RESUMEN
In a patient with interstitial lung disease (ILD) of known or unknown etiology other than idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF) is defined by worsening lung fibrosis on high-resolution computed tomography (HRCT), decline in lung function, and/or deterioration in symptoms. The INBUILD trial involved 663 patients with PPF who were randomized to receive nintedanib or placebo. The median exposure to trial medication was approximately 19 months. The INBUILD trial provided valuable learnings about the course of PPF and the efficacy and safety of nintedanib. The relative effect of nintedanib on reducing the rate of forced vital capacity decline was consistent across subgroups based on ILD diagnosis, HRCT pattern, and disease severity at baseline, and between patients who were and were not taking glucocorticoids or disease-modifying anti-rheumatic drugs and/or glucocorticoids at baseline. The adverse events most frequently associated with nintedanib were gastrointestinal, particularly diarrhea, but nintedanib was discontinued in only a minority of cases. The results of the INBUILD trial highlight the importance of prompt detection and treatment of PPF and the utility of nintedanib as a treatment option.
What did we find out from the INBUILD trial about progressive lung fibrosis?Lung fibrosis is a rare disease in which the lung tissue becomes scarred and hardened. This makes it more difficult for the lungs to inflate and for the lungs to exchange oxygen with the blood. In some patients, lung fibrosis gets worse over time. This is known as progressive lung fibrosis. In the INBUILD trial, researchers looked at the effects of a drug called nintedanib in patients with progressive lung fibrosis. In this trial, 663 patients were randomly allocated to receive either nintedanib or a placebo and then followed for approximately 19 months. The patients and the researchers did not know which patients were taking the active drug (nintedanib) and which patients were taking placebo. The results showed that the criteria used to find patients with progressive lung fibrosis to take part in the trial successfully identified patients whose disease would continue to worsen. These criteria were based on a decline in the volume (size) of the lungs, worsening symptoms such as shortness of breath, and worsening of changes seen on a scan of the chest. The trial results also showed that nintedanib slowed down loss of lung function and had a similar benefit in patients with different severities of disease at the start of the trial. The most common side-effects of nintedanib were gastrointestinal problems, particularly diarrhea, but most patients given nintedanib were able to cope with these side-effects without needing to stop treatment. Large trials like the INBUILD trial are important for helping us understand how diseases progress and in which patients particular drugs should be used.
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Progresión de la Enfermedad , Indoles , Fibrosis Pulmonar , Tomografía Computarizada por Rayos X , Humanos , Indoles/efectos adversos , Indoles/uso terapéutico , Indoles/administración & dosificación , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/fisiopatología , Capacidad Vital , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Pulmón/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/fisiopatología , Enfermedades Pulmonares Intersticiales/diagnóstico , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/fisiopatología , Fibrosis Pulmonar Idiopática/diagnóstico , Masculino , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificaciónRESUMEN
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.
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Antifibróticos , Progresión de la Enfermedad , Fibrosis Pulmonar , Humanos , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/terapia , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/diagnóstico , Antifibróticos/uso terapéutico , Capacidad Vital , Enfermedades Pulmonares Intersticiales/fisiopatología , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/terapia , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Aging-associated left ventricular dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in a left ventricular dysfunction model. METHODS AND RESULTS: Left ventricular dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone mice, a subset of mice that received sham surgery. Three weeks after surgery, mice underwent simultaneous PET-MRI at 4.7 T. Collagen-targeted PET and fibrogenesis magnetic resonance (MR) probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio. Percent signal intensity increase and Δ lung-to-muscle ratio were computed from the pre-/postinjection magnetic resonance images. Elevated allysine in the heart (P=0.02) and lungs (P=0.17) of TAC mice corresponded to an increase in myocardial magnetic resonance imaging percent signal intensity increase (P<0.0001) and Δlung-to-muscle ratio (P<0.0001). Hydroxyproline in the heart (P<0.0001) and lungs (P<0.01) were elevated in TAC mice, which corresponded to an increase in heart (myocardium-to-muscle ratio, P=0.02) and lung (lung-to-muscle ratio, P<0.001) PET measurements. Pressure-volume loop and echocardiography demonstrated adverse left ventricular remodeling, function, and increased right ventricular systolic pressure in TAC mice. CONCLUSIONS: Administration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-magnetic resonance imaging signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-magnetic resonance imaging protocol.
