The integrin receptor beta7 subunit mediates airway remodeling and hyperresponsiveness in allergen exposed mice.

BACKGROUND: Fibroblast differentiation to a myofibroblast phenotype is a feature of airway remodeling in asthma. Lung fibroblasts express the integrin receptor α4ß7 and fibronectin induces myofibroblast differentiation via this receptor. OBJECTIVES: To investigate the role of the ß7 integrin receptor subunit and α4ß7 integrin complex in airway remodeling and airway hyperresponsiveness (AHR) in a murine model of chronic allergen exposure. METHODS: C57BL/6 wild type (WT) and ß7 integrin null mice (ß7 -/-) were sensitized (days 1,10) and challenged with ovalbumin (OVA) three times a week for one or 4 weeks. Similar experiments were performed with WT mice in the presence or absence of α4ß7 blocking antibodies. Bronchoalveolar (BAL) cell counts, AHR, histological evaluation, soluble collagen content, Transforming growth factor-ß (TGFß) and Interleukin-13 (IL13) were measured. Phenotype of fibroblasts cultured from WT and ß7 -/- saline (SAL) and OVA treated mice was evaluated. RESULTS: Eosinophil numbers were similar in WT vs ß7-/- mice. Prolonged OVA exposure in ß7-/- mice was associated with reduced AHR, lung collagen content, peribronchial smooth muscle, lung tissue TGFß and IL13 expression as compared to WT. Similar findings were observed in WT mice treated with α4ß7 blocking antibodies. Fibroblast migration was enhanced in response to OVA in WT but not ß7 -/- fibroblasts. α-SMA and fibronectin expression were reduced in ß7-/- fibroblasts relative to WT. CONCLUSIONS: The ß7 integrin subunit and the α4ß7 integrin complex modulate AHR and airway remodeling in a murine model of allergen exposure. This effect is, at least in part, explained by inhibition of fibroblast activation and is independent of eosinophilic inflammation.

Epidemiology and Healthcare Service Utilization among Adults with Chronic Cough.

Background and objective: Chronic cough (CC) is a prevalent yet underexplored medical condition, with limited real-world data regarding its healthcare burden. This study investigates the epidemiology, associated comorbidities, and healthcare service utilization among patients with CC. Methods: In this retrospective cohort study, adult patients with at least 3 physician diagnoses of cough over a period spanning a minimum of 8 weeks and a maximum of 12 months anytime between 2009 and 2018, were defined as patients with CC (PwCC). The reference group were adults without cough matched in a 1:1 ratio for age, sex, and place of residence. Results: The study included 91,757 PwCC, reflecting a prevalence of 5.5%. Of those, 59,296 patients (mean [SD] age, 53.9 [16.8] years; 59.6% females) were first diagnosed with CC during the study period, representing a 10-year incidence rate of 3.26% (95%CI: 3.24-3.29%). Diseases associated with the highest OR for CC included lung cancer (OR = 3.32; 95%CI: 2.90-4.25), whooping cough (OR = 3.04; 95%CI: 2.70-3.60), and respiratory infections (OR = 2.81; 95%CI: 2.74-2.88). Furthermore, PwCC demonstrated increased healthcare service utilization, leading to a higher adjusted annual estimated mean cost (USD 4038 vs. USD 1833, p < 0.001). Conclusions: Chronic cough emerges as a relatively prevalent complaint within community care, exerting a considerable economic burden. This study underscores the need for heightened awareness, comprehensive management strategies, and resource allocation to address the multifaceted challenges associated with chronic cough.

Is there a role for lung or bronchial biopsies for the diagnosis of mycobacterial pulmonary disease in patients with bronchiectasis?

