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1.
Respirology ; 28(11): 1043-1052, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37642207

RESUMEN

BACKGROUND AND OBJECTIVE: There is increasing interest in the role of lipids in processes that modulate lung fibrosis with evidence of lipid deposition in idiopathic pulmonary fibrosis (IPF) histological specimens. The aim of this study was to identify measurable markers of pulmonary lipid that may have utility as IPF biomarkers. STUDY DESIGN AND METHODS: IPF and control lung biopsy specimens were analysed using a unbiased lipidomic approach. Pulmonary fat attenuation volume (PFAV) was assessed on chest CT images (CTPFAV ) with 3D semi-automated lung density software. Aerated lung was semi-automatically segmented and CTPFAV calculated using a Hounsfield-unit (-40 to -200HU) threshold range expressed as a percentage of total lung volume. CTPFAV was compared to pulmonary function, serum lipids and qualitative CT fibrosis scores. RESULTS: There was a significant increase in total lipid content on histological analysis of IPF lung tissue (23.16 nmol/mg) compared to controls (18.66 mol/mg, p = 0.0317). The median CTPFAV in IPF was higher than controls (1.34% vs. 0.72%, p < 0.001) and CTPFAV correlated significantly with DLCO% predicted (R2 = 0.356, p < 0.0001) and FVC% predicted (R2 = 0.407, p < 0.0001) in patients with IPF. CTPFAV correlated with CT features of fibrosis; higher CTPFAV was associated with >10% reticulation (1.6% vs. 0.94%, p = 0.0017) and >10% honeycombing (1.87% vs. 1.12%, p = 0.0003). CTPFAV showed no correlation with serum lipids. CONCLUSION: CTPFAV is an easily quantifiable non-invasive measure of pulmonary lipids. In this pilot study, CTPFAV correlates with pulmonary function and radiological features of IPF and could function as a potential biomarker for IPF disease severity assessment.


Asunto(s)
Fibrosis Pulmonar Idiopática , Lipidómica , Humanos , Proyectos Piloto , Pulmón , Tomografía Computarizada por Rayos X/métodos , Biomarcadores , Lípidos , Fibrosis , Estudios Retrospectivos
2.
Blood ; 123(3): 366-76, 2014 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-24196071

RESUMEN

Neutrophil lifespan and function are regulated by hypoxia via components of the hypoxia inducible factor (HIF)/von Hippel Lindau/hydroxylase pathway, including specific roles for HIF-1α and prolyl hydroxylase-3. HIF-2α has both distinct and overlapping biological roles with HIF-1α and has not previously been studied in the context of neutrophil biology. We investigated the role of HIF-2α in regulating key neutrophil functions. Human and murine peripheral blood neutrophils expressed HIF-2α, with expression up-regulated by acute and chronic inflammatory stimuli and in disease-associated inflammatory neutrophil. HIF2A gain-of-function mutations resulted in a reduction in neutrophil apoptosis both ex vivo, through the study of patient cells, and in vivo in a zebrafish tail injury model. In contrast, HIF-2α-deficient murine inflammatory neutrophils displayed increased sensitivity to nitrosative stress induced apoptosis ex vivo and increased neutrophil apoptosis in vivo, resulting in a reduction in neutrophilic inflammation and reduced tissue injury. Expression of HIF-2α was temporally dissociated from HIF-1α in vivo and predominated in the resolution phase of inflammation. These data support a critical and selective role for HIF-2α in persistence of neutrophilic inflammation and provide a platform to dissect the therapeutic utility of targeting HIF-2α in chronic inflammatory diseases.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Regulación de la Expresión Génica , Inflamación , Neutrófilos/metabolismo , Animales , Apoptosis , Hipoxia de la Célula , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Muramidasa , Neutrófilos/citología , Fagocitosis , Fenotipo , ARN/metabolismo , Estallido Respiratorio , Pez Cebra
3.
Lung ; 192(1): 119-24, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24232978

