Caveolin-1-derived peptide attenuates cigarette smoke-induced airway and alveolar epithelial injury.

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease with no effective treatment that can reduce mortality or slow the disease progression. COPD is the third leading cause of global death and is characterized by airflow limitations due to chronic bronchitis and alveolar damage/emphysema. Chronic cigarette smoke (CS) exposure damages airway and alveolar epithelium and remains a major risk factor for the pathogenesis of COPD. We found that the expression of caveolin-1, a tumor suppressor protein; p53; and plasminogen activator inhibitor-1 (PAI-1), one of the downstream targets of p53, was markedly increased in airway epithelial cells (AECs) as well as in type II alveolar epithelial (AT2) cells from the lungs of patients with COPD or wild-type mice with CS-induced lung injury (CS-LI). Moreover, p53- and PAI-1-deficient mice resisted CS-LI. Furthermore, treatment of AECs, AT2 cells, or lung tissue slices from patients with COPD or mice with CS-LI with a seven amino acid caveolin-1 scaffolding domain peptide (CSP7) reduced mucus hypersecretion in AECs and improved AT2 cell viability. Notably, induction of PAI-1 expression via increased caveolin-1 and p53 contributed to mucous cell metaplasia and mucus hypersecretion in AECs, and reduced AT2 viability, due to increased senescence and apoptosis, which was abrogated by CSP7. In addition, treatment of wild-type mice having CS-LI with CSP7 by intraperitoneal injection or nebulization via airways attenuated mucus hypersecretion, alveolar injury, and significantly improved lung function. This study validates the potential therapeutic role of CSP7 for treating CS-LI and COPD. NEW & NOTEWORTHY Chronic cigarette smoke (CS) exposure remains a major risk factor for the pathogenesis of COPD, a debilitating disease with no effective treatment. Increased caveolin-1 mediated induction of p53 and downstream plasminogen activator inhibitor-1 (PAI-1) expression contributes to CS-induced airway mucus hypersecretion and alveolar wall damage. This is reversed by caveolin-1 scaffolding domain peptide (CSP7) in preclinical models, suggesting the therapeutic potential of CSP7 for treating CS-induced lung injury (CS-LI) and COPD.

Venous thromboembolism in lung transplant recipients real world experience from a high volume center.

BACKGROUND: Venous thromboembolism (VTE) post lung transplantation is common and has been associated with worse post transplant survival. We report a comprehensive single center review of VTE incidence in the first post transplant year, investigate modifiable risk factors and assess impact on short term outcomes. METHODS: Retrospective review of all lung transplant recipients between August 2016 to 2018 at Temple University Hospital. Patients were followed for 1 year post transplant. All patients were screened for deep venous thrombosis (DVT) within the first 2 weeks with a venous duplex study. Pre transplant, intra operative, post operative variables, and peri-operative practice patterns were compared between VTE positive and VTE negative groups. Logistic regression modeling was used to identify risk factors for early VTE (VTE within 30 days after transplant). RESULTS: A total of 235 patients were included in the study, 58 patients (24.7%) developed a VTE in the first post transplant year. Median time to diagnosis was 17 days. Of the patients with VTE, 76% had an isolated DVT, 13.5 % had an isolated pulmonary embolism (PE), and 10.3% had concomitant DVT and PE. In a multivariate logistic regression model, cardiopulmonary bypass (CPB) (OR 1.93 p = 0.015) and interruption of VTE prophylaxis (OR 4.42 p < 0.0001) were predictive of early VTE. CONCLUSION: VTE post lung transplant is common despite the use of prophylactic anticoagulation. CPB use and interruption of DVT prophylaxis are risk factors for early post transplant VTE. Measures to ensure consistent and uninterrupted prophylaxis may help decrease VTE incidence after lung transplantation.

Machine Learning Characterization of COPD Subtypes: Insights From the COPDGene Study.

COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.

