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1.
Nursing ; 51(1): 22-29, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33346613

RESUMO

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease in which the cause cannot be determined. This article discusses restrictive lung diseases that fall under the general category of interstitial lung disease with a focus on IPF-a fatal disease characterized by progressive fibrosis and interstitial pneumonia, dyspnea, and decreasing pulmonary function.


Assuntos
Fibrose Pulmonar Idiopática/enfermagem , Técnicas e Procedimentos Diagnósticos/enfermagem , Humanos , Fibrose Pulmonar Idiopática/epidemiologia , Fibrose Pulmonar Idiopática/fisiopatologia , Diagnóstico de Enfermagem , Fatores de Risco
2.
Curr Opin Pulm Med ; 27(1): 54-60, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065600

RESUMO

PURPOSE OF REVIEW: Matrix metalloproteinases (MMPs) are a family of over 20 zinc-dependent proteases with different biological and pathological activities, and many have been implicated in several diseases. Although nonselective MMP inhibitors are known to induce serious side-effects, targeting individual MMPs may offer a safer therapeutic potential for several diseases. Hence, we provide a concise overview on MMP-12, given its association with pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and other progressive pulmonary fibrosis (PPF), which may also occur in coronavirus disease 2019. RECENT FINDINGS: In asthma, COPD, and PPF, increased MMP-12 levels have been associated with inflammation and/or structural changes within the lungs and negatively correlated with functional parameters. Increased pulmonary MMP-12 levels and MMP-12 gene expression have been related to disease severity in asthma and COPD. Targeting MMP-12 showed potential in animal models of pulmonary diseases but human data are still very scarce. SUMMARY: Although there may be a potential role of MMP-12 in asthma, COPD and PPF, several pathophysiological aspects await elucidation. Targeting MMP-12 may provide further insights into MMP-12 related mechanisms and how this translates into clinical outcomes; this warrants further research.


Assuntos
Asma/enzimologia , Fibrose Pulmonar Idiopática/enzimologia , Metaloproteinase 12 da Matriz/metabolismo , Doença Pulmonar Obstrutiva Crônica/enzimologia , Animais , Asma/tratamento farmacológico , Asma/etiologia , Asma/fisiopatologia , Biomarcadores/metabolismo , /etiologia , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/fisiopatologia , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia
3.
JAMA ; 324(22): 2282-2291, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33289822

RESUMO

Importance: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited treatment options. Patients with IPF have altered lung microbiota, with bacterial burden within the lungs associated with mortality; previous studies have suggested benefit with co-trimoxazole (trimethoprim-sulfamethoxazole). Objective: To determine the efficacy of co-trimoxazole in patients with moderate and severe IPF. Design, Setting, and Participants: Double-blind, placebo-controlled, parallel randomized trial of 342 patients with IPF, breathlessness (Medical Research Council dyspnea scale score >1), and impaired lung function (forced vital capacity ≤75% predicted) conducted in 39 UK specialist interstitial lung disease centers between April 2015 (first patient visit) and April 2019 (last patient follow-up). Interventions: Study participants were randomized to receive 960 mg of oral co-trimoxazole twice daily (n = 170) or matched placebo (n = 172) for between 12 and 42 months. All patients received 5 mg of folic acid orally once daily. Main Outcomes and Measures: The primary outcome was time to death (all causes), lung transplant, or first nonelective hospital admission. There were 15 secondary outcomes, including the individual components of the primary end point respiratory-related events, lung function (forced vital capacity and gas transfer), and patient-reported outcomes (Medical Research Council dyspnea scale, 5-level EuroQol 5-dimension questionnaire, cough severity, Leicester Cough Questionnaire, and King's Brief Interstitial Lung Disease questionnaire scores). Results: Among 342 individuals who were randomized (mean age, 71.3 years; 46 [13%] women), 283 (83%) completed the trial. The median (interquartile range) duration of follow-up was 1.02 (0.35-1.73) years. Events per person-year of follow-up among participants randomized to the co-trimoxazole and placebo groups were 0.45 (84/186) and 0.38 (80/209), respectively, with a hazard ratio of 1.2 ([95% CI, 0.9-1.6]; P = .32). There were no statistically significant differences in other event outcomes, lung function, or patient-reported outcomes. Patients in the co-trimoxazole group had 696 adverse events (nausea [n = 89], diarrhea [n = 52], vomiting [n = 28], and rash [n = 31]) and patients in the placebo group had 640 adverse events (nausea [n = 67], diarrhea [n = 84], vomiting [n = 20], and rash [n = 20]). Conclusions and Relevance: Among patients with moderate or severe IPF, treatment with oral co-trimoxazole did not reduce a composite outcome of time to death, transplant, or nonelective hospitalization compared with placebo. Trial Registration: ISRCTN Identifier: ISRCTN17464641.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Administração Oral , Idoso , Tosse/etiologia , Método Duplo-Cego , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/mortalidade , Transplante de Pulmão , Masculino , Náusea/induzido quimicamente , Gravidade do Paciente , Falha de Tratamento , Combinação Trimetoprima e Sulfametoxazol/efeitos adversos
4.
Medicine (Baltimore) ; 99(49): e23460, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33285745

