Analysis of tissue lipidomics and computed tomography pulmonary fat attenuation volume (CTPFAV ) in idiopathic pulmonary fibrosis.

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.

The performance of high-volume bronchoalveolar lavage for the evaluation and diagnosis of interstitial lung disease.

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.

Fractional exhaled nitric oxide in the interpretation of specific inhalational challenge tests for occupational asthma.

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.

Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish.

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.

The Toll-like receptor 3 L412F polymorphism and disease progression in idiopathic pulmonary fibrosis.

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.

Is stent insertion via flexible bronchoscopy a feasible alternative to surgery in inoperable thyroid related tracheobronchial stenosis?

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.

Bronchoalveolar neutrophilia inversely correlates with DLCO at diagnosis in asbestosis but not lung function decline at 1 year.

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.

Deficiency of tumour necrosis factor-related apoptosis-inducing ligand exacerbates lung injury and fibrosis.

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.

Implantación de prótesis metálicas autoexpansibles con broncoscopia flexible bajo sedación para estenosis traqueobronquiales malignas: análisis retrospectivo de un solo centro / The Insertion of Self Expanding Metal Stents With Flexible Bronchoscopy Under Sedation for Malignant Tracheobronchial Stenosis: A Single-Center Retrospective Analysis

Objetivo: Describir la experiencia de 10 años con la implantación de prótesis metálicas autoexpansibles (PMAE) Ultraflex™ bajo sedación, con el empleo de broncoscopia flexible para el tratamiento de las estenosis traqueobronquiales malignas en un centro de referencia terciario. Métodos: Se revisaron retrospectivamente las historias clínicas de todos los pacientes a los que se implantó una PMAE entre 1999 y 2009. Resultados: Se llevó a cabo un análisis de los datos de 68 pacientes a los que se implantó una PMAE Ultraflex™ bajo sedación. Un total de 33 varones y 35 mujeres, de una media de edad de 67,9 años (rango: 35-94), presentaron manifestaciones clínicas consistentes en disnea/dificultad respiratoria (39 pacientes), estridor (16 pacientes) y hemoptisis/disnea (13 pacientes). La etiología de la estenosis fue la siguiente: cáncer de pulmón (46 pacientes), cáncer de esófago (14 pacientes) y otras enfermedades malignas (8 pacientes). La dosis media de midazolam administrada fue de 5mg (rango: 0-10mg). La tráquea fue la localización más frecuente de la implantación de la prótesis, seguida del bronquio principal derecho e izquierdo, respectivamente. Se utilizó laserterapia adyuvante en alguna fase en el 31% del total de casos y se usó quimioterapia y/o radioterapia en al menos el 64% de los pacientes con enfermedades malignas. La hemoptisis y la migración de la prótesis fueron las complicaciones más frecuentes (5 y 4 pacientes, respectivamente). La media de tiempo de supervivencia en los pacientes con cáncer de pulmón no microcítico a los que se implantaron prótesis fue de 214 días (rango: 5-1.233 días), y la de los pacientes con cáncer esofágico fue de 70 días (rango: 12-249 días). La media de consumo de tabaco en paquetes-años en los individuos con cáncer de pulmón en los que fue necesaria la implantación de una prótesis fue de 37 (rango: 2-100)(AU)

Conclusión: Las prótesis Ultraflex proporcionan un tratamiento seguro y eficaz para los pacientes inoperables o con tumores inextirpables en los que no se dispone de ninguna otra terapia alternativa. Tienen un efecto inmediato que proporciona una acción beneficiosa a los pacientes, no solo por el alivio de los síntomas, sino también en algunos casos por la prolongación de la vida. Los datos de supervivencia no son peores que los presentados en otros estudios en los que se han utilizado variedades diferentes de prótesis y distintas técnicas de implantación, lo cual indica su eficacia a más largo plazo. Además, este análisis subraya la viabilidad de prestar este servicio de manera satisfactoria en una unidad respiratoria, sin necesidad de anestesia general(AU)

Objective: To describe a 10-year experience of inserting Ultraflex™ self-expanding metal stents (SEMS) under sedation using flexible bronchoscopy for the treatment of malignant tracheobronchial stenosis in a tertiary referral centre. Methods: Medical notes were retrospectively reviewed for all patients who underwent SEMS insertion between 1999 and 2009. Results: A data analysis of 68 patients who had Ultraflex™ SEMS inserted under sedation was completed. Thirty three males and 35 females with a mean age of 67.9 years (range 35-94) presented with features including dyspnea/respiratory distress (39 patients), stridor (16 patients) and hemoptysis/dyspnea (13 patients). Etiology of stenosis included lung cancer (46 patients) esophageal cancer (14 patients) and other malignancies (8 patients). Mean dose of midazolam administered was 5mg (range 0-10mg). The trachea was the most common site of stent insertion followed by the right and left main bronchus, respectively. Adjuvant laser therapy was applied at some stage in 31% of all cases, and chemotherapy and/or radiotherapy was administered to at least 64% of patients with malignant disease.Hemoptysis and stent migration were the most frequent complications (5 and 4 patients, respectively). The mean survival time of stented non-small cell lung cancer (NSCLC) patients was 214 days (range 5-1233) and that of esophageal malignancy was 70 days (range 12-249). Mean pack-year history of individuals with lung cancer requiring stent insertion was 37 (range 2-100)(AU)

Conclusion: Ultraflex stents offer a safe and effective therapy for patients who are inoperable or unresectable that otherwise would have no alternative therapy. It has an immediate beneficial effect upon patients, not only through symptom relief but, in some, through prolongation of life. Survival data is no worse than other studies using different varieties of stents and insertion techniques indicating its longer-term efficacy. Moreover, this report highlights the feasibility of performing this procedure successfully in a respiratory unit, without the need for general anesthesia(AU)

The insertion of self expanding metal stents with flexible bronchoscopy under sedation for malignant tracheobronchial stenosis: a single-center retrospective analysis.

