RESUMEN
To explore the causal relationship between gut microbiota (GM) and Idiopathic pulmonary fibrosis (IPF), we performed a two-sample Mendelian randomization (MR). GM was used as an exposure factor, and instrumental variables were determined from the GWAS of 18,340 participants. GWAS of IPF (including 1028 IPF patients and 196,986 controls) from the FinnGen was used as the outcome factor. The primary analysis method is the inverse variance weighted (IVW) method, and sensitivity analysis was used to validate the reliability. Family Bacteroidaceae (ORâ =â 1.917 95% CIâ =â 1.083-3.393, Pâ =â .026), order Gastranaerophilales (ORâ =â 1.441 95% CIâ =â 1.019-2.036, Pâ =â .039), genus Senegalimassilia (ORâ =â 2.28 95% CIâ =â 1.174-4.427, Pâ =â .015), phylum Cyanobacteria (ORâ =â 1.631 95% CIâ =â 1.035-2.571, Pâ =â .035) were positively correlated with IPF. FamilyXIII(ORâ =â 0.452 95% CIâ =â 0.249-0.82, Pâ =â .009), order Selenomonadale (ORâ =â 0.563 95% CIâ =â 0.337-0.941, Pâ =â .029), genus Veillonella (ORâ =â 0.546 95% CIâ =â 0.304-0.982, Pâ =â .043) (ORâ =â 0.717 95% CIâ =â 0.527-0.976, Pâ =â .034), genus Ruminococcusgnavus (ORâ =â 0.717 95% CIâ =â 0.527-0.976, Pâ =â .034), genus Oscillibacter (ORâ =â 0.571 95% CIâ =â 0.405-0.806, Pâ =â .001) was negatively correlated with IPF. Sensitivity analysis showed no evidence of pleiotropy or heterogeneity (Pâ >â .05). The results of MR demonstrated a causal relationship between GM and IPF. Further studies are needed to investigate the intrinsic mechanisms of the GM in the pathogenesis of IPF.
Asunto(s)
Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Fibrosis Pulmonar Idiopática , Análisis de la Aleatorización Mendeliana , Humanos , Microbioma Gastrointestinal/genética , Fibrosis Pulmonar Idiopática/microbiología , Fibrosis Pulmonar Idiopática/genética , MasculinoRESUMEN
Background: The microbiota-gut-lung axis has elucidated a potential association between gut microbiota and idiopathic pulmonary fibrosis (IPF). However, there is a paucity of population-level studies with providing robust evidence for establishing causality. This two-sample Mendelian randomization (MR) analysis aimed to investigate the causal relationship between the gut microbiota and IPF as well as lung function. Materials and methods: Adhering to Mendel's principle of inheritance, this MR analysis utilized summary-level data from respective genome-wide association studies (GWAS) involving 211 gut microbial taxa, IPF, and lung function indicators such as FEV1, FVC, and FEV1/FVC. A bidirectional two-sample MR design was employed, utilizing multiple MR analysis methods, including inverse variance-weighted (IVW), weighted median, MR-Egger, and weighted mode. Multivariable MR (MVMR) was used to uncover mediating factors connecting the exposure and outcome. Additionally, comprehensive sensitivity analyses were conducted to ensure the robustness of the results. Results: The MR results confirmed four taxa were found causally associated with the risk of IPF. Order Bifidobacteriales (OR=0.773, 95% CI: 0.610-0.979, p=0.033), Family Bifidobacteriaceae (OR=0.773, 95% CI: 0.610-0.979, p=0.033), and Genus RuminococcaceaeUCG009 (OR=0.793, 95% CI: 0.652-0.965, p=0.020) exerted protective effects on IPF, while Genus Coprococcus2 (OR=1.349, 95% CI: 1.021-1.783, p=0.035) promote the development of IPF. Several taxa were causally associated with lung function, with those in Class Deltaproteobacteria, Order Desulfovibrionales, Family Desulfovibrionaceae, Class Verrucomicrobiae, Order Verrucomicrobiales and Family Verrucomicrobiaceae being the most prominent beneficial microbiota, while those in Family Lachnospiraceae, Genus Oscillospira, and Genus Parasutterella were associated with impaired lung function. As for the reverse analysis, MR results confirmed the effects of FEV1 and FVC on the increased abundance of six taxa (Phylum Actinobacteria, Class Actinobacteria, Order Bifidobacteriales, Family Bifidobacteriaceae, Genus Bifidobacterium, and Genus Ruminiclostridium9) with a boosted level of evidence. MVMR suggested monounsaturated fatty acids, total fatty acids, saturated fatty acids, and ratio of omega-6 fatty acids to total fatty acids as potential mediating factors in the genetic association between gut microbiota and IPF. Conclusion: The current study suggested the casual effects of the specific gut microbes on the risk of IPF and lung function. In turn, lung function also exerted a positive role in some gut microbes. A reasonable dietary intake of lipid substances has a certain protective effect against the occurrence and progression of IPF. This study provides novel insights into the potential role of gut microbiota in IPF and indicates a possible gut microbiota-mediated mechanism for the prevention of IPF.