RESUMO

INTRODUCTION: With dissatisfaction of western medicine, traditional Chinese medicine becomes alternative treatment for idiopathic pulmonary fibrosis patients. The common syndrome of idiopathic pulmonary fibrosis (IPF) is qi and yin deficiency syndrome. The prescription, Modified Maimendong Decoction (MMD), is usually used for IPF patients with qi and yin deficiency syndrome. However, there is no convinced evidence for the efficacy and safety of MMD to treat IPF. METHODS: A double-blind, placebo-controlled, randomized clinical trial was put forward by us. After a 1-day run-in period, 60 eligible patients will be included in the study. These subjects will be allocated to the experiment group or control group in a 1:1 ratio. Patients in the experiment group will take MMD plus Pirfenidone capsule. At the same time, patients in the control group will receive a matched placebo plus Pirfenidone capsule. All subjects will receive 24 weeks of treatment and follow-up period. The primary outcomes are the mean change from the baseline in forced vital capacity and times of acute exacerbations at week 4, 12, 24. Secondary outcomes are the mean change from baseline in the St. George's respiratory questionnaire total score, forced expiratory volume in 1 second percentage/forced vital capacity, diffusing capacity of Carbon monoxide, brain natriuretic peptide, and curative effect of traditional Chinese medicine syndrome at week 4, 12, and 24. Any side effects of the treatment will be recorded. DISCUSSION: The results of this trial will provide the evidence for the effect of MMD in patients with idiopathic pulmonary fibrosis.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Qi , Deficiência da Energia Yin/tratamento farmacológico , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Fibrose Pulmonar Idiopática/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Capacidade Vital/efeitos dos fármacos , Deficiência da Energia Yin/etiologia , Adulto Jovem
5.
PLoS One ; 15(12): e0242900, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33264345

RESUMO

COVID-19, caused by SARS-CoV-2, has rapidly spread to more than 160 countries worldwide since 2020. Despite tremendous efforts and resources spent worldwide trying to explore antiviral drugs, there is still no effective clinical treatment for COVID-19 to date. Approximately 15% of COVID-19 cases progress to pneumonia, and patients with severe pneumonia may die from acute respiratory distress syndrome (ARDS). It is believed that pulmonary fibrosis from SARS-CoV-2 infection further leads to ARDS, often resulting in irreversible impairment of lung function. If the mechanisms by which SARS-CoV-2 infection primarily causes an immune response or immune cell infiltration can be identified, it may be possible to mitigate excessive immune responses by modulating the infiltration and activation of specific targets, thereby reducing or preventing severe lung damage. However, the extent to which immune cell subsets are significantly altered in the lung tissues of COVID-19 patients remains to be elucidated. This study applied the CIBERSORT-X method to comprehensively evaluate the transcriptional estimated immune infiltration landscape in the lung tissues of COVID-19 patients and further compare it with the lung tissues of patients with idiopathic pulmonary fibrosis (IPF). We found a variety of immune cell subtypes in the COVID-19 group, especially naïve B cells were highly infiltrated. Comparison of functional transcriptomic analyses revealed that non-differentiated naïve B cells may be the main cause of the over-active humoral immune response. Using several publicly available single-cell RNA sequencing data to validate the genetic differences in B-cell populations, it was found that the B-cells collected from COVID-19 patients were inclined towards naïve B-cells, whereas those collected from IPF patients were inclined towards memory B-cells. Further differentiation of B cells between COVID-19 mild and severe patients showed that B cells from severe patients tended to be antibody-secreting cells, and gene expression showed that B cells from severe patients were similar to DN2 B cells that trigger extrafollicular response. Moreover, a higher percentage of B-cell infiltration seems associated with poorer clinical outcome. Finally, a comparison of several specific COVID-19 cases treated with targeted B-cell therapy suggests that appropriate suppression of naïve B cells might potentially be a novel strategy to alleviate the severe symptoms of COVID-19.