OBJECTIVE: To describe a 10-year experience of inserting Ultraflex™ self-expanding metal stents (SEMS) under sedation using flexible bronchoscopy for the treatment of malignant tracheobronchial stenosis in a tertiary referral centre. METHODS: Medical notes were retrospectively reviewed for all patients who underwent SEMS insertion between 1999 and 2009. RESULTS: A data analysis of 68 patients who had Ultraflex™ SEMS inserted under sedation was completed. Thirty three males and 35 females with a mean age of 67.9 years (range 35-94) presented with features including dyspnea/respiratory distress (39 patients), stridor (16 patients) and hemoptysis/dyspnea (13 patients). Etiology of stenosis included lung cancer (46 patients) esophageal cancer (14 patients) and other malignancies (8 patients). Mean dose of midazolam administered was 5mg (range 0-10mg). The trachea was the most common site of stent insertion followed by the right and left main bronchus, respectively. Adjuvant laser therapy was applied at some stage in 31% of all cases, and chemotherapy and/or radiotherapy was administered to at least 64% of patients with malignant disease. Hemoptysis and stent migration were the most frequent complications (5 and 4 patients, respectively). The mean survival time of stented non-small cell lung cancer (NSCLC) patients was 214 days (range 5-1233) and that of esophageal malignancy was 70 days (range 12-249). Mean pack-year history of individuals with lung cancer requiring stent insertion was 37 (range 2-100). CONCLUSION: Ultraflex stents offer a safe and effective therapy for patients who are inoperable or unresectable that otherwise would have no alternative therapy. It has an immediate beneficial effect upon patients, not only through symptom relief but, in some, through prolongation of life. Survival data is no worse than other studies using different varieties of stents and insertion techniques indicating its longer-term efficacy. Moreover, this report highlights the feasibility of performing this procedure successfully in a respiratory unit, without the need for general anesthesia.

OPG/RANKL/RANK pathway as a therapeutic target in cancer.

Bone metastases play an important role in the morbidity and mortality of patients with malignant disease. Despite therapeutic advances in the treatment of solid organ malignancy such as lung cancer, less development on metastasis interventions has been forthcoming. More recent research has focused on molecular pathway manipulation in the prevention and treatment of metastatic bone disease and associated complications such as bone pain and hypercalcemia. The osteoprotegerin/receptor activator of nuclear factor-Ðºß ligand/receptor activator of nuclear factor-Ðºß pathway, which is physiologically involved in bone turnover, has been of considerable interest, and recent promising data have been revealed. In this study, we describe this molecular pathway in terms of its natural physiological function, manipulation for therapeutic benefit, and recent clinical trial results.

Is there a beneficial role for a flexible bronchoscopic approach to oesophageal tumour-related tracheobronchial stenosis?

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.

The tumor necrosis factor-related apoptosis-inducing ligand and lung cancer: still following the right TRAIL?

Tumor necrosis factor-related apoptosis-inducing ligand is a type II membrane-bound protein whose C-terminal extracellular domain shows clear homology to other tumor necrosis factor family members. It is constitutively expressed on macrophages, T cells, natural killer cells, and dendritic cells and selectively kills transformed cells leaving most of the normal cells alone. This selectivity has led to great interest in it use as a therapeutic agent for the treatment of malignancy. In this review, this critical pathway is described, highlighting its mechanistic manipulation for therapeutic benefit and the recent phase I and II trials in lung cancer that have been performed or are currently ongoing are also discussed.

TNF-related apoptosis-inducing ligand (TRAIL) regulates inflammatory neutrophil apoptosis and enhances resolution of inflammation.

Novel therapeutics targeting neutrophilic inflammation are a major unmet clinical need in acute and chronic inflammation. The timely induction of neutrophil apoptosis is critical for inflammation resolution, and it is thought that acceleration of apoptosis may facilitate resolution at inflammatory sites. We previously demonstrated that a death receptor ligand, TRAIL, accelerates neutrophil apoptosis in vitro. We examined the role of TRAIL in neutrophil-dominant inflammation in WT and TRAIL-deficient mice. TRAIL deficiency did not alter constitutive neutrophil apoptosis, whereas exogenous TRAIL accelerated apoptosis of murine peripheral blood neutrophils. We compared TRAIL-deficient and WT mice in two independent models of neutrophilic inflammation: bacterial LPS-induced acute lung injury and zymosan-induced peritonitis. In both models, TRAIL-deficient mice had an enhanced inflammatory response with increased neutrophil numbers and reduced neutrophil apoptosis. Correction of TRAIL deficiency and supraphysiological TRAIL signaling using exogenous protein enhanced neutrophil apoptosis and reduced neutrophil numbers in both inflammatory models with no evidence of effects on other cell types. These data indicate the potential therapeutic benefit of TRAIL in neutrophilic inflammation.