RESUMEN

PURPOSE: Fractional exhaled nitric oxide (FENO) measurements are recommended for the assessment of eosinophilic airway inflammation in asthma. Clinically relevant increases in FENO have been reported 24 h after positive specific inhalational challenge (SIC) tests in occupational asthma. We aimed to determine whether positive SICs could be discriminated from control tests, on the basis of change in FENO. METHODS: We reviewed all positive SICs to a variety of agents performed at our institution 2008-2012 and gathered data on age, sex, asthmatic response (immediate/dual/late), smoking status, inhaled corticosteroid usage, and FENO pre- and 24-h postcontrol and positive SIC from each worker. Changes in FENO after positive SICs were compared with control SICs from each worker, by using paired Student's t tests. RESULTS: In 16 workers, negative control challenges were associated with mean changes in FENO of 9 % (95 % CI -1.14 to 19.01) or 1.1 ppb (95 % CI -3.59 to 5.84); 2 of 16 (13 %) workers tested showed increases in FENO that were clinically relevant based on recent guidelines. Subsequent positive SICs were associated with mean changes in FENO of 7 % (95 % CI −15.73 to 29.6) or 2.1 ppb (95 % CI -6.07 to 10.19), which were not significantly different to controls; only 2 of 16 (13 %) workers had FENO changes that were clinically relevant. CONCLUSIONS: FENO changes above the upper confidence limits of ≥20 % or ≥6 ppb may be considered to be outside the range of normality. However, the majority of workers who had clearly positive SICs to common low molecular weight agents also had no statistically or clinically relevant increase in FENO. Therefore, change in FENO does not predict a positive SIC in this group.


Asunto(s)
Contaminantes Ocupacionales del Aire , Asma Ocupacional/diagnóstico , Pruebas Respiratorias , Pruebas de Provocación Bronquial , Espiración , Exposición por Inhalación , Pulmón/metabolismo , Óxido Nítrico/metabolismo , Adulto , Asma Ocupacional/metabolismo , Asma Ocupacional/fisiopatología , Biomarcadores/metabolismo , Pruebas de Provocación Bronquial/normas , Estudios de Casos y Controles , Femenino , Volumen Espiratorio Forzado , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Salud Laboral , Valor Predictivo de las Pruebas , Espirometría
4.
Am J Respir Crit Care Med ; 188(12): 1442-50, 2013 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-24070541

RESUMEN

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive interstitial pneumonia. The innate immune system provides a crucial function in the recognition of tissue injury and infection. Toll-like receptor 3 (TLR3) is an innate immune system receptor. We investigated the role of a functional TLR3 single-nucleotide polymorphism in IPF. OBJECTIVES: To characterize the effects of the TLR3 Leu412Phe polymorphism in primary pulmonary fibroblasts from patients with IPF and disease progression in two independent IPF patient cohorts. To investigate the role of TLR3 in a murine model of pulmonary fibrosis. METHODS: TLR3-mediated cytokine, type 1 IFN, and fibroproliferative responses were examined in TLR3 wild-type (Leu/Leu), heterozygote (Leu/Phe), and homozygote (Phe/Phe) primary IPF pulmonary fibroblasts by ELISA, real-time polymerase chain reaction, and proliferation assays. A murine model of bleomycin-induced pulmonary fibrosis was used in TLR3 wild-type (tlr3(+/+)) and TLR3 knockout mice (tlr3(-/-)). A genotyping approach was used to investigate the role of the TLR3 L412F polymorphism in disease progression in IPF using survival analysis and longitudinal decline in FVC. MEASUREMENTS AND MAIN RESULTS: Activation of TLR3 in primary lung fibroblasts from TLR3 L412F-variant patients with IPF resulted in defective cytokine, type I IFN, and fibroproliferative responses. We demonstrate increased collagen and profibrotic cytokines in TLR3 knockout mice (tlr3(-/-)) compared with wild-type mice (tlr3(+/+)). TLR3 L412F was also associated with a significantly greater risk of mortality and an accelerated decline in FVC in patients with IPF. CONCLUSIONS: This study reveals the crucial role of defective TLR3 function in promoting progressive IPF.


Asunto(s)
Progresión de la Enfermedad , Fibrosis Pulmonar Idiopática/genética , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 3/genética , Anciano , Anciano de 80 o más Años , Animales , Biomarcadores/metabolismo , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Marcadores Genéticos , Genotipo , Técnicas de Genotipaje , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/mortalidad , Fibrosis Pulmonar Idiopática/patología , Interferón Tipo I/metabolismo , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Supervivencia , Receptor Toll-Like 3/deficiencia , Receptor Toll-Like 3/metabolismo
5.
Thorax ; 67(9): 796-803, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22496351