Asunto(s)
Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Fibrosis Pulmonar Idiopática , Pulmón , Análisis de la Aleatorización Mendeliana , Humanos , Fibrosis Pulmonar Idiopática/microbiología , Microbioma Gastrointestinal/genética , Pulmón/microbiología , Pruebas de Función Respiratoria , Predisposición Genética a la EnfermedadRESUMEN
Interstitial Lung Disease (ILD) involves lung disorders marked by chronic inflammation and fibrosis. ILDs include pathologies like idiopathic pulmonary fibrosis (IPF), connective tissue disease-associated ILD (CTD-ILD), hypersensitivity pneumonitis (HP) or sarcoidosis. Existing data covers pathogenesis, diagnosis (especially using high-resolution computed tomography), and treatments like antifibrotic agents. Despite progress, ILD diagnosis and management remains challenging with significant morbidity and mortality. Recent focus is on Progressive Fibrosing ILD (PF-ILD), characterized by worsening symptoms and fibrosis on HRCT. Prevalence is around 30%, excluding IPF, with a poor prognosis. Early diagnosis is crucial for optimizing outcomes in PF-ILD individuals. The lung microbiome comprises all the microorganisms that are in the respiratory tract. Relatively recent research try to evaluate its role in respiratory disease. Healthy lungs have a diverse microbial community. An imbalance in bacterial composition, changes in bacterial metabolic activities, or changes in bacterial distribution within the lung termed dysbiosis is linked to conditions like COPD, asthma and ILDs. We conducted a systematic review of three important scientific data base using a focused search strategy to see how the lung microbiome is involved in the progression of ILDs. Results showed that some differences in the composition and quality of the lung microbiome exist in ILDs that show progressive fibrosing phenotype. The results seem to suggest that the lung microbiota could be involved in ILD progression, but more studies showing its exact pathophysiological mechanisms are needed.
Asunto(s)
Enfermedades Pulmonares Intersticiales , Pulmón , Microbiota , Humanos , Enfermedades Pulmonares Intersticiales/microbiología , Pulmón/microbiología , Pulmón/patología , Fibrosis Pulmonar Idiopática/microbiología , Fibrosis Pulmonar Idiopática/patologíaRESUMEN
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial pneumonia of unknown aetiology with a mean survival rate of less than 3 years. No previous studies have been performed on the role of co-infection (viral and bacterial infection) in the pathogenesis and progression of IPF. In this study, we investigated the role of viral/bacterial infection and coinfection and their possible association with pathogenesis and progression of IPF. METHODS: We investigated the prevalence and impact of bacterial and viral coinfection in IPF patients (n = 67) in the context of pulmonary function (FVC, FEV1 and DLCO), disease status and mortality risk. Using principal component analysis (PCA), we also investigated the relationship between distribution of bacterial and viral co-infection in the IPF cohort. RESULTS: Of the 67 samples, 17.9% samples were positive for viral infection, 10.4% samples were positive for bacterial infection and 59.7% samples were positive coinfection. We demonstrated that IPF patients who were co-infected had a significantly increased risk of mortality compared (p = 0.031) with IPF patients who were non-infected [Hazard ratio: 8.12; 95% CI 1.3-26.9]. CONCLUSION: In this study, we report for the first time that IPF patients who were coinfected with bacterial and viral infection have significantly decreased FVC and DLCO (% predicted). Besides, the results demonstrated the increased AE-IPF, increased incidence of death and risk of mortality in infected/coinfected patients compared to non-infected IPF patients.
