Emphysema Phenotype Research Articles

A role of budesonide/formoterol fixed combination in the treatment of stable chronic obstructive pulmonary disease. A conclusion of the Expert Council of the Volga Federal district of Russia

Late diagnosis of chronic obstructive pulmonary disease (COPD) at advanced stage, high risk of exacerbations, low compliance of patients, and adverse effects of treatment have been still unresolved problems in the treatment of COPD despite the development of new drugs. The personalized medicine rneeds distinct indications and predictors of efficacy and safety of treatment. Budesonide/formoterol fixed combination is recommended for patients with asthma – COPD overlap syndrome and bronchitis phenotype, blood eosinophilia > 300 cells/mm3, if other causes were excluded, post-bronchodilator forced expiratory volume in 1 second (FEV1) < 50% pred.; and ≥ 2 exacerbations or ≥ 1 hospitalization related to exacerbation during the previous year. Budesonide/formoterol fixed combination is not recommended for regular use in patients with emphysema phenotype of COPD and rare exacerbations (< 2 exacerbations and without hospitalizations in the previous year).

Frequency of Epidermal Growth Factor Receptor Mutation in Smokers with Lung Cancer Without Pulmonary Emphysema.

Chronic obstructive pulmonary disease is a smoking-related disease, and is categorized into the emphysema and airway dominant phenotypes. We examined the relationship between emphysematous changes and epidermal growth factor receptor (EGFR) mutation status in patients with lung adenocarcinoma. The medical records for 250 patients with lung adenocarcinoma were retrospectively reviewed. All patients were categorized into the emphysema or non-emphysema group. Wild-type EGFR was detected in 136 (54%) and mutant EGFR in 48 (19%). Emphysematous changes were observed in 87 (36%) patients. EGFR mutation was highly frequent in the non-emphysema group (p=0.0014). Multivariate logistic regression analysis showed that emphysema was an independent risk factor for reduced frequency of EGFR mutation (Odds Ratio=3.47, p=0.005). Our data showed a relationship between emphysematous changes and EGFR mutation status. There might be mutually exclusive genetic risk factors for carcinogenesis and development of emphysematous changes.

Effects of human umbilical cord blood mononuclear cells on respiratory system mechanics in a murine model of neonatal lung injury

ABSTRACTBackground: Mononuclear cells (MNCs) have well-documented beneficial effects in a wide range of adult pulmonary diseases. The effects of human umbilical cord blood-derived MNCs on neonatal lung injury, highly relevant for potential autologous application in preterm newborns at risk for bronchopulmonary dysplasia (BPD), remain incompletely established. The aim of this study was to determine the long-term morphologic and functional effects of systemically delivered MNCs in a murine model of neonatal lung injury. Materials and Methods: MNCs from cryopreserved cord blood (1 × 106 cells per pup) were given intravenously to newborn mice exposed to 90% O2 from birth; controls received cord blood total nucleated cells (TNCs) or granular cells, or equal volume vehicle buffer (sham controls). In order to avoid immune rejection, we used SCID mice as recipients. Lung mechanics (flexiVent™), engraftment, growth, and alveolarization were evaluated eight weeks postinfusion. Results: Systemic MNC administration to hyperoxia-exposed newborn mice resulted in significant attenuation of methacholine-induced airway hyperreactivity, leading to reduction of central airway resistance to normoxic levels. These bronchial effects were associated with mild improvement of alveolarization, lung compliance, and elastance. TNCs had no effects on alveolar remodeling and were associated with worsened methacholine-induced bronchial hyperreactivity. Granular cell administration resulted in a marked morphologic and functional emphysematous phenotype, associated with high mortality. Pulmonary donor cell engraftment was sporadic in all groups. Conclusions: These results suggest that cord blood MNCs may have a cell type-specific role in therapy of pulmonary conditions characterized by increased airway resistance, such as BPD and asthma. Future studies need to determine the active MNC subtype(s), their mechanisms of action, and optimal purification methods to minimize granular cell contamination.

