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1.
Artigo em Inglês | MEDLINE | ID: mdl-39350729

RESUMO

Introduction IPF is a devastating lung disease with limited therapeutic options. FGFR4 is a known receptor for several paracrine Fibroblast growth factors (FGFs). FGFR4 is also the main receptor for FGF19, an endocrine FGF that was demonstrated by our group to have anti-fibrotic properties in the lung. We aimed to determine whether FGFR4 could modulate pulmonary fibrogenesis. Methods We assessed FGFR4 mRNA and protein levels in IPF and control lungs. In vitro, we determined the effect of TGF-b, Endothelin-1 and PDGF on FGFR4 expression in human lung fibroblasts. We determined the effect FGFR4 inhibition, using a specific pharmacological inhibitor (FGF401), or genetic deletion in murine embryonic fibroblasts (MEFs) on TGF-b-induced myofibroblastic differentiation. In vivo, we evaluated the development of bleomycin-induced lung fibrosis in Fgfr4-deficient (Fgfr4-/-) mice compared to Wild Type littermates (WT), and after FGF401 treatment in WT mice compared to a control group receiving the solvent only. Results FGFR4 was decreased in IPF lungs as compared to control lungs, at mRNA and protein levels. In vitro, FGFR4 was downregulated after treatment by TGF- ß, Endothelin-1 and PDGF. In vitro, FGFR4 inhibition by FGF401 prevented TGF-b1-induced collagen and ACTA2 increase in lung fibroblasts. Similar results were observed in Fgfr4-/- MEFs. In vivo, FGFR4 genetic deficiency or FGFR4 pharmacological inhibition did not modulate bleomycin-induced pulmonary fibrosis. Conclusion Our data suggest that FGFR4 exerts pro-fibrotic properties by enhancing TGF- ß signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo.

2.
Am J Respir Cell Mol Biol ; 67(2): 173-187, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35549849

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited therapeutic possibilities. FGF19 (fibroblast growth factor 19), an endocrine FGF, was recently shown to decrease liver fibrosis. To ask whether FGF19 had antifibrotic properties in the lung and decipher its effects on common features associated with lung fibrogenesis, we assessed, by ELISA, FGF19 concentrations in plasma and BAL fluids obtained from control subjects and patients with IPF. In vivo, using an intravenously administered adeno11-associated virus, we overexpressed FGF19 at the fibrotic phase of two experimental models of murine lung fibrosis and assessed its effect on lung morphology, lung collagen content, fibrosis markers, and profibrotic mediator expression at mRNA and protein levels. In vitro, we investigated whether FGF19 could modulate the TGF-ß-induced differentiation of primary human lung fibroblasts into myofibroblasts and the apoptosis of murine alveolar type II cells. Although FGF19 was not detected in BAL fluid, FGF19 concentration was decreased in the plasma of patients with IPF compared with control subjects. In vivo, the overexpression of FGF19 was associated with a marked decrease of lung fibrosis and fibrosis markers, with a decrease of profibrotic mediator expression and lung collagen content. In vitro, FGF19 decreased alveolar type 2 epithelial cell apoptosis through the decrease of the proapoptotic BIM protein expression and prevented TGF-ß-induced myofibroblast differentiation through the inhibition of JNK phosphorylation. Altogether, these data identify FGF19 as an antifibrotic molecule with potential therapeutic interest in fibrotic lung disorders.


Assuntos
Fibrose Pulmonar Idiopática , Animais , Bleomicina/farmacologia , Colágeno/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Fatores de Crescimento de Fibroblastos/uso terapêutico , Fibroblastos/metabolismo , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Camundongos , Miofibroblastos/metabolismo , Fator de Crescimento Transformador beta/metabolismo
3.
Eur Respir J ; 60(2)2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35144991

RESUMO

Patients diagnosed with coronavirus disease 2019 (COVID-19) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection frequently experience symptom burden post-acute infection or post-hospitalisation. We aimed to identify optimal strategies for follow-up care that may positively impact the patient's quality of life (QoL). A European Respiratory Society (ERS) Task Force convened and prioritised eight clinical questions. A targeted search of the literature defined the timeline of "long COVID" as 1-6 months post-infection and identified clinical evidence in the follow-up of patients. Studies meeting the inclusion criteria report an association of characteristics of acute infection with persistent symptoms, thromboembolic events in the follow-up period, and evaluations of pulmonary physiology and imaging. Importantly, this statement reviews QoL consequences, symptom burden, disability and home care follow-up. Overall, the evidence for follow-up care for patients with long COVID is limited.


