Lower respiratory tract microbiome composition and community interactions in smokers.

The lung microbiome impacts on lung function, making any smoking-induced changes in the lung microbiome potentially significant. The complex co-occurrence and co-avoidance patterns between the bacterial taxa in the lower respiratory tract (LRT) microbiome were explored for a cohort of active (AS), former (FS) and never (NS) smokers. Bronchoalveolar lavages (BALs) were collected from 55 volunteer subjects (9 NS, 24 FS and 22 AS). The LRT microbiome composition was assessed using 16S rRNA amplicon sequencing. Identification of differentially abundant taxa and co-occurrence patterns, discriminant analysis and biomarker inferences were performed. The data show that smoking results in a loss in the diversity of the LRT microbiome, change in the co-occurrence patterns and a weakening of the tight community structure present in healthy microbiomes. The increased abundance of the genus Ralstonia in the lung microbiomes of both former and active smokers is significant. Partial least square discriminant and DESeq2 analyses suggested a compositional difference between the cohorts in the LRT microbiome. The groups were sufficiently distinct from each other to suggest that cessation of smoking may not be sufficient for the lung microbiota to return to a similar composition to that of NS. The linear discriminant analysis effect size (LEfSe) analyses identified several bacterial taxa as potential biomarkers of smoking status. Network-based clustering analysis highlighted different co-occurring and co-avoiding microbial taxa in the three groups. The analysis found a cluster of bacterial taxa that co-occur in smokers and non-smokers alike. The clusters exhibited tighter and more significant associations in NS compared to FS and AS. Higher degree of rivalry between clusters was observed in the AS. The groups were sufficiently distinct from each other to suggest that cessation of smoking may not be sufficient for the lung microbiota to return to a similar composition to that of NS.

Impact of a Computerized Clinical Decision Support System to Improve Chronic Obstructive Pulmonary Disease Diagnosis and Testing for Alpha-1 Antitrypsin Deficiency.

Rationale: Chronic obstructive pulmonary disease (COPD) and alpha-1 antitrypsin deficiency (AATD) are underrecognized diseases. This is in part due to the underdiagnosis and lack of confirmation of COPD but also from poor adherence to AATD screening recommendations. Objectives: A clinical decision support system (CDSS) to guide primary care providers improves spirometry testing and confirmation of COPD diagnosis in subjects at risk and improves AATD screening in patients with confirmed COPD. Methods: A CDSS was created to be applied to all Veterans attending single-center Veterans Affairs primary care clinics. The CDSS had an algorithmic dialogue with components executed in phases during different clinic visits: screening for COPD risk using the COPD population screening (COPD-PS) questionnaire, spirometry recommendation, and ordering tool for subjects with a prior diagnosis of COPD or subjects considered high risk by the COPD-PS, dialogue to confirm or discard the diagnosis of COPD, and recommendations for AATD screening in subjects with confirmed COPD. The latter was performed by ordering alpha-1 antitrypsin (AAT) serum levels. Each step of the CDSS algorithm approach was recorded and available to be retrieved at a later date for analysis. Results: Over 6 years, a total of 6,235 Veterans >40 years of age completed the CDSS. According to the COPD-PS questionnaire, 962 (18.5%) subjects were identified as high risk for COPD. An additional 579 subjects with a prior diagnosis of COPD also entered the subsequent steps of the CDSS algorithm. Of the high-risk cohort, the CDSS led to an increase in spirometry testing from 24% to 83% and led to a new diagnosis of COPD in 342 (43%). In the prior COPD diagnosis group, spirometry testing increased from 58% to 84%, leading to COPD reconfirmation in only 326 (67%). A total of 489 (68%) subjects with confirmed COPD completed AAT testing prompted by the CDSS, with 23 subjects identified with AATD and one with severe AATD. Conclusions: In the Veterans Affairs system, the use of a clinical decision support system algorithm that incorporates screening for COPD and AATD improves COPD over- and underdiagnosis and screening rates of AATD in a primary care setting.

Persistence of airway inflammation in smokers who switch to electronic cigarettes.

As opposed to smoking cessation with nicotine-replacement therapy and/or varenicline, nicotine-containing e-cigarette use does not improve some airway inflammatory markers. https://bit.ly/3FyqIt9.

Distinct Exosomal miRNA Profiles from BALF and Lung Tissue of COPD and IPF Patients.