Cytological and oxidant characteristics of local cellular immunity in acute severe exacerbation of chronic obstructive pulmonary disease

The purpose of this study was to investigate cytologic and chemiluminescence (ChL) parameters of phagocytes in induced sputum and bronchoalveolar lavage fluid (BALF) of patients with severe acute exacerbation of COPD (AECOPD). Methods: Eighty-eight patients aged 45 to 75 years (56 males and 32 females) with severe AECOPD were included in the study. The control group included 16 healthy individuals. Cytological examination of induced sputum was done. The luminol-dependent ChL of BALF phagocytes obtained during bronchoscopy was investigated. Results : Leukocyte cell count and neutrophil/eosinophil ratio were increased and macrophages/lymphocyte ratio was decreased in induced sputum (p < 0.05). Exacerbations of infectious etiology were characterized by higher eosinophil count. Leukocyte cell count has been still significantly increased after resolution of the exacerbation. Eosinophil/macrophage ratio was significantly higher in bronchitis phenotype and neutrophil/lymphocyte ratio was higher in emphysema phenotype (p < 0.05). Phagocyte ChL in patients with AECOPD of infectious etiology was significantly higher compared to that in patients with AECOPD of other etiologies, both in exacerbation (spontaneous ChL, 10,049 ± 1,828 vs 8,886 ± 2,672; induced ChL, 19,912 ± 4,037 vs 10,751 ± 1,354, respectively) and in stable state (spontaneous ChL, 3,878 ± 1,147 vs 2,335 ± 1,277; induced ChL, 4,804 ± 1,284 vs 4,253 ± 1,174, respectively). This could be due to a relatively high eosinophil count in AECOPD of non-infectious etiology and in the bronchitis phenotype of COPD; eosinophils could contribute to phagocytosis and oxidative mechanisms. Conclusion . Cytological and oxidant characteristics of the airway inflammation and phagocyte-related features of the local immunity are thought to be different in AECOPD of infectious compared to non-infectious etiology and in exacerbation compared to the stable state. The luminol-dependent ChL could reliably assess phagocyte functional activity in the airway material. This method could be proposed to distinguish between infectious vs non-infectious etiologies of AECOPD in patients with bronchitis phenotype or emphysema phenotype and to evaluate the efficacy of anti-inflammatory treatment.

A study of chronic obstructive pulmonary disease-specific causes of osteoporosis with emphasis on the emphysema phenotype.

BACKGROUND:Osteoporosis, the most common extra-pulmonary complication of chronic obstructive pulmonary disease (COPD), may be related to general causes or COPD-specific causes such as low forced expiratory volume in 1 s (FEV1) and hypoxia. A few studies reported that emphysema is an independent risk factor for osteoporosis. However, other workers considered the association to be confounded by low FEV1 and low body mass index (BMI) which cluster with emphysema.AIMS:To study the association between osteoporosis and emphysema in a model that includes these potentially confounding factors.METHODS:We studied prospectively 52 COPD patients with both high resolution computed tomography and carbon monoxide diffusion coefficient as diagnostic markers of emphysema. Dual-energy X-ray absorptiometry was used to measure the bone mass density (BMD) of lumbar vertebrae and neck of the femur. Vertebral fractures were evaluated using the Genant semiquantitative score. Multiple linear regression analysis was used to identify the following independent variables: age, BMI, FEV1% predicted, PaO2, emphysema score, C-reactive protein (CRP), and dyspnea score as related to BMD. P ≤ 0.05 was considered statistically significant.RESULTS:There was no significant difference in the serum Vitamin D levels, vertebral fracture score, or BMD between the emphysematous and nonemphysematous patients. Multivariate analysis showed that (in a model including age, BMI, FEV1, PaO2, emphysema score, CRP, and dyspnea score) only reduced BMI, FEV1, and PaO2 were independent risk factors for low BMD.CONCLUSIONS:The emphysematous phenotype is not a risk factor for osteoporosis independently of BMI, FEV1, and PaO2.

