


Assuntos
Envelhecimento , Doenças Pulmonares Intersticiais/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Fibrose Pulmonar/patologia , Fumantes/estatística & dados numéricos , Fumar/efeitos adversos , Idoso , Humanos , Doenças Pulmonares Intersticiais/etiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Fibrose Pulmonar/etiologia
12.
Immunity ; 54(11): 2650-2669.e14, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34592166

RESUMO

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.


Assuntos
COVID-19/imunologia , Interferon-alfa/imunologia , Células Matadoras Naturais/imunologia , SARS-CoV-2/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Sequência de Bases , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Interferon-alfa/sangue , Fibrose Pulmonar/patologia , RNA-Seq , Índice de Gravidade de Doença , Transcriptoma/genética , Reino Unido , Estados Unidos
13.
Sci Rep ; 11(1): 18513, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531421

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease characterized by an excessive production and accumulation of collagen in the skin and internal organs often associated with interstitial lung disease (ILD). Its pathogenetic mechanisms are unknown and the lack of animal models mimicking the features of the human disease is creating a gap between the selection of anti-fibrotic drug candidates and effective therapies. In this work, we intended to pharmacologically validate a SSc-ILD model based on 1 week infusion of bleomycin (BLM) by osmotic minipumps in C57/BL6 mice, since it will serve as a tool for secondary drug screening. Nintedanib (NINT) has been used as a reference compound to investigate antifibrotic activity either for lung or skin fibrosis. Longitudinal Micro-CT analysis highlighted a significant slowdown in lung fibrosis progression after NINT treatment, which was confirmed by histology. However, no significant effect was observed on lung hydroxyproline content, inflammatory infiltrate and skin lipoatrophy. The modest pharmacological effect reported here could reflect the clinical outcome, highlighting the reliability of this model to better profile potential clinical drug candidates. The integrative approach presented herein, which combines longitudinal assessments with endpoint analyses, could be harnessed in drug discovery to generate more reliable, reproducible and robust readouts.


Assuntos
Indóis/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Animais , Bleomicina , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Indóis/administração & dosagem , Pulmão/efeitos dos fármacos , Pulmão/patologia , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/patologia , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/patologia
14.
Front Immunol ; 12: 678457, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489932

RESUMO

This mini-review summarizes the current evidence for the role of macrophage activation and polarization in inflammation and immune response pertinent to interstitial lung disease, specifically pulmonary fibrosis. In the fibrosing lung, the production and function of inflammatory and fibrogenic mediators involved in the disease development have been reported to be regulated by the effects of polarized M1/M2 macrophage populations. The M1 and M2 macrophage phenotypes were suggested to correspond with the pro-inflammatory and pro-fibrogenic signatures, respectively. These responses towards tissue injury followed by the development and progression of lung fibrosis are further regulated by macrophage-derived microRNAs (miRNAs). Besides cellular miRNAs, extracellular exosomal-miRNAs derived from M2 macrophages have also been proposed to promote the progression of pulmonary fibrosis. In a future perspective, harnessing the noncoding miRNAs with a key role in the macrophage polarization is, therefore, suggested as a promising therapeutic strategy for this debilitating disease.


Assuntos
Suscetibilidade a Doenças , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , MicroRNAs/genética , Fibrose Pulmonar/etiologia , Animais , Biomarcadores , Plasticidade Celular , Citocinas/metabolismo , Exossomos/metabolismo , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Modelos Biológicos , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia
15.
Front Immunol ; 12: 690375, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489937

RESUMO

Immunostimulation is recognized as an important contribution in lung fibrosis in some animal models and patient subsets. With this review, we illustrate an additional scenario covering the possible implication of immunoregulation during fibrogenesis. Available animal and human data indicate that pulmonary fibrosis also includes diverse and discrete immunoregulating populations comprising regulatory lymphocytes (T and B regs) and myeloid cells (immunosuppressive macrophages and myeloid-derived suppressive cells; MDSC). They are initially recruited to limit the establishment of deleterious inflammation but participate in the development of lung fibrosis by producing immunoregulatory mediators (mainly TGF-ß1 and IL-10) that directly or indirectly stimulate fibroblasts and matrix protein deposition. The existence of this silent immunoregulatory environment sustains an alternative mechanism of fibrosis that explains why in some conditions neither pro-inflammatory cytokine deficiency nor steroid and immunosuppressive therapies limit lung fibrosis. Therefore, the persistent presence of immunoregulation is an important parameter to consider for refining therapeutical strategies in lung fibrotic disorders under non-immunostimulatory conditions.