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are chronic, progressive lung ailments that are characterized by distinct pathologies. Early detection biomarkers and disease mechanisms for these debilitating diseases are lacking. Extracellular vesicles (EVs), including exosomes, are small, lipid-bound vesicles attributed to carry proteins, lipids, and RNA molecules to facilitate cell-to-cell communication under normal and diseased conditions. Exosomal miRNAs have been studied in relation to many diseases. However, there is little to no knowledge regarding the miRNA population of bronchoalveolar lavage fluid (BALF) or the lung-tissue-derived exosomes in COPD and IPF. Here, we determined and compared the miRNA profiles of BALF- and lung-tissue-derived exosomes of healthy non-smokers, smokers, and patients with COPD or IPF in independent cohorts. Results: Exosome characterization using NanoSight particle tracking and TEM demonstrated that the BALF-derived exosomes were ~89.85 nm in size with a yield of ~2.95 × 1010 particles/mL in concentration. Lung-derived exosomes were larger in size (~146.04 nm) with a higher yield of ~2.38 × 1011 particles/mL. NGS results identified three differentially expressed miRNAs in the BALF, while there was one in the lung-derived exosomes from COPD patients as compared to healthy non-smokers. Of these, miR-122-5p was three- or five-fold downregulated among the lung-tissue-derived exosomes of COPD patients as compared to healthy non-smokers and smokers, respectively. Interestingly, there were a large number (55) of differentially expressed miRNAs in the lung-tissue-derived exosomes of IPF patients compared to non-smoking controls. Conclusions: Overall, we identified lung-specific miRNAs associated with chronic lung diseases that can serve as potential biomarkers or therapeutic targets.

Management of lung disease in alpha-1 antitrypsin deficiency: what we do and what we do not know.

Management of lung disease in patients with alpha-1 antitrypsin deficiency (AATD) includes both non-pharmacological and pharmacological approaches. Lifestyle changes with avoidance of environmental pollutants, including tobacco smoke, improving exercise levels and nutritional status, all encompassed under a disease management program, are crucial pillars of AATD management. Non-pharmacological therapies follow conventional treatment guidelines for chronic obstructive pulmonary disease. Specific pharmacological treatment consists of administering exogenous alpha-1 antitrypsin (AAT) protein intravenously (augmentation therapy). This intervention raises AAT levels in serum and lung epithelial lining fluid, increases anti-elastase capacity, and decreases several inflammatory mediators in the lung. Radiologically, augmentation therapy reduces lung density loss over time, thus delaying disease progression. The effect of augmentation therapy on other lung-related outcomes, such as exacerbation frequency/length, quality of life, lung function decline, and mortality, are less clear and questions regarding dose optimization or route of administration are still debatable. This review discusses the rationale and available evidence for these interventions in AATD.

A 28-day clinical trial of aerosolized hyaluronan in alpha-1 antiprotease deficiency COPD using desmosine as a surrogate marker for drug efficacy.

INTRODUCTION: A previous 2-week clinical trial of aerosolized hyaluronan (HA) in COPD showed a rapid reduction in lung elastic fiber breakdown, as measured by sputum levels of the unique elastin crosslinks, desmosine and isodesmosine (DID). To further assess the therapeutic efficacy of HA and the utility of DID as surrogate markers for the development of pulmonary emphysema, we have conducted a 28-day randomized, double-blind, placebo-controlled, phase 2 trial of HA involving 27 subjects with alpha-1 antiprotease deficiency COPD. METHODS: The study drug consisted of a 3 ml inhalation solution containing 0.03% HA with an average molecular weight of 150 kDa that was self-administered twice daily. DID levels were measured in urine, sputum, and plasma using tandem mass spectrometry. RESULTS: Free urine DID in the HA group showed a significant negative correlation with time between days 14 and 35 (r = -1.0, p = 0.023) and was statistically significantly decreased from baseline at day 35 (15.4 vs 14.2 ng/mg creatinine, p = 0.035). A marked decrease in sputum DID was also seen in the HA group between days 1 and 28 (0.96 vs 0.18 ng/mg protein), but the difference was not significant, possibly due to the small number of adequate specimens. Plasma DID remained unchanged following HA treatment and no significant reductions in urine, sputum, or plasma DID were seen in the placebo group. CONCLUSIONS: The results support additional clinical trials to further evaluate the therapeutic effect of HA and the use of DID as a real-time marker of drug efficacy.

State-Level Disparity in Lung Cancer Survival in the United States.

