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Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic disease. Recent studies have highlighted the persistence of an intermediate state of alveolar stem cells in IPF lungs. In this study, we discovered a close correlation between the distribution pattern of intermediate alveolar stem cells and the progression of fibrotic changes. We showed that amphiregulin (AREG) expression is significantly elevated in intermediate alveolar stem cells of mouse fibrotic lungs and IPF patients. High levels of serum AREG correlate significantly with profound deteriorations in lung function in IPF patients. We demonstrated that AREG in alveolar stem cells is both required and sufficient for activating EGFR in fibroblasts, thereby driving lung fibrosis. Moreover, pharmacological inhibition of AREG using a neutralizing antibody effectively blocked the initiation and progression of lung fibrosis in mice. Our study underscores the therapeutic potential of anti-AREG antibodies in attenuating IPF progression, offering a promising strategy for treating fibrotic diseases.
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INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) is increasingly used to diagnose interstitial lung disease (ILD). The 1.1-mm cryoprobe has recently been available in clinical practice. The diagnostic yield and safety of TBLC using a 1.1-mm cryoprobe need to be confirmed. METHODS: A prospective, randomized controlled trial was conducted in patients with suspected ILD and randomly assigned to 1.1-mm and 1.9-mm cryoprobe groups. The primary outcome was the diagnostic yield of multidisciplinary discussion. Secondary outcomes were sample quality and incidence of complications. The tension and stress effects during TBLC onto the target lobe caused by 1.1-mm and 1.9-mm cryoprobes were also evaluated using finite element analysis. RESULTS: A total of 224 patients were enrolled. No significant differences were observed in the diagnostic yield (80.4% vs. 79.5%, p = 0.845) and sample quality scores (5.73 ± 0.64 vs. 5.66 ± 0.77; p = 0.324) between the 1.9-mm cryoprobe group and 1.1-mm cryoprobe group. The average surface areas of samples in 1.1-mm cryoprobe group were smaller, while no difference in sample weights was observed. A decreased incidence of moderate bleeding was found in the 1.1-mm cryoprobe group (17.0% vs. 6.2%, p = 0.027), while there was no difference in the incidence of the pneumothorax, there was a trend to higher rate of pneumothorax in 1.1-mm group. In finite element analysis, the 1.1-mm cryoprobe required the largest tension and produced the largest stress. CONCLUSION: Compared with a 1.9-mm cryoprobe, there was no difference in specimen quality or diagnostic rate but smaller sample size with a 1.1-mm cryoprobe. There was a decreased risk of moderate bleeding, but a trend towards increased risk for pneumothorax with 1.1-mm cryoprobe. TRAIL REGISTRATION: Clinicaltrials.gov identifier NCT04047667; registered August 4, 2019.
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Idiopathic pulmonary fibrosis, a fatal interstitial lung disease, is characterized by fibroblast activation and aberrant extracellular matrix accumulation. Effective therapeutic development is limited because of incomplete understanding of the mechanisms by which fibroblasts become aberrantly activated. Here, we show aldehyde dehydrogenase 2 (ALDH2) in fibroblasts as a potential therapeutic target for pulmonary fibrosis. A decrease in ALDH2 expression was observed in patients with idiopathic pulmonary fibrosis and bleomycin-treated mice. ALDH2 deficiency spontaneously induces collagen accumulation in the lungs of aged mice. Furthermore, young ALDH2 knockout mice exhibited exacerbated bleomycin-induced pulmonary fibrosis and increased mortality compared with that in control mice. Mechanistic studies revealed that transforming growth factor (TGF)-ß1 induction and ALDH2 depletion constituted a positive feedback loop that exacerbates fibroblast activation. TGF-ß1 down-regulated ALDH2 through a TGF-ß receptor 1/Smad3-dependent mechanism. The subsequent deficiency in ALDH2 resulted in fibroblast dysfunction that manifested as impaired mitochondrial autophagy and senescence, leading to fibroblast activation and extracellular matrix production. ALDH2 overexpression markedly suppressed fibroblast activation, and this effect was abrogated by PTEN-induced putative kinase 1 (PINK1) knockdown, indicating that the profibrotic effects of ALDH2 are PINK1- dependent. Furthermore, ALDH2 activated by N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1) reversed the established pulmonary fibrosis in both young and aged mice. In conclusion, ALDH2 expression inhibited the pathogenesis of pulmonary fibrosis. Strategies to up-regulate or activate ALDH2 expression could be potential therapies for pulmonary fibrosis.