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Modelos Animales de Enfermedad , Fibrosis , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Disfunción Ventricular Izquierda , Animales , Tomografía de Emisión de Positrones/métodos , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/metabolismo , Imagen por Resonancia Magnética/métodos , Ratones , Miocardio/patología , Miocardio/metabolismo , Fibrosis Pulmonar/diagnóstico por imagen , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/etiología , Función Ventricular Izquierda , Masculino , Pulmón/diagnóstico por imagen , Pulmón/patología , Pulmón/fisiopatología , Pulmón/metabolismo , Imagen Multimodal/métodos , Colágeno/metabolismo , Remodelación Ventricular , Lisina/análogos & derivadosRESUMEN
Lysophosphatidic acid (LPA)-mediated activation of LPA receptor 1 (LPAR1) contributes to the pathophysiology of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). These diseases are associated with high morbidity and mortality despite current treatment options. The LPA-producing enzyme autotaxin (ATX) and LPAR1 activation contribute to inflammation and mechanisms underlying fibrosis in preclinical fibrotic models. Additionally, elevated levels of LPA have been detected in bronchoalveolar lavage fluid from patients with IPF and in serum from patients with SSc. Thus, ATX and LPAR1 have gained considerable interest as pharmaceutical targets to combat fibrotic disease and inhibitors of these targets have been investigated in clinical trials for IPF and SSc. The goals of this review are to summarise the current literature on ATX and LPAR1 signalling in pulmonary fibrosis and to help differentiate the novel inhibitors in development. The mechanisms of action of ATX and LPAR1 inhibitors are described and preclinical studies and clinical trials of these agents are outlined. Because of their contribution to numerous physiologic events underlying fibrotic disease, ATX and LPAR1 inhibition presents a promising therapeutic strategy for IPF, SSc and other fibrotic diseases that may fulfil unmet needs of the current standard of care.
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Fibrosis Pulmonar Idiopática , Hidrolasas Diéster Fosfóricas , Receptores del Ácido Lisofosfatídico , Transducción de Señal , Humanos , Receptores del Ácido Lisofosfatídico/antagonistas & inhibidores , Receptores del Ácido Lisofosfatídico/metabolismo , Animales , Transducción de Señal/efectos de los fármacos , Hidrolasas Diéster Fosfóricas/metabolismo , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/metabolismo , Terapia Molecular Dirigida , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Pulmón/metabolismo , Antifibróticos/uso terapéutico , Lisofosfolípidos/metabolismo , Resultado del Tratamiento , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/fisiopatología , Inhibidores de Fosfodiesterasa/uso terapéuticoRESUMEN
The increasing prevalence of type 2 diabetes mellitus (T2DM) is a significant worldwide health concern caused by sedentary lifestyles and unhealthy diets. Beyond glycemic control, T2DM impacts multiple organ systems, leading to various complications. While traditionally associated with cardiovascular and microvascular complications, emerging evidence indicates significant effects on pulmonary health. Pulmonary vascular dysfunction and fibrosis, characterized by alterations in vascular tone and excessive extracellular matrix deposition, are increasingly recognized in individuals with T2DM. The onset of T2DM is often preceded by prediabetes, an intermediate hyperglycemic state that is associated with increased diabetes and cardiovascular disease risk. This review explores the relationship between T2DM, pulmonary vascular dysfunction and pulmonary fibrosis, with a focus on potential links with prediabetes. Pulmonary vascular function, including the roles of nitric oxide (NO), prostacyclin (PGI2), endothelin-1 (ET-1), thromboxane A2 (TxA2) and thrombospondin-1 (THBS1), is discussed in the context of T2DM and prediabetes. Mechanisms linking T2DM to pulmonary fibrosis, such as oxidative stress, dysregulated fibrotic signaling, and chronic inflammation, are explained. The impact of prediabetes on pulmonary health, including endothelial dysfunction, oxidative stress, and dysregulated vasoactive mediators, is highlighted. Early detection and intervention during the prediabetic stage may reduce respiratory complications associated with T2DM, emphasizing the importance of management strategies targeting blood glucose regulation and vascular health. More research that looks into the mechanisms underlying pulmonary complications in T2DM and prediabetes is needed.