Rationale: The cancer mortality-to-incidence ratio (MIR) can serve as a population-based indicator for cancer care outcomes. In the US, evaluation of lung cancer survival by individual states has not been evaluated. Objective: To assess the association between lung cancer survival by using MIRs and state-level health disparities in the United States. Methods: We calculated 5-year lung cancer MIR averages from 2011 to 2015 using the United States Cancer Statistics (USCS) data. America's Health Rankings (AHR) is a platform using weighted measures in five different categories to calculate annual state health rankings. Five-year averages from 2011 to 2015 of the health uninsured rate and 4-year averages from 2011 to 2014 of health spending per capita were obtained from the U.S. Census Bureau and Centers for Medicare & Medicaid Services. Linear regression analyses were performed to determine the associations between cancer survival value (CSV) = (1 - MIR) × 100% and state health variables. Results: During the study period, the 5-year averages of age-adjusted incidence, mortality rates, and CSVs were 60.3 ± 2.1 per 100,000 population, 43.4 ± 2.1 per 100,000, and 27.9 ± 3.9%, respectively. Among the 50 states, Connecticut had the highest CSV (38.6 ± 1.7%) whereas Nevada had the lowest CSV (18.7 ± 6.5%). Hawaii had the highest health ranking and Mississippi had the lowest ranking in 2016. States with better health rankings, lower health uninsured rates, and higher health spending were significantly associated with higher CSVs (R 2 = 0.418, P < 0.001; R 2 = 0.352, P < 0.001; R 2 = 0.142, P = 0.007, respectively). Conclusions: There are significant differences in lung cancer survival within the United States. Lung cancer survival by using CSV was strongly associated with state health disparities, and it can be an applicable measure to evaluate the state-level health disparities in the United States.

Cigarette smoke induction of S100A9 contributes to chronic obstructive pulmonary disease.

S100 calcium-binding protein A9 (S100A9) is elevated in plasma and bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), and aging enhances S100A9 expression in several tissues. Currently, the direct impact of S100A9-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated S100A9 levels in human BALF correlated with age. Elevated lung levels of S100A9 were higher in older mice compared with in young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced S100A9 levels in age-matched mice. To examine the direct role of S100A9 on the development of COPD, S100a9-/- mice or mice administered paquinimod were exposed to chronic cigarette smoke. S100A9 depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and forced expiratory volume in 0.05 s/forced vital capacity, compared with age-matched wild-type or vehicle-administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK and c-RAF phosphorylation, matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and keratinocyte-derived chemokine (KC) release into the airways. Paquinimod administered to nonsmoked, aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor LY3214996 or the c-RAF inhibitor GW5074, resulting in less S100A9-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing Toll-like receptor 4 (TLR4), receptor for advanced glycation endproducts (RAGE), or extracellular matrix metalloproteinase inducer (EMMPRIN) prevented S100A9-induced phosphorylation of ERK and c-RAF. Our data suggest that S100A9 signaling contributes to the progression of smoke-induced and age-related COPD.

A presentation of E-Cigarette vaping associated lung injury (EVALI) caused by THC-Containing electronic smoking device.

Several cases have recently been reported concerning the development of a syndrome of acute lung injury associated with the use of electronic cigarettes, leading to respiratory failure and several deaths. We present a case of a young veteran who presented with e-cigarette vaping associated lung injury (EVALI) to a primary care clinic and who required subsequent inpatient admission and home oxygen therapy after discharge. The patient afterwards improved after a three-month course of steroids and cessation of THC-containing electronic cigarettes, consistent with previously reported cases. Furthermore, evidence on bronchoscopy and biopsy demonstrated intracellular lipid droplets in the patient's macrophages. This outpatient case of EVALI prompts primary care providers to raise suspicion of this condition, and enquire about the use of e-cigarettes, particularly THC-containing vaping products. Furthermore, in the setting of the COVID-19 pandemic, similar clinical and radiographic presentations between COVID-19 and EVALI can be seen.

Anti-inflammatory effects of α-MSH through p-CREB expression in sarcoidosis like granuloma model.