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Aldehído Deshidrogenasa Mitocondrial , Bleomicina , Senescencia Celular , Fibroblastos , Ratones Noqueados , Mitocondrias , Animales , Fibroblastos/metabolismo , Fibroblastos/patología , Aldehído Deshidrogenasa Mitocondrial/metabolismo , Aldehído Deshidrogenasa Mitocondrial/genética , Aldehído Deshidrogenasa Mitocondrial/deficiencia , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Humanos , Bleomicina/toxicidad , Bleomicina/efectos adversos , Factor de Crecimiento Transformador beta1/metabolismo , Ratones Endogámicos C57BL , Masculino , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/genética , Transducción de Señal , Pulmón/patología , Pulmón/metabolismoRESUMEN
RATIONALE AND OBJECTIVES: Bleeding is a major complication of transbronchial lung cryobiopsy (TBLC), and pre-placing a bronchial balloon is one of the clinical practices used to prevent it, but with very weak evidence, which should be confirmed. This study aimed to conduct whether pre-placing a bronchial balloon in TBLC for diagnosing interstitial lung disease (ILD) is more safety. MATERIALS AND METHODS: In this prospective, single-center, randomized controlled trial, patients with suspected ILD were enrolled and randomly assigned to pre-placed balloon and none-pre-placed balloon groups. The primary outcome was incidence of moderate bleeding in each group. The secondary endpoints were the incidence of severe bleeding, pneumothorax, and other procedural complications. RESULTS: Exactly 250 patients were enrolled between August 2019 and March 2022, with 125 in each group. There were no significant differences in severe bleeding between the none-pre-placed balloon group and pre-placed balloon group (1.6% vs. 0.8%; adjusted p = 0.520), while more moderate bleeding occurred in the none-pre-placed balloon group (26.4% vs. 6.4%, adjusted p = 0.001), as well as more use of hemostatic drug (28.0% vs. 6.4%, adjusted p = 0.001). Three patients in the none-pre-placed balloon group used the bronchial balloon. More samples could be acquired in the pre-placed balloon group than in the none-pre-placed balloon group (3.8 ± 0.9 vs. 3.1 ± 0.9, p < 0.001). There were no significant differences in multidisciplinary discussion (MDD) between the two groups (89.6% vs. 91.2%, adjusted p = 0.182). CONCLUSION: A pre-placed bronchial balloon can reduce the incidence of moderate bleeding and increase the confidence of the bronchoscopists. However, it had no effect on increasing the diagnostic rate of MDD and reducing severe bleeding. REGISTRATION NUMBER: NCT04047667 ( www. CLINICALTRIALS: gov identifier).
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Broncoscopía , Criocirugía , Enfermedades Pulmonares Intersticiales , Humanos , Masculino , Femenino , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/patología , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Broncoscopía/métodos , Broncoscopía/efectos adversos , Criocirugía/métodos , Criocirugía/efectos adversos , Biopsia/métodos , Biopsia/efectos adversos , Hemorragia/etiología , Hemorragia/diagnóstico , Hemorragia/prevención & control , Pulmón/patología , Bronquios/patologíaAsunto(s)
Bronquitis , Humanos , Bronquitis/complicaciones , Bronquitis/diagnóstico por imagen , Bronquitis/diagnóstico , Bronquitis/etiología , Femenino , Masculino , Enfermedades Linfáticas/diagnóstico por imagen , Enfermedades Linfáticas/etiología , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Safely implementing transbronchial lung cryobiopsy (TBLC) in patients with interstitial lung disease (ILD) requires accurate navigation. Traditional fluoroscopy falls short in reducing the risk of post-procedure pneumothorax. The potential of electromagnetic navigation bronchoscopy (ENB) as a more precise navigation method warrants further exploration. METHODS: A prospective cohort study was conducted on ILD patients undergoing TBLC. Patients were assigned either fluoroscopy or ENB for cryoprobe positioning. Navigation accuracy was evaluated using cone beam computed tomography (CBCT) images as the standard. Safety and diagnostic yield were also observed. RESULTS: Seventeen patients underwent TBLC, with 10 guided by fluoroscopy and seven by ENB. Fluoroscopy-guided cryoprobe navigation required more adjustments [9/15 (60%) v.s. 1/9 (11%), p = 0.018] for subsequent TBLC compared to ENB, as confirmed by CBCT images. Clinical characteristics, post-procedure complications, and biopsy specimen size showed no significant differences between the groups. Fourteen patients obtained a pathological diagnosis, and 15 received a multidisciplinary discussion (MDD) diagnosis. In the fluoroscopy group, three patients failed to obtain a pathological diagnosis, and two failed to obtain an MDD diagnosis. CONCLUSIONS: ENB demonstrates significantly superior accuracy in TBLC navigation compared to traditional fluoroscopy when CBCT images are used as a reference. Further studies are necessary to determine the value of ENB in TBLC navigation for ILD patients.
