Development Of Obstructive Lung Disease Research Articles

CC16 drives VLA-2-dependent SPLUNC1 expression.

CC16 (Club Cell Secretory Protein) is a protein produced by club cells and other non-ciliated epithelial cells within the lungs. CC16 has been shown to protect against the development of obstructive lung diseases and attenuate pulmonary pathogen burden. Despite recent advances in understanding CC16 effects in circulation, the biological mechanisms of CC16 in pulmonary epithelial responses have not been elucidated. We sought to determine if CC16 deficiency impairs epithelial-driven host responses and identify novel receptors expressed within the pulmonary epithelium through which CC16 imparts activity. We utilized mass spectrometry and quantitative proteomics to investigate how CC16 deficiency impacts apically secreted pulmonary epithelial proteins. Mouse tracheal epithelial cells (MTECS), human nasal epithelial cells (HNECs) and mice were studied in naïve conditions and after Mp challenge. We identified 8 antimicrobial proteins significantly decreased by CC16-/- MTECS, 6 of which were validated by mRNA expression in Severe Asthma Research Program (SARP) cohorts. Short Palate Lung and Nasal Epithelial Clone 1 (SPLUNC1) was the most differentially expressed protein (66-fold) and was the focus of this study. Using a combination of MTECs and HNECs, we found that CC16 enhances pulmonary epithelial-driven SPLUNC1 expression via signaling through the receptor complex Very Late Antigen-2 (VLA-2) and that rCC16 given to mice enhances pulmonary SPLUNC1 production and decreases Mycoplasma pneumoniae (Mp) burden. Likewise, rSPLUNC1 results in decreased Mp burden in mice lacking CC16 mice. The VLA-2 integrin binding site within rCC16 is necessary for induction of SPLUNC1 and the reduction in Mp burden. Our findings demonstrate a novel role for CC16 in epithelial-driven host defense by up-regulating antimicrobials and define a novel epithelial receptor for CC16, VLA-2, through which signaling is necessary for enhanced SPLUNC1 production.

Occupational exposures and small airway obstruction in the UK Biobank Cohort.

Small airways obstruction (SAO) is a key feature of both COPD and asthma, which have been associated with workplace exposures. Whether SAO, which may occur early in the development of obstructive lung disease and without symptoms, also associates with occupational exposures is unknown. Using UK Biobank data, we derived measurements of SAO from the 65 145 participants with high-quality spirometry and lifetime occupational histories. The ALOHA+ Job Exposure Matrix was used to assign lifetime occupational exposures to each participant. The association between SAO and lifetime occupational exposures was evaluated using a logistic regression model adjusted for potential confounders. A second logistic regression model was also run to account for potential co-exposures. SAO was present in varying proportions of the population depending on definition used: 5.6% (forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75) < lower limit of normal (LLN)) and 21.4% (forced expiratory volume in 3 s (FEV3)/forced expiratory volume in 6 s (FEV6) <LLN). After adjustment for confounders and co-exposures, people in the highest category of exposure to pesticides were significantly more likely to have SAO (FEV3/FEV6 <LLN: OR 1.24, 95% CI 1.06-1.44). The association between pesticides and SAO showed an exposure-response pattern. SAO was also less likely among people in the highest exposure categories of aromatic solvents (FEV3/FEV6 <LLN: OR 0.85, 95% CI 0.73-0.99) and metals (FEV3/FEV6 <LLN: OR 0.77, 95% CI 0.62-0.94). Our findings suggest that occupational exposure to pesticides play a role in the SAO. However, further work is needed to determine causality, and identify the specific component(s) responsible and the underlying mechanisms involved.

A population-based cohort study on the risk of obstructive lung disease after bilateral oophorectomy

There is increasing evidence that sex hormones may impact the development of obstructive lung disease (OLD). Therefore, we studied the effect of bilateral oophorectomy (oophorectomy) on the development of OLD. Women were identified from the Mayo Clinic Cohort Study of Oophorectomy and Aging-2. Data were collected using the Rochester Epidemiology Project records-linkage system. A total of 1653 women who underwent oophorectomy and 1653 referent women of similar age were assessed for OLD using diagnostic codes and medical record abstraction. Women who underwent oophorectomy had an overall higher risk of all OLD, all chronic obstructive pulmonary disease (COPD), emphysema, and chronic bronchitis but not of all asthma, confirmed asthma, or confirmed COPD. The association with all OLD was stronger in women who were age ≤45 years at oophorectomy, never smokers, non-obese, and in women with benign indications; however, the interactions were not statistically significant. There was an increased risk of all asthma in women age ≤45 years at oophorectomy who took estrogen therapy. Never smokers of all ages had a stronger association of oophorectomy with all asthma and all COPD, whereas smokers had a stronger association of oophorectomy with emphysema and chronic bronchitis. Non-obese women of all ages had a stronger association of oophorectomy with all COPD, emphysema, and chronic bronchitis. The results of this study combined with the increased risk of several chronic diseases reported in previous studies suggest that oophorectomy in premenopausal women should be avoided unless there is clear evidence of a high genetic risk of ovarian cancer.