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Infecciones Bacterianas/epidemiología , Fibrosis Pulmonar Idiopática/microbiología , Fibrosis Pulmonar Idiopática/virología , Virosis/epidemiología , Anciano , Infecciones Bacterianas/complicaciones , Coinfección/mortalidad , Progresión de la Enfermedad , Femenino , Humanos , Fibrosis Pulmonar Idiopática/mortalidad , Masculino , Persona de Mediana Edad , Prevalencia , Tasa de Supervivencia , Virosis/complicacionesRESUMEN
Rationale: The Toll-like receptor 3 Leu412Phe (TLR3 L412F) polymorphism attenuates cellular antiviral responses and is associated with accelerated disease progression in idiopathic pulmonary fibrosis (IPF). The role of TLR3 L412F in bacterial infection in IPF or in acute exacerbations (AE) has not been reported. Objectives: To characterize the association between TLR3 L412F and AE-related death in IPF. To determine the effect of TLR3 L412F on the lung microbiome and on antibacterial TLR responses of primary lung fibroblasts from patients with IPF. Methods: TLR-mediated antibacterial and antiviral responses were quantitated in L412F wild-type and 412F-heterozygous primary lung fibroblasts from patients with IPF using ELISA, Western blot analysis, and quantitative PCR. Hierarchical heatmap analysis was employed to establish bacterial and viral clustering in nasopharyngeal lavage samples from patients with AE-IPF. 16S ribosomal RNA quantitative PCR and pyrosequencing were used to determine the effect of TLR3 L412F on the IPF lung microbiome. Measurements and Main Results: A significant increase in AE-related death in patients with 412F-variant IPF was reported. We established that 412F-heterozygous IPF lung fibroblasts have reduced antibacterial TLR responses to LPS (TLR4), Pam3CYSK4 (TLR1/2), flagellin (TLR5), and FSL-1 (TLR6/1) and have reduced responses to live Pseudomonas aeruginosa infection. Using 16S ribosomal RNA sequencing, we demonstrated that 412F-heterozygous patients with IPF have a dysregulated lung microbiome with increased frequencies of Streptococcus and Staphylococcus spp. Conclusions: This study reveals that TLR3 L412F dysregulates the IPF lung microbiome and reduces the responses of IPF lung fibroblasts to bacterial TLR agonists and live bacterial infection. These findings identify a candidate role for TLR3 L412F in viral- and bacterial-mediated AE death.
Asunto(s)
Fibrosis Pulmonar Idiopática , Receptor Toll-Like 3/genética , Antibacterianos , Antivirales , Progresión de la Enfermedad , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/microbiología , ARN Ribosómico 16SRESUMEN
BACKGROUND: The lower airways microbiome and host immune response in chronic pulmonary diseases are incompletely understood. We aimed to investigate possible microbiome characteristics and key antimicrobial peptides and proteins in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). METHODS: 12 IPF patients, 12 COPD patients and 12 healthy controls were sampled with oral wash (OW), protected bronchoalveolar lavage (PBAL) and right lung protected sterile brushings (rPSB). The antimicrobial peptides and proteins (AMPs), secretory leucocyte protease inhibitor (SLPI) and human beta defensins 1 and 2 (hBD-1 & hBD-2), were measured in PBAL by enzyme linked immunosorbent assay (ELISA). The V3V4 region of the bacterial 16S rDNA gene was sequenced. Bioinformatic analyses were performed with QIIME 2. RESULTS: hBD-1 levels in PBAL for IPF were lower compared with COPD. The predominant phyla in IPF were Firmicutes, Bacteroides and Actinobacteria; Proteobacteria were among top three in COPD. Differential abundance analysis at genus level showed significant differences between study groups for less abundant, mostly oropharyngeal, microbes. Alpha diversity was lower in IPF in PBAL compared to COPD (p = 0.03) and controls (p = 0.01), as well as in rPSB compared to COPD (p = 0.02) and controls (p = 0.04). Phylogenetic beta diversity showed significantly more similarity for IPF compared with COPD and controls. There were no significant correlations between alpha diversity and AMPs. CONCLUSIONS: IPF differed in microbial diversity from COPD and controls, accompanied by differences in antimicrobial peptides. Beta diversity similarity between OW and PBAL in IPF may indicate that microaspiration contributes to changes in its microbiome.