Assuntos
COVID-19 , COVID-19/complicações , Seguimentos , Humanos , Qualidade de Vida , SARS-CoV-2 , Síndrome de COVID-19 Pós-Aguda
4.
Curr Opin Pulm Med ; 28(5): 399-406, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35938200

RESUMO

PURPOSE OF REVIEW: The aim of this review was to summarize the recent data concerning interstitial lung disease after COVID-19, a field where knowledge is evolving very quickly. RECENT FINDINGS: It has been found that a proportion of patients displayed fibrotic-like pattern on chest computed tomography shortly after COVID-19 pneumonia. Those lesions can potentially represent precursors of fibrosis, although most of them will resolve until 1 year postinfection. There was a wide range of the prevalence of post-COVID-19 interstitial lung disease detected in the literature, which can be attributed to the heterogeneous definition of lung abnormalities and the discrepancy of study design. The severity of acute COVID-19 disease has been linked to increased risk of residual imaging and functional abnormalities, while reduced DLco was the most common functional abnormality in long-term survivors. Studies indicated that pathophysiology of post-COVID interstitial lung disease shares common mechanisms with idiopathic pulmonary fibrosis. Regarding therapeutic strategies of post-COVID-19 interstitial lung disease, the role of immunosuppressive and antifibrotic treatment is currently under investigation. SUMMARY: We still need to learn about the natural history of COVID-19 disease, allowing for a better targeting of therapeutic interventions through a multidisciplinary approach.


Assuntos
COVID-19 , Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , COVID-19/complicações , Humanos , Pulmão , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/etiologia , Testes de Função Respiratória
5.
J Ultrasound Med ; 41(5): 1077-1084, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34291845

RESUMO

OBJECTIVES: In this study, we sought to assess the validity of lung ultrasound (LUS) during the follow-up of patients with a wide spectrum of interstitial lung diseases (ILDs). METHODS: Twenty-four patients (13 males, 11 females; mean age ± SD, 65.4 ± 14.3 years; age range, 40-84 years) with a diagnosis of ILDs who were admitted to the Interstitial Lung Disease Unit were prospectively enrolled. Patients were examined with a 56-lung intercostal space LUS protocol in lateral decubitus position, at baseline, 6-months, and 1-year. The LUS score was defined as the sum of B-lines counted in each intercostal space. All patients underwent complete pulmonary function tests at baseline and follow-up time-points. High-resolution computed tomography (HRCT) was performed at baseline and during follow-up, according to personalized patients' needs. All HRCT studies were graded according to the Warrick scoring system (WS). RESULTS: Pooled data analysis showed a significant correlation between WS and LUS scores (P < .001). For separate time-point analysis, a significant correlation between LUS scores and WS was found at baseline (P < .001) and 1 year (P = .005). LUS scores negatively correlated with alveolar volume (VA) (P < .046) and diffusing capacity for carbon monoxide (DLCO) (P < .001) at 6 months and with transfer coefficient of the lung for carbon monoxide (KCO) (P < .031) and DLCO (P = .002) at 12-months. A multivariate regression model showed DLCO to be an independent predictor of LUS score at 1 year (P = .026). CONCLUSIONS: Our results highlight the validity and potential applicability of LUS for disease monitoring in a wide spectrum of ILDs.


Assuntos
Monóxido de Carbono , Doenças Pulmonares Intersticiais , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória/métodos , Ultrassonografia/métodos
6.
Respir Res ; 22(1): 140, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952261