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Broncoscopía , Enfermedades Pulmonares Intersticiales , Humanos , Estudios Prospectivos , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Fluoroscopía , Pulmón/diagnóstico por imagen , Fenómenos ElectromagnéticosAsunto(s)
Enfermedades Pulmonares Intersticiales , Sarcoidosis Pulmonar , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/etiología , Sarcoidosis Pulmonar/complicaciones , Sarcoidosis Pulmonar/diagnóstico por imagenRESUMEN
Accurate detection of fibrotic interstitial lung disease (f-ILD) is conducive to early intervention. Our aim was to develop a lung graph-based machine learning model to identify f-ILD. A total of 417 HRCTs from 279 patients with confirmed ILD (156 f-ILD and 123 non-f-ILD) were included in this study. A lung graph-based machine learning model based on HRCT was developed for aiding clinician to diagnose f-ILD. In this approach, local radiomics features were extracted from an automatically generated geometric atlas of the lung and used to build a series of specific lung graph models. Encoding these lung graphs, a lung descriptor was gained and became as a characterization of global radiomics feature distribution to diagnose f-ILD. The Weighted Ensemble model showed the best predictive performance in cross-validation. The classification accuracy of the model was significantly higher than that of the three radiologists at both the CT sequence level and the patient level. At the patient level, the diagnostic accuracy of the model versus radiologists A, B, and C was 0.986 (95% CI 0.959 to 1.000), 0.918 (95% CI 0.849 to 0.973), 0.822 (95% CI 0.726 to 0.904), and 0.904 (95% CI 0.836 to 0.973), respectively. There was a statistically significant difference in AUC values between the model and 3 physicians (p < 0.05). The lung graph-based machine learning model could identify f-ILD, and the diagnostic performance exceeded radiologists which could aid clinicians to assess ILD objectively.
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Acute lung injury (ALI) is an important pathological process of acute respiratory distress syndrome, yet there are limited therapies for its treatment. Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been shown to be effective in suppressing inflammation. However, the effects of MSCs-Exo on ALI and the underlying mechanisms have not been well elucidated. Our data showed that MSCs-Exo, but not exosomes derived from MRC-5 cells (MRC-5-Exo), which are human fetal lung fibroblast cells, significantly improved chest imaging, histological observations, alveolocapillary membrane permeability, and reduced inflammatory response in ALI mice model. According to miRNA sequencing and proteomic analysis of MSCs-Exo and MRC-5-Exo, MSCs-Exo may inhibit pyroptosis by miRNAs targeting caspase-1-mediated pathway, and by proteins with immunoregulation functions. Taken together, our study demonstrated that MSCs-Exo were effective in treating ALI by inhibiting the pyroptosis of alveolar macrophages and reducing inflammation response. Its mechanism may be through pyroptosis-targeting miRNAs and immunoregulating proteins delivered by MSCs-Exo. Therefore, MSCs-Exo may be a new treatment option in the early stage of ALI.
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Lesión Pulmonar Aguda , Exosomas , Células Madre Mesenquimatosas , MicroARNs , Ratones , Animales , Humanos , Macrófagos Alveolares/metabolismo , Piroptosis , Exosomas/metabolismo , Proteómica , Lesión Pulmonar Aguda/terapia , MicroARNs/genética , MicroARNs/metabolismo , Inflamación/metabolismo , Células Madre Mesenquimatosas/metabolismoRESUMEN
BACKGROUND: Maternal smoking during pregnancy (MSDP) is a known risk factor for offspring developing chronic obstructive pulmonary disease (COPD), but the underlying mechanism remains unclear. OBJECTIVE: This study aimed to explore whether the increased COPD risk associated with MSDP could be attributed to tobacco dependence (TD). METHODS: This case-control study used data from the nationwide cross-sectional China Pulmonary Health study, with controls matched for age, sex, and smoking status. TD was defined as smoking within 30 minutes of waking, and the severity of TD was assessed using the Fagerstrom Test for Nicotine Dependence. COPD was diagnosed when the ratio of forced expiratory volume in 1 second to forced vital capacity was <0.7 in a postbronchodilator pulmonary function test according to the 2017 Global Initiative for Chronic Obstructive Lung Disease criteria. Logistic regression was used to examine the correlation between MSDP and COPD, adjusting for age, sex, BMI, educational attainment, place of residence, ethnic background, occupation, childhood passive smoking, residential fine particulate matter, history of childhood pneumonia or bronchitis, average annual household income, and medical history (coronary heart disease, hypertension, and diabetes). Mediation analysis examined TD as a potential mediator in the link between MSDP and COPD risk. The significance of the indirect effect was assessed through 1000 iterations of the "bootstrap" method. RESULTS: The study included 5943 participants (2991 with COPD and 2952 controls). Mothers of the COPD group had higher pregnancy smoking rates (COPD: n=305, 10.20%; controls: n=211, 7.10%; P<.001). TD was more prevalent in the COPD group (COPD: n=582, 40.40%; controls: n=478, 33.90%; P<.001). After adjusting for covariates, MSDP had a significant effect on COPD (ß=.097; P<.001). There was an association between MSDP and TD (ß=.074; P<.001) as well as between TD and COPD (ß=.048; P=.007). Mediation analysis of TD in the MSDP-COPD association showed significant direct and indirect effects (direct: ß=.094; P<.001 and indirect: ß=.004; P=.03). The indirect effect remains present in the smoking population (direct: ß=.120; P<.001 and indirect: ß=.002; P=.03). CONCLUSIONS: This study highlighted the potential association between MSDP and the risk of COPD in offspring, revealing the mediating role of TD in this association. These findings contribute to a deeper understanding of the impact of prenatal tobacco exposure on lung health, laying the groundwork for the development of relevant prevention and treatment strategies.