Asunto(s)
Péptidos Antimicrobianos/análisis , Bacterias/clasificación , Fibrosis Pulmonar Idiopática/microbiología , Enfermedad Pulmonar Obstructiva Crónica/microbiología , ARN Ribosómico 16S/genética , beta-Defensinas/análisis , Anciano , Anciano de 80 o más Años , Bacterias/genética , Bacterias/aislamiento & purificación , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/microbiología , Estudios de Casos y Controles , Femenino , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Masculino , Microbiota , Persona de Mediana Edad , Filogenia , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , Análisis de Secuencia de ADNRESUMEN
Interstitial lung diseases represent a heterogeneous and wide group of diseases in which factors leading to disease initiation and progression are not fully understood. Recent evidence suggests that the lung microbiome might influence the pathogenesis and progression of interstitial lung diseases. In recent years, the utilization of culture-independent methodologies has allowed the identification of complex and dynamic communities of microbes, in patients with interstitial lung diseases. However, the potential mechanisms by which these changes may drive disease pathogenesis and progression are largely unknown. The aim of this review is to discuss the role of the altered lung microbiome in several interstitial lung diseases. Untangling the host-microbiome interaction in the lung and airway of interstitial lung disease patients is a research priority. Thus, lung dysbiosis is a potentially treatable trait across several interstitial lung diseases, and its proper characterization and treatment might be crucial to change the natural history of these diseases and improve outcomes.
Asunto(s)
Bacterias/clasificación , Fibrosis Pulmonar Idiopática/microbiología , Enfermedades Pulmonares Intersticiales/microbiología , Bacterias/aislamiento & purificación , Progresión de la Enfermedad , Humanos , Pulmón/microbiología , MicrobiotaRESUMEN
Rationale: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises after repeated exposure and sensitization to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease, but, to date, no study has investigated the composition of microbial communities in the lower airways in CHP.Objectives: To characterize and compare the airway microbiome in subjects with CHP, subjects with idiopathic pulmonary fibrosis (IPF), and control subjects.Methods: We prospectively recruited individuals with a CHP diagnosis (n = 110), individuals with an IPF diagnosis (n = 45), and control subjects (n = 28). Subjects underwent BAL and bacterial DNA was isolated, quantified by quantitative PCR and the 16S ribosomal RNA gene was sequenced to characterize the bacterial communities in the lower airways.Measurements and Main Results: Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both subjects with IPF and subjects with CHP included Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. However, in IPF, Firmicutes dominated, whereas the percentage of reads assigned to Proteobacteria in the same group was significantly lower than the percentage found in subjects with CHP. At the genus level, the Staphylococcus burden was increased in CHP, and Actinomyces and Veillonella burdens were increased in IPF. The lower airway bacterial burden in subjects with CHP was higher than that in control subjects but lower than that of those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP.Conclusions: The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF, and, notably, the bacterial burden in individuals with CHP fails to predict survival.