Assuntos
Pulmão/imunologia , Linfócitos/imunologia , Células Supressoras Mieloides/imunologia , Fibrose Pulmonar/imunologia , Animais , Microambiente Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Linfócitos/metabolismo , Células Supressoras Mieloides/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Transdução de Sinais
16.
Immunity ; 54(9): 2042-2056.e8, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34407391

RESUMO

Recruitment of immune cells to the site of inflammation by the chemokine CCL1 is important in the pathology of inflammatory diseases. Here, we examined the role of CCL1 in pulmonary fibrosis (PF). Bronchoalveolar lavage fluid from PF mouse models contained high amounts of CCL1, as did lung biopsies from PF patients. Immunofluorescence analyses revealed that alveolar macrophages and CD4+ T cells were major producers of CCL1 and targeted deletion of Ccl1 in these cells blunted pathology. Deletion of the CCL1 receptor Ccr8 in fibroblasts limited migration, but not activation, in response to CCL1. Mass spectrometry analyses of CCL1 complexes identified AMFR as a CCL1 receptor, and deletion of Amfr impaired fibroblast activation. Mechanistically, CCL1 binding triggered ubiquitination of the ERK inhibitor Spry1 by AMFR, thus activating Ras-mediated profibrotic protein synthesis. Antibody blockade of CCL1 ameliorated PF pathology, supporting the therapeutic potential of targeting this pathway for treating fibroproliferative lung diseases.


Assuntos
Quimiocina CCL1/metabolismo , Fibroblastos/metabolismo , Proteínas de Membrana/metabolismo , Miofibroblastos/metabolismo , Fosfoproteínas/metabolismo , Fibrose Pulmonar/metabolismo , Receptores do Fator Autócrino de Motilidade/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Diferenciação Celular/fisiologia , Fibroblastos/patologia , Humanos , Camundongos , Miofibroblastos/patologia , Fibrose Pulmonar/patologia , Transdução de Sinais/fisiologia
17.
Sci Rep ; 11(1): 16654, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404841

RESUMO

Fibrotic diseases are characterized by progressive and often irreversible scarring of connective tissue in various organs, leading to substantial changes in tissue mechanics largely as a result of alterations in collagen structure. This is particularly important in the lung because its bulk modulus is so critical to the volume changes that take place during breathing. Nevertheless, it remains unclear how fibrotic abnormalities in the mechanical properties of pulmonary connective tissue can be linked to the stiffening of its individual collagen fibers. To address this question, we developed a network model of randomly oriented collagen and elastin fibers to represent pulmonary alveolar wall tissue. We show that the stress-strain behavior of this model arises via the interactions of collagen and elastin fiber networks and is critically dependent on the relative fiber stiffnesses of the individual collagen and elastin fibers themselves. We also show that the progression from linear to nonlinear stress-strain behavior of the model is associated with the percolation of stress across the collagen fiber network, but that the location of the percolation threshold is influenced by the waviness of collagen fibers.