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Enfermedad Pulmonar Obstructiva Crónica , Tabaquismo , Femenino , Embarazo , Humanos , Estudios de Casos y Controles , Estudios Transversales , Fumar , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/etiologíaRESUMEN
OBJECTIVE: To assess lung deformation in patients with idiopathic pulmonary fibrosis (IPF) using with elastic registration algorithm applied to three-dimensional ultrashort echo time (3D-UTE) MRI and analyze relationship of lung deformation with the severity of IPF. METHODS: Seventy-six patients with IPF (mean age: 62 ± 6 years) and 62 age- and gender-matched healthy controls (mean age: 58 ± 4 years) were prospectively enrolled. End-inspiration and end-expiration images acquired with a single breath-hold 3D-UTE sequence were registered using elastic registration algorithm. Jacobian determinants were calculated from deformation fields and represented on color maps. Jac-mean (absolute value of the log means of Jacobian determinants) and the Dice similarity coefficient (Dice) were compared between different groups. RESULTS: Compared with healthy controls, the Jac-mean of IPF patients significantly decreased (0.21 ± 0.08 vs. 0.27 ± 0. 07, p < 0.001). Furthermore, the Jac-mean and Dice correlated with the metrics of pulmonary function tests and the composite physiological index. The lung deformation in IPF patients with dyspnea Medical Research Council (MRC) ≥ 3 (Jac-mean: 0.16 ± 0.03; Dice: 0.06 ± 0.02) was significantly lower than MRC1 (Jac-mean: 0. 25 ± 0.03, p < 0.001; Dice: 0.10 ± 0.01, p < 0.001) and MRC 2 (Jac-mean: 0.22 ± 0.11, p = 0.001; Dice: 0.08 ± 0.03, p = 0.006). Meanwhile, Jac-mean and Dice correlated with health-related quality of life, 6 min-walk distance, and the extent of pulmonary fibrosis. Jac-mean correlated with pulmonary vascular-related indexes on high-resolution CT. CONCLUSION: The decreased lung deformation in IPF patients correlated with the clinical severity of IPF patients. Elastic registration of inspiratory-to-expiratory 3D UTE MRI may be a new morphological and functional marker for non-radiation and noninvasive evaluation of IPF. CRITICAL RELEVANCE STATEMENT: This prospective study demonstrated that lung deformation decreased in idiopathic pulmonary fibrosis (IPF) patients and correlated with the severity of IPF. Elastic registration of inspiratory-to-expiratory three-dimensional ultrashort echo time (3D UTE) MRI may be a new morphological and functional marker for non-radiation and noninvasive evaluation of IPF. KEY POINTS: ⢠Elastic registration of inspiratory-to-expiratory three-dimensional ultrashort echo time (3D UTE) MRI could evaluate lung deformation. ⢠Lung deformation significantly decreased in idiopathic pulmonary fibrosis (IPF) patients, compared with the healthy controls. ⢠Reduced lung deformation of IPF patients correlated with worsened pulmonary function and the composite physiological index (CPI).