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Diabetes Mellitus Tipo 2 , Fibrosis Pulmonar , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Fibrosis Pulmonar/fisiopatología , Estado Prediabético/complicaciones , Estado Prediabético/fisiopatología , Estado Prediabético/metabolismo , Animales , Pulmón/fisiopatología , Pulmón/patologíaRESUMEN
Research on the condition of the lungs in senile people is an urgent task. This is due to the fact that degenerative or age-associated changes in the respiratory system play an important role in the formation of senile asthenia syndrome and a decrease in the age-related viability of the body as a whole. CT-scans of patients aged 80-90 years were analyzed (n=31). Age-associated changes were evaluated: the presence of linear fibrosis, increased pulmonary pattern by the type of reticular (reticular) changes, the presence of gross fibrous reticular changes with cystic cavities and air bullae (by the type of «cellular lung¼), as well as the presence of pulmonary emphysema. Most naturally, senile people show changes characteristic of linear pulmonary fibrosis and emphysema. The progression of the process leads to diffuse reticular changes in the interalveolar and intersegmental septa and, in adverse cases, to the formation of gross changes in the type of «cellular lung¼. Fibro-emphysematous changes are significantly more common in men. A microbiological study of the microbiota of the lower respiratory tract in elderly people was also carried out (n=16). When studying the microbiocenosis of the lower respiratory tract in elderly people, the following data were obtained: resident microflora was found in 71% and clinically significant microorganisms were found in 29%.
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Microbiota , Enfisema Pulmonar , Humanos , Anciano de 80 o más Años , Masculino , Femenino , Enfisema Pulmonar/microbiología , Enfisema Pulmonar/fisiopatología , Enfisema Pulmonar/diagnóstico , Microbiota/fisiología , Pulmón/microbiología , Tomografía Computarizada por Rayos X/métodos , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/microbiología , Fibrosis Pulmonar/diagnóstico , Fibrosis Pulmonar/etiología , Envejecimiento/fisiologíaRESUMEN
Assessment of lung function is an important clinical tool for the diagnosis and monitoring of chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). In mice, lung function maneuvers use algorithm-based ventilation strategies including forced oscillation technique (FOT), negative pressure-driven forced expiratory (NPFE) and pressure-volume (PV) maneuvers via the FlexiVent system. This lung function test (LFT) is usually performed as end-point measurement only, requiring several mice for each time point to be analyzed. Repetitive lung function maneuvers would allow monitoring of a disease process within the same individual while reducing the numbers of laboratory animals. However, its feasibility in mice and impact on developing lung fibrosis has not been studied so far. Using orotracheal cannulation without surgical exposure of the trachea, we examined the tolerability to repetitive lung function maneuvers (up to four times) in one and the same mouse, both under healthy conditions and in a model of AdTGF-ß1 induced lung fibrosis. In essence, we found that repetitive invasive lung function maneuvers were well tolerated and did not accentuate experimental lung fibrosis in mice. This study contributes to the 3R principle aiming to reduce the numbers of experimental animals used in biomedical research.
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Modelos Animales de Enfermedad , Pruebas de Función Respiratoria , Animales , Ratones , Pulmón/fisiopatología , Pulmón/patología , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/patología , Ratones Endogámicos C57BL , Masculino , Factor de Crecimiento Transformador beta1/metabolismo , Fibrosis Pulmonar Idiopática/fisiopatología , Fibrosis Pulmonar Idiopática/patologíaRESUMEN
Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (EUIP) pattern are at increased risk for ventilator-induced lung injury (VILI) and mortality when exposed to mechanical ventilation (MV). Yet, lack of a mechanical model describing UIP-lung deformation during MV represents a research gap. Aim of this study was to develop a constitutive mathematical model for UIP-lung deformation during lung protective MV based on the stress-strain behavior and the specific elastance of patients with EUIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung. Partitioned lung and chest wall mechanics were assessed for patients with EUIP and primary ARDS (1:1 matched based on body mass index and PaO2/FiO2 ratio) during a PEEP trial performed within 24 h from intubation. Patient's stress-strain curve and the lung specific elastance were computed and compared with those of healthy lungs, derived from literature. Respiratory mechanics were used to fit a novel mathematical model of the lung describing mechanical-inflation-induced lung parenchyma deformation, differentiating the contributions of elastin and collagen, the main components of lung extracellular matrix. Five patients with EUIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Overall specific elastance was significantly higher in EUIP as compared to ARDS (28.9 [22.8-33.2] cmH2O versus 11.4 [10.3-14.6] cmH2O, respectively). Compared to ARDS and healthy lung, the stress/strain curve of EUIP showed a steeper increase, crossing the VILI threshold stress risk for strain values greater than 0.55. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was prevalent at large strains. The stress/strain curve for collagen showed an upward shift passing from ARDS and healthy lungs to EUIP lungs. During MV, patients with EUIP showed different respiratory mechanics, stress-strain curve and specific elastance as compared to ARDS patients and healthy subjects and may experience VILI even when protective MV is applied. According to our mathematical model of lung deformation during mechanical inflation, the elastic response of UIP-lung is peculiar and different from ARDS. Our data suggest that patients with EUIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS.