Triglyceride-Glucose Index is a Risk Marker of Incident COPD Events in Women.

PurposeThe triglyceride-glucose index (TyG index) is a marker of insulin resistance and metabolic dysfunction and has the advantage of being universally available. Although recent evidence suggests the TyG index has relevance to respiratory health, there have been no prospective studies assessing its value as a biomarker for chronic lung diseases. We aim to assess the TyG index as a potential risk marker for future incident COPD events in the general population.Patients and MethodsBaseline TyG index was assessed in 28,282 middle-aged men and women without previous history of chronic obstructive pulmonary disease (COPD) from the Malmö Preventive Project (men between 1974 and 1982 and women between 1982 and 1992). All subjects were followed up prospectively, and Cox proportional hazards regression was used to assess incident COPD events according to quartiles of TyG index.ResultsAfter an average of 31 years of follow-up, TyG index was a strong predictor of future COPD events even after adjusting for potential confounders (Q4 (highest TyG index) HR (95% CI): 1.21 (1.09–1.35) vs Q1 (reference), p-trend <0.001). After stratifying by sex, the results remained statistically significant in women only (Q4 vs Q1 HR 1.72 (1.41–2.09)). Additionally, the risk remained significant in a cohort of life-long never smokers (Q4 vs Q1 HR 1.47 (1.08–2.01)).ConclusionA raised TyG index is a novel risk marker of future incident COPD events in women. Insulin resistance as reflected by the TyG index can precede the development of obstructive lung disease and as such may be an easily measurable and useful predictor of COPD in women.

Role of air pollutants in airway epithelial barrier dysfunction in asthma and COPD

Chronic exposure to environmental pollutants is a major contributor to the development and progression of obstructive airway diseases, including asthma and COPD. Understanding the mechanisms underlying the development of obstructive lung diseases upon exposure to inhaled pollutants will lead to novel insights into the pathogenesis, prevention and treatment of these diseases. The respiratory epithelial lining forms a robust physicochemical barrier protecting the body from inhaled toxic particles and pathogens. Inhalation of airborne particles and gases may impair airway epithelial barrier function and subsequently lead to exaggerated inflammatory responses and airway remodelling, which are key features of asthma and COPD. In addition, air pollutant-induced airway epithelial barrier dysfunction may increase susceptibility to respiratory infections, thereby increasing the risk of exacerbations and thus triggering further inflammation. In this review, we discuss the molecular and immunological mechanisms involved in physical barrier disruption induced by major airborne pollutants and outline their implications in the pathogenesis of asthma and COPD. We further discuss the link between these pollutants and changes in the lung microbiome as a potential factor for aggravating airway diseases. Understanding these mechanisms may lead to identification of novel targets for therapeutic intervention to restore airway epithelial integrity in asthma and COPD.

The adverse effects of solid biomass fuel exposure on lung functions in non-smoking female population.

ABSTRACTBackground:Though, smoking is the leading cause of chronic obstructive pulmonary disease worldwide, the household air pollution due to use of solid biomass fuel is considered as a major risk factor for the development of obstructive lung disease. The aim of the study was to assess the effect of solid biomass fuel exposure on lung functions in non-smoking female population.Methods:A hospital based, descriptive cross sectional study was carried out among 140 non-smoking female patients aged 40 or more and who had been exposed to solid biomass fuel. These patients underwent spirometry to assess their lung function and were classified as obstructive, restrictive or mixed. Modified medical research council (mMRC) dyspnoea scale for symptom assessment, 6-minute walk test (6 MWT) to determine the exercise capacity and Cumulative exposure index to assess the duration of exposure were also done.Results:All 140 (100%) patients having abnormal lung function, 4 (2.86%) had restrictive pattern, 5 (3.57%) had mixed pattern and 131 (93.57%) had obstructive pattern. Of 131 patients having obstructive pattern, 11 had mild obstruction, 49 had moderate obstruction, 39 had severe obstruction and 32 had very severe obstruction. Most commonly used biomass fuel was wood (43.57%). All the patients had shortness of breath, whereas cough was present in only 35.71% cases. 77 (55%) patients presented with a dyspnoea of mMRC grade 3 and above.Conclusion:Cumulative exposure index for solid biomass fuel is directly proportional to the severity of lung impairment as well as the symptom severity.