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Alveolitis Alérgica Extrínseca/microbiología , ADN Bacteriano/genética , ADN Bacteriano/aislamiento & purificación , Fibrosis Pulmonar Idiopática/microbiología , Pulmón/microbiología , Microbiota , Adulto , Anciano , Anciano de 80 o más Años , Alveolitis Alérgica Extrínseca/epidemiología , Carga Bacteriana , Femenino , Humanos , Fibrosis Pulmonar Idiopática/epidemiología , Londres/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Lung microbiota profiles in patients with early idiopathic pulmonary fibrosis (IPF) have been associated with disease progression; however, the topographic heterogeneity of lung microbiota and their roles in advanced IPF are unknown. METHODS: We performed a retrospective, case-control study of explanted lung tissue obtained at the time of lung transplantation or rapid autopsy from patients with IPF and other chronic lung diseases (connective tissue disease-associated interstitial lung disease (CTD-ILD), cystic fibrosis (CF), COPD and donor lungs unsuitable for transplant from Center for Organ Recovery and Education (CORE)). We sampled subpleural tissue and airway-based specimens (bronchial washings and airway tissue) and quantified bacterial load and profiled communities by amplification and sequencing of the 16S rRNA gene. FINDINGS: Explants from 62 patients with IPF, 15 patients with CTD-ILD, 20 patients with CF, 20 patients with COPD and 20 CORE patients were included. Airway-based samples had higher bacterial load compared with distal parenchymal tissue. IPF basilar tissue had much lower bacterial load compared with CF and CORE lungs (p<0.001). No microbial community differences were found between parenchymal tissue samples from different IPF lobes. Dirichlet multinomial models revealed an IPF cluster (29%) with distinct composition, high bacterial load and low alpha diversity, exhibiting higher odds for acute exacerbation or death. INTERPRETATION: IPF explants had low biomass in the distal parenchyma of all three lobes with higher bacterial load in the airways. The discovery of a distinct subgroup of patients with IPF with higher bacterial load and worse clinical outcomes supports investigation of personalised medicine approaches for microbiome-targeted interventions.
Asunto(s)
Fibrosis Pulmonar Idiopática/microbiología , Trasplante de Pulmón , Pulmón/microbiología , Microbiota/fisiología , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Líquido del Lavado Bronquioalveolar/microbiología , Estudios de Casos y Controles , Progresión de la Enfermedad , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/cirugía , Pulmón/diagnóstico por imagen , Pulmón/cirugía , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic disease mainly associated with aging and, to date, its causes are still largely unknown. It has been shown that dietary habits can accelerate or delay the occurrence of aging-related diseases; however, their potential role in IPF development has been underestimated so far. The present review summarizes the evidence regarding the relationship between diet and IPF in humans, and in animal models of pulmonary fibrosis, in which we discuss the bioactivity of specific dietary food ingredients, including fatty acids, peptides, amino acids, carbohydrates, vitamins, minerals and phytochemicals. Interestingly, many animal studies reveal preventive and therapeutic effects of particular compounds. Furthermore, it has been recently suggested that the lung and gut microbiota could be involved in IPF, a relationship which may be linked to changes in immunological and inflammatory factors. Thus, all the evidence so far puts forward the idea that the gut-lung axis could be modulated by dietary factors, which in turn have an influence on IPF development. Overall, the data reviewed here support the notion of identifying food ingredients with potential benefits in IPF, with the ultimate aim of designing nutritional approaches as an adjuvant therapeutic strategy.