Visual Assessment of Chest Computed Tomographic Images Is Independently Useful for Genetic Association Analysis in Studies of Chronic Obstructive Pulmonary Disease.

Automated analysis of computed tomographic (CT) lung images for epidemiologic and genetic association studies is increasingly common, but little is known about the utility of visual versus semiautomated emphysema and airway assessments for genetic association studies. Assess the relative utility of visual versus semiautomated emphysema and airway assessments for genetic association studies. A standardized inspection protocol was used to visually assess chest CT images for 1,540 non-Hispanic white subjects within the COPDGene Study for the presence and severity of radiographic features representing airway wall thickness and emphysema. A genome-wide association study (GWAS) was performed, and two sets of candidate single-nucleotide polymorphisms with a higher prior likelihood of association were specified a priori for separate analysis. For each visual CT examination feature, a corresponding semiautomated CT feature(s) was identified for comparison in the same subjects. GWAS for visual features of chest CT scans identified a genome-wide significant association with visual emphysema at the 15q25 locus (P = 6.3e-9). In the a priori-specified set of 19 previously identified GWAS loci, 7 and 8 loci were associated with airway measures or emphysema measures, respectively. In the a priori-specified candidate gene set, 13 of 196 candidate genes harbored a nearby single-nucleotide polymorphism significantly associated with an emphysema phenotype. Visual CT examination associations were robust to adjustment for semiautomated correlates in many cases. Standardized visual assessments of emphysema and airway disease are significantly associated with genetic loci previously associated with chronic obstructive pulmonary disease susceptibility or semiautomated CT examination phenotypes in GWAS. Visual CT measures of emphysema and airways disease offer independent information for genetic association studies in relation to standard semiautomated measures.

Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnoea

The overlap syndrome (OS) of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea (OSA) is common but often missed in clinical practice. Different clinical COPD phenotypes influence the likelihood of co-existing OSA with the predominant emphysema phenotype being protective whereas the predominant chronic bronchitis phenotype promotes the development of OSA. The management of OS differs from COPD alone, particularly the use of nocturnal positive airway pressure (PAP), and patients with OS not treated with PAP have a worse prognosis, which underlines the importance of correct diagnosis.

A Bayesian Nonparametric Model for Disease Subtyping: Application to Emphysema Phenotypes.

We introduce a novel Bayesian nonparametric model that uses the concept of disease trajectories for disease subtype identification. Although our model is general, we demonstrate that by treating fractions of tissue patterns derived from medical images as compositional data, our model can be applied to study distinct progression trends between population subgroups. Specifically, we apply our algorithm to quantitative emphysema measurements obtained from chest CT scans in the COPDGene Study and show several distinct progression patterns. As emphysema is one of the major components of chronic obstructive pulmonary disease (COPD), the third leading cause of death in the United States [1], an improved definition of emphysema and COPD subtypes is of great interest. We investigate several models with our algorithm, and show that one with age , pack years (a measure of cigarette exposure), and smoking status as predictors gives the best compromise between estimated predictive performance and model complexity. This model identified nine subtypes which showed significant associations to seven single nucleotide polymorphisms (SNPs) known to associate with COPD. Additionally, this model gives better predictive accuracy than multiple, multivariate ordinary least squares regression as demonstrated in a five-fold cross validation analysis. We view our subtyping algorithm as a contribution that can be applied to bridge the gap between CT-level assessment of tissue composition to population-level analysis of compositional trends that vary between disease subtypes.

Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases.