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BACKGROUND: Idiopathic pulmonary fibrosis is a progressive and fatal lung disease lacking effective therapeutics. Treatment with pirfenidone or nintedanib is recommended for patients to delay the progression of their disease. Adverse reactions caused by anti-fibrosis drugs can sometimes interrupt treatment and even change the progression of the disease. OBJECTIVE: This study aimed to investigate the clinical use, adverse reactions, tolerability of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis and the efficacy of antifibrotic therapy in a real world. METHODS: We recruited patients with idiopathic pulmonary fibrosis treated with pirfenidone or nintedanib at China-Japan Friendship Hospital from February 2017 to February 2022. We investigated the medication situation, adverse reactions, tolerability and survival of patients taking medications. RESULTS: A total of 303 patients with idiopathic pulmonary fibrosis were enrolled in the study. Treatment was divided between 205 patients receiving pirfenidone and 98 patients receiving nintedanib. Baseline data between the two groups were not significantly different. Patients treated with nintedanib had a higher overall discontinuation rate than those treated with pirfenidone (61.22 vs. 32.68 %, p < 0.001). Across all patient groups, the most common reason for discontinuing treatment was medication-related adverse effects. Compared to pirfenidone, nintedanib had a significantly higher discontinuation rate due to adverse events (48.98 % vs 27.80 %, p < 0.001). The most common side effect of both drugs was diarrhea. Pirfenidone was associated with a higher rate of extra-digestive adverse effects than nintedanib. Survival was not significantly different between the two drugs and using pirfenidone above 1200 mg/day did not confer significant survival benefits. The survival rate of patients who adhere to anti-fibrosis therapy for more than 6 months can be significantly improved (HR = 0.323, p = 0.0015). CONCLUSION: Gastrointestinal adverse effects were the most common adverse effects and the main reason of discontinuation of antifibrotic therapy, especially nintedanib. Consistent adherence to antifibrotic therapy may make the patients benefit from adjusting their antifibrotic medications, dosage, and active management of side effects.
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Fibrosis Pulmonar Idiopática , Humanos , Resultado del Tratamiento , Fibrosis , Tasa de Supervivencia , Piridonas/efectos adversos , JapónRESUMEN
BACKGROUND: There is a paucity of data on the natural trajectory of outcomes in survivors of COVID-19 beyond 2 years after symptom onset, and no evidence exists on the effect of re-infection in people with long COVID symptoms. We aimed to investigate the 3-year health outcomes of COVID-19 survivors and the effect of omicron re-infection. METHODS: In this single-centre, longitudinal cohort study, we recruited participants with confirmed COVID-19 who were discharged from the Jin Yin-tan hospital in Wuhan, China, between Jan 7 and May 29, 2020. Participants completed three follow-up visits at 6 months (June 16 to Sept 13, 2020), 1 year (Dec 16, 2020, to Feb 7, 2021), and 2 years (Nov 16, 2021, to Jan 10, 2022) since symptom onset (reported previously). At 1-year follow-up, community controls without a history of SARS-CoV-2 infection were recruited from two communities in Wuhan and at 2 years were matched (1:1) with survivors of COVID-19 who underwent pulmonary function tests. We did a 3-year follow-up from Feb 23, 2023, to April 20, 2023, after the omicron (B.1.1.529) wave in winter, 2022. All eligible survivors of COVID-19 and community controls matched at 2-year follow-up were invited to the outpatient clinic at the hospital to complete several face-to-face questionnaires, a 6-min walking test (6MWT), and laboratory tests. A subgroup of survivors of COVID-19 identified by stratified sampling on the basis of disease severity scale score during hospitalisation and community controls underwent pulmonary function tests. Survivors of COVID-19 who received high-resolution CT and showed abnormal lung images at 2-year follow-up were invited for another assessment. We identified participants with and without long COVID at 2 years. The primary outcomes were sequelae symptoms, omicron infection, lung function, and chest imaging at the 3-year follow-up. FINDINGS: Of 1359 COVID-19 survivors who completed 2-year and 3-year follow-up, 728 (54%) had at least one sequelae symptom at 3 years after symptom onset and before omicron infection, mainly mild to moderate severity. During the omicron wave, participants with long COVID at 2 years had a significantly higher proportion of re-infection (573 [76%] of 753 vs 409 [67%] of 606 without long COVID; p=0·0004), pneumonia (27 [5%] of 568 vs seven [2%] of 403; p=0·012). 3 months after omicron infection, 126 (62%) of 204 survivors with long COVID at 2 years had newly occurring or worse symptoms, which was significantly higher than the proportion in the non-long COVID group (85 [41%] of 205; p<0·0001) and community controls (81 [40%] of 205; p<0·0001), and not significantly different between COVID-19 survivors without long COVID and matched community controls (85 [41%] of 205 vs 81 [39%] of 206; p=0·66). Re-infection was a risk factor for dyspnoea (odds ratio 1·36 [95% CI 1·04 to 1·77]; p=0·023), anxiety or depression (OR 1·65 [1·24 to 2·20]; p=0·0007), EuroQol visual analogue scale score (ß -4·51 [-6·08 to -2·95]; p<0·0001), but not for reduced daily activity (0·72 [0·38 to 1·37]; p=0·32) at 3 years. Lung function of survivors at 3 years was similar to that of matched community controls. We found irregular line, traction bronchiectasis, subpleural lines and ground glass opacity at 3 years, but the volume ratio of lung lesion to total lung was only 0·2-0·3%. INTERPRETATION: Most long COVID symptoms at 3 years were mild to moderate, with lung function recovering to levels of matched controls. Survivors with long COVID had a higher proportion of participants with re-infection and newly occurring or worse symptoms 3 months after omicron infection than those without long COVID. Re-infection had increased symptom occurrence but not increased reduced daily activity. Although the organ function of survivors of COVID-19 recovered over time, those with severe long COVID symptoms, abnormal organ function, or limited mobility require urgent attention in future clinical practice and research. FUNDING: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China.