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Pulmón , Respiración Artificial , Síndrome de Dificultad Respiratoria , Humanos , Masculino , Femenino , Persona de Mediana Edad , Respiración Artificial/efectos adversos , Síndrome de Dificultad Respiratoria/fisiopatología , Anciano , Pulmón/fisiopatología , Pulmón/patología , Elasticidad , Lesión Pulmonar Inducida por Ventilación Mecánica/fisiopatología , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/metabolismo , Mecánica Respiratoria/fisiología , Estrés Mecánico , Enfermedades Pulmonares Intersticiales/fisiopatología , Modelos TeóricosRESUMEN
RATIONALE: The proportion of patients who develop progressive pulmonary fibrosis (PPF), along with risk factors for progression remain poorly understood. OBJECTIVES: To examine factors associated with an increased risk of developing PPF among patients at a referral center. METHODS: We identified patients with a diagnosis of interstitial lung disease (ILD) seen within the Cleveland Clinic Health System. Utilizing a retrospective observational approach we estimated the risk of developing progression by diagnosis group and identified key clinical predictors using the FVC component of both the original progressive fibrotic interstitial lung disease (PFILD) and the proposed PPF (ATS) criteria. RESULTS: We identified 5934 patients with a diagnosis of ILD. The cumulative incidence of progression over the 24 months was similar when assessed with the PFILD and PPF criteria (33.1 % and 37.9 % respectively). Of those who met the ATS criteria, 9.5 % did not meet the PFILD criteria. Conversely, 4.3 % of patients who met PFILD thresholds did not achieve the 5 % absolute FVC decline criteria. Significant differences in the rate of progression were seen based on underlying diagnosis. Steroid therapy (HR 1.46, CI 1.31-1.62) was associated with an increased risk of progressive fibrosis by both PFILD and PPF criteria. CONCLUSION: Regardless of the definition used, the cumulative incidence of progressive disease is high in patients with ILD in the 24 months following diagnosis. Some differences are seen in the risk of progression when assessed by PFILD and PPF criteria. Further work is needed to identify modifiable risk factors for the development of progressive fibrosis.
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Progresión de la Enfermedad , Enfermedades Pulmonares Intersticiales , Humanos , Enfermedades Pulmonares Intersticiales/fisiopatología , Enfermedades Pulmonares Intersticiales/epidemiología , Enfermedades Pulmonares Intersticiales/complicaciones , Masculino , Femenino , Estudios Retrospectivos , Capacidad Vital/fisiología , Persona de Mediana Edad , Anciano , Factores de Riesgo , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/complicaciones , Fibrosis Pulmonar/epidemiología , IncidenciaRESUMEN
PURPOSE: World Trade Center (WTC) exposure is associated with obstructive airway diseases and sarcoidosis. There is limited research regarding the incidence and progression of non-sarcoidosis interstitial lung diseases (ILD) after WTC-exposure. ILD encompasses parenchymal diseases which may lead to progressive pulmonary fibrosis (PPF). We used the Fire Department of the City of New York's (FDNY's) WTC Health Program cohort to estimate ILD incidence and progression. METHODS: This longitudinal study included 14,525 responders without ILD prior to 9/11/2001. ILD incidence and prevalence were estimated and standardized to the US 2014 population. Poisson regression modeled risk factors, including WTC-exposure and forced vital capacity (FVC), associated with ILD. Follow-up time ended at the earliest of incident diagnosis, end of study period/case ascertainment, transplant or death. RESULTS: ILD developed in 80/14,525 FDNY WTC responders. Age, smoking, and gastroesophageal reflux disease (GERD) prior to diagnosis were associated with incident ILD, though FVC was not. PPF developed in 40/80 ILD cases. Among the 80 cases, the average follow-up time after ILD diagnosis was 8.5 years with the majority of deaths occurring among those with PPF (PPF: n = 13; ILD without PPF: n = 6). CONCLUSIONS: The prevalence of post-9/11 ILD was more than two-fold greater than the general population. An exposure-response gradient could not be demonstrated. Half the ILD cases developed PPF, higher than previously reported. Age, smoking, and GERD were risk factors for ILD and PPF, while lung function was not. This may indicate that lung function measured after respirable exposures would not identify those at risk for ILD or PPF.