Assuntos
Linfócitos B/imunologia , Simulação por Computador , Pulmão/imunologia , Pulmão/virologia , Humanos , Fibrose Pulmonar Idiopática/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Transcrição Genética/imunologia
6.
PLoS One ; 15(11): e0241719, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33137121

RESUMO

INTRODUCTION: Interstitial lung disease (ILD) is a heterogeneous group of diseases characterized by varying degrees of lung inflammation and/or fibrosis. We investigated biomarkers to infer whether patients with collagen vascular diseases associated ILD (CVD-ILD) and interstitial pneumonia with autoimmune features (IPAF) benefit from immunosuppressive therapy. MATERIALS AND METHODS: We retrospectively investigated patients with CVD-ILD, IPAF, and idiopathic pulmonary fibrosis (IPF) between June 2013 and May 2017 at our department. First, we assessed differences in serum and bronchoalveolar lavage fluid (BALF) levels of cytokines between groups. Second, we assessed the associations of patient's clinical variables with serum and BALF levels of those cytokines that were different between groups. Finally, we assessed the associations of diagnosis and response to immunosuppressive therapy with serum levels of those cytokines that were different between groups. RESULTS: We included 102 patients (51 with IPF, 35 with IPAF, and 16 with CVD-ILD). Serum and BALF levels of CXCL9, CXCL10, and CXCL11 were significantly elevated in patients with IPAF or CVD-ILD compared with those in patients with IPF. BALF levels of CXCL9 and CXCL10 were correlated with the percentages of lymphocytes and macrophages in BALF. Serum levels of CXCL9 and CXCL10 were correlated with BALF levels. Serum levels of CXCL9, CXCL10, and CXCL11 were correlated C-reactive protein, percent predicted forced vital capacity, alveolar-arterial oxygen difference, and the percentages of lymphocytes and macrophages in BALF. Serum levels of CXCL9, CXCL10, and CXCL11 showed moderate accuracy to distinguish patients with CVD-ILD from those with IPAF and IPF. Pre-treatment serum levels of CXCL9 and CXCL11 showed strong positive correlations with the annual forced vital capacity changes in patients with IPAF and CVD-ILD treated with immunosuppressive drugs. CONCLUSIONS: Serum CXCL9, CXCL10, and CXCL11 are potential biomarkers for autoimmune inflammation and predictors of the immunosuppressive therapy responses in ILD with background autoimmunity.


Assuntos
Biomarcadores/sangue , Quimiocina CXCL10/sangue , Quimiocina CXCL11/sangue , Quimiocina CXCL9/sangue , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Vasculares/complicações , Idoso , Autoimunidade , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Proteína C-Reativa/análise , Quimiocina CXCL10/análise , Quimiocina CXCL11/análise , Quimiocina CXCL9/análise , Colágeno/metabolismo , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Linfócitos/citologia , Linfócitos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doenças Vasculares/patologia , Capacidade Vital
7.
PLoS One ; 15(11): e0242860, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33253258