RESUMO

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) represents a chronic lung disease with unpredictable course. METHODS: We aimed to investigate prognostic performance of complete blood count parameters in IPF. Treatment-naïve patients with IPF were retrospectively enrolled from two independent cohorts (derivation and validation) and split into subgroups (high and low) based on median baseline monocyte count and red cell distribution width (RDW). RESULTS: Overall, 489 patients (derivation cohort: 300, validation cohort: 189) were analyzed. In the derivation cohort, patients with monocyte count ≥ 0.60 K/µL had significantly lower median FVC%pred [75.0, (95% CI 71.3-76.7) vs. 80.9, (95% CI 77.5-83.1), (P = 0.01)] and DLCO%pred [47.5, (95% CI 44.3-52.3) vs. 53.0, (95% CI 48.0-56.7), (P = 0.02)] than patients with monocyte count < 0.60 K/µL. Patients with RDW ≥ 14.1% had significantly lower median FVC%pred [75.5, (95% CI 71.2-79.2) vs. 78.3, (95% CI 76.0-81.0), (P = 0.04)] and DLCO%pred [45.4, (95% CI 43.3-50.5) vs. 53.0, (95% CI 50.8-56.8), (P = 0.008)] than patients with RDW < 14.1%. Cut-off thresholds from the derivation cohort were applied to the validation cohort with similar discriminatory value, as indicated by significant differences in median DLCO%pred between patients with high vs. low monocyte count [37.8, (95% CI 35.5-41.1) vs. 45.5, (95% CI 41.9-49.4), (P < 0.001)] and RDW [37.9, (95% CI 33.4-40.7) vs. 44.4, (95% CI 41.5-48.9), (P < 0.001)]. Patients with high monocyte count and RDW of the validation cohort exhibited a trend towards lower median FVC%pred (P = 0.09) and significantly lower median FVC%pred (P = 0.001), respectively. Kaplan-Meier analysis in the derivation cohort demonstrated higher all-cause mortality in patients with high (≥ 0.60 K/µL) vs. low monocyte count (< 0.60 K/µL) [HR 2.05, (95% CI 1.19-3.53), (P = 0.01)]. CONCLUSIONS: Increased monocyte count and RDW may represent negative prognostic biomarkers in patients with IPF.


Assuntos
Índices de Eritrócitos , Eritrócitos , Fibrose Pulmonar Idiopática/diagnóstico , Monócitos , Idoso , Feminino , Grécia/epidemiologia , Humanos , Fibrose Pulmonar Idiopática/sangue , Fibrose Pulmonar Idiopática/mortalidade , Fibrose Pulmonar Idiopática/fisiopatologia , Contagem de Leucócitos , Pulmão/fisiopatologia , Masculino , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Capacidade Vital
7.
Respir Res ; 20(1): 264, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775876

RESUMO

BACKGROUND: Impaired mitochondria homeostasis and function are established hallmarks of aging and increasing evidence suggests a link with lung fibrosis. Mitochondria homeostasis may be also affected in alveolar macrophages (AMs) in idiopathic pulmonary fibrosis (IPF). In this study, we used bronchoalveolar lavage (BAL), a tool for both clinical and research purposes, and a rich source of AMs. METHODS: BAL samples were examined from 52 patients with IPF and 19 healthy individuals. Measurements of mitochondria reactive oxygen species (mtROS), mitochondria morphology and related gene expression were performed. Additionally, autophagy and mitophagy levels were analysed. RESULTS: Mitochondria in AMs from IPF patients had prominent morphological defects and impaired transcription paralleled to a significant reduction of mitochondria homeostasis regulators PINK1, PARK2 and NRF1. mtROS, was significantly higher in IPF and associated with reduced expression of mitochondria-encoded oxidative phosphorylation (OXPHOS) genes. Age and decline in lung function correlated with higher mtROS levels. Augmentation of damaged, oxidised mitochondria in IPF AMs however was not coupled to increased macroautophagy and mitophagy, central processes in the maintenance of healthy mitochondria levels. CONCLUSION: Our results suggest a perturbation of mitochondria homeostasis in alveolar macrophages in IPF.


Assuntos
Fibrose Pulmonar Idiopática/genética , Macrófagos Alveolares/metabolismo , Fosforilação Oxidativa , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Western Blotting , Líquido da Lavagem Broncoalveolar/citologia , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Hospitais Universitários , Humanos , Fibrose Pulmonar Idiopática/patologia , Macrófagos Alveolares/patologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitofagia/genética , Estudos Prospectivos , Espécies Reativas de Oxigênio/metabolismo , Valores de Referência
8.
BMC Pulm Med ; 18(1): 177, 2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30470213