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Progresión de la Enfermedad , Enfermedades Pulmonares Intersticiales , Fibrosis Pulmonar , Ataques Terroristas del 11 de Septiembre , Humanos , Estudios Longitudinales , Masculino , Enfermedades Pulmonares Intersticiales/epidemiología , Enfermedades Pulmonares Intersticiales/fisiopatología , Persona de Mediana Edad , Femenino , Incidencia , Capacidad Vital , Adulto , Prevalencia , Factores de Riesgo , Fibrosis Pulmonar/epidemiología , Fibrosis Pulmonar/fisiopatología , Ciudad de Nueva York/epidemiología , Reflujo Gastroesofágico/epidemiología , Exposición Profesional/efectos adversos , Fumar/efectos adversos , Fumar/epidemiología , Anciano , Factores de Tiempo , Socorristas/estadística & datos numéricosRESUMEN
INTRODUCTION: Pulmonary fibrosis is a characteristic of various interstitial lung diseases (ILDs) with differing etiologies. Clinical trials in progressive pulmonary fibrosis (PPF) enroll patients based on previously described clinical criteria for past progression, which include a clinical practice guideline for PPF classification and inclusion criteria from the INBUILD trial. In this study, we compared the ability of past FVC (forced vital capacity) progression and baseline biomarker levels to predict future progression in a cohort of patients from the PFF Patient Registry. METHODS: Biomarkers previously associated with pathobiology and/or progression in pulmonary fibrosis were selected to reflect cellular senescence (telomere length), pulmonary epithelium (SP-D, RAGE), myeloid activation (CXCL13, YKL40, CCL18, OPN) and fibroblast activation (POSTN, COMP, PROC3). RESULTS: PFF or INBUILD-like clinical criteria was used to separate patients into past progressor and non-past progressor groups, and neither clinical criterion appeared to enrich for patients with greater future lung function decline. All baseline biomarkers measured were differentially expressed in patient groups compared to healthy controls. Baseline levels of SP-D and POSTN showed the highest correlations with FVC slope over one year, though correlations were low. CONCLUSIONS: Our findings provide further evidence that prior decline in lung function may not predict future disease progression for ILD patients, and elevate the need for molecular definitions of a progressive phenotype. Across ILD subtypes, certain shared pathobiologies may be present based on the molecular profile of certain biomarker groups observed. In particular, SP-D may be a common marker of pulmonary injury and future lung function decline across ILDs.
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Biomarcadores , Progresión de la Enfermedad , Enfermedades Pulmonares Intersticiales , Sistema de Registros , Humanos , Masculino , Femenino , Persona de Mediana Edad , Capacidad Vital , Anciano , Enfermedades Pulmonares Intersticiales/fisiopatología , Enfermedades Pulmonares Intersticiales/diagnóstico , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/diagnóstico , Proteína D Asociada a Surfactante Pulmonar/sangre , Pulmón/fisiopatología , Valor Predictivo de las Pruebas , Proteína 1 Similar a Quitinasa-3/sangre , Quimiocinas CC , Osteopontina , Receptor para Productos Finales de Glicación Avanzada/sangre , Fibrosis Pulmonar Idiopática/fisiopatología , Fibrosis Pulmonar Idiopática/diagnósticoRESUMEN
Rationale: A visual analog scale (VAS) is a simple and easily administered tool for measuring the impact of disease; however, little is known about the use of a dyspnea VAS in interstitial lung disease (ILD). Objectives: To validate the use of a dyspnea VAS in a large and heterogeneous cohort of patients with fibrotic ILD, including its minimal clinically important difference (MCID), responsiveness to change, and prognostic significance. Methods: Patients with fibrotic ILD were identified from a large prospective registry. The validity of a 100-mm dyspnea VAS was assessed by testing its correlation in change score with other measures of ILD severity, including the University of California San Diego Shortness of Breath Questionnaire, the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain, the European Quality of Life VAS, forced vital capacity, and diffusing capacity of the lung for carbon monoxide. The responsiveness of the dyspnea VAS was qualitatively confirmed on the basis of there being an observable difference in the change in dyspnea VAS across tertiles of change in anchor variables. The MCID in dyspnea VAS was calculated using both anchor (linear regression) and distribution (one-half standard deviation) approaches, with anchors including the above variables that had a correlation with dyspnea VAS (|r| ≥ 0.30). The association of dyspnea VAS with time to death or transplant was determined. Results: The cohort included 826 patients with fibrotic ILD, including 127 patients with follow-up measurements at 6 months. The mean baseline dyspnea VAS was 53 ± 24 mm. Dyspnea VAS change scores were moderately correlated with the University of California San Diego Shortness of Breath Questionnaire (|r| = 0.55) and the King's Brief Interstitial Lung Disease quality of life questionnaire Breathlessness and Activities Domain (|r| = 0.44) and weakly correlated with the European Quality of Life VAS (|r| = 0.19), forced vital capacity percent predicted (|r| = 0.21), and diffusing capacity of the lung for carbon monoxide percent predicted (|r| = 0.05). The MCID was 2.7 to 4.5 using the more reliable anchor-based methods and 12.0 based on distribution-based methods. Dyspnea VAS was associated with time to death or transplant in unadjusted models and after adjustment for age and sex (hazard ratios, 1.16 and 1.15, respectively; P < 0.05 for both). Conclusions: This study provides support for the use of the dyspnea VAS in patients with fibrotic ILD, with an estimated anchor-based MCID of 5 mm.
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Disnea , Enfermedades Pulmonares Intersticiales , Calidad de Vida , Escala Visual Analógica , Humanos , Disnea/etiología , Disnea/diagnóstico , Masculino , Femenino , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/fisiopatología , Enfermedades Pulmonares Intersticiales/diagnóstico , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Pronóstico , Sistema de Registros , Encuestas y Cuestionarios , Capacidad Vital , Fibrosis Pulmonar/complicaciones , Fibrosis Pulmonar/fisiopatologíaRESUMEN
Rationale: The use of race-specific reference values to evaluate pulmonary function has long been embedded into clinical practice; however, there is a growing consensus that this practice may be inappropriate and that the use of race-neutral equations should be adopted to improve access to health care. Objectives: To evaluate whether the use of race-neutral equations to assess percent predicted forced vital capacity (FVC%pred) impacts eligibility for clinical trials, antifibrotic therapy, and referral for lung transplantation in Black, Hispanic/Latino, and White patients with interstitial lung disease (ILD). Methods: FVC%pred values for patients from the Pulmonary Fibrosis Foundation Patient Registry were calculated using race-specific (Hankinson and colleagues, 1999), race-agnostic (Global Lung Function Initiative [GLI]-2012), and race-neutral (GLI-2022 or GLI-Global) equations. Eligibility for ILD clinical trials (FVC%pred >45% and <90%), antifibrotic therapy (FVC%pred >55% and <82%), and lung transplantation referral (FVC%pred <70%) based on GLI-2022 and GLI-2012 equations were compared with those based on the Hankinson 1999 equation. Results: Baseline characteristics were available for 1,882 patients (Black, n = 104; Hispanic/Latino, n = 103; White, n = 1,675), and outcomes were evaluated in 1,531 patients with FVC%pred within ±90 days of registry enrollment (Black, n = 78; Hispanic/Latino, n = 72; White, n = 1,381). Black patients were younger at the time of consent and more likely to be female compared with Hispanic/Latino or White patients. Compared with GLI-2022, the Hankinson 1999 equation misclassified 22% of Black patients, 14% of Hispanic/Latino patients, and 12% of White patients for ILD clinical trial eligibility; 21% of Black patients, 17% of Hispanic/Latino patients, and 19% of White patients for antifibrotic therapy eligibility; and 6% of Black patients, 14% of Hispanic/Latino patients, and 12% of White patients for lung transplantation referral. Similar trends were observed when comparing the GLI-2012 and Hankinson 1999 equations. Conclusions: Misclassification of patients for critical interventions is highly prevalent when using the Hankinson 1999 equation and highlights the need to consider adopting the race-neutral GLI-2022 equation for enhanced accuracy and more equitable representation in pulmonary health care. Our results make a compelling case for reevaluating the use of race as a physiological variable and emphasize the pressing need for continuous innovation to ensure equal and optimal care for all patients regardless of their race or ethnicity. Clinical trial registered with www.clinicaltrials.gov (NCT02758808).