Blood Cadmium Levels and Oxygen Desaturation during the 6-Minute Walk Test in Patients with Chronic Obstructive Pulmonary Disease

Background and Objectives: chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and a history of exposure to noxious stimuli. Cigarette smoking is the most important causal factor for developing COPD. Cadmium, a minor metallic element, is one of the main inorganic components in tobacco smoke. Inhaled cadmium was associated with a decline in lung function, gas exchange impairment, and the development of obstructive lung disease. Patients with COPD who had oxygen desaturation during the 6-min walk test (6MWT) had a significantly worse prognosis than non-desaturation in COPD patients. Nonetheless, few studies have addressed the influence of blood cadmium levels on exercise-induced oxygen desaturation in COPD patients. Our objective was to assess the potential impact of blood cadmium levels on oxygen desaturation during the 6MWT among COPD patients. Materials and Methods: we performed a retrospective analysis of patients with COPD who were examined for blood cadmium levels in a tertiary care referral center in Taiwan, between March 2020 and May 2021. The 6-min walk test was performed. Normal control subjects who had no evidence of COPD were also enrolled. Results: a total of 73 COPD patients were analyzed and stratified into the high-blood cadmium group (13 patients) and low-blood cadmium group (60 patients). A total of 50 normal control subjects without a diagnosis of COPD were enrolled. The high-blood cadmium group had a significantly higher extent of desaturation than the low-blood cadmium group. The frequency of desaturation during 6MWT revealed a stepwise-increasing trend with an increase in blood cadmium levels. A multivariable logistic regression model revealed that blood cadmium levels were independently associated with desaturation during the 6MWT (odds ratio 12.849 [95% CI 1.168–141.329]; p = 0.037). Conclusions: our findings indicate that blood cadmium levels, within the normal range, were significantly associated with desaturation during 6MWT in patients with COPD.

Accelerated decline in lung function in adults with a history of remitted childhood asthma.

A significant number of children with asthma show remission in adulthood. Although these adults are often diagnosed with COPD in later life, the effect of clinically remitted childhood asthma on the decline in lung function during adulthood is uncertain. We examined whether clinical remission of childhood asthma was associated with an accelerated decline in lung function in apparently nonasthmatic adults. 3584 participants (mean (range) age 48.1 (35-65) years) who did not have adulthood asthma and other lung diseases and had normal lung function at the baseline visit were included. They were categorised as those with remitted childhood asthma (n=121) and healthy controls (n=3463) according to their self-reported childhood asthma history. Spirometry was performed at baseline and follow-up visits. The mean follow-up was 5.3 years. Multivariate regression analysis showed that remitted childhood asthma and smoking were independently associated with a rapid decline in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). Smoking was an independent predictor of a rapid decline in FEV1/FVC. The annual decline in FEV1 and FVC was significantly greater in participants with remitted childhood asthma than in healthy controls, and the differences remained significant after adjusting for the propensity score. A history of clinically remitted childhood asthma is an independent risk factor for accelerated decline in lung function in adults. Remitted childhood asthma and smoking may additively accelerate the development of obstructive lung disease.

Understanding the genetics of chronic obstructive pulmonary disease, α1-antitrypsin deficiency, and implications for clinical practice.

Cigarette smoking and poor air quality are the greatest risk factors for developing chronic obstructive pulmonary disease (COPD), but growing evidence indicates that genetic factors also affect predisposition to and clinical expression of disease. With the exception of α1-antitrypsin deficiency (AATD), a rare autosomal recessive disorder that is present in 1-3% of individuals with COPD, no single gene is associated with the development of obstructive lung disease. Instead, a complex interplay of genetic, epigenetic, and environmental factors is the basis for persistent inflammatory responses, accelerated cell aging, cell death, and fibrosis, leading to the clinical symptoms of COPD and different phenotypic presentations. In this brief review, we discuss current understanding of the genetics of COPD, pathogenetics of AATD, epigenetic influences on the development of obstructive lung disease, and how classifying COPD by phenotype can influence clinical treatment and patient outcomes.