Asunto(s)
Ingredientes Alimentarios , Fibrosis Pulmonar Idiopática/microbiología , Microbiota/fisiología , Envejecimiento , Aminoácidos/metabolismo , Animales , Avitaminosis/complicaciones , Grasas Insaturadas en la Dieta/farmacología , Grasas Insaturadas en la Dieta/uso terapéutico , Ingredientes Alimentarios/efectos adversos , Microbioma Gastrointestinal , Humanos , Fibrosis Pulmonar Idiopática/dietoterapia , Pulmón/microbiología , Micronutrientes/metabolismo , Micronutrientes/farmacología , Fitoquímicos/farmacología , Vitaminas/farmacologíaRESUMEN
BACKGROUND: Literature about the lung microbiota (LM) in dogs is sparse. Influence of breed and living conditions on the LM in healthy dogs is currently unknown, as well as the influence of chronic respiratory diseases such as canine idiopathic pulmonary fibrosis (CIPF) in West highland white terriers (WHWTs). Aims of this study were (1) to assess the characteristics of the healthy LM according to breed and living conditions, and (2) to study LM changes associated with CIPF in WHWTs. Forty-five healthy dogs divided into 5 groups: domestic terriers (n = 10), domestic shepherds (n = 11), domestic brachycephalic dogs (n = 9), domestic WHWTs (n = 6) (H-WHWTs) and experimental beagles (n = 9) and 11 diseased WHWTs affected with CIPF (D-WHWTs) were included in the study to achieve those objectives. RESULTS: In healthy domestic dogs, except in H-WHWTs, the presence of few discriminant genera in each type of breed was the only LM modification. LM of experimental dogs displayed a change in b-diversity and an increased richness compared with domestic dogs. Moreover, Prevotella_7 and Dubosiella genera were more abundant and 19 genera were discriminant in experimental dogs. LM of both H-WHWTs and D-WHWTs revealed increased abundance of 6 genera (Brochothrix, Curvibacter, Pseudarcicella, Flavobacteriaceae genus, Rhodoluna and Limnohabitans) compared with other healthy domestic dogs. Brochothrix and Pseudarcicella were also discriminant in D-WHWTs compared with H-WHWTs and other healthy domestic dogs. CONCLUSIONS: In domestic conditions, except for H-WHWT, the breed appears to have minor influence on the LM. LM modifications were found in experimental compared with domestic living conditions. LM modifications in H-WHWTs and D-WHWTs compared with other healthy domestic dogs were similar and seemed to be linked to the breed. Whether this breed difference might be related with the high susceptibility of WHWTs for CIPF requires further studies.
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Bacterias/clasificación , Enfermedades de los Perros/microbiología , Fibrosis Pulmonar Idiopática/veterinaria , Pulmón/microbiología , ARN Ribosómico 16S/genética , Animales , Bacterias/genética , Bacterias/aislamiento & purificación , Cruzamiento , ADN Bacteriano/genética , ADN Ribosómico/genética , Perros , Femenino , Fibrosis Pulmonar Idiopática/microbiología , Masculino , Filogenia , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis.
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Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas Bacterianas/inmunología , Fibrosis Pulmonar Idiopática/inmunología , Péptidos/inmunología , Staphylococcus/inmunología , Anciano , Animales , Apoptosis/inmunología , Proteínas Reguladoras de la Apoptosis/análisis , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Bacterianas/análisis , Proteínas Bacterianas/metabolismo , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Células Epiteliales/inmunología , Células Epiteliales/patología , Femenino , Voluntarios Sanos , Humanos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/microbiología , Fibrosis Pulmonar Idiopática/patología , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Macrófagos/inmunología , Masculino , Ratones , Ratones Transgénicos , Péptidos/análisis , Péptidos/metabolismo , Staphylococcus/metabolismo , Staphylococcus/patogenicidad , Brote de los Síntomas , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/inmunologíaRESUMEN
Patients with idiopathic pulmonary fibrosis (IPF) can experience life-threatening episodes of acute worsening of their disease, termed acute exacerbation of IPF, which may be caused by bacterial and/or viral infections. The potential for regulatory T cells (Tregs) to limit disease progression in bacterially triggered fibrosis exacerbation has not been explored so far. In the current study, we show that the number of Tregs was significantly increased in mice with established AdTGF-ß1-induced lung fibrosis and further increased in mice with pneumococcal infection-induced lung fibrosis exacerbation. Diphtheria toxin-induced depletion of Tregs significantly worsened infection-induced fibrosis exacerbation as determined by increased lung collagen deposition, lung histology, and elevated pulmonary Th1/Th2 cytokine levels. Conversely, IL-2 complex-induced Treg expansion in wild-type mice with established lung fibrosis completely inhibited pneumococcal infection-induced fibrosis exacerbation as efficaciously as antibiotic treatment while preserving lung antibacterial immunity in mice. Collectively, these findings demonstrate the efficacy of Tregs as "silencers," suppressing infection-induced exacerbation of lung fibrosis in mice, and their expansion may offer a novel adjunctive treatment to limit acute exacerbations in patients with IPF.