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Trasplante de Pulmón , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Capacidad Vital , Estados Unidos , Determinación de la Elegibilidad/métodos , Pruebas de Función Respiratoria , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/terapia , Fibrosis Pulmonar/etnología , Hispánicos o Latinos/estadística & datos numéricos , Sistema de Registros , Selección de Paciente , Población Blanca/estadística & datos numéricos , Negro o Afroamericano , Enfermedades Pulmonares Intersticiales/fisiopatología , Enfermedades Pulmonares Intersticiales/terapia , Enfermedades Pulmonares Intersticiales/etnología , Enfermedades Pulmonares Intersticiales/diagnóstico , Valores de ReferenciaRESUMEN
Circadian regulation causes the activity of biological processes to vary over a 24-h cycle. The pathological effects of this variation are predominantly studied using two different approaches: pre-clinical models or observational clinical studies. Both these approaches have provided useful insights into how underlying circadian mechanisms operate and specifically which are regulated by the molecular oscillator, a key time-keeping mechanism in the body. This review compares and contrasts findings from these two approaches in the context of four common respiratory diseases (asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and respiratory infection). Potential methods used to identify and measure human circadian oscillations are also discussed as these will be useful outcome measures in future interventional human trials that target circadian mechanisms.
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Relojes Circadianos , Enfermedades Pulmonares , Humanos , Asma/fisiopatología , Relojes Circadianos/fisiología , Enfermedades Pulmonares/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Fibrosis Pulmonar/fisiopatología , Infecciones del Sistema Respiratorio/fisiopatología , Factores de Tiempo , Ensayos Clínicos como Asunto , Proyectos de InvestigaciónRESUMEN
Our previous study showed that triggering receptors expressed on myeloid cell-1 (TREM-1) was upregulated in bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model. However, the role of TREM-1 in the development of PF and its underlying mechanism remain unclear. Herein, we report that the prophylactical blockade of TREM-1 using a decoy peptide dodecapeptide (LR12) exerted protective effects against BLM-induced PF in mice, with a higher survival rate, attenuated tissue injury, and less extracellular matrix deposition. Interestingly, therapeutic blockade of TREM-1 at the early stage of fibrosis also attenuated BLM-induced PF, suggesting a non-inflammatory effect. More importantly, we observed that TREM-1 blockade with LR12 significantly reduced the expression of the senescence-relative protein, including p16, p21, p53, and γ-H2AX in the lungs of PF mice. Notably, TREM-1 was upregulated in alveolar epithelial cells (AECs) and correlated with the levels of senescence markers in BLM-treated mice. In vitro, activating TREM-1 with an agonistic antibody exacerbated BLM-induced senescence in MLE12 cells, a murine AEC cell line. Furthermore, prophylactic or therapeutic blockade of TREM-1 protected MLE12 cells from senescence induced by BLM or H2O2. In conclusion, our findings elucidate a pro-fibrotic effect of TREM-1 by inducing AECs senescence in PF, providing a potential strategy for fibrotic disease treatment.
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Células Epiteliales Alveolares , Fibrosis Pulmonar , Receptor Activador Expresado en Células Mieloides 1 , Animales , Ratones , Células Epiteliales Alveolares/patología , Bleomicina/toxicidad , Peróxido de Hidrógeno/metabolismo , Células Mieloides , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/fisiopatología , Receptor Activador Expresado en Células Mieloides 1/metabolismoRESUMEN
The warning cytokine interleukin-33 receptor (IL-33R) mediates local inflammatory responses and plays crucial roles in the pathogenesis of immune diseases such as pulmonary fibrosis and rheumatoid arthritis. Whether and how IL-33R is regulated remain enigmatic. Here, we identified ubiquitin-specific protease 38 (USP38) as a negative regulator of IL-33Rmediated signaling. USP38 deficiency promotes interleukin-33 (IL-33)induced downstream proinflammatory responses in vitro and in vivo. Usp38−/− mice are more susceptible to inflammatory damage and death and developed more serious pulmonary fibrosis after bleomycin treatment. USP38 is constitutively associated with IL-33R and deconjugates its K27-linked polyubiquitination at K511, resulting in its autophagic degradation. We further show that the E3 ubiquitin ligase tumor necrosis factor receptorassociated factor 6 (TRAF6) catalyzes K27-linked polyubiquitination of IL-33R at K511, and that deficiency of TRAF6 inhibits IL-33mediated signaling. Our findings suggest that K27-linked polyubiquitination and deubiquitination of IL-33R by TRAF6 and USP38 reciprocally regulate IL-33R level and signaling, which represents a critical mechanism in the regulation of IL-33triggered lung inflammatory response and pulmonary fibrosis.