Background: Workup of bronchiectasis patients mandates microbiological characterization often being sought via Bronchoscopy. However, whether to perform bronchial or lung biopsies, is unknown, especially for the diagnosis of NTM pulmonary disease. We aimed to assess the current practice and yield of the different bronchoscopic procedures in this setting. Methods: Data from an adult cohort with bronchiectasis referred for bronchoscopy for microbiologic sampling was reviewed, including demographics, etiology, imaging and results of the different bronchoscopic procedures performed. Results: 127 subjects were analyzed (mean age 61, 56% female). BAL culture was positive in 44%. Frequent pathogens were Hemophilus Influenza (20%), pseudomonas aeruginosa (8%) and Staphylococcus aureus (7%). NTM and tuberculosis were found in 6% and 1.5% respectively. BAL cytology was sent in 125 procedures, EBB was performed in 51 patients (40%) and TBLB in 38 patients (30%). BAL cytology and both EBB and TBB (including tissue cultures) had no benefit over BAL with respect to microbiological diagnosis, including identification of mycobacterial disease. Conclusions: In adult subjects with Non-CF bronchiectasis requiring bronchoscopy for microbiological characterization, BAL cytology and lung tissue biopsies were frequently performed but were of minimal additional benefit over BAL culture (including for mycobacterial pulmonary disease), and are most likely futile.

Prevalence and Clinical Implications of Nontuberculous Mycobacteria Isolation and Infection among Patients with Bronchiectasis in the Jerusalem Area.

BACKGROUND: Bronchiectasis is an obstructive chronic lung disease characterized by structural changes in large and small airways, namely permanent widening of bronchial lumen resulting in chronic inflammation and infection. Nontuberculous mycobacteria (NTM) are environmental mycobacteria that may cause human infection or colonization with over 150 species identified to date. Bronchiectasis with NTM colonization or infection is often encountered but with varying prevalence and unknown clinical or prognostic significance. OBJECTIVES: To find the prevalence of NTM among patients with bronchiectasis in the Jerusalem district. To assess whether there were clinical differences between patients with bronchiectasis who were isolated with NTM and those without. METHODS: In this retrospective observational research study, we reviewed all computerized medical charts of patients over 18 years of age, who were diagnosed with bronchiectasis at Hadassah Medical Centers in Jerusalem between 2012 and 2017. We assessed the prevalence of NTM pulmonary disease. To compare patients with and without NTM, we reviewed and analyzed clinical, radiological, and microbiological data of all NTM patients and a group of controls in a 4:1 ratio. RESULTS: Prevalence of NTM among bronchiectasis patients was 5.1%, slightly lower than previously reported in Israel. We did not find clinically or radiological significant differences in patients with NTM disease compared to controls. This result included a similar number of exacerbations, hospitalization rates, number of lobes involved, and pulmonary function tests. CONCLUSIONS: Bronchiectasis patients with isolation of Pseudomonas aeruginosa experienced more exacerbations than patients with other isolates, consistent with previous studies.

How Accurate Is the Diagnosis of "Chronic Obstructive Pulmonary Disease" in Patients Hospitalized with an Acute Exacerbation?

Rationale: COPD diagnosis requires relevant symptoms and an FEV1/FVC ratio of <0.7 post-bronchodilator on spirometry. Patients are frequently labeled as COPD based on clinical presentation and admitted to the hospital with this diagnosis even though spirometry is either not available or has never been performed. The aim of this study was to evaluate the accuracy of COPD diagnosis based on post-bronchodilator spirometry, following hospital admission for COPD exacerbation. Methods: This is a retrospective study with a cross-sectional analysis of a subgroup of patients. Demographic and clinical data and pre-admission spirometry were collected from electronic records of patients hospitalized with a primary diagnosis of COPD. Patients without available spirometry were contacted for a pulmonary consultation and spirometry. Three groups were compared: patients with a confirmed COPD diagnosis (FEV1/FVC < 0.7), without COPD (FEV1/FVC > 0.7), and those who have never performed spirometry. Results: A total of 1138 patients with a recorded diagnosis of COPD were identified of which 233 patients were included in the analysis. Only 44.6% of patients had confirmed COPD according to GOLD criteria. In total, 32.6% of the patients had never undergone spirometry but were treated as COPD, and 22.7% had performed spirometry without evidence of COPD. Recurrent admission due to COPD was a strong predictor of a confirmed COPD diagnosis. Conclusions: Among the patients admitted to the hospital with a COPD diagnosis, a high proportion were not confirmed by the current GOLD report or had never performed spirometry. Stricter implementation of the diagnostic criteria of COPD in admitted patients is necessary to improve diagnosis and the treatment outcomes in these patients.

Single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol versus dual therapy in current and former smokers with COPD: IMPACT trial post hoc analysis.