Assuntos
Colágeno/análise , Elastina/análise , Alvéolos Pulmonares/patologia , Fenômenos Biomecânicos , Humanos , Modelos Biológicos , Fibrose Pulmonar/patologia , Estresse Mecânico
18.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445094

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a refractory interstitial lung disease for which there is no effective treatment. Although the pathogenesis of IPF is not fully understood, TGF-ß and epithelial-mesenchymal transition (EMT) have been shown to be involved in the fibrotic changes of lung tissues. Kurarinone is a prenylated flavonoid isolated from Sophora Flavescens with antioxidant and anti-inflammatory properties. In this study, we investigated the effect of kurarinone on pulmonary fibrosis. Kurarinone suppressed the TGF-ß-induced EMT of lung epithelial cells. To assess the therapeutic effects of kurarinone in bleomycin (BLM)-induced pulmonary fibrosis, mice were treated with kurarinone daily for 2 weeks starting 7 days after BLM instillation. Oral administration of kurarinone attenuated the fibrotic changes of lung tissues, including accumulation of collagen and improved mechanical pulmonary functions. Mechanistically, kurarinone suppressed phosphorylation of Smad2/3 and AKT induced by TGF-ß1 in lung epithelial cells, as well as in lung tissues treated with BLM. Taken together, these results suggest that kurarinone has a therapeutic effect on pulmonary fibrosis via suppressing TGF-ß signaling pathways and may be a novel drug candidate for pulmonary fibrosis.


Assuntos
Flavonoides/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Animais , Bleomicina , Linhagem Celular , Transição Epitelial-Mesenquimal , Flavonoides/farmacologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia
19.
Wiad Lek ; 74(7): 1767-1769, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34459785

RESUMO

Tumorlet is a disease rarely diagnosed in clinical practice. It is characterized by pulmonary neuroendocrine cell (PNEC) proliferation which invades the bronchiolar basement membrane and forms nodules with a diameter smaller than 5 mm. Case report: 72-year-old female patient was suffered for many years from progressive dyspnea and coughing with evidence of pulmonary fibrosis on high resolution computed tomography (HRCT). As a result of a lung biopsy, based on immunohistochemical tests, a 2 mm cluster of neuroendocrine cells (NEC) was found and it was diagnosed as tumorlet. Due to a long-term, insidious progress of the disease, as well as sex and age of the patient, the case emphasizes that differential diagnosis should include tumorlet as well as diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) as a more extensive manifestation of neuroendocrine cell proliferation in the respiratory tract.


Assuntos
Neoplasias Pulmonares , Células Neuroendócrinas , Fibrose Pulmonar , Idoso , Proliferação de Células , Dispneia , Feminino , Humanos , Hiperplasia/patologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Células Neuroendócrinas/patologia , Fibrose Pulmonar/patologia
20.
Biomolecules ; 11(8)2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34439751

RESUMO

Periostin is known to be a useful biomarker for various diseases. In this article, we focus on allergic diseases and pulmonary fibrosis, for which we and others are now developing detection systems for periostin as a biomarker. Biomarker-based precision medicine in the management of type 2 inflammation and fibrotic diseases since heterogeneity is of utmost importance. Periostin expression is induced by type 2 cytokines (interleukin-4/-13) or transforming growth factor-ß, and plays a vital role in the pathogenesis of allergic inflammation or interstitial lung disease, respectively, andits serum levels are correlated disease severity, prognosis and responsiveness to the treatment. We first summarise the importance of type 2 biomarker and then describe the pathological role of periostin in the development and progression of type 2 allergic inflammation and pulmonary fibrosis. In addition, then, we summarise the recent development of assay methods for periostin detection, and analyse the diseases in which periostin concentration is elevated in serum and local biological fluids and its usefulness as a biomarker. Furthermore, we describe recent findings of periostin as a biomarker in the use of biologics or anti-fibrotic therapy. Finally, we describe the factors that influence the change in periostin concentration under the healthy conditions.


Assuntos
Biomarcadores/metabolismo , Moléculas de Adesão Celular/química , Inflamação/metabolismo , Fibrose Pulmonar/metabolismo , Doença Crônica , Citocinas/metabolismo , Eosinofilia/metabolismo , Fibrose/patologia , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Imunoglobulina E/química , Inflamação/patologia , Interleucina-13/metabolismo , Pulmão/metabolismo , Medicina de Precisão , Prognóstico , Fibrose Pulmonar/patologia , Rinite/metabolismo , Sinusite/metabolismo , Fator de Crescimento Transformador beta/metabolismo
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