Asunto(s)
Fibrosis Pulmonar Idiopática/inmunología , Infecciones Neumocócicas/inmunología , Streptococcus pneumoniae/inmunología , Linfocitos T Reguladores/inmunología , Animales , Citocinas/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Fibrosis Pulmonar Idiopática/microbiología , Interleucina-2/inmunología , Pulmón/inmunología , Pulmón/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Infecciones Neumocócicas/microbiología , Células TH1/inmunología , Células Th17/inmunologíaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic, pulmonary-limited, interstitial lung disease with a poor prognosis. This condition is characterized by different clinical scenarios, ranging from the most typical slow and progressive deterioration of symptoms to a rapid and abrupt decline of lung function. Rapid worsening of clinical course is due to superimposed complications and comorbidities that can develop in IPF patients, with a higher incidence rate compared to the general population. These conditions may require a different management of the patient and a therapy adjustment, and thus it is fundamental to recognize them. High Resolution Computed Tomography (HRCT) is sensitive, but not specific, in detecting these complications, and can evaluate the presence of radiological variations when previous examinations are available; it recognizes ground glass opacities or consolidation that can be related to a large spectrum of comorbidities, such as infection, lung cancer, or acute exacerbation. To reach the final diagnosis, a multidisciplinary discussion is required, particularly when the clinical context is related to imaging findings.
Asunto(s)
Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Humanos , Fibrosis Pulmonar Idiopática/complicaciones , Fibrosis Pulmonar Idiopática/microbiología , Fibrosis Pulmonar Idiopática/patología , Pulmón/patología , Masculino , Tomografía Computarizada por Rayos X/métodosRESUMEN
OBJECTIVE: Changes in the composition of the lung microbiome influence many lung diseases, including idiopathic pulmonary fibrosis (IPF), with a demonstrated association between the progression of IPF and the assessed pulmonary microbial community. A hypothesis to explain the pathogenesis of IPF is that an oxidant-antioxidant imbalance causes repeated epithelial cell injury and endogenous and exogenous antioxidants/redox modulators influence fibrogenesis, protect the lung against fibrosis, and prevent its progression. MATERIALS AND METHODS: The present article is focused on Lung Microbiome in Idiopathic Pulmonary Fibrosis and the role of Antioxidant/Antibiotic Combination Therapy. RESULTS: N-Acetylcysteine (NAC) at concentrations possibly achievable by nebulization showed an in vitro synergy with colistin against S. maltophilia isolates (a common coloniser of the respiratory tract of patients with chronic lung disease). Combined NAC plus colistin seems to have a beneficial role in restoring oxidant injury which may be related to its antioxidant effect. Progress has been made in the identification of the lung microbiome and the possible causal role of bacteria in the IPF pathogenesis. Recent studies suggest that antibacterial therapy in combination with antioxidant therapy may be a promising avenue for the treatment of this untreatable disease. Novel routes of administration are also an important area of research and studies assessing the use of inhaled NAC in patients with IPF could be considered.
Asunto(s)
Antibacterianos/uso terapéutico , Antioxidantes/uso terapéutico , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Pulmón/microbiología , Acetilcisteína/farmacología , Acetilcisteína/uso terapéutico , Antibacterianos/farmacología , Antioxidantes/farmacología , Colistina/farmacología , Colistina/uso terapéutico , Progresión de la Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/microbiología , Pulmón/efectos de los fármacos , Microbiota/efectos de los fármacosRESUMEN
Idiopathic pulmonary fibrosis (IPF) arises in genetically susceptible individuals as a result of an aberrant wound-healing response following repetitive alveolar injury. The clinical course of the disease remains both variable and unpredictable with periods of more rapid decline, termed acute exacerbation of IPF (AE-IPF), often punctuating the disease trajectory. Exacerbations carry a significant morbidity and mortality, and their exact pathogenesis remains unclear. Given the emerging evidence that disruption and alteration in the lung microbiome plays a role in the pathogenesis and progression of IPF, this review discusses the current knowledge of the contribution of infection and the respiratory microbiome to AE-IPF.