Protease-antiprotease imbalance and oxidative stress are considered to be major pathophysiological hallmarks of severe obstructive lung diseases including chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), but limited information is available on their direct roles in the regulation of pulmonary phenotypes. Here, we utilized βENaC-transgenic (Tg) mice, the previously established mouse model of severe obstructive lung diseases, to produce lower-mortality but pathophysiologically highly useful mouse model by backcrossing the original line with C57/BL6J mice. C57/BL6J-βENaC-Tg mice showed higher survival rates and key pulmonary abnormalities of COPD/CF, including mucous hypersecretion, inflammatory and emphysematous phenotypes and pulmonary dysfunction. DNA microarray analysis confirmed that protease- and oxidative stress-dependent pathways are activated in the lung tissue of C57/BL6J-βENaC-Tg mice. Treatments of C57/BL6J-βENaC-Tg mice with a serine protease inhibitor ONO-3403, a derivative of camostat methylate (CM), but not CM, and with an anti-oxidant N-acetylcystein significantly improved pulmonary emphysema and dysfunction. Moreover, depletion of a murine endogenous antioxidant vitamin C (VC), by genetic disruption of VC-synthesizing enzyme SMP30 in C57/BL6J-βENaC-Tg mice, exaggerated pulmonary phenotypes. Thus, these assessments clarified that protease-antiprotease imbalance and oxidative stress are critical pathways that exacerbate the pulmonary phenotypes of C57/BL6J-βENaC-Tg mice, consistent with the characteristics of human COPD/CF.

Segmental bronchi collapsibility: computed tomography-based quantification in patients with chronic obstructive pulmonary disease and correlation with emphysema phenotype, corresponding lung volume changes and clinical parameters.

Global pulmonary function tests lack region specific differentiation that might influence therapy in severe chronic obstructive pulmonary disease (COPD) patients. Therefore, the aim of this work was to assess the degree of expiratory 3rd generation bronchial lumen collapsibility in patients with severe COPD using chest-computed tomography (CT), to evaluate emphysema-phenotype, lobar volumes and correlate results with pulmonary function tests. Thin-slice chest-CTs acquired at end-inspiration & end-expiration in 42 COPD GOLD IV patients (19 females, median-age: 65.9 y) from November 2011 to July 2014 were re-evaluated. The cross-sectional area of all segmental bronchi was measured 5 mm below the bronchial origin in both examinations. Lung lobes were semi-automatically segmented, volumes calculated at end-inspiratory and end-expiratory phase and visually defined emphysema-phenotypes defined. Results of CT densitometry were compared with lung functional tests including forced expiratory volume at 1 s (FEV1), total lung capacity (TLC), vital capacity (VC), residual volume (RV), diffusion capacity parameters and the maximal expiratory flow rates (MEFs). Mean expiratory bronchial collapse was 31%, stronger in lobes with homogenous (38.5%) vs. heterogeneous emphysema-phenotype (27.8%, P=0.014). The mean lobar expiratory volume reduction was comparable in both emphysema-phenotypes (volume reduction 18.6%±8.3% in homogenous vs. 17.6%±16.5% in heterogeneous phenotype). The degree of bronchial lumen collapsibility, did not correlate with expiratory volume reduction. MEF25 correlated weakly with 3rd generation airway collapsibility (r=0.339, P=0.03). All patients showed a concentric expiratory reduction of bronchial cross-sectional area. Changes in collapsibility of 3rd generation bronchi in COPD grade IV patients is significantly lower than that in the trachea and the main bronchi. Collapsibility did not correlate with the reduction in lung volume but was significantly higher in lobes with homogeneous vs. heterogeneous emphysema phenotype. Changes in the 3rd generation bronchial calibres between inspiration and expiration are not predictive for the degree of small airway collapsibility and related airflow limitation.

Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care.

In the past five decades, alpha-1 antitrypsin deficiency has been the only known genetic cause of emphysema, yet it explains the genetics in only 1-2% of severe cases. Recently, mutations in telomerase genes were found to induce susceptibility to young-onset, severe, and familial emphysema at a frequency comparable to that of alpha-1 antitrypsin deficiency. Telomerase mutation carriers with emphysema report a family history of idiopathic pulmonary fibrosis, and both lung phenotypes show autosomal dominant inheritance within families. The data so far point to a strong gene-environment interaction that determines the lung disease type. In never-smokers, pulmonary fibrosis predominates, while smokers, especially females, are at risk for developing emphysema alone or in combination with pulmonary fibrosis. The telomere-mediated emphysema phenotype appears to have clinically recognizable features that are distinct from alpha-1 antitrypsin deficiency, and patients are prone to developing short telomere syndrome comorbidities that influence clinical outcomes. In animal models, telomere dysfunction causes alveolar epithelial stem cell senescence, which is sufficient to drive lung remodeling and recruit inflammation. Here, we review the implications of these discoveries for understanding emphysema biology as well as for patient care.