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COVID-19 , SARS-CoV-2 , Humanos , Estudios Longitudinales , Síndrome Post Agudo de COVID-19 , Alta del Paciente , Reinfección , Estudios de Cohortes , China/epidemiologíaRESUMEN
BACKGROUND: Among present reports, the T/G allelic variation at the rs2609255 locus of the family sequence similarity gene 13A (FAM13A) was considerable associated with susceptibility to interstitial lung diseases (ILDs). In this study, we summarized relevant studies and applied a meta-analysis to explore whether the polymorphism of rs2609255 site of the FAM13A gene can be utilized to predict susceptibility to idiopathic pulmonary fibrosis (IPF) patients or rheumatoid arthritis-associated interstitial lung disease (RA-ILD) or silicosis patients in different populations for the first time. METHODS: We compared the frequency of G allele on rs2609255 site of FAM13A between the control subjects and IPF or RA-ILD or silicosis patients from different races by using meta-analysis. Nine studies were involved in this meta-analysis, including five IPF studies, two RA-ILD studies, and two silicosis studies, and containing 14 subgroups. We conducted separate meta-analyses for different races. RESULTS: In all individuals, a substantial link between the G allele of the FAM13A rs2609255 polymorphism and IPF (OR: 1.47, 95% CI: 1.33-1.63, p < 0.00001) was indicated. After dividing by ethnicity, the G allele was illustrated to be considerable correlation with IPF in Asian (OR: 2.63, 95% CI: 1.81-3.81, p < 0.00001) and with RA-ILD individuals (OR: 3.27, 95% CI: 1.26-8.49, p = 0.01). Conversely, there was no correlation with the G allele and IPF in European individuals (OR: 1.27, 95% CI: 0.89-1.83, p = 0.13) or silicosis in Chinese individuals (OR: 1.20, 95% CI: 0.99-1.46, p = 0.07). CONCLUSION: This is the first meta-analysis that provides evidence that the rs2609255 of FAM13A might increase susceptibility to RA-ILD, and IPF especially in Asian but not in European individuals, and not be correlated with silicosis in Chinese individuals, which indicated the differences in susceptibility to disease by race were noteworthy.
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Artritis Reumatoide , Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Silicosis , Humanos , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/complicaciones , Fibrosis Pulmonar Idiopática/complicaciones , Fibrosis Pulmonar Idiopática/genética , Polimorfismo Genético , Silicosis/complicaciones , Proteínas Activadoras de GTPasa/genéticaRESUMEN
What is already known about this topic?: Pneumoconiosis, recognized as one of the most detrimental occupational diseases in China, exhibits a multimorbidity profile due to a plethora of comorbidities and complications. These factors significantly influence the treatment outcomes, progression, prognosis, and overall quality of life of the afflicted patients. What is added by this report?: The present study examined the prevalence and types of comorbidities, encompassing 13 common diseases or conditions, within cases of pneumoconiosis across 27 provincial-level administrative divisions (PLADs) in China. Distinctions in multimorbidity distribution by gender, urban vs. rural areas, stages of pneumoconiosis, and the smoking index were considered. Furthermore, the study investigated the patterns of multimorbidity. What are the implications for public health practice?: This study serves as a reference point for the formulation of treatment strategies and health policy development concerning pneumoconiosis in China.