RESUMO

Acute exacerbation of ILD (AE-ILD) is a common reason for hospitalization; it is also associated with significant mortality. Less is known about the prognostic significance of other events causing acute, non-elective hospitalizations in ILD patients. ILD patients hospitalized due to acute respiratory worsening were collected from medical records. Reasons for respiratory deterioration were classified into AE-ILDs and other causes. Clinical features and survival data of idiopathic pulmonary fibrosis (IPF) and other types of ILDs were evaluated and compared. In all, 237 patients (138 with IPF and 99 with other ILD) fulfilled the inclusion criteria. Of the non-IPF ILD types, the most prevalent subgroups were connective tissue disease-associated ILD (n = 33) and asbestosis (n = 22). The most common cause for hospitalization was AE-ILD explaining 41% of hospitalizations. Lower respiratory tract infection (22%), subacute progression of ILD (12%) and cardiovascular causes (7.2%) were other common reasons for hospital treatment. Patients with a lower respiratory tract infection had a more favorable prognosis compared with patients with AE-ILD. AE-ILDs were less fatal than cardiovascular or concurrent non-ILD-related causes for hospitalizations in non-IPF patients. High Gender-Age-Physiology (GAP) index was a marker for shortened survival and earlier AE-ILDs in all patients. IPF patients had a significantly shorter overall and post-hospitalization survival time compared with other ILDs. Most respiratory hospitalizations in ILD patients were related to causes other than AE-ILD, which highlights the importance of accurate differential diagnosis in order to target the appropriate treatment for each ILD patient.


Assuntos
Fibrose Pulmonar Idiopática/epidemiologia , Doenças Pulmonares Intersticiais/epidemiologia , Pneumonia/epidemiologia , Infecções Respiratórias/epidemiologia , Adolescente , Adulto , Idoso , Criança , Gerenciamento Clínico , Progressão da Doença , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/patologia , Hospitalização , Humanos , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/terapia , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/terapia , Masculino , Pessoa de Meia-Idade , Pneumonia/patologia , Pneumonia/terapia , Prognóstico , Fibrose Pulmonar , Fenômenos Fisiológicos Respiratórios , Infecções Respiratórias/patologia , Infecções Respiratórias/terapia , Fatores de Risco , Adulto Jovem
8.
PLoS One ; 15(11): e0241323, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33141839

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with a high morbidity and mortality. Some of the mechanisms of fibrosis development have been described using rodent models; however, the relevance of findings in these animal models is difficult to assess. New innovative models are needed that closely mimic IPF disease pathology. METHODS: To overcome this unmet need of investigating IPF with a relevant model, we utilized tree shrews, which are genetically, anatomically, and metabolically similar to primates and humans. Using human antibodies and primers, we investigated the role of macrophage phenotypic switching in normal and IPF subjects and bleomycin-injured tree shrews. RESULTS: Bronchoalveolar lavage (BAL) cells from tree shrews expressed human markers, and there was recruitment of monocyte-derived macrophages (MDMs) to the lung in IPF subjects and bleomycin-injured tree shrews. MDMs were polarized to a profibrotic phenotype in IPF and in bleomycin-injured tree shrews. Resident alveolar macrophages (RAMs) expressed proinflammatory markers regardless of bleomycin exposure. Tree shrews developed bleomycin-induced pulmonary fibrosis with architectural distortion in parenchyma and widespread collagen deposition. CONCLUSION: The profibrotic polarization of macrophages has been demonstrated to be present in IPF subjects and in fibrotic mice. Although the lung macrophages have long been considered to be homogeneous, recent evidence indicates that these cells are heterogeneous during multiple chronic lung diseases. Here, we show new data that indicate a critical and essential role for macrophage-fibroblast crosstalk promoting fibroblast differentiation and collagen production. in the development and progression of fibrosis. The current data strongly suggest development of therapeutics that attenuate of the profibrotic activation of MDMs may mitigate macrophage-fibroblast interaction. These observations demonstrate that tree shrews are an ideal animal model to investigate the pathogenesis of IPF as they are genetically, anatomically, and metabolically closer to humans than the more commonly used rodent models.


Assuntos
Fibrose Pulmonar Idiopática/patologia , Tupaiidae/fisiologia , Adulto , Animais , Lavagem Broncoalveolar , Diferenciação Celular/genética , Polaridade Celular , Modelos Animais de Doenças , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/genética , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Fenótipo , Capacidade Vital
9.
Rev Med Suisse ; 16(715): 2218-2223, 2020 Nov 18.
Artigo em Francês | MEDLINE | ID: mdl-33206479

RESUMO

Interstitial lung disease is a frequent complication of systemic sclerosis and has now become the leading cause of death in this disorder. It mainly occurs during the first five years after the diagnosis of systemic sclerosis. Various risk factors are associated with the occurrence of interstitial lung disease, including the presence of anti-topoisomerase I antibodies (Scl-70) and the diffuse cutaneous form of systemic sclerosis. The most common radio-pathological presentation is nonspecific interstitial pneumonia, followed by usual interstitial pneumonia. The classical immunosuppressive treatment of systemic sclerosis-associated interstitial lung disease is evolving, as recent studies suggest a beneficial effect of biological agents such as rituximab and tocilizumab, and antifibrotic drugs such as nintedanib.