Association between prevalence of obstructive lung disease and obesity: results from The Vermont Diabetes Information System

BackgroundThe association of obesity with the development of obstructive lung disease, namely asthma and/or chronic obstructive pulmonary disease, has been found to be significant in general population studies, and weight loss in the obese has proven beneficial in disease control. Obese patients seem to present with a specific obstructive lung disease phenotype including a reduced response to corticosteroids. Obesity is increasingly recognized as an important factor to document in obstructive lung disease patients and a critical comorbidity to report in diabetic patients, as it may influence disease management. This report presents data that contributes to establishing the relationship between obstructive lung disease in a diabetic cohort, a population highly susceptible to obesity.MethodsA total of 1003 subjects in community practice settings were interviewed at home at the time of enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any history of obstructive lung disease. Laboratory data were obtained directly from the clinical laboratory, and current medications were obtained by direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between obstructive lung disease history and obesity.ResultsIn a multivariate logistic regression model, a history of obstructive lung disease was significantly associated with obesity (body mass index ≥30) even after correcting for potential confounders including gender, low income (<$30,000/year), number of comorbidities, number of prescription medications, cigarette smoking, and alcohol problems (adjusted odds ratio (OR) = 1.58, P = 0.03, 95% confidence interval (CI) = 1.05, 2.37). This association was particularly strong and significant among female patients (OR = 2.18, P = < 0.01, CI = 1.27, 3.72) but not in male patients (OR = 0.97, P = 0.93, CI = 0.51, 1.83).ConclusionThese data suggest an association between obesity and obstructive lung disease prevalence in patients with diabetes, with women exhibiting a stronger association. Future studies are needed to identify the mechanism by which women disproportionately develop obstructive lung disease in this population.

Blood eosinophil counts and the development of obstructive lung disease: the Kangbuk Samsung Health Study.

The impact of blood eosinophil counts on the development of chronic obstructive lung disease (COPD) is unknown. We investigated whether a higher blood eosinophil count was associated with the risk of developing obstructive lung disease (OLD) in a large cohort of men and women free from lung disease at baseline. This was a cohort study of 359 456 Korean adults without a history of asthma and without OLD at baseline who participated in health screening examinations including spirometry. OLD was defined as pre-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7 and FEV1 <80% predicted. After a median (interquartile range) follow-up of 5.6 (2.9-9.2) years, 5008 participants developed incident OLD (incidence rate 2.1 (95% CI 2.1-2.2) per 1000 person-years). In the fully adjusted model, the hazard ratios for incident OLD comparing eosinophil counts of 100- <200, 200- <300, 300- <500 and ≥500 versus <100 cells·μL-1 were 1.07 (95% CI 1.00-1.15), 1.30 (95% CI 1.20-1.42), 1.46 (95% CI 1.33-1.60) and 1.72 (95% CI 1.51-1.95), respectively (ptrend<0.001). These associations were consistent in clinically relevant subgroups, including never-, ex- and current smokers. In this large longitudinal cohort study, blood eosinophil counts were positively associated with the risk of developing of OLD. Our findings indicate a potential role of the eosinophil count as an independent risk factor for developing COPD.

GUAIFENESIN MODIFIES AIRWAY MUCUS, REDUCES MUCUS-CELL SURFACE INTERACTIONS, AND INCREASES MUCOCILIARY TRANSPORT IN AN ORGANOTYPIC IN VITRO MODEL OF MUCUS HYPERSECRETION