RESUMO

BACKGROUND: Pirfenidone is an antifibrotic compound approved for the treatment of idiopathic pulmonary fibrosis (IPF). We present our real-world experience in terms of Pirfenidone's effect on mortality and adverse events profile outside the restrictions of a clinical trial. METHODS: This is a retrospective observational intention to treat study of 82 consecutive IPF patients (UHH cohort). RESULTS: We observed a high 3-years survival rate of 73% without excluding patients who discontinued treatment for different reasons. The survival was compared to the survival of an IPF cohort from a tertiary referral center (RBH cohort). After exclusion of severe cases (DLco< 30%), in unadjusted analysis, the survival in the UHH cohort was better than in the RBH cohort (HR:0.32, 95% CI: 0.19-0.53, p < 0.0001). After adjustment for age, gender and FVC, the survival remained higher in the UHH cohort (HR:0.28, 95% CI: 0.16-0.48, p < 0.0001). We observed a similar safety profile compared to previously published data and a lower rate of drug discontinuation due to photosensitivity reactions. CONCLUSION: Pirfenidone provides a survival benefit in a real-life IPF cohort compared to previously used medications. Counselling patients and proactively managing possible adverse effects can reduce the necessity to discontinue pirfenidone.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/mortalidade , Piridonas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Capacidade Vital
9.
Eur Respir J ; 47(3): 910-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26743485

RESUMO

In this study we investigated the implication of NLRP3 inflammasomes in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-usual interstitial pneumonia (RA-UIP).NLRP3 inflammasome activation at baseline and following stimulation with lipopolysaccharide/ATP was evaluated by measuring interleukin (IL)-1ß and IL-18 levels released in the bronchoalveolar lavage fluid (BALF) fluid and by cultures of BALF cells. IL-1ß and IL-18 levels were significantly elevated in the BALF and BALF macrophage cultures from RA-UIP patients, consistent with pre-existing inflammasome activation in these patients. In contrast, in IPF, BALF levels of IL-1ß were significantly less elevated relative to RA-UIP and IL-18 was lower than controls. Furthermore, upon inflammasome stimulation, IPF BALF macrophage cultures failed to upregulate IL-1ß and partly IL-18 secretion, in contrast to controls, which showed robust IL-1ß and IL-18 upregulation. Interestingly, RA-UIP BALF cell cultures treated with lipopolysaccharide/ATP showed a potent stimulation of IL-18 secretion but not IL-1ß, the latter being already elevated in the unstimulated cultures, while examination of the intracellular IL-1ß levels in RA-UIP BALF cells upon NLRP3 inflammasome stimulation showed a significant upregulation of IL-1ß suggesting the NLRP3 pathway could be further activated.Taken together, our results suggest distinct inflammasome activation profiles between autoimmune and idiopathic lung fibrosis.


Assuntos
Fibrose Pulmonar Idiopática/metabolismo , Inflamassomos/metabolismo , Doenças Pulmonares Intersticiais/metabolismo , Pulmão/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/metabolismo , Líquido da Lavagem Broncoalveolar , Feminino , Grécia , Humanos , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Interleucina-18/metabolismo , Lipopolissacarídeos , Pulmão/fisiopatologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Transdução de Sinais
11.
Can Respir J ; 2024: 4919951, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38283656

RESUMO

Hypersensitivity pneumonitis (HP) is a complex interstitial lung disease caused by chronic inhalation of a wide variety of antigens in susceptible and sensitized individuals, commonly associated with an occupational exposure. An impressive number of inciting antigens causing hypersensitivity pneumonitis have been found to cover a wide range of occupations. As working practices have changed over time, especially in industrialized countries, new names for occupational HP have emerged. This review emphasizes the main diagnostic issues arising from the high variability of clinical presentation and the broad spectrum of causal antigens. Furthermore, it provides an overview of current methods to unveil possible causes of hypersensitivity pneumonitis, highlights HP's current diagnostic and treatment challenges and the remaining areas of uncertainty, and presents prevention strategies.