Distribution and Outcomes of a Phenotype-Based Approach to Guide COPD Management: Results from the CHAIN Cohort.

RationaleThe Spanish guideline for COPD (GesEPOC) recommends COPD treatment according to four clinical phenotypes: non-exacerbator phenotype with either chronic bronchitis or emphysema (NE), asthma-COPD overlap syndrome (ACOS), frequent exacerbator phenotype with emphysema (FEE) or frequent exacerbator phenotype with chronic bronchitis (FECB). However, little is known on the distribution and outcomes of the four suggested phenotypes.ObjectiveWe aimed to determine the distribution of these COPD phenotypes, and their relation with one-year clinical outcomes.MethodsWe followed a cohort of well-characterized patients with COPD up to one-year. Baseline characteristics, health status (CAT), BODE index, rate of exacerbations and mortality up to one year of follow-up were compared between the four phenotypes.ResultsOverall, 831 stable COPD patients were evaluated. They were distributed as NE, 550 (66.2%); ACOS, 125 (15.0%); FEE, 38 (4.6%); and FECB, 99 (11.9%); additionally 19 (2.3%) COPD patients with frequent exacerbations did not fulfill the criteria for neither FEE nor FECB. At baseline, there were significant differences in symptoms, FEV1 and BODE index (all p<0.05). The FECB phenotype had the highest CAT score (17.1±8.2, p<0.05 compared to the other phenotypes). Frequent exacerbator groups (FEE and FECB) were receiving more pharmacological treatment at baseline, and also experienced more exacerbations the year after (all p<0.05) with no differences in one-year mortality. Most of NE (93%) and half of exacerbators were stable after one year.ConclusionsThere is an uneven distribution of COPD phenotypes in stable COPD patients, with significant differences in demographics, patient-centered outcomes and health care resources use.

Can computed tomography and carbon monoxide transfer coefficient diagnose an asthma‐like phenotype in COPD?

Post-mortem and computed tomography (CT) studies indicated that emphysema is a feature of COPD even in the 'blue bloater/chronic bronchitis' type. We aim to test the hypothesis that the non-emphysematous patients are distinct from the main body of COPD and are more akin to asthmatic patients. We studied 54 patients with COPD. Emphysema was measured by Goddard's visual scoring of CT scan and the carbon monoxide transfer coefficient (KCO). Bronchial biopsy was offered for thickness of basement membrane (BM) (≥7 µm) as a marker of remodelling in irreversible asthma. Spirometry was repeated after therapy with Budesonide/Formoterol for 1 year. The non-emphysematous phenotype were 24 of 54 patients (44%) by CT scan and 23 of 54 patients (43%) by KCO, showing agreement in 53 out of 54 patients. The non-emphysematous patients were younger, had higher forced expiratory volume in 1 s (FEV1 ) (median 61% vs 49.7%), greater prevalence of hypertrophy of nasal turbinates and higher serum IgE. The emphysematous phenotype had lower BMI and greater dyspnoea score. The BM was thickened in 11 of 14 and 0 of 10 patients in the non-emphysematous and emphysematous groups, respectively. Three patients without emphysema and a normal BM normalized their FEV1 upon receiving inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA). All the non-emphysematous improved their FEV1 after ICS/LABA (median = 215 mL). The median decline in the emphysematous was -65 mL. The non-emphysematous phenotype of COPD displays important features of asthma: clinical picture, histology and response to ICS. CT and KCO can predict spirometric response to ICS/LABA.