RESUMEN

BACKGROUND: The death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) shows considerable clinical promise as a therapeutic agent. TRAIL induces leukocyte apoptosis, reducing acute inflammatory responses in the lung. It is not known whether TRAIL modifies chronic lung injury or whether TRAIL has a role in human idiopathic pulmonary fibrosis (IPF). We therefore explored the capacity of TRAIL to modify chronic inflammatory lung injury and studied TRAIL expression in patients with IPF. METHODS: TRAIL(-/-) and wild-type mice were instilled with bleomycin and inflammation assessed at various time points by bronchoalveolar lavage and histology. Collagen deposition was measured by tissue hydroxyproline content. TRAIL expression in human IPF lung samples was assessed by immunohistochemistry and peripheral blood TRAIL measured by ELISA. RESULTS: TRAIL(-/-) mice had an exaggerated delayed inflammatory response to bleomycin, with increased neutrophil numbers (mean 3.19±0.8 wild type vs 11.5±5.4×10(4) TRAIL(-/-), p<0.0001), reduced neutrophil apoptosis (5.42±1.6% wild type vs 2.47±0.5% TRAIL(-/-), p=0.0003) and increased collagen (3.45±0.2 wild type vs 5.8±1.3 mg TRAIL(-/-), p=0.005). Immunohistochemical analysis showed induction of TRAIL in bleomycin-treated wild-type mice. Patients with IPF demonstrated lower levels of TRAIL expression than in control lung biopsies and their serum levels of TRAIL were significantly lower compared with matched controls (38.1±9.6 controls vs 32.3±7.2 pg/ml patients with IPF, p=0.002). CONCLUSION: These data suggest TRAIL may exert beneficial, anti-inflammatory actions in chronic pulmonary inflammation in murine models and that these mechanisms may be compromised in human IPF.


Asunto(s)
Lesión Pulmonar/metabolismo , Fibrosis Pulmonar/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/deficiencia , Animales , Biomarcadores/metabolismo , Bleomicina , Lavado Broncoalveolar , Estudios de Casos y Controles , Colágeno/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Hidroxiprolina/metabolismo , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Ratones , Ratones Endogámicos C57BL , Pruebas de Función Respiratoria
6.
Lung ; 189(5): 401-7, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21688114

RESUMEN

BACKGROUND: Interventional pulmonology, in particular, tracheobronchial stent insertion, has been well described in the treatment of tracheobronchial malignant disease. Its benefits are particularly obvious in patients with inoperable malignancy or in those unfit for surgery and have been extensively described. Fewer data exist on the benefits of using self-expanding metal stents (SEMS) inserted via flexible bronchoscopy in the treatment of tracheobronchial stenosis due to extrinsic compression or infiltration from primary oesophageal malignancy. METHODS: We retrospectively reviewed all patients who had stent insertion via flexible bronchoscopy from 2002 to 2010 at our institution. RESULTS: We found 14 patients who had Ultraflex™ self-expanding metal stent insertion for this condition. We analysed this group of patients with respect to their presentation; indications for stent insertion over surgery; size, location, and number of stents inserted; sedative dose; complications of therapy; and survival time. CONCLUSION: We conclude that insertion of SEMS via flexible bronchoscopy is a safe and effective therapy for those individuals who require palliation or are too unfit for the general anaesthesia required for surgery. Moreover, this form of stent insertion may be performed by respiratory physicians in the bronchoscopy suite, rather than by their cardiothoracic counterparts in theatre.


Asunto(s)
Broncoscopía/métodos , Carcinoma de Células Escamosas/cirugía , Neoplasias Esofágicas/cirugía , Stents , Estenosis Traqueal/cirugía , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento
7.
Pulm Pharmacol Ther ; 23(5): 389-96, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20542128

RESUMEN

Non-tuberculous mycobacteria (NTM) are a group of alcohol fast, aerobic, nonmotile bacteria that are found in the environment. Recent reports indicate that their incidence and prevalence is increasing and guidelines have been developed laying down criteria for diagnosis. The treatment of these mycobacteria may be difficult, in many cases involving complex regimens containing multiple drugs. While traditional anti-tuberculosis medications are frequently used, specific therapeutic regimens depend on the organism isolated, in vitro susceptibility testing, drug tolerance and toxicity and concomitant medical disorders. In this review, we describe the diagnosis and treatment of the more important lung pathogens, describing complexities and controversies surrounding treatment with traditional, adjunctive and the newer and more experimental agents.