Assuntos
Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Humanos , Imunossupressores , Pulmão , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/terapia , Rituximab/uso terapêutico , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/terapia
10.
Medicine (Baltimore) ; 99(47): e23143, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33217820

RESUMO

Hospitalizations are common in patients with idiopathic pulmonary fibrosis (IPF) and are associated with high mortality. We used data from the Premier Healthcare Database to determine in-hospital mortality rates and the factors associated with in-hospital mortality in patients with IPF in the era of approved antifibrotic drugs.The Premier Healthcare Database is a detailed and broadly representative database of hospital admissions and discharges in the US. Patients with IPF who were hospitalized between 1 January 2015 and 28 February 2018 were identified using a diagnostic algorithm comprising International Classification of Diseases -9 and International Classification of Diseases -10 diagnostic codes and billing data. Associations between patient-, hospital- and treatment-related factors and a composite outcome of death during the index visit, lung transplant during the index visit but >1 day after admission, or death during a readmission within 90 days of the index visit were analyzed using logistic regression.The cohort comprised 9667 hospitalized patients with IPF. In total, 1414 patients (14.6%) met the composite outcome: 1036 (10.7%) died during the index visit, 371 (3.8%) died during a readmission within 90 days; 7 (0.1%) underwent lung transplant >1 day after admission. Factors significantly associated with a higher risk of the composite outcome included mechanical ventilation (odds ratio 6.41 [95% CI: 5.24, 7.84]), admission to the intensive care unit (1.73 [1.49, 2.00]), attendance by a critical care physician (2.12 [1.33, 3.38]), older age (1.20 [1.12, 1.28] per 10-year increase), and use of intravenous steroids (1.16 [1.00, 1.34]), intravenous antibiotics (1.49 [1.22, 1.83]) and opioids (3.41 [2.95, 3.93]). Factors significantly associated with a lower risk of the composite outcome included female sex (0.70 [0.61, 0.80]), comorbid chronic obstructive pulmonary disease (0.69 [0.60, 0.78]), attendance by a family medicine physician (0.67 [0.48, 0.94]) or internal medicine physician (0.59 [0.46, 0.75]), and use of oral steroids (0.62 [0.51, 0.77]), statins (0.76 [0.67, 0.87]) and proton pump inhibitors (0.80 [0.70, 0.92]).In conclusion, patients with IPF are at risk of mortality during a hospital stay or readmission within 90 days, particularly those who receive mechanical ventilation.


Assuntos
Mortalidade Hospitalar , Fibrose Pulmonar Idiopática/mortalidade , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia
11.
Mol Med ; 26(1): 95, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054759

RESUMO

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.


Assuntos
Infecções por Coronavirus/imunologia , Epigênese Genética/imunologia , Fibrose Pulmonar Idiopática/imunologia , Mecanotransdução Celular/imunologia , Pneumonia Viral/imunologia , Embolia Pulmonar/imunologia , Insuficiência Respiratória/imunologia , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/patologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Fenômenos Biomecânicos , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Fibroblastos/imunologia , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/virologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/patologia , Mecanotransdução Celular/genética , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Embolia Pulmonar/genética , Embolia Pulmonar/patologia , Embolia Pulmonar/virologia , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Insuficiência Respiratória/virologia , Estresse Mecânico
12.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 148-157, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093778