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PURPOSE: To quantitatively analyze lung elasticity in idiopathic pulmonary fibrosis (IPF) using elastic registration based on 3-dimensional pulmonary magnetic resonance imaging (3D-PMRI) and to assess its' correlations with the severity of IPF patients. MATERIAL AND METHODS: Thirty male patients with IPF (mean age: 62±6 y) and 30 age-matched male healthy controls (mean age: 62±6 y) were prospectively enrolled. 3D-PMRI was acquired with a 3-dimensional ultrashort echo time sequence in end-inspiration and end-expiration. MR images were registered from end-inspiration to end-expiration with the elastic registration algorithm. Jacobian determinants were calculated from deformation fields on color maps. The log means of the Jacobian determinants (Jac-mean) and Dice similarity coefficient were used to describe lung elasticity between 2 groups. Then, the correlation of lung elasticity with dyspnea Medical Research Council (MRC) score, exercise tolerance, health-related quality of life, lung function, and the extent of pulmonary fibrosis on chest computed tomography were analyzed. RESULTS: The Jac-mean of IPF patients (-0.19, [IQR: -0.22, -0.15]) decreased (absolute value), compared with healthy controls (-0.28, [IQR: -0.31, -0.24], P<0.001). The lung elasticity in IPF patients with dyspnea MRC≥3 (Jac-mean: -0.15; Dice: 0.06) was significantly lower than MRC 1 (Jac-mean: -0.22, P=0.001; Dice: 0.10, P=0.001) and MRC 2 (Jac-mean: -0.21, P=0.007; Dice: 0.09, P<0.001). In addition, the Jac-mean negatively correlated with forced vital capacity % (r=-0.487, P<0.001), forced expiratory volume 1% (r=-0.413, P=0.004), TLC% (r=-0.488, P<0.001), diffusing capacity of the lungs for carbon monoxide % predicted (r=-0.555, P<0.001), 6-minute walk distance (r=-0.441, P=0.030) and positively correlated with respiratory symptoms (r=0.430, P=0.042). Meanwhile, the Dice similarity coefficient positively correlated with forced vital capacity % (r=0.577, P=0.004), forced expiratory volume 1% (r=0.526, P=0.012), diffusing capacity of the lungs for carbon monoxide % predicted (r=0.435, P=0.048), 6-minute walk distance (r=0.473, P=0.016), final peripheral oxygen saturation (r=0.534, P=0.004), the extent of fibrosis on chest computed tomography (r=-0.421, P=0.021) and negatively correlated with activity (r=-0.431, P=0.048). CONCLUSION: Lung elasticity decreased in IPF patients and correlated with dyspnea, exercise tolerance, health-related quality of life, lung function, and the extent of pulmonary fibrosis. The lung elasticity based on elastic registration of 3D-PMRI may be a new nonradiation imaging biomarker for quantitative evaluation of the severity of IPF.
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OBJECTIVE: primary Sjögren's syndrome (pSS) is an autoimmune disease, of which the most common complication is interstitial lung disease (ILD). This study aimed to analyze the clinical value of Krebs von den Lungen-6 (KL-6), carcinoembryonic antigen (CEA), and carbohydrate antigen 153(CA153) in patients with pSS complicated with ILD (pSS-ILD), given that only few studies have evaluated this. METHODS: This is a cross-sectional study. Serum KL-6 levels (U/mL) were measured using chemiluminescence immunoassay, and concentrations of serum tumor markers were determined using the immunofluorescence method in 64 cases of pSS-ILD (pSS-ILD group), 23 cases without ILD (non-ILD group), and 45 healthy controls. The correlation between KL-6 and tumor markers as well as lung function was analyzed, and the factors that were associated with pSS-ILD were screened. RESULTS: The serum KL-6 was more abnormally increased in patients with pSS-ILD, and the serum KL-6, CEA, carbohydrate antigen 125 (CA125), and CA153 levels were significantly higher in the pSS-ILD group than in the non-ILD and healthy control groups (p < 0.05). KL-6, CEA, and CA153 were negatively correlated with forced vital capacity (FVC%), forced expiratory volume in 1 s (FEV1%), total lung capacity (TLC%), and diffusing capacity for carbon monoxide (DLCO%) (all p < 0.05). Multivariate logistic analysis showed that KL-6 was an independent factor associated with pSS-ILD. CONCLUSIONS: In conclusion, we evaluated the association between clinical values of KL-6, tumor markers, and pSS-ILD, and found that KL-6 and tumor markers such as CEA, CA153, and CA125 in patients with pSS-ILD were higher than in patients with non-ILD, and KL-6 was more abnormally increased and significantly associated with ILD development in patients with pSS.
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Impaired differentiation of alveolar stem cells has been identified in a variety of acute and chronic lung diseases. In this study, we investigate the mechanisms that modulate alveolar regeneration and understand how aging impacts this process. We have discovered that the process of alveolar type II (AT2) cells differentiating into AT1 cells is an energetically costly process. During alveolar regeneration, activated AMPK-PFKFB2 signaling upregulates glycolysis, which is essential to support the intracellular energy expenditure that is required for cytoskeletal remodeling during AT2 cell differentiation. AT2 cells in aged lungs exhibit reduced AMPK-PFKFB2 signaling and ATP production, resulting in impaired alveolar regeneration. Activating AMPK-PFKFB2 signaling in aged AT2 cells can rescue defective alveolar regeneration in aged mice. Thus, beyond demonstrating that cellular energy metabolism orchestrates with stem cell differentiation during alveolar regeneration, our study suggests that modulating AMPK-PFKFB2 signaling promotes alveolar repair in aged lungs.