Asunto(s)
Antituberculosos/uso terapéutico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Tuberculosis Pulmonar/tratamiento farmacológico , Quimioterapia Combinada , Humanos , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas/efectos de los fármacos , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/microbiología
8.
Lung ; 188(4): 269-82, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20379826

RESUMEN

Nontuberculous mycobacteria (NTM) are resilient bacteria that grow in virtually any environment, especially those where competing microorganisms are destroyed, such as in chlorinated water. They have been discovered in soil, dust, food, water, and domestic and wild animals. Nontuberculous mycobacteria tend to infect individuals with local (e.g., damaged skin or lung) or systemic (e.g., HIV, drugs, malignancy) defects in host defence, and their incidence and prevalence have consistently increased in the last decade. Difficulty may arise in determining whether an isolated NTM from a microbiological sample is in fact a contaminant or a pathogenic organism. In this review, we discuss the important mycobacteria involved in lung disease, factors that predispose individuals to infection, and their diagnosis and treatment according to updated guidelines. English language publications in MEDLINE and references from relevant articles from January 1, 1990 to June 28, 2009 were reviewed. Keywords searched were "nontuberculous,""mycobacteria," "diagnosis," and "treatment."


Asunto(s)
Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Micobacterias no Tuberculosas/efectos de los fármacos , Etambutol/uso terapéutico , Femenino , Humanos , Enfermedades Pulmonares/microbiología , Macrólidos/uso terapéutico , Masculino , Rifamicinas/uso terapéutico
15.
Ann Thorac Surg ; 97(2): 720-2, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24484827

RESUMEN

Although high-volume bronchoalveolar lavage (BAL) is an excellent research tool, its use in the evaluation of interstitial lung disease remains controversial, particularly in the age of lung biopsy in video-assisted thoracic surgery. Recently, a new practice guideline made several important recommendations for the performance of the procedure and the handling, processing, and analysis of samples. Here we describe this recommended technique, our experience performing BAL in 42 patients, and the usefulness of our differential cell count results. We demonstrate that BAL is straightforward and safe to perform and conclude that it may offer valuable data in evaluating interstitial lung disease, particularly in patients with an acute presentation or who are not fit for lung biopsy.


Asunto(s)
Lavado Broncoalveolar/métodos , Enfermedades Pulmonares Intersticiales/patología , Lavado Broncoalveolar/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto
19.
J Thorac Dis ; 5(3): 302-5, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23825763

RESUMEN

The use of endobronchial stents in the treatment of tumour related tracheobronchial stenosis has been well described. While many forms of stent exist, their use has invariably been described in the context of rigid bronchoscopy and general anaesthesia. Few reports exist on the use of endobronchial stents for the treatment of thyroid goitre related stenosis.Our objective was to retrospectively analyse the use of self expanding metal stent (SEMS) insertion for thyroid related tracheobronchial stenosis under sedation with flexible bronchoscopy in the treatment of this condition. Patient charts were reviewed on all patients who had stent insertion in our unit since 1999-2005. We analysed the indication for stenting, pathology, stent size and location and detail any complications of therapy. Particular attention was paid to those with benign disease to evaluate the recommendation made by the U.S Food and Drug Administration (FDA) in 2005 on the use of metal stents in benign airways disease. A total of five patients (4 female, 1 male) who were too unfit for surgery had stent insertion for thyroid related tracheobronchial stenosis over this period. All patients experienced complications which became prolonged and recurrent in those with benign disease who survived longer. We conclude that SEMS insertion via flexible bronchoscopy is not appropriate for the treatment of benign thyroid goitre related tracheobronchial stenosis until all other interventions have been exhaustively explored.

20.
J Thorac Dis ; 5(3): 314-6, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23825766

RESUMEN

The role of bronchoalveolar lavage (BAL) in the assessment of interstitial lung disease (ILD) remains controversial. Previous studies have demonstrated that BAL cell differential is useful in predicting disease progression in many forms of ILD. We wished to investigate whether BAL had a similar use in predicting disease progression in asbestosis. 21 patients who had significant asbestos exposure, findings of UIP radiologically and BAL performed as part of their investigation were reviewed. There was a significant inverse correlation between percentage BAL neutrophils and percentage predicted DLCO at diagnosis (n=21; P=0.02; r(2)=(-)0.25; CI, (-)0.77(-)0.08), but not with DLCO decline over 1 year. Unlike previous reports in IPF, BAL cell differential is not predictive of decline in classic asbestosis with a UIP pattern and its routine use in this cohort of patients provides little if any additional benefit.

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