BACKGROUND: Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status. METHODS: IMPACT was a double-blind, 52-week trial. Patients aged ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg. Endpoints assessed by smoking status at screening included rate and risk of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score at Week 52. Safety was also assessed. RESULTS: Of the 10,355 patients in the intent-to-treat population, 3,587 (35%) were current smokers. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in current (rate ratio 0.85 [95% confidence interval: 0.77-0.95]; P = 0.003 and 0.86 [0.76-0.98]; P = 0.021) and former smokers (0.85 [0.78-0.91]; P < 0.001 and 0.70 [0.64-0.77]; P < 0.001). FF/UMEC/VI significantly reduced time-to-first on-treatment moderate/severe exacerbation versus FF/VI and UMEC/VI in former smokers, and versus FF/VI in current smokers. Similar trends were seen for lung function and health status. Former smokers receiving inhaled corticosteroid-containing therapy had higher pneumonia incidence than current smokers. CONCLUSIONS: FF/UMEC/VI improved clinical outcomes versus dual therapy regardless of smoking status. Benefits of FF/UMEC/VI versus UMEC/VI were greatest in former smokers, potentially due to relative corticosteroid resistance in current smokers. CLINICAL TRIAL REGISTRATION: GSK (CTT116855/NCT02164513).

Residual symptoms, lung function, and imaging findings in patients recovering from SARS-CoV-2 infection.

Symptoms following acute COVID-19 infection are common, but their relationship to initial COVID-19 severity is unclear. We hypothesize that residual symptoms are related to disease severity, and severe acute COVID-19 infection is more likely to cause residual pulmonary damage. This study aims to evaluate symptoms, lung function, and abnormal imaging within 3 months following COVID-19 infection, and to determine whether they are related to initial disease severity. A cross-sectional study was carried out at a designated post-COVID clinic in Hadassah Medical Center, Jerusalem, Israel. Patients with PCR-confirmed SARS-CoV-2 infection were evaluated within 12 weeks following infection and included both admitted and non-admitted subjects. All study participants underwent assessment of symptoms, quality of life (SGRQ), pulmonary function tests, and imaging. A total of 208 patients (age 49.3 ± 16 years) were included in the study. Initial disease severity was mild in 86, moderate in 49, and severe in 73 patients. At the time of follow-up, there were no differences in frequency of residual symptoms or in SGRQ score between groups. Patients with severe COVID-19 were more likely to have residual dyspnea (p = 0.04), lower oxygen saturation (p < 0.01), lower FVC and TLC (p < 0.001, p = 0.03 respectively), abnormal CXR (p < 0.01), and abnormal CT scan (p < 0.01) compared to other groups.Frequency of symptoms and impairment of quality of life at 12 week follow-up are common and are not related to severity of initial COVID-19 disease. In contrast, reduced lung function and abnormal pulmonary imaging are more common in patients with more severe acute COVID-19 infection.

Lung Regeneration by Transplantation of Allogeneic Lung Progenitors Using a Safer Conditioning Regimen and Clinical-grade Reagents.

Over the last decades, several studies demonstrated the possibility of lung regeneration through transplantation of various lung progenitor populations. Recently, we showed in mice that fetal or adult lung progenitors could potentially provide donor cells for transplantation, provided that the lung stem cell niche in the recipient is vacated of endogenous lung progenitors by adequate conditioning. Accordingly, marked lung regeneration could be attained following i.v. infusion of a single cell suspension of lung cells into recipient mice conditioned with naphthalene (NA) and 6Gy total body irradiation (TBI). As clinical translation of this approach requires the use of allogenic donors, we more recently developed a novel transplantation modality based on co-infusion of hematopoietic and lung progenitors from the same donor. Thus, by virtue of hematopoietic chimerism, which leads to immune tolerance toward donor antigens, the lung progenitors can be successfully engrafted without any need for post-transplant immune suppression. In the present study, we demonstrate that it is possible to replace NA in the conditioning regimen with Cyclophosphamide (CY), approved for the treatment of many diseases and that a lower dose of 2 GY TBI can successfully enable engraftment of donor-derived hematopoietic and lung progenitors when CY is administered in 2 doses after the stem cell infusion. Taken together, our results suggest a feasible and relatively safe protocol that could potentially be translated to clinical transplantation of lung progenitors across major MHC barriers in patients with terminal lung diseases.