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Inflamación/fisiopatología , Interleucina-33/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fibrosis Pulmonar/fisiopatología , Proteasas Ubiquitina-Específicas/metabolismo , Autofagia , Regulación hacia Abajo , Humanos , Inflamación/metabolismo , Interleucina-33/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Transducción de Señal , Proteasas Ubiquitina-Específicas/genética , UbiquitinaciónRESUMEN
This study aimed to investigate the correlation between prenatal dexamethasone exposure (PDE) and susceptibility to pulmonary fibrosis in offspring. Healthy female Wistar rats were given dexamethasone (0.2 mg/kg.d) or an equal volume of normal saline subcutaneously from 9 to 20 days after conception. Some of their female offspring underwent ovariectomy (OV) at 22 weeks after birth. All animals were euthanized at 28 weeks after birth. The morphological changes related to pulmonary fibrosis and extracellular matrix-related gene expression were detected, and Two-way ANOVA analyzed the interaction between PDE and OV. The results showed that adult offspring rats in FD group (female rats with PDE treatment) had early pulmonary fibrosis changes, such as pulmonary interstitial thickening, and increased expression of type IV collagen (COL4), α -smooth muscle actin (α-SMA) and fibronectin (FN) in lung tissues compared with those in FC group (female rats with saline treatment). In addition, adult offspring rats in FDO group (female rats with PDE and OV treatment) showed signs of pulmonary fibrosis, including apparent extracellular matrix deposition, increased lung injury scores (Pï¼0.01, Pï¼0.05), and extracellular matrix related gene expression (Pï¼0.01, Pï¼0.05), compared with rats in FDS (female rats with PDE treatment alone) or rats in FCO group (female rats with OV treatment alone). Moreover, PDE and OV had an interactive effect on the development of pulmonary fibrosis in female adult offspring. This study first reported the correlation between PDE and susceptibility to pulmonary fibrosis in female offspring rats, as well as the synergistic effect of PDE and OV in this pathological event, which provided a basis for further understanding of the pathogenesis of fetal originated pulmonary fibrosis.
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Dexametasona/toxicidad , Susceptibilidad a Enfermedades/inducido químicamente , Desarrollo Fetal/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/fisiopatología , Animales , Modelos Animales de Enfermedad , Femenino , Desarrollo Fetal/genética , Humanos , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Ratas , Ratas Wistar , Factores SexualesRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial disease of the lung tissue that causes symptoms such as coughing and asthma. It is caused by inflammatory factors and oxidative stress. In vivo model of IPF is induced by bleomycin (BLM,) a chemotherapeutic agent. We have investigated the effect of dapsone on bleomycin-induced IPF in adult male Wistar rats due to its anti-inflammatory and anti-oxidative stress effects. The animals were randomly divided into 5 groups (Control, BLM, BLM + dapsone 1, BLM + Dapsone 3, BLM + Dapsone 10). The control group received normal water and food. In the fibrosis group, bleomycin (BLM) (5 mg/kg) was used to induce pulmonary fibrosis by intratracheal administration. Three groups of animals were treated daily with single doses of 1, 3, and 10 mg dapsone by intraperitoneal injection 1 h after receiving BLM for 2 weeks. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and oxidative stress markers such as myeloperoxidase (MPO), malondialdehyde (MDA), protein carbonyl (PC) and nitrite were measured to evaluate bleomycin and therapeutic effect of dapsone. The histological assays of lung tissues were done by Hematoxylin-eosin (H & E) and Masson's trichrome staining. BLM reduced the activity of oxidative enzymes and increased the oxidative stress markers, while treatment with dapsone has reversed the results. In addition, the total number of cells as inflammatory cells such as neutrophils and eosinophils were examined. It has been indicated BLM increased these cells, and dapsone decreased them. The results of H & E and Masson's trichrome staining showed that dapsone reduced inflammation and alveolar wall thickness and BLM-induced pulmonary fibrosis. According to the findings of this study, dapsone seems to have therapeutic effects on pulmonary fibrosis through its anti-inflammatory and anti-oxidative stress properties and reduction of the toxic effects of bleomycin.