Lung inflammation due to sarcoidosis is characterized by a complex cascade of immunopathologic events, including leukocyte recruitment and granuloma formation. α-melanocyte stimulating hormone (α-MSH) is a melanocortin signaling peptide with anti-inflammatory properties. We aimed to evaluate the effects of α-MSH in a novel in vitro sarcoidosis model. An in vitro sarcoidosis-like granuloma model was developed by challenging peripheral blood mononuclear cells (PBMCs) derived from patients with confirmed treatment-naïve sarcoidosis with microparticles generated from Mycobacterium abscessus cell walls. Unchallenged PBMCsand developed granulomas were treated daily with 10 µM α-MSH or saline as control. Cytokine concentrations in supernatants of culture and in cell extracts were measured using Illumina multiplex Elisa and western blot, respectively. Gene expression was analyzed using RNA-Seq and RT-PCR. Protein secretion and gene expression of IL-7, IL-7R, IFN-γ, MC1R, NF-κB, phosphorylated NF-κB (p-NF-κB), MARCO, and p-CREB were measured with western blot and RNAseq. A significant increase in IL-7, IL-7R, and IFN-γ protein expression was found in developed granulomas comparing to microparticle unchallenged PBMCs. IL-7, IL-7R, and IFN-γ protein expression was significantly reduced in developed granulomas after exposure to α-MSH compared with saline treated granulomas. Compared with microparticle unchallenged PBMCs, total NF-κB and p-NF-κB were significantly increased in developed granulomas, while expression of p-CREB was not changed. Treatment with α-MSH promoted a significantly higher concentration of p-CREB in granulomas. The anti-inflammatory effects of α-MSH were blocked by specific p-CREB inhibition. α-MSH has anti-inflammatory properties in this in vitro granuloma model, which is an effect mediated by induction of phosphorylation of CREB.

Decreased surfactant lipids correlate with lung function in chronic obstructive pulmonary disease (COPD).

Smoke exposure is known to decrease total pulmonary surfactant and alter its composition, but the role of surfactant in chronic obstructive pulmonary disease (COPD) remains unknown. We aimed to analyze the compositional changes in the surfactant lipidome in COPD and identify specific lipids associated with pulmonary function decline. Bronchoalveolar lavage (BAL) fluid was obtained from 12 former smokers with COPD and 5 non-smoking, non-asthmatic healthy control volunteers. Lipids were extracted and analyzed by liquid chromatography and mass spectrometry. Pulmonary function data were obtained by spirometry, and correlations of lung function with lipid species were determined. Wild-type C57BL/6 mice were exposed to 6 months of second-hand smoke in a full-body chamber. Surfactant lipids were decreased by 60% in subjects with COPD. All phospholipid classes were dramatically decreased, including ether phospholipids, which have not been studied in pulmonary surfactant. Availability of phospholipid, cholesterol, and sphingomyelin in BAL strongly correlated with pulmonary function and this was attributable to specific lipid species of phosphatidylcholine with surface tension reducing properties, and of phosphatidylglycerol with antimicrobial roles, as well as to other less studied lipid species. Mice exposed to smoke for six months recapitulated surfactant lipidomic changes observed in human subjects with COPD. In summary, we show that the surfactant lipidome is substantially altered in subjects with COPD, and decreased availability of phospholipids correlated with decreased pulmonary function. Further investigation of surfactant alterations in COPD would improve our understanding of its physiopathology and reveal new potential therapeutic targets.

Metabolomic and metallomic profile differences between Veterans and Civilians with Pulmonary Sarcoidosis.

Sarcoidosis is a disorder characterized by granulomatous inflammation of unclear etiology. In this study we evaluated whether veterans with sarcoidosis exhibited different plasma metabolomic and metallomic profiles compared with civilians with sarcoidosis. A case control study was performed on veteran and civilian patients with confirmed sarcoidosis. Proton nuclear magnetic resonance spectroscopy (1H NMR), hydrophilic interaction liquid chromatography mass spectrometry (HILIC-MS) and inductively coupled plasma mass spectrometry (ICP-MS) were applied to quantify metabolites and metal elements in plasma samples. Our results revealed that the veterans with sarcoidosis significantly differed from civilians, according to metabolic and metallomics profiles. Moreover, the results showed that veterans with sarcoidosis and veterans with COPD were similar to each other in metabolomics and metallomics profiles. This study suggests the important role of environmental risk factors in the development of different molecular phenotypic responses of sarcoidosis. In addition, this study suggests that sarcoidosis in veterans may be an occupational disease.

Long Noncoding Transcriptome in Chronic Obstructive Pulmonary Disease.