Predictors of malignant lymph node involvement in patients with mediastinal lymphadenopathy and previous cancer: A cohort study.

BACKGROUND: Mediastinal lymphadenopathy is a common finding in follow-up after diagnosis of malignancy, and may represent recurrence of malignancy, or benign processes such as sarcoidosis. CT and PET-CT are commonly used, despite limited ability to discriminate between benign and malignant disease, and although EBUS-guided bronchoscopy is often performed, it is relatively invasive and may not always be safe in high-risk patients. Clinical and radiological predictors for cancer recurrence could therefore be of value. METHODS: A retrospective cohort analysis of all patients with mediastinal lymphadenopathy and previous malignancy undergoing mediastinal lymph node sampling via bronchoscopy was undertaken. Demographics, smoking status, details of previous malignancy, time since cancer diagnosis, and imaging data were collected, as well as follow-up in the years following the procedure. We then compared specific characteristics of patients with malignant and benign lymphadenopathy in order to identify predictors of malignant versus benign lymphadenopathy. RESULTS: A total of 113 patients were analyzed of which 63% had tumor recurrence, while the rest had benign disease including sarcoidosis. Smoking history and previous lung cancer were both correlated with lymph node malignancy, while symmetric hilar enlargement, and the presence of multiple pathological stations were correlated with benign outcome. Size, maximal SUV uptake or time interval since cancer diagnosis were not associated with the final diagnosis. CONCLUSIONS: These findings may help in assessing the pretest probability of tumor recurrence in patients with mediastinal lymphadenopathy, thus aiding in the clinical decision-making in such scenarios.

The nitroxide/antioxidant 3-carbamoyl proxyl attenuates disease severity in murine models of severe asthma.

Asthma is characterized by airway inflammation, hyper-responsiveness, symptoms of dyspnea, wheezing and coughing. In most patients, asthma is well controlled using inhaled corticosteroids and bronchodilators. A minority of patients with asthma develop severe disease, which is frequently only partially responsive or even resistant to treatment with corticosteroids. Severe refractory asthma is associated with structural changes in the airways, termed "airway remodeling", and/or with neutrophilic rather than eosinophilic airway inflammation. While oxidative stress plays an important role in the pathophysiology of asthma, cyclic nitroxide stable radicals, which are unique and efficient catalytic antioxidants, effectively protect against oxidative injury. We have demonstrated that the nitroxide 3-carbamoyl proxyl (3-CP) attenuates airway inflammation and hyperresponsiveness in allergic asthma as well as bleomycin-induced fibrosis both using murine models, most probably through modulation of oxidative stress. The present study evaluates the effect of 3-CP on airway inflammation and remodeling using two murine models of severe asthma where mice are sensitized and challenged either by ovalbumin (OVA) or by house dust mite (HDM). 3-CP was orally administered during the entire period of the experiment or during the challenge period alone where its effect was compared to that of dexamethasone. The induced increase by OVA and by HDM of BALf cell counts, airway hyperresponsiveness, fibrosis, transforming growth factor-beta (TGF-ß) levels in BALf and protein nitration levels of the lung tissue was significantly reduced by 3-CP. The effect of 3-CP, using two different murine models of severe asthma, is associated at least partially with attenuation of oxidative stress and with TGF-ß expression in the lungs. The results of this study suggest a potential use of 3-CP as a novel therapeutic agent in different forms of severe asthma.

Possible association between SP-C mutations and lung cancer: Two case reports and review of literature.

Surfactant protein C (SP-C) is one of four surfactant proteins produced by type II pneumocytes. Mutations in surfactant protein A are strongly associated with development of lung cancer. Mutations in the SP-C gene are rare and are associated with interstitial lung disease in the pediatric age group. We describe two patients with SP-C mutations who developed lung cancer. Both patients had concurrent interstitial lung disease, although the clinical phenotype was variable. In both cases, mutations were in translated region of the SP-C gene; one in the BRICHOS domain and the other in the transmembrane domain. Our paper suggests that patients with SP-C mutations can be at increased risk for the development of lung cancer, and it's reasonable to follow them routinely.