Oxygen therapy in COPD patients with isolated nocturnal hypoxemia; comparison of quality of life and sleep between bronchitis and emphysema phenotype: A prospective observational study

BackgroundCOPD is a heterogeneous disease composed by two main phenotypes: bronchitis (COPDb) and emphysema (COPDe) with different clinical presentation, physiology, imaging, response to therapy and decline in lung function.The aim of this study is to evaluate whether nocturnal hypoxemic COPDb and COPDe have a different behaviour during sleep and the effect of nocturnal oxygen supplementation (nO2LT). Materials and methods75 COPDb and 120 COPDe were enrolled. All patients performed polysomnography, Pittsburgh and Maugeri Foundation Respiratory Failure questionnaire, and pulmonary function before and after six months of nO2LT. ResultsAt baseline, compared to COPDb, COPDe have decreased sleep efficiency (SE) (67.5±6% vs. 76.9±3% p<0.05) and higher arousals (A/I) (18.1±3 event/h vs. 8.7±1 event/h p<0.05). Oxygen desaturation index (ODI) was increased during REM (7.1±1 event/h vs. 2.3±0.5 event/h p<0.05).nO2LT in COPDe improves SE (77±4% vs. 67.5±6% p<0.05) and decreases A/I (9±5 event/h vs. 18.1±3 event/h p<0.05). ODI during REM (3.5±2 event/h vs. 7.1±1 p<0.05) decreases and quality of life (QoL) improves (MFR-28 total 56±22 vs 45±20 p<0.05), due to an improvement in cognitive abilities (45±30 vs 33±31 p<0.05) and daily activities (61±29 vs 53±21 p>0.05). In COPDb nO2LT reduces ST90 (15±6% vs. 43±8% p<0.05) less than in COPDe (15±6% vs. 8±4% p<0.05); improves A/I (10±2 event/h vs. 8.7±1 p<0.05) and there is no evidence of an improvement in QoL. ConclusionsSix months of nO2LT improve quality of life in COPDe, not in COPDb. We found a difference in sleep quality between COPDe and COPDb.

B cells in chronic obstructive pulmonary disease: moving to center stage.

Chronic inflammatory responses in the lungs contribute to the development and progression of chronic obstructive pulmonary disease (COPD). Although research studies focused initially on the contributions of the innate immune system to the pathogenesis of COPD, more recent studies have implicated adaptive immune responses in COPD. In particular, studies have demonstrated increases in B cell counts and increases in the number and size of B cell-rich lymphoid follicles in COPD lungs that correlate directly with COPD severity. There are also increases in lung levels of mediators that promote B cell maturation, activation, and survival in COPD patients. B cell products such as autoantibodies directed against lung cells, components of cells, and extracellular matrix proteins are also present in COPD lungs. These autoantibodies may contribute to lung inflammation and injury in COPD patients, in part, by forming immune complexes that activate complement components. Studies of B cell-deficient mice and human COPD patients have linked B cells most strongly to the emphysema phenotype. However, B cells have protective activities during acute exacerbations of COPD by promoting adaptive immune responses that contribute to host defense against pathogens. This review outlines the evidence that links B cells and B cell-rich lymphoid follicles to the pathogenesis of COPD and the mechanisms involved. It also reviews the potential and limitations of B cells as therapeutic targets to slow the progression of human COPD.

Office-based DLCO tests help pulmonologists to make important clinical decisions.