Assuntos
Alveolite Alérgica Extrínseca , Doenças Pulmonares Intersticiais , Exposição Ocupacional , Humanos , Pulmão , Alveolite Alérgica Extrínseca/diagnóstico , Alveolite Alérgica Extrínseca/etiologia , Alveolite Alérgica Extrínseca/tratamento farmacológico , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/terapia , Antígenos/uso terapêutico , Exposição Ocupacional/efeitos adversos
12.
J Pers Med ; 14(2)2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38392595

RESUMO

Coronavirus disease 2019 (COVID-19) pneumonia is associated with extensive pulmonary microangiopathy and the enlargement of the pulmonary artery (PA), while its progression after the remission of the disease has not been investigated yet. The aim was to assess the diametral increase in the PA in COVID-19 pneumonia, as revealed on chest computed tomography (CT), and further investigate its progression. This was a retrospective cohort study of patients with COVID-19 pneumonia, without prior history of pulmonary hypertension, who underwent CT pulmonary angiography before, during, and after the infection. Pulmonary embolism was excluded in all cases. The main PA diameter (MPAD) was assessed in consecutive chest imaging. Statistical analysis was performed with the non-parametric Wilcoxon and Kruskal-Wallis tests, while correlations were performed with the non-parametric Spearman test. A mean ± SD MPAD of 3.1 ± 0.3 cm in COVID-19 pneumonia was significantly decreased to 2.8 ± 0.3 cm in the post-infectious state after 2-18 months in 31 patients (p-value: <0.0001). In a subgroup of six patients with more than one post-COVID-19 CT, a significant further decline in the diameter was observed (p-value: 0.0313). On the other hand, in accordance with the literature, a significant increase in the MPAD during COVID-19 pneumonia was noted in a group of 10 patients with a pre-COVID-19 CT (p-value: 0.0371). The enlargement of the PA is a common finding in COVID-19 pneumonia that regresses after the remission of the disease, indicating that this reversible cardiovascular event is a potential marker of disease activity, while its course in long COVID is yet to be determined.

13.
Breathe (Sheff) ; 20(2): 240029, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-39206278

RESUMO

Hypoxaemia due to right-to-left atrial shunt with normal pressures in the right heart cavities represents an underdiagnosed condition. A systematic approach to hypoxaemic respiratory failure based on pathophysiology can lead to an accurate diagnosis. https://bit.ly/4bTP8fJ.

14.
Rheumatol Adv Pract ; 8(2): rkae059, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38854416

RESUMO

Objective: Recently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950. Methods: In this genetic case-control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin. Results: Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P = 1.1 × 10-11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (P = 0.70). Conclusion: Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population.

15.
Sarcoidosis Vasc Diffuse Lung Dis ; 40(2): e2023022, 2023 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-37382071

RESUMO

BACKGROUND: In Primary Health Care (PHC) many interstitial lung disease (ILD) cases may remain at diagnostic delay, due to their challenging presentation and the limited experience of general practitioners (GPs) in recognizing their early symptoms. OBJECTIVE: We have designed a feasibility study to investigate early ILD case-finding competency between PHC and tertiary care. METHODS: A cross-sectional prospective case-finding study was launched at two private health care centers of Heraklion, Crete, Greece, during nine months (2021-2022). After clinical assessment by GP, PHC attenders, who agreed to participate in the study, were referred to the Respiratory Medicine Department, University Hospital of Heraklion, Crete, underwent Lung Ultrasound (LUS) and those with an overall suspicion for ILDs underwent high resolution computed tomography (HRCT) scan. Descriptive statistics and chi-square tests were used. Multiple Poisson regression analysis was performed to explain positive LUS and HRCT decision with selected variables. RESULTS: One hundred and nine patients out of 183 were finally included (54.1% females; mean age 61, SD: 8.3 years). Thirty-five (32.1%) were current smokers. Overall, two out of ten cases were assessed to need HRCT due to a moderate or high suspicion (19.3%; 95%CI 12.7, 27.4). However, in those who had dyspnea in relation to counterparts, a significantly higher percentage of patients with LUS findings (57.9% vs. 34.0%, p=0.013) was found, as in those who had crackles (100.0% vs. 44.2%, p= 0.005). Detected possible ILD provisional labelling cases were 6, and most importantly, 5 of those cases were considered highly suspicious for further evaluation based on LUS findings. CONCLUSIONS: This is a feasibility study exploring potentials by combining data of medical history, basic auscultation skills, as crackles detection, and inexpensive and radiation-free imaging technique, such as LUS. Cases of ILD labeling may be hidden within PHC, sometimes, much before any clinical manifestation.