RESUMO

Background: Patients with idiopathic pulmonary fibrosis (IPF) often do not tolerate pirfenidone in the recommended dose of 2400 mg/day. The proportion of patients requiring dose reduction and its impact on survival in the real-world remain unclear. Methods: Consecutive subjects with IPF were enrolled between March 2017 and June 2019. The maximum tolerated dose of pirfenidone (primary outcome) and adverse drug reactions (ADRs) were recorded. A post hoc logistic regression analysis was performed to evaluate the predictors of drug discontinuation due to ADRs. We also compared survival between the full-dose (2400 mg/day), reduced-dose (< 2400 mg/day), and the no-pirfenidone groups, with age and percentage of the predicted forced vital capacity (%pred FVC) as covariates. Results: Of the 128 subjects (mean age, 67.4 years; 77.3% men) included, 115 were initiated on pirfenidone. Forty-nine (42.6%) and 51 (44.3%) subjects tolerated the full dose and reduced doses, respectively. Ninety-six (83.5%) subjects developed at least one ADR; anorexia dyspepsia, and nausea being the most common. Twenty-two subjects discontinued the drug; 15 of them due to ADRs. Body mass index < 20 kg/m2 was the only predictor of drug discontinuation due to ADRs. Among subjects newly initiated on treatment during the study period (n = 80), survival was longer (hazard ratio [interquartile range], 0.19 [0.04-0.96]; p = 0.045) in the full-dose but not the reduced-dose group (p = 0.08) compared with the no-pirfenidone group, after adjusting for covariates. Conclusion: Pirfenidone was tolerated in the full dose in a minority of patients with IPF and appears to improve survival only with the full dose. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 148-157).


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Piridonas/administração & dosagem , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/mortalidade , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/fisiopatologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Segurança do Paciente , Estudos Prospectivos , Piridonas/efeitos adversos , Recuperação de Função Fisiológica , Resultado do Tratamento , Capacidade Vital
13.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 192-202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093783

RESUMO

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive loss of pulmonary function and exercise capacity, leading to loss of quality of life and often social isolation. A new walking aid, the walk-bike, showed an improvement in exercise performance in COPD patients. Aims of this pilot study were to evaluate feasibility of a homebased walk-bike intervention study in IPF patients and to explore the effect of the walk-bike on quality of life (QoL) and exercise capacity. Twenty-three patients with IPF were included in a randomized multicenter crossover study with 8 weeks of standard care and 8 weeks of walk-bike use at home. Ten patients completed both study phases. Study barriers included reluctance to participate and external factors (e.g. weather and road conditions) that hampered adherence. Patients' satisfaction and experience with the walk-bike varied greatly. After training with the walk-bike, health-related QoL (St. George's Respiratory and King's Brief Interstitial Lung Disease questionnaires) demonstrated a tendency towards improvement, exercise capacity did not. A clinically important difference was found between 6-minute walk test with the walk-bike and the standard test; median (range) respectively 602 m (358-684) and 486 m (382-510). Conclusions: Due to practical barriers a larger study with the walk-bike in patients with IPF seems not feasible. Individual patients may benefit from the use of a walk-bike as it improved action radius and showed a tendency towards improvement in QoL. No effect on exercise capacity was observed. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 192-202).


Assuntos
Deambulação com Auxílio , Terapia por Exercício/instrumentação , Tolerância ao Exercício , Fibrose Pulmonar Idiopática/terapia , Limitação da Mobilidade , Qualidade de Vida , Caminhada , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Desenho de Equipamento , Estudos de Viabilidade , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/fisiopatologia , Fibrose Pulmonar Idiopática/psicologia , Masculino , Pessoa de Meia-Idade , Países Baixos , Satisfação do Paciente , Projetos Piloto , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento
14.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 212-217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093785

RESUMO

Background: Zonal aggregates of elastic fibres (zonal elastosis) and intraalveolar collagenosis with septal elastosis are histologic components of subpleural fibroelastosis of idiopathic pleuroparenchymal fibroelastosis (IPPFE). Zonal elastosis is considered to result from alveolar collapse, but this mechanism has not been fully justified. Methods: We immunohistochemically attempted to identify epithelial cells in zonal elastosis of 10 patients with IPPFE. The thickness of the zonal elastosis in relation to the total thickness of the fibroelastosis was examined to estimate the influence of zonal elastosis on the occurrence and development of IPPFE. Results: In 9 of the 10 patients, multi-cytokeratin-positive cells were found lining the inner surface of slit-like spaces embedded in the zonal elastosis. Zonal elastosis was predominant when fibroelastosis was < 1 mm thick but less predominant when it was ≥1 mm. Conclusion: The zonal elastosis was proven to result from alveolar collapse, which might be an initial lesion in IPPFE. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 212-217).