Waterpipe smoking: a review of pulmonary and health effects.

Waterpipe smoking is an old form of tobacco smoking, originating in Persia and the Middle East. The popularity of the waterpipe is increasing worldwide, particularly among young adults, and there are widespread misconceptions regarding its negative health effects. The inhaled smoke of the waterpipe contain several toxic and hazardous materials including nicotine, tar, polyaromatic hydrocarbons and heavy metals, all of which are proven to be related to lung diseases and cancer. Regular waterpipe smoking is associated with respiratory symptoms, a decrease in pulmonary function and increased risk for lung disease such as COPD. Additional negative health effects include increased risk for arterial stiffness, ischaemic heart disease and several cancer types including lung cancer. This review summarises the negative health effects of waterpipe smoking, with emphasis on cardiorespiratory complications. Increased awareness and knowledge amongst healthcare professionals will hopefully help identify waterpipe smokers and promote patient education. Applying World Health Organization (WHO) regulations will provide a synergistic effect in reducing waterpipe use and associated disease.

3-Carbamoyl-proxyl nitroxide radicals attenuate bleomycin-induced pulmonary fibrosis in mice.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a poor prognosis and limited treatment options. Oxidative and nitrosative stress is implicated as one of the main pathogenic pathways in IPF. The rationale for the use of antioxidants to treat lung fibrosis is appealing, however to date a consistent beneficial effect for such an approach has not been observed. We have recently demonstrated that nitroxides, particularly 3-carbamoyl-proxyl (3-CP), markedly reduce airway inflammation, airway hyper-responsiveness, and protein nitration of the lung tissue in a mouse model of ovalbumin-induced acute asthma, thus prompting its use for the treatment of IPF. The present study investigates the effect of 3-CP on the development of lung fibrosis using the murine intratracheal bleomycin model. 3-CP was administered either intranasally or orally during the entire experiment or starting 7 days after induction of the lung injury. 3-CP was found to be both a preventive and a therapeutic drug reducing the lung fibrosis (histological score), the increase in collagen content, protein nitration, TGF-ß levels, the degree of weight loss as well as inhibiting the impairment of lung function. Nitroxides are catalytic antioxidants that preferentially detoxify radicals, and therefore the effect of 3-CP on the severity of the disease supports the involvement of reactive oxygen and nitrogen species in the disease pathology.

The Effect of a Multidisciplinary Integrated Approach on Outcomes in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic obstructive pulmonary disease(COPD) is a common and debilitating condition, often accompanied by other co-morbidities. The Hadassah Medical Center'smulti-disciplinary approach in treating COPD patients in a one-stop shopfor COPD patients is the first of its kind in Israel. It includes pulmonary physicians, a nurse coordinator, dietitian, psychotherapist, physiotherapist, and a smoking cessation program. OBJECTIVES: To characterize efficacy of such a program in COPD patients. METHODS: Demographic and clinical data from patients referred to the Hadassah COPD center, including co-morbidities, baseline symptoms (using the CAT questioner), spirometry results, 6-minute walking distance (6MWD) test and current treatment were collected and compared to the same data after 6-12 months of treatment. RESULTS: Some 154 patients were evaluated; mean age 64 years; 67% male; 53% current smokers. Only 74% received chronic treatment for COPD. Average body mass index was 28, CAT score 21.3, and mean FEV1 was 1.38 liters (53% of predicted).The mean exacerbation rate during the year prior to referral was 1.72 with a 1.07 annual admission rate. Following treatment, a small increase was noted in FEV1 to 1.47 liters, 54.4% of predicted; improvement in CAT scores to 16.5 with improvement seen in 70% of patients, and a 42 meter increase in the 6MWD (from 344 to 386 meters) with some improvement of effort capacity in 77% of patients. The rate of smokers decreased to 21%, and 97% of patients received medical treatment for COPD. CONCLUSIONS: Multidisciplinary approach is feasible and efficacious in patients with COPD.