16.
Biomedicines ; 10(2)2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35203522

RESUMO

Idiopathic pulmonary fibrosis (IPF) is associated with several hallmarks of aging including telomere shortening, which can result from germline mutations in telomere related genes (TRGs). Here, we assessed the length and stability of telomeres as well as the integrity of chromosomes in primary lung fibroblasts from 13 IPF patients (including seven patients with pathogenic variants in TRGs) and seven controls. Automatized high-throughput detection of telomeric FISH signals highlighted lower signal intensity in lung fibroblasts from IPF patients, suggesting a telomere length defect in these cells. The increased detection of telomere loss and terminal deletion in IPF cells, particularly in TRG-mutated cells (IPF-TRG), supports the notion that these cells have unstable telomeres. Furthermore, fibroblasts from IPF patients with TRGs mutations exhibited dicentric chromosomes and anaphase bridges. Collectively, our study indicates that fibroblasts from IPF patients exhibit telomere and chromosome instability that likely contribute to the physiopathology.

17.
Front Med (Lausanne) ; 9: 1096203, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36698813

RESUMO

Introduction: Myositis associated interstitial lung disease (ILD) seems to be an under-recognized entity. Methods: In this multicenter, retrospective study, we recorded between 9/12/2019 and 30/9/2021 consecutive patients who presented in five different ILD centers from two European countries (Greece, France) and received a multidisciplinary diagnosis of myositis associated-ILD. The primary outcome was all-cause mortality over 1 year in specific subgroups of patients. Secondary outcomes included comparison of disease characteristics between patients diagnosed with the amyopathic subtype and patients with evidence of myopathy at diagnosis. Results: We identified 75 patients with myositis associated-ILD. Median age (95% CI) at the time of diagnosis was 64.0 (61.0-65.0) years. Antinuclear antibody testing was positive in 40% of the cohort (n = 30/75). Myopathy onset occurred first in 40.0% of cases (n = 30), ILD without evidence of myopathy occurred in 29 patients (38.7%), while 16 patients (21.3%) were diagnosed concomitantly with ILD and myopathy. The commonest radiographic pattern was cellular non-specific interstitial pneumonia (NSIP) and was observed in 29 patients (38.7%). The radiographic pattern of organizing pneumonia was significantly more common in patients diagnosed with the amyopathic subtype compared to patients that presented with myopathy [24.1% (n = 7/29) vs. 6.5% (n = 3/46), p = 0.03]. One year survival was 86.7% in the overall population. Kaplan-Meier analysis demonstrated significantly higher all-cause 1-year mortality in patients with the amyopathic subtype compared to patients with evidence of myopathy [H R 4.24 (95% CI: 1.16-15.54), p = 0.03]. Patients diagnosed following hospitalization due to acute respiratory failure experienced increased risk of 1-year all-cause mortality compared to patients diagnosed in outpatient setting [HR 6.70 (95% CI: 1.19-37.81), p = 0.03]. Finally, patients with positive anti-MDA5 presented with higher 1-year all-cause mortality compared to anti-MDA5 negative patients [HR 28.37 (95% CI: 5.13-157.01), p = 0.0001]. Conclusion: Specific ILD radiographic patterns such as NSIP and organizing pneumonia may herald underlying inflammatory myopathies. Hospitalized patients presenting with bilateral organizing pneumonia refractory to antibiotics should be meticulously evaluated for myositis associated-ILD even if there is no overt muscular involvement. Incorporation of ILD radiological patterns in the diagnostic criteria of inflammatory myopathies may lead to timely therapeutic interventions and positively impact patients' survival.