Measurement of diffusing capacity of the lungs for carbon monoxide (DLCO), also known as transfer factor, is the second most important pulmonary function test (PFT), after spirometry. Previously available only in hospital-based PFT labs, DLCO testing is now available at outpatient clinics using a portable device. Compared to spirometry tests, assessments with these devices require very little effort. The patient breathes quietly, inhales the test gas, holds the breath for ten seconds, and then exhales. In adult smokers with post-bronchodilator airway obstruction, a low DLCO greatly increases the probability of the emphysema phenotype of COPD due to cigarette smoking, while a normal DLCO makes chronic asthma more likely. In patients with spirometric restriction (a low FVC with a normal FEV1/FVC), a low DLCO increases the pre-test probability of an interstitial lung disease (ILD), while a normal DLCO makes a chest wall type of restriction more likely. A normal TLC (VA from the single-breath helium dilution provided by a DLCO test) rules out restriction of lung volumes without the need for a body box measurement. In patients with dyspnea of unknown cause, the pattern of a low DLCO with normal spirometry increases the likelihood of pulmonary vascular disease, but this pattern also occurs with several other diseases such as a mild ILD. Once a diagnosis is made, the percent predicted DLCO provides an objective index of disease severity and prognosis. A DLCO below 40% predicted, or a decline in DLCO of more than 4 units, is associated with increased morbidity and mortality.

167. Genome Editing to Generate the First Mouse Model of Alpha-One Antitrypsin Deficiency, the Leading Cause of Genetic COPD

Alpha-one antitrypsin (AAT) deficiency is a common autosomal co-dominant genetic disorder. This condition affects 1:2500 individuals of European ancestry, leading to the development of lung and liver disease. Within North American and Northern European populations, an estimated 4% of individuals are carriers of mutant alleles. AAT deficiency presents with an emphysema phenotype in the lungs of older subjects. AAT deficient subjects can also suffer from liver disease of varying severity; however, lung disease is the principle cause of death. AAT is a protease inhibitor predominantly synthesized in the liver that belongs to the serine protease inhibitor (serpin) family. Upon secretion into the blood stream, AAT enters the lungs where it inactivates excess neutrophil elastase, thereby preventing damage to the alveoli. Mutations of the Serpina1 gene can lead to reduced serum levels of AAT and decreased protein functionality, allowing for unrestricted elastin breakdown, pulmonary inflammation and eventual emphysema. Currently, an animal model simulating the lung condition does not exist, which severely limits the development of therapeutics. This is due to the higher genomic complexity of mice compared to humans. Indeed due to amplification events, C57BL/6 mice have five genes that are homologous to human SERPINA1. To address this we generated a quintuple gene knockout using CRISPR/Cas9 system via zygote microinjection. We generated three founding lines in which all 5 copies of the gene were disrupted. Mice from all three lines demonstrate absence of hepatic and circulatory AAT protein as well as a reduced capability to inactivate neutrophil elastase. We also characterized the lung phenotype in response to a lipopolysaccharide challenge, where the model recapitulated many characteristics of the human lung disease including decreased elastance and increased compliance, and lung morphometry was also affected. Genomic and transcriptomic characterization will be presented. Future work will include challenges with cigarette smoke, a well-known disease accelerator in patients. Further, the ongoing generation of a new transgenic model carrying both the quintuple disruption of the murine Serpina1 genes and a single copy of the Z variant of human SERPINA1 will bring to the field the ultimate disease model that will finally allow researchers to evaluate the effects of liver-directed gene augmentation in the presence of Z-AAT polymers.

Macrophage Migration Inhibitory Factor: A Novel Inhibitor of Apoptosis Signal-Regulating Kinase 1–p38–Xanthine Oxidoreductase–Dependent Cigarette Smoke–Induced Apoptosis