Prophylactic use of tranexamic acid for prevention of bleeding during transbronchial lung biopsies - A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although massive bleeding following transbronchial lung biopsies (TBLB) is rare, even minor hemorrhage may prolong the procedure and result in inadequate sampling. Tranexamic acid (TXA) is an antifibrinolytic agent, which reduces bleeding in numerous scenarios, however, its prophylactic use in mitigating post-TBLB bleeding has not been investigated. We conducted a prospective, randomized, double-blind, placebo-controlled trial to determine whether topical infusion of TXA prior to TBLB would reduce bleeding, shorten procedure duration and increase the number of biopsies obtained. METHODS: We blindly randomized patients undergoing TBLB to receive topical TXA or placebo in the lobar bronchus prior to biopsies. Vital signs, procedure length, fluid balance (as a measure of the amount of bleeding), operator's assessment of bleeding, and number of biopsies obtained were measured. Data was analyzed using the two-tailed Student's T-Test, Chi-square or Mann-Whitney tests as appropriate. RESULTS: Fifty patients were randomized, 26 to the TXA arm. The bleeding in the TXA group was significantly lower (P = 0.0037), with more specimens being obtained (placebo 7 (6, 9) (median and interquartile range) vs. TXA 9 (8, 10), P = 0.023) and no difference in procedure length (placebo 30 min (29.3, 34.3) vs. TXA 30 (24.8, 36), P = 0.90). There were no clinically significant adverse events in any of the groups up to one month of follow up. CONCLUSION: Endobronchial installation of TXA prior to obtaining TBLB results in less bleeding and allows more biopsies to be obtained with no additional adverse events. The prophylactic use of TXA during TBLB may be considered as standard.

SIRT1 Deficiency, Specifically in Fibroblasts, Decreases Apoptosis Resistance and Is Associated with Resolution of Lung-Fibrosis.

In contrast to normal regenerating tissue, resistance to Fas- and FasL-positive T cell-induced apoptosis were detected in myofibroblasts from fibrotic-lungs of humans and mice following bleomycin (BLM) exposure. In this study we show, decreased FLIP expression in lung-tissues with resolution of BLM-induced fibrosis and in isolated-lung fibroblasts, with decreased resistance to apoptosis. Using a FLIP-expression vector or a shFLIP-RNA, we further confirmed the critical need for FLIP to regain/lose susceptibility of fibrotic-lung myofibroblast to Fas-induced apoptosis. Our study further show that FLIP is regulated by SIRT1 (Sirtuin 1) deacetylase. Chimeric mice, with SIRT1-deficiency in deacetylase domain (H355Y-Sirt1y/y), specifically in mesenchymal cells, were not only protected from BLM-induced lung fibrosis but, as assessed following Ku70 immunoprecipitation, had also decreased Ku70-deacetylation, decreasedKu70/FLIP complex, and decreased FLIP levels in their lung myofibroblasts. In addition, myofibroblasts isolated from lungs of BLM-treated miR34a-knockout mice, exposed to a miR34a mimic, which we found here to downregulate SIRT1 in the luciferase assay, had a decreased Ku70-deacetylation indicating decrease in SIRT1 activity. Thus, SIRT1 may mediate, miR34a-regulated, persistent FLIP levels by deacetylation of Ku70 in lung myofibroblasts, promoting resistance to cell-death and lung fibrosis.

Forefront: MiR-34a-Knockout Mice with Wild Type Hematopoietic Cells, Retain Persistent Fibrosis Following Lung Injury.

MicroRNAs (miRs) are known to limit gene expression at the post-transcriptional level and have important roles in the pathogenesis of various conditions, including acute lung injury (ALI) and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). In this study, we found increased levels of miR-34 at times of fibrosis resolution following injury, in myofibroblasts from Bleomycin-treated mouse lungs, which correlates with susceptibility to cell death induced by immune cells. On the contrary, a substantial downregulation of miR-34 was detected at stages of evolution, when fibroblasts resist cell death. Concomitantly, we found an inverse correlation between miR-34 levels with that of the survival molecule FLICE-like inhibitory protein (FLIP) in lung myofibroblasts from humans with IPF and the experimental model. Forced upregulation of miR-34 with miR-34 mimic in human IPF fibrotic-lung myofibroblasts led to decreased cell survival through downregulation of FLIP. Using chimeric miR-34 knock-out (KO)-C57BL/6 mice with miR34KO myofibroblasts but wild-type (WT) hematopoietic cells, we found, in contrast to WT mice, increased and persistent FLIP levels with a more severe fibrosis and with no signs of resolution as detected in pathology and collagen accumulation. Moreover, a mimic of miR-34a decreased FLIP expression and susceptibility to cell death was regained in miR-34KO fibroblasts. Through this study, we show for the first time an inverse correlation between miR-34a and FLIP expression in myofibroblasts, which affects survival, and accumulation in lung fibrosis. Reprogramming fibrotic-lung myofibroblasts to regain susceptibility to cell-death by specifically increasing their miR34a and downregulating FLIP, may be a useful strategy, enabling tissue regeneration following lung injury.