SESSION TITLE: Phenotyping and Management of COPD SESSION TYPE: Original Investigations PRESENTED ON: October 18-21, 2020 PURPOSE: Airway mucus hypersecretion is a hallmark of chronic bronchitis (CB) and is strongly associated with cough discomfort, reduced pulmonary function, recurring respiratory infections, and the development of obstructive lung disease. Guaifenesin (GGE) is currently the only FDA-approved oral expectorant and the most common active ingredient in prescription and over-the-counter medicines for treatment of acute respiratory congestion and stable CB. Studies in patients with CB demonstrate that GGE reduces airway secretion viscoelasticity and mucus adhesion, inhibits cough reflex sensitivity, and increases mucociliary clearance (MCC). However, despite its broad use, the mechanism of action for GGE remains unclear. Here, we investigate whether GGE acts directly on the respiratory epithelium to modify epithelial cell secretions, reduce mucus/mucosa interactions, and enhance mucociliary transport (MCT) using an organotypic in vitro model of mucus hypersecretion. METHODS: Primary human bronchial epithelial cells (hBECs) were collected from healthy (HC), heavy smoker (HS; 48.3±18.9 pack year), and COPD (51.3±10.3 pack year) donor lungs (N=3 per group), and differentiated at an air-liquid interface to a mucociliary phenotype. At culture day 35, 20µg/ml GGE was supplemented to the basolateral medium and cultures were maintained in the presence of drug for an additional 15 days. Apical secretions were allowed to accumulate for the duration of the 15-day treatment. Following treatment, mucus concentration, mucus/mucosa interaction strength, in vitro MCT, ciliary beat frequency (CBF), and mucin protein expression were compared. RESULTS: Apical secretions collected from HS and COPD cultures had a higher mucus concentration (12.3±3.0 and 11.1±2.2 % solids, respectively) than HC cultures (7.6±1.1). Moreover, increased mucus concentration was associated with greater mucus/mucosa interaction strength and lower baseline MCT as compared to HC. In all donor groups, 15-day GGE treatment reduced mucus concentration (? % solids: 2.2±1.2 HC, 1.9±0.6 HS, and 2.4±1.8 COPD) and mucus/mucosa interaction strength (? mN/cm: 1.8±0.4 HC, 3.6±1.9 HS, and 1.6±0.4 COPD). GGE-mediated reductions in mucus concentration and mucus/mucosa interaction strength translated to increased in vitro MCT (? µm/sec: 35.1±21.9 HC, 19.6±30.1 HS, and 4.7±0.8 COPD). GGE treatment did not significantly alter MUC5AC or MUC5B secreted protein levels, or CBF. CONCLUSIONS: Our findings indicate that GGE significantly reduces airway mucus concentration, reduces mucus-cell surface interaction strength, and increases MCT in vitro through direct interactions with airways epithelial cells in all donor groups (HC, HS, and COPD). CLINICAL IMPLICATIONS: These data suggest that GGE may act directly at the level of the respiratory epithelium to modify airway mucus and improve MCC in conditions characterized by mucus hypersecretions. DISCLOSURES: Global Medical Lead Respiratory relationship with Reckitt Benckiser Please note: $1001 - $5000 Added 04/10/2020 by Graça Maria Alves da Cunha Coutinho, source=Web Response, value=Salary No relevant relationships by Brian Button, source=Web Response Receive research support relationship with Reckitt Benckiser Please note: >$100000 Added 04/09/2020 by Phillip Clapp, source=Web Response, value=Grant/Research Support No relevant relationships by Miriam Figueira, source=Web Response no disclosure on file for Ly Nguyen; Employee relationship with Rekitt Benckiser Please note: >$100000 Added 06/11/2020 by Karin Nicholson, source=Web Response, value=Salary No relevant relationships by Timother Shea, source=Web Response No relevant relationships by Holly Thacker, source=Web Response