18.
Front Immunol ; 12: 661811, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220810

RESUMO

Fibrotic Interstitial lung diseases (ILDs) are complex disorders of variable clinical behaviour. The majority of them cause significant morbidity, whilst Idiopathic Pulmonary Fibrosis (IPF) is recognised as the most relentless. NLRP3, AIM2, and NLRC4 inflammasomes are multiprotein complexes driving IL-1ß release; a proinflammatory and profibrotic cytokine. Several pathogenetic factors associated with IPF are identified as inflammasome activators, including increases in mtROS and bacterial burden. Mitochondrial oxidation and alterations in bacterial burden in IPF and other ILDs may lead to augmented inflammasome activity in airway macrophages (AMs). IPF (n=14), non-IPF-ILDs (n=12) patients and healthy subjects (n=12) were prospectively recruited and AMs were isolated from bronchoalveolar lavage. IL-1ß release resulting from NLRP3, AIM2 and NLRC4 inflammasomes stimulation in AMs were determined and baseline levels of mitochondrial ROS and microbial burden were also measured. Our results showed that NLRP3 was more inducible in IPF and other ILDs compared to controls. Additionally, following AIM2 activation IL-1ß release was significantly higher in IPF compared to controls, whereas similar trends were observed in Non-IPF-ILDs. NLRC4 activation was similar across groups. mtROS was significantly associated with heightened NLRP3 and AIM2 activation, and mitochondrial antioxidant treatment limited inflammasome activation. Importantly, microbial burden was linked to baseline IL-1ß release and AIM2 and IL-18 relative expression independently of mtROS. In conclusion, the above findings suggested a link between the overactivation of NLRP3 and AIM2 inflammasomes, driven by mitochondrial oxidation, in the pathogenesis of lung fibrosis while changes in the microbiota may prime the inflammasome in the lungs.


Assuntos
Proteínas de Ligação a DNA/imunologia , Fibrose Pulmonar Idiopática/imunologia , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Interleucina-1beta/análise , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologia , Pulmão/citologia , Pulmão/imunologia , Macrófagos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
19.
Curr Opin Pharmacol ; 57: 71-80, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33556824

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic chronic lung disease affecting predominantly older adults, with a history of smoking. The current model of disease natural course is that recurrent injury of the alveolar epithelium in the context of advanced aging/cellular senescence is followed by defective re-epithelialization and scar tissue formation. Currently, two drugs, nintedanib and pirfenidone, that modify disease progression have been approved worldwide for the treatment of IPF. However, despite treatment, patients with IPF are not cured, and eventually, disease advances in most treated patients. Enhancing biogenomic and metabolic research output, its translation into clinical precision and optimal service delivery through patient-centeredness are key elements to support effective IPF care. In this review, we summarize therapeutic options currently investigated for IPF based on the major pathogenetic pathways and molecular targets that drive pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática , Medicina de Precisão , Idoso , Fibrose , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Assistência Centrada no Paciente , Pesquisa Translacional Biomédica
20.
Front Immunol ; 12: 645548, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867934

RESUMO

Within the Interstitial Lung Diseases (ILD), patients with idiopathic pulmonary fibrosis (IPF) and a subset of those with non-IPF fibrotic ILD have a distinct clinical phenotype of progression despite management. This group of patients has been collectively termed the progressive fibrotic phenotype (PFP). Their early recognition may facilitate access to antifibrotic therapies to prevent or slow progression. Macrophages/monocytes within the lung orchestrate the progression and maintenance of fibrosis. A novel role for monocyte-derived macrophages during tissue damage and wound healing is the expression of collagens. We examined Collagen 1a1 expression in airway macrophages from ILD patients at diagnosis. COL1A1 mRNA levels from BAL cells were elevated in IPF and Non-IPF patients. The presence of a UIP pattern and a subsequent progressive phenotype were significantly associated with the higher BAL COL1A1 levels. In Non-IPF patients, higher COL1A1 levels were associated with a more than twofold increase in mortality. The intracellular localisation of COL1A1 in airway macrophages was demonstrated by confocal microscopy in CD45 and CD163 co-staining assays. Additionally, airway macrophages co-expressed COL1A1 with the profibrotic SPP1 gene product osteopontin. The levels of SPP1 mRNA and OPN in the BAL were significantly higher in IPF and Non-IPF patients relative to healthy. Our results suggest that profibrotic airway macrophages are increased in the BAL of patients with IPF and other ILDs and co-express COL1A1 and OPN. Importantly, COL1A1 expression by pro-fibrotic airway macrophages could be a marker of disease progression and poor survival in ILDs.


Assuntos
Cadeia alfa 1 do Colágeno Tipo I/metabolismo , Doenças Pulmonares Intersticiais/metabolismo , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Adulto , Idoso , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Estudos de Casos e Controles , Cadeia alfa 1 do Colágeno Tipo I/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/mortalidade , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Osteopontina/genética , Osteopontina/metabolismo , Estudos Prospectivos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Capacidade Vital
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