Ventilatory compensation during the incremental exercise test is inversely correlated with air trapping in COPD.

Background: Air trapping and gas exchange abnormalities are major causes of exercise limitation in chronic obstructive pulmonary disease (COPD). During incremental cardiopulmonary exercise testing, ventilatory equivalents for carbon dioxide (V E/VCO 2) and oxygen (V E/VO 2) may be difficult to identify in COPD patients because of limited ventilatory compensation capacity. Therefore, we aimed to detect a possible correlation between the magnitude of ventilation augmentation, as manifested by increments in ventilatory equivalents from nadir to peak effort values and air trapping, detected with static testing.    Methods: In this observational study, we studied data obtained previously from 20 COPD patients who, during routine follow-up, underwent a symptom-limited incremental exercise test and in whom a plethysmography was obtained concurrently. Air trapping at rest was assessed by measurement of the residual volume (RV) to total lung capacity (TLC) ratio (RV/TLC). Gas exchange data collected during the symptom-limited incremental cardiopulmonary exercise test allowed determination of the nadir and peak effort values of V E/VCO 2 and V E/VO 2, thus enabling calculation of the difference between peak effort value and nadir values of  V E/VCO 2 and V E/VO 2, designated ΔV E/VCO 2 and ΔV E/VO 2, respectively. Results: We found a statistically significant inverse correlation between both ΔV E/VCO 2 (r = -0. 5058, 95% CI -0.7750 to -0.08149, p = 0.0234) and ΔV E/VO 2 (r = -0.5588, 95% CI -0.8029 to -0.1545, p = 0.0104) and the degree of air trapping (RV/TLC). There was no correlation between                ΔV E/VCO 2 and peak oxygen consumption, forced expiratory volume in the first second, or body mass index.  Conclusions: The ventilatory equivalents increment to compensate for acidosis during incremental exercise testing was inversely correlated with air trapping (RV/TLC) and may be a candidate prognostic biomarker.

Rapid shortening of leukocyte telomeres is associated with poorer pulmonary function among healthy adults.

AIM: The study aimed to examine the association between leukocyte telomere length (LTL) attrition over 13 years (between mean age 30 and mean age 43) and lung function at mean age 50. MATERIALS & METHODS: In a longitudinal observational study LTL was determined twice on a population-based sample of 481 Jewish residents of Jerusalem at mean ages 30 and 43 years. Pulmonary function was determined at mean age 50 years. Multiple linear regression and multivariable ordinal logistic modeling were applied. Akaike's Information Criteria (AIC) was used for model selection. RESULTS: In unadjusted analysis, Forced Expiratory Volume in 1 s (FEV1%) was inversely associated with the LTL attrition rate (standardized beta = -0.110, P = 0.023) but not with the baseline LTL. Forced Vital Capacity (FVC%) was inversely associated with the LTL attrition rate (standardized beta = -0.108, P = 0.026). Multivariable adjustment mildly attenuated the association with the LTL attrition rate (standardized beta = -0.100, P = 0.034 for FEV1% and -0.093, P = 0.042 for FVC%). This would be consistent with a 3.3% [95% Confidence Interval (CI): 3.1-3.4%] decline in FEV1% and a 3.0% (95% CI:2.8-3.1%) decline in FVC% per year. In linear regression models the LTL-pulmonary function association did not differ by sex, social mobility, pack-years smoking exposure, or level of GlycA, a novel systemic inflammatory marker. CONCLUSIONS: Greater LTL attrition between mean age 30 and mean age 43 was associated with poorer lung function at mean age 50 years. The availability of longitudinal data on LTL attrition for the first time in the current study strengthens the case for LTL change preceding change in lung function.