Chronic airway inflammation from recurring exposures to noxious environmental stimuli results in a progressive and irreversible airflow limitation and the lung parenchymal damage that characterizes chronic obstructive pulmonary disease (COPD). The large variability observed in the onset and progression of COPD is primarily driven by complex gene-environment interactions. The transcriptomic and epigenetic memory potential of lung epithelial and innate immune cells drive responses, such as mucus hyperreactivity and airway remodeling, that are tightly regulated by various molecular mechanisms, for which several candidate susceptibility genes have been described. However, the recently described noncoding RNA species, in particular the long noncoding RNAs, may also have an important role in modulating pulmonary responses to chronic inhalation of toxic substances and the development of COPD. This review outlines the features of long noncoding RNAs that have been implicated in regulating the airway inflammatory responses to cigarette smoke exposure and their possible association with COPD pathogenesis. As COPD continues to debilitate the increasingly aging population and contribute to higher morbidity and mortality rates worldwide, the search for better biomarkers and alternative therapeutic options is pivotal.

Cigarette smoke exposure reduces leukemia inhibitory factor levels during respiratory syncytial viral infection.

Background: Viral infections are considered a major driving factor of chronic obstructive pulmonary disease (COPD) exacerbations and thus contribute to disease morbidity and mortality. Respiratory syncytial virus (RSV) is a frequently detected pathogen in the respiratory tract of COPD patients during an exacerbation. We previously demonstrated in a murine model that leukemia inhibitory factor (LIF) expression was increased in the lungs during RSV infection. Subduing LIF signaling in this model enhanced lung injury and airway hypersensitivity. In this study, we investigated lung LIF levels in COPD patient samples to determine the impact of disease status and cigarette smoke exposure on LIF expression. Materials and methods: Bronchoalveolar lavage fluid (BALF) was obtained from healthy never smokers, smokers, and COPD patients, by written informed consent. Human bronchial epithelial (HBE) cells were isolated from healthy never smokers and COPD patients, grown at the air-liquid interface and infected with RSV or stimulated with polyinosinic:polycytidylic acid (poly (i:c)). Mice were exposed to cigarette smoke daily for 6 months and were subsequently infected with RSV. LIF expression was profiled in all samples. Results: In human BALF, LIF protein was significantly reduced in both smokers and COPD patients compared to healthy never smokers. HBE cells isolated from COPD patients produced less LIF compared to never smokers during RSV infection or poly (i:c) stimulation. Animals exposed to cigarette smoke had reduced lung levels of LIF and its corresponding receptor, LIFR. Smoke-exposed animals had reduced LIF expression during RSV infection. Two possible factors for reduced LIF levels were increased LIF mRNA instability in COPD epithelia and proteolytic degradation of LIF protein by serine proteases. Conclusions: Cigarette smoke is an important modulator for LIF expression in the lungs. Loss of LIF expression in COPD could contribute to a higher degree of lung injury during virus-associated exacerbations.

Fibroblast Growth Factor 23 is Associated with a Frequent Exacerbator Phenotype in COPD: A Cross-Sectional Pilot Study.

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory airway disease punctuated by exacerbations (AECOPD). Subjects with frequent AECOPD, defined by having at least two exacerbations per year, experience accelerated loss of lung function, deterioration in quality of life and increase in mortality. Fibroblast growth factor (FGF)23, a hormone associated with systemic inflammation and altered metabolism is elevated in COPD. However, associations between FGF23 and AECOPD are unknown. In this cross-sectional study, individuals with COPD were enrolled between June 2016 and December 2016. Plasma samples were analyzed for intact FGF23 levels. Logistic regression analyses were used to measure associations between clinical variables, FGF23, and the frequent exacerbator phenotype. Our results showed that FGF23 levels were higher in frequent exacerbators as compared to patients without frequent exacerbations. FGF23 was also independently associated with frequent exacerbations (OR 1.02; 95%CI 1.004-1.04; p = 0.017), after adjusting for age, lung function, smoking, and oxygen use. In summary, FGF23 was associated with the frequent exacerbator phenotype and correlated with number of exacerbations recorded retrospectively and prospectively. Further studies are needed to explore the role of FGF 23 as a possible biomarker for AECOPD to better understand the pathobiology of COPD and to help develop therapeutic targets.

The Biological Effects of Double-Dose Alpha-1 Antitrypsin Augmentation Therapy. A Pilot Clinical Trial.