Cigarette smoke (CS) exposure is the leading cause of emphysema. CS mediates pathologic emphysematous remodeling of the lung via apoptosis of lung parenchymal cells resulting in enlargement of the airspaces, loss of the capillary bed, and diminished surface area for gas exchange. Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, is reduced both in a preclinical model of CS-induced emphysema and in patients with chronic obstructive pulmonary disease, particularly those with the most severe disease and emphysematous phenotype. MIF functions to antagonize CS-induced DNA damage, p53-dependent apoptosis of pulmonary endothelial cells (EndoCs) and resultant emphysematous tissue remodeling. Using primary alveolar EndoCs and a mouse model of CS-induced lung damage, we investigated the capacity and molecular mechanism(s) by which MIF modifies oxidant injury. Here, we demonstrate that both the activity of xanthine oxidoreductase (XOR), a superoxide-generating enzyme obligatory for CS-induced DNA damage and EndoC apoptosis, and superoxide concentrations are increased after CS exposure in the absence of MIF. Both XOR hyperactivation and apoptosis in the absence of MIF occurred via a p38 mitogen-activated protein kinase-dependent mechanism. Furthermore, a mitogen-activated protein kinase kinase kinase family member, apoptosis signal-regulating kinase 1 (ASK1), was necessary for CS-induced p38 activation and EndoC apoptosis. MIF was sufficient to directly suppress ASK1 enzymatic activity. Taken together, MIF suppresses CS-mediated cytotoxicity in the lung, in part by antagonizing ASK1-p38-XOR-dependent apoptosis.

Pulmonary Physiology of Chronic Obstructive Pulmonary Disease, Cystic Fibrosis, and Alpha-1 Antitrypsin Deficiency.

Cystic fibrosis is predominantly an airway disease with marked bronchiectatic changes associated with inflammation, chronic colonization, and progressive airflow obstruction. The condition can be identified in childhood and monitored with detectable airway changes early in life while conventional spirometry remains in the normal range. Alpha-1 antitrypsin deficiency can also be detected early in life through blood spot and genetic testing and leads (in some) to the development of airflow obstruction and a predominant emphysema phenotype with bronchiectatic changes in about 30%. Early detection also allows the natural history of the pulmonary physiological changes to be determined. Chronic obstructive pulmonary disease is usually detected late in the disease process when significant damage has occurred. The condition consists of varying combinations of airway disease, bronchiectasis, colonization, and emphysema. Lessons learned from the physiological evolution of airway disease in cystic fibrosis and the emphysema of alpha-1 antitrypsin deficiency provide strategies to enable early detection of chronic obstructive pulmonary disease in general and its phenotypes.

COPD phenotypes on computed tomography and its correlation with selected lung function variables in severe patients.

BackgroundComputed tomography (CT) phenotypic characterization helps in understanding the clinical diversity of chronic obstructive pulmonary disease (COPD) patients, but its clinical relevance and its relationship with functional features are not clarified. Volumetric capnography (VC) uses the principle of gas washout and analyzes the pattern of CO2 elimination as a function of expired volume. The main variables analyzed were end-tidal concentration of carbon dioxide (ETCO2), Slope of phase 2 (Slp2), and Slope of phase 3 (Slp3) of capnogram, the curve which represents the total amount of CO2 eliminated by the lungs during each breath.ObjectiveTo investigate, in a group of patients with severe COPD, if the phenotypic analysis by CT could identify different subsets of patients, and if there was an association of CT findings and functional variables.Subjects and methodsSixty-five patients with COPD Gold III–IV were admitted for clinical evaluation, high-resolution CT, and functional evaluation (spirometry, 6-minute walk test [6MWT], and VC). The presence and profusion of tomography findings were evaluated, and later, the patients were identified as having emphysema (EMP) or airway disease (AWD) phenotype. EMP and AWD groups were compared; tomography findings scores were evaluated versus spirometric, 6MWT, and VC variables.ResultsBronchiectasis was found in 33.8% and peribronchial thickening in 69.2% of the 65 patients. Structural findings of airways had no significant correlation with spirometric variables. Air trapping and EMP were strongly correlated with VC variables, but in opposite directions. There was some overlap between the EMP and AWD groups, but EMP patients had signicantly lower body mass index, worse obstruction, and shorter walked distance on 6MWT. Concerning VC, EMP patients had signicantly lower ETCO2, Slp2 and Slp3. Increases in Slp3 characterize heterogeneous involvement of the distal air spaces, as in AWD.ConclusionVisual assessment and phenotyping of CT in COPD patients is feasible and may help identify functional and clinically different subsets of patients. VC may provide useful information about the heterogeneous involvement of lung structures in COPD.