Assuntos
Tecido Elástico/patologia , Fibrose Pulmonar Idiopática/patologia , Alvéolos Pulmonares/metabolismo , Adulto , Idoso , Células Epiteliais Alveolares/química , Células Epiteliais Alveolares/patologia , Biomarcadores/análise , Tecido Elástico/química , Feminino , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Imuno-Histoquímica , Queratinas/análise , Masculino , Pessoa de Meia-Idade , Alvéolos Pulmonares/química , Estudos Retrospectivos , Adulto Jovem
15.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 218-224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093786

RESUMO

Introduction: Pirfenidone has been shown to reduce the decline in forced vital capacity (FVC) compared to placebo in patients with idiopathic pulmonary fibrosis (IPF). Previous studies have suggested that patients with a more rapid decline in FVC during the period before starting pirfenidone experience the greatest benefit from treatment. The purpose of this retrospective observational study was to investigate the response to pirfenidone in IPF patients, comparing two groups stratified by the annual rate of decline in FVC % predicted prior to treatment. Methods: Using the rate of decline in FVC % predicted in the 12 months prior to pirfenidone, patients were stratified into slow (<5%) or rapid (≥5%) decliner groups. Comparisons in the lung function response to pirfenidone in these two groups were performed. Results: Pirfenidone resulted in no statistically significant reduction in the median annual rate of decline in FVC or FVC % predicted. In the rapid decliners, pirfenidone significantly reduced the median (IQR) annual rate of decline in FVC % predicted (-8.7 (-14.2 - -7.0) %/yr vs 2.0 (-7.1 - 6.0) %/yr; n=17; p<0.01). In the slow decliners, pirfenidone did not reduce the median (IQR) annual rate of decline in FVC % predicted (-1.3 (-3.2 - 1.3) %/yr vs -5.0 (-8.3 - -0.35) %/yr; n=17; p=0.028). Conclusions: We demonstrate the greater net effect of pirfenidone in IPF patients declining rapidly. We suggest that using an annual rate of decline in FVC of <5% and ≥5% may be useful in counselling patients with regard to pirfenidone treatment. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 218-224).


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Piridonas/uso terapêutico , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Progressão da Doença , Inglaterra , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/fisiopatologia , Masculino , Piridonas/efeitos adversos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Capacidade Vital
16.
Medicine (Baltimore) ; 99(44): e22991, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126376

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with unknown etiology and hidden onset, which causes major health problems worldwide. Cough is a typical manifestation of IPF, which is usually characterized by cough without phlegm, and seriously affects the quality of life (QOL) of patients. At present, the treatment of IPF is mainly focused on prolonging survival time and improving lung function, such as pirfenidone, nintedanib, and N-acetylcysteine (NAC), but lack of effective measures to improve the QOL. Chinese herbal medicines (CHMs) is widely used in the clinical treatment of IPF. The adjuvant treatment of CHMs can effectively reduce the clinical symptoms of patients. Therefore, we designed this study to evaluate the role of CHMs in the treatment of cough in IPF. METHOD: This systematic review and meta-analysis will extract all randomized controlled trials (RCTs) related to the treatment of IPF from the following electronic database without date or language restrictions: PubMed, EMBASE, Cochrane CENTRAL, CNKI, VIP, CBM, and Wanfang database. The primary outcomes will be cough frequency and QOL, while secondary outcomes will include safety events. The methodologic quality of RCTs will be assessed using the Cochrane risk assessment tool. The I test will be used to identify the extent of heterogeneity, and funnel plot analysis will be used to test the publication deviation (the number of studies included >10). We will use RevMan5.3 software for data synthesis and analysis. RESULT: This review evaluates the efficacy and safety of CHMs in combination therapy on cough frequency, the quality of life, adverse reactions and safety incidents in patients with IPF. CONCLUSION: This study protocol will be used to evaluate the efficacy and safety of CHMs in combination with conventional therapy in treatment of cough in IPF. OSF REGISTRATION DOI: 10.17605/OSF.IO/JKQYV.