RISK FOR OBSTRUCTIVE LUNG DISEASE DEVELOPMENT AFTER BILATERAL OOPHORECTOMY

SESSION TITLE: Obstructive Lung Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Obstructive lung diseases (OLD) affect women disproportionately with higher risk of disease development and greater symptom burden. Female reproductive hormones, namely estrogen and progesterone, have been implicated as mediators in lung physiology as women advance in their reproductive lifespan. However, conflicting evidence exists on the effects of hormonal changes during menopause on lung function. We therefore studied the effect of bilateral oophorectomy (BO) on the development of OLD. METHODS: The Rochester Epidemiology Project (REP) medical records-linkage system was used to identify all premenopausal women who underwent BO for benign indications before age 50, between 1988 and 2007 in Olmsted County, Minnesota (N=1,653). Each woman was randomly matched to a referent woman born in the same year (+/-1) who had not undergone BO (N=1,653). OLD diagnostic codes were obtained from REP electronic indexes. Medical records were reviewed through 12/31/2018. Global Initiative for Chronic OLD (GOLD) and Global Initiative for Asthma (GINA) 2019 definitions were used to classify OLD on pulmonary function testing. Radiologist-interpreted reports were used to evaluate changes on computed tomography. Each woman could have more than one type of OLD. Hazard ratios were derived from Cox proportional hazards models adjusted for chronic conditions and other possible confounders at the index date, separately for each type of OLD (asthma, chronic obstructive pulmonary disease [COPD], emphysema without documented airflow limitation, or chronic bronchitis). RESULTS: Over a median of 18 years of follow up, de novo OLD was identified in 259 women who underwent BO (219 asthma, 15 COPD, 19 emphysema, 60 chronic bronchitis) and 202 referent women (168 asthma, 15 COPD, 13 emphysema, 36 chronic bronchitis). Women who underwent BO had a higher risk of asthma overall (HR 1.23, 95% CI 1.01-1.51). This was most notable in younger women age ≤45 years at BO (HR 1.54, 95% CI 1.19-1.99), especially those who did not receive estrogen treatment (ET) (HR 2.49, 95% CI 1.08-5.75). No significant risk of COPD (HR 1.01, 95% CI 0.49-2.10), emphysema (HR 1.29, 95% CI 0.66-2.53), or chronic bronchitis (HR 1.41, 95% 0.94-2.13) was found. CONCLUSIONS: Women who underwent BO, especially young women ≤45 years of age and those who did not receive ET, had an increased risk of asthma. CLINICAL IMPLICATIONS: Some studies suggest that as sex hormones wane in natural menopause, there is a decreased risk of asthma, and that ET may increase the risk. However, other studies suggest that menopause is associated with lower lung function and worse asthma symptom severity. This study suggests that age of onset of menopause and ET may influence the risks of asthma. Although a clear sexual dimorphism in airway pathology exists, further investigation is warranted to understand the impact of hormonal changes on lung pathology. DISCLOSURES: No relevant relationships by Megan Dulohery Scrodin, source=Web Response No relevant relationships by Trinh Nguyen, source=Web Response No relevant relationships by Walter Rocca, source=Web Response No relevant relationships by Carin Smith, source=Web Response Recipient of grant funding relationship with Bristol Myers Squibb Please note: >$100000 Added 03/23/2020 by Robert Vassallo, source=Web Response, value=Grant/Research Support Recipient of grant funding relationship with Sun Pharmaceuticals Please note: >$100000 Added 03/23/2020 by Robert Vassallo, source=Web Response, value=Grant/Research Support Recipient of grant funding relationship with Pfizer Please note: >$100000 Added 03/23/2020 by Robert Vassallo, source=Web Response, value=Grant/Research Support

HIV infection is associated with elevated biomarkers of immune activation in Ugandan adults with pneumonia.

IntroductionPneumonia is an important cause of morbidity and mortality in persons living with human immunodeficiency virus (HIV) infection. How immune activation differs among HIV-infected and HIV-uninfected adults with pneumonia is unknown.MethodsThe Inflammation, Aging, Microbes, and Obstructive Lung Disease (I AM OLD) Cohort is a prospective cohort of adults with pneumonia in Uganda. In this cross-sectional analysis, plasma was collected at pneumonia presentation to measure the following 12 biomarkers: interleukin 6 (IL-6), soluble tumor necrosis factor receptors 1 and 2 (sTNFR-1 and sTNFR-2), high sensitivity C-reactive protein (hsCRP), fibrinogen, D-dimer, soluble CD27 (sCD27), interferon gamma-inducible protein 10 (IP-10), soluble CD14 (sCD14), soluble CD163 (sCD163), hyaluronan, and intestinal fatty acid binding protein. We asked whether biomarker levels differed between HIV-infected and HIV-uninfected participants, and whether higher levels of these biomarkers were associated with mortality.ResultsOne hundred seventy-three participants were enrolled. Fifty-three percent were HIV-infected. Eight plasma biomarkers—sTNFR-1, sTNFR-2, hsCRP, D-dimer, sCD27, IP-10, sCD14, and hyaluronan—were higher among participants with HIV infection, after adjustment for pneumonia severity. Higher levels of 8 biomarkers—IL-6, sTNFR-1, sTNFR-2, hsCRP, IP-10, sCD14, sCD163, and hyaluronan—were associated with increased 2-month mortality.ConclusionsAs in other clinical contexts, HIV infection is associated with a greater degree of immune activation among Ugandan adults with pneumonia. Some of these are also associated with short-term mortality. Further study is needed to explore whether these biomarkers might predict poor long-term outcomes—such as the development of obstructive lung disease—in patients with HIV who have recovered from pneumonia.

Local and Systemic Inflammation May Mediate Diesel Engine Exhaust-Induced Lung Function Impairment in a Chinese Occupational Cohort.