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Proteínas Quinasas Activadas por AMP , Células Epiteliales Alveolares , Ratones , Animales , Proteínas Quinasas Activadas por AMP/metabolismo , Células Epiteliales Alveolares/metabolismo , Pulmón , Células Madre , Diferenciación Celular , GlucólisisRESUMEN
BACKGROUND: The presence of fibrosis is a criterion for subtype classification in the newly updated hypersensitivity pneumonitis (HP) guidelines. The present study aimed to summarize differences in clinical characteristics and prognosis of non-fibrotic hypersensitivity pneumonitis (NFHP) and fibrotic hypersensitivity pneumonitis (FHP) and explore factors associated with the presence of fibrosis. METHODS: In this prospective cohort study, patients diagnosed with HP through a multidisciplinary discussion were enrolled. Collected data included demographic and clinical characteristics, laboratory findings, and radiologic and histopathological features. Logistic regression analyses were performed to explore factors related to the presence of fibrosis. RESULTS: A total of 202 patients with HP were enrolled, including 87 (43.1%) NFHP patients and 115 (56.9%) FHP patients. Patients with FHP were older and more frequently presented with dyspnea, crackles, and digital clubbing than patients with NFHP. Serum levels of carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 153, gastrin-releasing peptide precursor, squamous cell carcinoma antigen, and antigen cytokeratin 21-1, and count of bronchoalveolar lavage (BAL) eosinophils were higher in the FHP group than in the NFHP group. BAL lymphocytosis was present in both groups, but less pronounced in the FHP group. Multivariable regression analyses revealed that older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors for the development of FHP. Twelve patients developed adverse outcomes, with a median survival time of 12.5 months, all of whom had FHP. CONCLUSIONS: Older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors associated with the development of FHP. Prognosis of patients with NFHP was better than that of patients with FHP. These results may provide insights into the mechanisms of fibrosis in HP.
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Alveolitis Alérgica Extrínseca , Humanos , Líquido del Lavado Bronquioalveolar , Estudios Prospectivos , Alveolitis Alérgica Extrínseca/diagnóstico , Fibrosis , CarbohidratosRESUMEN
Rationale: Sarcoidosis is a granulomatous interstitial lung disease involving a complex interplay among different cluster of differentiation 4 (CD4+) thymus cell (T-cell) subsets. Originally described as a type 1 T-helper (Th1) inflammatory disease, recent evidence suggests that both effector and regulatory T-cell subgroups play a critical role in sarcoidosis, but this remains controversial. Objectives: We aimed to investigate the distribution of CD4+ T-cell subpopulations in sarcoidosis patients and its potential associations with clinical disease activity and a radiographic fibrotic phenotype. Methods: We measured the frequencies of regulatory T cells (Tregs), Th1, Th17, and Th17.1 cells in the peripheral blood and/or bronchoalveolar lavage fluid (BALF) of 62 sarcoidosis patients, 66 idiopathic pulmonary fibrosis (IPF) patients, and 41 healthy volunteers using flow cytometry. We also measured the changes in these T-cell subpopulations in the blood at the follow-up visits of 11 sarcoidosis patients. Measurements and results: An increased percentage of Tregs was observed in the peripheral blood of sarcoidosis patients, with a positive association to disease activity and a fibrotic radiographic phenotype. We found a higher frequency of Tregs, a lower proportion of Th17.1 cells, and a lower ratio of Th17.1 cells to total Tregs in the peripheral blood of both active and fibrotic sarcoidosis patients, compared with IPF patients or healthy donors. In contrast, a lower frequency of Tregs and a higher proportion of Th17.1 cells was found in the BALF of sarcoidosis patients than in that of IPF patients. There was an imbalance of Tregs and Th17.1 cells between the peripheral blood and BALF in sarcoidosis patients. Following immunoregulatory therapy, the proportion of circulating Tregs in sarcoidosis patients decreased. Conclusion: A higher proportion of Tregs in the peripheral blood of sarcoidosis patients was related to disease activity, fibrotic phenotype, and the need for immunoregulatory therapy. The imbalanced distribution of Tregs and Th17.1 cells in patients' peripheral blood and BALF suggests that the lung microenvironment has an effect on the immunological pathogenesis of sarcoidosis. Therefore, further studies on the functional analysis of Tregs and Th17.1 cells in sarcoidosis patients are warranted.