Assuntos
Tosse/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Tosse/etiologia , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Fibrose Pulmonar Idiopática/complicações , Resultado do Tratamento
18.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L675-L682, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877221

RESUMO

Mucosal surfaces are constantly exposed to a microbiome consisting of microorganisms that heavily influence human immunity and health. In the lung these microorganisms consist of bacteria, viruses, and fungi and exist in a relatively low biomass state. Bacterial communities of the lung modulate local inflammation and correlate with changes in pulmonary physiology and clinical outcomes in patients with lung disease. Instrumental to this progress has been the study of these bacterial communities in the pathogenesis of pulmonary fibrosis, a fatal and progressive disease culminating in respiratory failure. Key pathophysiological mechanisms in pulmonary fibrosis include recurrent idiopathic alveolar epithelial injury, unchecked collagen deposition, mucociliary dysfunction due to muc5b overexpression, hypoxia, and altered host defense. These key mechanisms and their related consequences promote severe progressive architectural lung destruction and loss of local homeostasis. As such, pulmonary fibrosis is an appropriate target disease for the study of the lung microbiome. Herein, we discuss recent advances in our understanding of the role of the lung microbiome in the pathogenesis of pulmonary fibrosis. We highlight fundamental clinical observations and mechanistic insights and identify crucial areas for further discovery science. An improved understanding of how the lung microbiome acts to influence outcomes in patients with pulmonary fibrosis will lead to enhanced therapies for this devastating lung disease.


Assuntos
Fibrose Pulmonar Idiopática/patologia , Inflamação/patologia , Pulmão/patologia , Microbiota/fisiologia , Animais , Bactérias/patogenicidade , Progressão da Doença , Humanos , Inflamação/microbiologia , Pulmão/microbiologia
19.
J Med Chem ; 63(20): 11639-11662, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32969660

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a rare and devastating chronic lung disease of unknown etiology. Despite the approved treatment options nintedanib and pirfenidone, the medical need for a safe and well-tolerated antifibrotic treatment of IPF remains high. The human prostaglandin F receptor (hFP-R) is widely expressed in the lung tissue and constitutes an attractive target for the treatment of fibrotic lung diseases. Herein, we present our research toward novel quinoline-based hFP-R antagonists, including synthesis and detailed structure-activity relationship (SAR). Starting from a high-throughput screening (HTS) hit of our corporate compound library, multiple parameter improvements-including increase of the relative oral bioavailability Frel from 3 to ≥100%-led to a highly potent and selective hFP-R antagonist with complete oral absorption from suspension. BAY-6672 (46) represents-to the best of our knowledge-the first reported FP-R antagonist to demonstrate in vivo efficacy in a preclinical animal model of lung fibrosis, thus paving the way for a new treatment option in IPF.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Quinolinas/síntese química , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Animais , Modelos Animais de Doenças , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Estrutura Molecular , Quinolinas/química , Quinolinas/uso terapêutico , Ratos , Ratos Wistar , Relação Estrutura-Atividade
20.
Am J Respir Cell Mol Biol ; 63(6): 819-830, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32926636

RESUMO

Pathological changes in the biomechanical environment are implicated in the progression of idiopathic pulmonary fibrosis (IPF). Stiffened matrix augments fibroblast proliferation and differentiation and activates TGF-ß1 (transforming growth factor-ß1). Stiffened matrix impairs the synthesis of the antifibrogenic lipid mediator prostaglandin E2 (PGE2) and reduces the expression of the rate-limiting prostanoid biosynthetic enzyme cyclooxygenase-2 (COX-2). We now show that prostaglandin E synthase (PTGES), the final enzyme in the PGE2 biosynthetic pathway, is expressed at lower levels in the lungs of patients with IPF. We also show substantial induction of COX-2, PTGES, prostaglandin E receptor 4 (EP4), and cytosolic phospholipase A2 (cPLA2) expression in human lung fibroblasts cultured in soft collagen hydrogels or in spheroids compared with conventional culture on stiff plastic culture plates. Induction of COX-2, cPLA2, and PTGES expression in spheroid cultures was moderately inhibited by the p38 mitogen-activated protein kinase inhibitor SB203580. The induction of prostanoid biosynthetic enzyme expression was accompanied by an increase in PGE2 levels only in non-IPF-derived fibroblast spheroids. Our study reveals an extensive dysregulation of prostanoid biosynthesis and signaling pathways in IPF-derived fibroblasts, which are only partially abrogated by culture in soft microenvironments.


Assuntos
Microambiente Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Imidazóis/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Fibroblastos/metabolismo , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Prostaglandina-E Sintases/metabolismo
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