Diesel exhaust (DE) as the major source of vehicle-emitted particle matter in ambient air impairs lung function. The objectives were to assess the contribution of local (eg, the fraction of exhaled nitric oxide [FeNO] and serum Club cell secretory protein [CC16]) and systemic (eg, serum C-reaction protein [CRP] and interleukin-6 [IL-6]) inflammation to DE-induced lung function impairment using a unique cohort of diesel engine testers (DETs, n = 137) and non-DETs (n = 127), made up of current and noncurrent smokers. Urinary metabolites, FeNO, serum markers, and spirometry were assessed. A 19% reduction in CC16 and a 94% increase in CRP were identified in DETs compared with non-DETs (all p values <10-4), which were further corroborated by showing a dose-response relationship with internal dose for DE exposure (all p values <.04) and a time-course relationship with DE exposure history (all p values <.005). Mediation analysis showed that 43% of the difference in FEV1 between DETs and non-DETs can be explained by circulating CC16 and CRP (permuted p < .001). An inverse dose-dependent relationship between FeNO and internal dose for cigarette smoke was identified (p = .0003). A range of 95% lower bounds of benchmark dose of 1.0261-1.4513 μg phenanthrols/g creatinine in urine as an internal dose was recommended for regulatory risk assessment. Local and systemic inflammation may be key processes that contribute to the subsequent development of obstructive lung disease in DE-exposed populations.

Longitudinal analysis of the lung microbiota of cynomolgous macaques during long-term SHIV infection.

BackgroundLongitudinal studies of the lung microbiome are challenging due to the invasive nature of sample collection. In addition, studies of the lung microbiome in human disease are usually performed after disease onset, limiting the ability to determine early events in the lung. We used a non-human primate model to assess lung microbiome alterations over time in response to an HIV-like immunosuppression and determined impact of the lung microbiome on development of obstructive lung disease. Cynomolgous macaques were infected with the SIV-HIV chimeric virus SHIV89.6P. Bronchoalveolar lavage fluid samples were collected pre-infection and every 4 weeks for 53 weeks post-infection. The microbiota was characterized at each time point by 16S ribosomal RNA (rRNA) sequencing.ResultsWe observed individual variation in the composition of the lung microbiota with a proportion of the macaques having Tropheryma whipplei as the dominant organism in their lungs. Bacterial communities varied over time both within and between animals, but there did not appear to be a systematic alteration due to SHIV infection. Development of obstructive lung disease in the SHIV-infected animals was characterized by a relative increase in abundance of oral anaerobes. Network analysis further identified a difference in community composition that accompanied the development of obstructive disease with negative correlations between members of the obstructed and non-obstructed groups. This emphasizes how species shifts can impact multiple other species, potentially resulting in disease.ConclusionsThis study is the first to investigate the dynamics of the lung microbiota over time and in response to immunosuppression in a non-human primate model. The persistence of oral bacteria in the lung and their association with obstruction suggest a potential role in pathogenesis. The lung microbiome in the non-human primate is a valuable tool for examining the impact of the lung microbiome in human health and disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-016-0183-0) contains supplementary material, which is available to authorized users.

Hepatitis C Virus Infection Is Not An Independent Risk Factor For Obstructive Lung Disease

Several epidemiological studies have suggested that hepatitis C virus (HCV) infection is associated with the presence of obstructive lung disease (OLD). However, there is a strong link between HCV infection and tobacco abuse, a major risk factor for the development of OLD. In this study we analyzed clinical, laboratory and spirometric data from 1068 study participants to assess whether HCV infection, viremia, or HCV-associated end organ damage were associated with OLD. Demographics, risk behavior, serologic status for HCV and HIV, and spirometric measurements were collected from a cross-sectional analysis of the Acquired Immunodeficiency Syndrome (AIDS) Linked to the IntraVenous Experience (ALIVE) study, an observational cohort of IDUs followed in Baltimore, MD since 1988. Of 1,068 participants, 890 (83%) were HCV positive and 174 (16%) met spirometric criteria for OLD. Factors independently associated with OLD were age and BMI. HCV infection, viral load and HCV-associated end organ damage were similar in participants with and without OLD. In summary, there was no independent association between markers of HCV exposure, chronicity, viremia, or HCV-associated end-organ damage with OLD. Our findings support the strong correlation between HCV status, injection drug use, and smoking. These data suggest that HCV may not be a sole contributor to the increased prevalence of OLD described in previous studies of HCV-infected individuals.

Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony.

Chronic obstructive pulmonary disease, metabolic syndrome and diabetes mellitus are common and underdiagnosed medical conditions. It was predicted that chronic obstructive pulmonary disease will be the third leading cause of death worldwide by 2020. The healthcare burden of this disease is even greater if we consider the significant impact of chronic obstructive pulmonary disease on the cardiovascular morbidity and mortality.Chronic obstructive pulmonary disease may be considered as a novel risk factor for new onset type 2 diabetes mellitus via multiple pathophysiological alterations such as: inflammation and oxidative stress, insulin resistance, weight gain and alterations in metabolism of adipokines.On the other hand, diabetes may act as an independent factor, negatively affecting pulmonary structure and function. Diabetes is associated with an increased risk of pulmonary infections, disease exacerbations and worsened COPD outcomes. On the top of that, coexistent OSA may increase the risk for type 2 DM in some individuals.The current scientific data necessitate a greater outlook on chronic obstructive pulmonary disease and chronic obstructive pulmonary disease may be viewed as a risk factor for the new onset type 2 diabetes mellitus. Conversely, both types of diabetes mellitus should be viewed as strong contributing factors for the development of obstructive lung disease. Such approach can potentially improve the outcomes and medical control for both conditions, and, thus, decrease the healthcare burden of these major medical problems.

Assessment of dietary fat intake and innate immune activation as risk factors for impaired lung function

Preservation of lung health with aging is an important health issue in the general population, as loss of lung function with aging can lead to the development of obstructive lung disease and is a predictor of all-cause and cardiovascular mortality. Inflammation is increasingly linked to loss of lung function and evidence suggests that consumption of dietary fat exacerbates inflammation. We aimed to determine the association between dietary fat intake and lung function in older people. Participants from the Hunter community study, a population-based cohort, were recruited during 2004 and 2005. Participants received a clinical assessment, including spirometry, and provided a blood sample. Diets were analyzed using food-frequency questionnaires. Plasma interleukin (IL)-6 and C-reactive protein was measured by Enzyme-Linked immunosorbent assay. Using backward stepwise linear regression, %energy from dietary fat, age and plasma IL-6 were considered as negative predictors of forced expiratory volume in one second (FEV(1)) in men. Also in men, % energy intake from dietary fat, age, body mass index and IL-6 were negative predictors of %predicted forced vital capacity (FVC). Smoking and age were negative predictors of FEV(1)/FVC. In women, plasma IL-6 and age were negative predictors of %FVC, whereas obesity was positively associated with FEV(1)/FVC. An increased proportion of fat in the diet is associated with the reduced lung function in older men. Dietary-fat induced innate immune activation and IL-6 release may contribute to this effect. Dietary interventions involving fat restriction should be further investigated as means of preserving lung function with aging.

Diet and Airway Obstruction: A Cross Sectional Study from the Second Korean National Health and Nutrition Examination Survey

Background/AimsSeveral dietary factors, such as antioxidant vitamins, have potential roles in the development of obstructive lung diseases. However, the results of studies on the relationships between dietary factors and obstructive lung diseases are inconsistent. The aim of this study was to determine which nutrients are related to airway obstruction (AO) in the Korean population.MethodsWe used data obtained as part of the Korean National Health and Nutrition Examination Survey (NHANES II) in 2001. Analysis was restricted to 1,005 adults who were 18 years of age and older, who had two or more acceptable spirometry curves, and who had participated in the nutrition examination survey. AO was defined as the ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) of less than 0.7.ResultsOf the 1,005 study subjects, 78 (7.8%) had AO. Statistically significant factors associated with AO were 55 years of age or older (p = 0.032), central obesity (p = 0.047), hypertension (p < 0.001), smoking of 20 pack-years or more (p < 0.001), low income (p < 0.001), and low dietary protein intake expressed as a ratio of protein to recommended dietary allowance for Koreans (p = 0.037). Multiple logistic regression analyses revealed four factors that were independently associated with AO: smoking of 20 pack-years or more (odds ratio [OR], 5.801; p < 0.001), hypertension (OR, 3.905; p < 0.001), low protein intake (OR, 0.992; p = 0.004), and low income (OR, 1.962; p = 0.018).ConclusionsIn the Korean NHANES, smoking, hypertension, and low income were related to AO. Among dietary factors, only low protein intake was associated with AO.