Rationale: Augmentation therapy with intravenous AAT (alpha-1 antitrypsin) is the only specific therapy for individuals with pulmonary disease from AAT deficiency (AATD). The recommended standard dose (SD; 60 mg/kg/wk) elevates AAT trough serum levels to around 50% of normal; however, outside of slowing emphysema progression, its effects in other clinical outcomes have not been rigorously proven.Objectives: To evaluate the biological effects of normalizing AAT trough levels with double-dose (DD) therapy (120 mg/kg/wk) in subjects with AATD already receiving SD therapy.Methods: Clinically stable subjects were evaluated after 4 weeks of SD therapy, followed by 4 weeks of DD therapy, and 4 weeks after return to SD therapy. At the end of each phase, BAL fluid (BALF) and plasma samples were obtained.Measurements and Main Results: DD therapy increased trough AAT levels to normal and, compared with SD therapy, reduced serine protease activity in BALF (elastase and cathepsin G), plasma elastase footprint (Aα-Val360), and markers of elastin degradation (desmosine/isodesmosine) in BALF. DD therapy also further downregulated BALF ILs and cytokines including Jak-STAT (Janus kinases-signal transducer and activator of transcription proteins), TNFα (tumor necrosis factor-α), and T-cell receptor signaling pathways, cytokines involved in macrophage migration, eosinophil recruitment, humoral and adaptive immunity, neutrophil activation, and cachexia. On restarting SD after DD treatment, a possible carryover effect was seen for several biological markers.Conclusions: Subjects with AATD on SD augmentation therapy still exhibit inflammation, protease activity, and elastin degradation that can be further improved by normalizing AAT levels. Higher AAT dosing than currently recommended may lead to enhanced clinical benefits and should be explored further.Clinical trial registered with www.clinicaltrials.gov (NCT01669421).

ROLE OF GENETIC SUSCEPTIBILITY IN NICOTINE ADDICTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in developed countries. Although cigarette smoking is the major risk factor, only 10-20% of smokers develop COPD. The extent of cigarette smoking (pack-years and smoking duration) accounts for only 15% of the variation in lung function, indicating that differences in susceptibility to COPD must exist. We provide an overview of the complexity of nicotine addiction and COPD, with special attention to the involvement of genetic factors. The following aspects are discussed in the present article: (1) epidemiology in Mexico and (2) a review of the published literature on genetic association studies using the National Center for Biotechnology Information database of the United States as a search tool. COPD is unique among complex genetic diseases where an environmental risk factor is known and the level of exposure can be documented with some precision. The high morbidity and mortality associated with COPD and its chronic and progressive nature has prompted the use of molecular genetic studies to identify susceptibility factors for the disease. Biomedical research has a remarkable set of tools to aid in the discovery of genes and polymorphisms. We present a review of the most relevant genetic associations in nicotine addiction and COPD.

Higher serum levels of systemic inflammatory markers are linked to greater inspiratory muscle dysfunction in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with an inflammatory response that becomes more pronounced in acute exacerbations. Considerable attention has recently focused on the value of several inflammatory mediators in predicting worsening of COPD-related symptoms. Whereas respiratory muscle dysfunction is also widely present in this population, little is known about how systemic inflammation relates to inspiratory muscle dysfunction in COPD. METHODS: Fifty-three males with mild-to-very severe airflow obstruction underwent blood sampling for 23 inflammatory markers, including acute-phase proteins, cytokines and adipokines. Inspiratory muscle performance was assessed via the test of incremental respiratory endurance, providing measures of maximal (MIP) and sustained maximal (SMIP) inspiratory pressures. RESULTS: The mean ± SD MIP and SMIP were 75.32 ± 19.62 cmH2 O and 406.15 ± 124.55 PTU. MIP negatively correlated with CRP, SAA and cystatin C (r-values from -0.333 to -0.378, P < 0.02), while SMIP was inversely related to SAA and cystatin C (r = -0.534 and r = -0.396, P = 0.00). Significant differences in CRP, SAA, cystatin C and PARC were also found between subjects with and without inspiratory muscle weakness. No additional significant relationships were observed between either MIP or SMIP and other inflammatory markers in the study. CONCLUSIONS: MIP and SMIP are markedly reduced with greater degrees of inflammation in COPD as expressed by higher levels of CRP, SAA and cystatin C. Future research is needed to further examine the above findings and determine the impact of systemic inflammation along with its underlying mechanisms on inspiratory muscle function in COPD.