Caveolin-1-derived peptide limits development of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with a median 5-year survival of ~20%. Current U.S. Food and Drug Administration-approved pharmacotherapies slow progression of IPF, providing hope that even more effective treatments can be developed. Alveolar epithelial progenitor type II cell (AEC) apoptosis and proliferation, and accumulation of activated myofibroblasts or fibrotic lung fibroblasts (fLfs) contribute to the progression of IPF. Full-length caveolin-1 scaffolding domain peptide (CSP; amino acids 82 to 101 of Cav1: DGIWKASFTTFTVTKYWFYR) inhibits AEC apoptosis and fLf activation and expansion and attenuates PF in bleomycin (BLM)-induced lung injury in mice. Like full-length CSP, a seven-amino acid deletion fragment of CSP, CSP7 (FTTFTVT), demonstrated antifibrotic effects in murine models of lung fibrosis. When CSP7 was administered during the fibrotic phase in three preclinical models [single-dose BLM, repeated-dose BLM, and adenovirus expressing constitutively active transforming growth factor-ß1 (Ad-TGF-ß1)-induced established PF], CSP7 reduced extracellular matrix (ECM) markers characteristic of PF, increased AEC survival, and improved lung function. CSP7 is amenable to both systemic (intraperitoneal) or direct lung delivery in a nebulized or dry powder form. Furthermore, CSP7 treatment of end-stage human IPF lung tissue explants attenuated ECM production and promoted AEC survival. Ames testing for mutagenicity and in vitro human peripheral blood lymphocyte and in vivo mouse micronucleus transformation assays indicated that CSP7 is not carcinogenic. Together, these findings support the further development of CSP7 as an antifibrotic treatment for patients with IPF or other interstitial lung diseases.

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility. OBJECTIVES: To identify coding variants associated with COPD. METHODS: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts. MEASUREMENTS AND MAIN RESULTS: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10(-14)) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10(-6)) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10(-8)) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM. CONCLUSIONS: In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.

Exome Sequencing Analysis in Severe, Early-Onset Chronic Obstructive Pulmonary Disease.

RATIONALE: Genomic regions identified by genome-wide association studies explain only a small fraction of heritability for chronic obstructive pulmonary disease (COPD). Alpha-1 antitrypsin deficiency shows that rare coding variants of large effect also influence COPD susceptibility. We hypothesized that exome sequencing in families identified through a proband with severe, early-onset COPD would identify additional rare genetic determinants of large effect. OBJECTIVES: To identify rare genetic determinants of severe COPD. METHODS: We applied filtering approaches to identify potential causal variants for COPD in whole exomes from 347 subjects in 49 extended pedigrees from the Boston Early-Onset COPD Study. We assessed the power of this approach under different levels of genetic heterogeneity using simulations. We tested genes identified in these families using gene-based association tests in exomes of 204 cases with severe COPD and 195 resistant smokers from the COPDGene study. In addition, we examined previously described loci associated with COPD using these datasets. MEASUREMENTS AND MAIN RESULTS: We identified 69 genes with predicted deleterious nonsynonymous, stop, or splice variants that segregated with severe COPD in at least two pedigrees. Four genes (DNAH8, ALCAM, RARS, and GBF1) also demonstrated an increase in rare nonsynonymous, stop, and/or splice mutations in cases compared with resistant smokers from the COPDGene study; however, these results were not statistically significant. We demonstrate the limitations of the power of this approach under genetic heterogeneity through simulation. CONCLUSIONS: Rare deleterious coding variants may increase risk for COPD, but multiple genes likely contribute to COPD susceptibility.

Older adults with chronic lung disease report less limitation compared with younger adults with similar lung function impairment.

RATIONALE: Disability guidelines are often based on pulmonary function testing, but factors other than lung function influence how an individual experiences physiologic impairment. Age may impact the perception of impairment in adults with chronic lung disease. OBJECTIVES: To determine if self-report of physical functional impairment differs between older adults with chronic lung disease compared with younger adults with similar degrees of lung function impairment. METHODS: The Lung Tissue Research Consortium provided data on 981 participants with chronic obstructive pulmonary disease and interstitial lung disease who were well characterized with clinical, radiological, and pathological diagnoses. We used multiple logistic regression to determine if responses to health status questions (from the Short Form-12 and St. George's Respiratory Questionnaire) related to perception of impairment differed in older adults (age ≥ 65 yr, n = 427) compared with younger adults (age < 65 yr, n = 393). MEASUREMENTS AND MAIN RESULTS: Pulmonary function was higher in older adults (median FEV1 %, 70) compared with younger adults (median FEV1 %, 62) (P < 0.001), whereas the median 6-minute-walk distance was similar between groups (372 m vs. 388 m, P = 0.21). After adjusting for potential confounders, older adults were less likely to report that their health limited them significantly in performing moderate activities (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.22-0.58) or climbing several flights of stairs (OR, 0.51; 95% CI, 0.34-0.77). The odds of reporting that their physical health limited the kinds of activities they performed were reduced by 63% in older adults (OR, 0.37; 95% CI, 0.24-0.58), and, similarly, the odds of reporting that their health caused them to accomplish less than they would like were also lower in older adults (OR, 0.39; 95% CI, 0.25-0.60). The OR for reporting that their breathing problem stops them from doing most things or everything was 0.35 (95% CI, 0.22-0.55) in older adults versus younger adults. CONCLUSIONS: Older adults with chronic lung disease were less likely to report significant impairment in their activities compared with younger adults, suggesting they may perceive less limitation.

Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema.

BACKGROUND: There is notable heterogeneity in the clinical presentation of patients with COPD. To characterise this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene study. METHODS: We applied a clustering method, k-means, to data from 10 192 smokers in the COPDGene study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. FINDINGS: We identified four clusters that can be characterised as (1) relatively resistant smokers (ie, no/mild obstruction and minimal emphysema despite heavy smoking), (2) mild upper zone emphysema-predominant, (3) airway disease-predominant and (4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnoea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations). INTERPRETATION: Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.

Computed tomographic-based quantification of emphysema and correlation to pulmonary function and mechanics.

Computed tomographic based indices of emphysematous lung destruction may highlight differences in disease pathogenesis and further enable the classification of subjects with Chronic Obstructive Pulmonary Disease. While there are multiple techniques that can be utilized for such radiographic analysis, there is very little published information comparing the performance of these methods in a clinical case series. Our objective was to examine several quantitative and semi-quantitative methods for the assessment of the burden of emphysema apparent on computed tomographic scans and compare their ability to predict lung mechanics and function. Automated densitometric analysis was performed on 1094 computed tomographic scans collected upon enrollment into the National Emphysema Treatment Trial. Trained radiologists performed an additional visual grading of emphysema on high resolution CT scans. Full pulmonary function test results were available for correlation, with a subset of subjects having additional measurements of lung static recoil. There was a wide range of emphysematous lung destruction apparent on the CT scans and univariate correlations to measures of lung function were of modest strength. No single method of CT scan analysis clearly outperformed the rest of the group. Quantification of the burden of emphysematous lung destruction apparent on CT scan is a weak predictor of lung function and mechanics in severe COPD with no uniformly superior method found to perform this analysis. The CT based quantification of emphysema may augment pulmonary function testing in the characterization of COPD by providing complementary phenotypic information.

The effect of lung volume reduction surgery on chronic obstructive pulmonary disease exacerbations.

RATIONALE: Lung volume reduction surgery (LVRS) has been demonstrated to provide a functional and mortality benefit to a select group of subjects with chronic obstructive pulmonary disease (COPD). The effect of LVRS on COPD exacerbations has not been as extensively studied, and whether improvement in postoperative lung function alters the risk of disease exacerbations is not known. OBJECTIVES: To examine the effect, and mechanism of potential benefit, of LVRS on COPD exacerbations by comparing the medical and surgical cohorts of the National Emphysema Treatment Trial (NETT). METHODS: A COPD exacerbation was defined using Centers for Medicare and Medicaid Services data and International Classification of Diseases, Ninth Revision, discharge diagnosis. MEASUREMENTS AND MAIN RESULTS: There was no difference in exacerbation rate or time to first exacerbation between the medical and surgical cohorts during the year before study randomization (P = 0.58 and 0.85, respectively). Postrandomization, the surgical cohort experienced an approximate 30% reduction in exacerbation frequency (P = 0.0005). This effect was greatest in those subjects with the largest postoperative improvement in FEV(1) (P = 0.04) when controlling for changes in other spirometric measures of lung function, lung capacities, and room air arterial blood gas tensions. Finally, LVRS increased the time to first exacerbation in both those subjects with and those without a prior history of exacerbations (P = 0.0002 and P < 0.0001, respectively). CONCLUSIONS: LVRS reduces the frequency of COPD exacerbations and increases the time to first exacerbation. One explanation for this benefit may be the postoperative improvement in lung function.