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28.  Evaluating the NET Influence of Inflammation on Pneumonia Biology 
doi:10.1164/rccm.201209-1702ED
PMCID: PMC3530208  PMID: 23155213
36.  Waiting in Anticipation 
doi:10.1164/rccm.201209-1666ED
PMCID: PMC3530217  PMID: 23118082
38.  Interferon-λ1 and Viral Wheeze in Asthma: A Gothic Duality? 
doi:10.1164/rccm.201112-2195ED
PMCID: PMC3297104  PMID: 22383563
39.  The Pros and Cons of Airway Lining Fluid Composition Analysis 
doi:10.1164/rccm.201111-2010ED
PMCID: PMC3297111  PMID: 22298360
40.  Straining to Make Mechanical Ventilation Safe and Simple 
doi:10.1164/rccm.201102-0195ED
PMCID: PMC3114057  PMID: 21596829
41.  (Too) Great Expectations 
doi:10.1164/rccm.200903-0456ED
PMCID: PMC4263324  PMID: 19498061
42.  Just a Spoonful of Technology Makes the Protocol Go Down 
doi:10.1164/rccm.200607-933ED
PMCID: PMC2648053  PMID: 17021356
43.  Genome-Wide Study of Percent Emphysema on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study 
Rationale: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.
Objectives: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.
Methods: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than −950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.
Measurements and Main Results: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10−8) and PPT2 (rs10947233; P = 3.2 × 10−8), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase–related gene MAN2B1 (rs10411619; P = 1.1 × 10−9; minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10−10; MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10−8; MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase–related gene, MAN1C1 (rs12130495; P = 9.9 × 10−6; MAF, 13.3%) was associated with percent emphysema.
Conclusions: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
doi:10.1164/rccm.201306-1061OC
PMCID: PMC3977717  PMID: 24383474
emphysema; computed tomography; multiethnic; cohort study; genetic association
44.  Estimates of the Need for Palliative Care Consultation across United States Intensive Care Units Using a Trigger-based Model 
Rationale: Use of triggers for palliative care consultation has been advocated in intensive care units (ICUs) to ensure appropriate specialist involvement for patients at high risk of unmet palliative care needs. The volume of patients meeting these triggers, and thus the potential workload for providers, is unknown.
Objectives: To estimate the prevalence of ICU admissions who met criteria for palliative care consultation using different sets of triggers.
Methods: Retrospective cohort study of ICU admissions from Project IMPACT for 2001–2008. We assessed the prevalence of ICU admissions meeting one or more primary palliative care triggers, and prevalence meeting any of multiple sets of triggers.
Measurements and Main Results: Overall, 53,124 (13.8%) ICU admissions met one or more primary triggers for palliative care consultation. Variation in prevalence was minimal across different types of units (mean 13.3% in medical ICUs to 15.8% in trauma/burn ICUs; P = 0.41) and individual units (mean 13.8%, median 13.0%, interquartile range, 10.2–16.5%). A comprehensive model combining multiple sets of triggers identified a total of 75,923 (19.7%) ICU admissions requiring palliative care consultation; of them, 85.4% were captured by five triggers: (1) ICU admission after hospital stay greater than or equal to 10 days, (2) multisystem organ failure greater than or equal to three systems, (3) stage IV malignancy, (4) status post cardiac arrest, and (5) intracerebral hemorrhage requiring mechanical ventilation.
Conclusions: Approximately one in seven ICU admissions met triggers for palliative care consultation using a single set of triggers, with an upper estimate of one in five patients using multiple sets of triggers; these estimates were consistent across different types of ICUs and individual units. These results may inform staffing requirements for providers to ensure delivery of specialized palliative care to ICU patients nationally.
doi:10.1164/rccm.201307-1229OC
PMCID: PMC3977718  PMID: 24261961
end-of-life care; critical care; palliative medicine
45.  Deficiency of Melanoma Differentiation–associated Protein 5 Results in Exacerbated Chronic Postviral Lung Inflammation 
Rationale: Respiratory viral infections can result in the establishment of chronic lung diseases. Understanding the early innate immune mechanisms that participate in the development of chronic postviral lung disease may reveal new targets for therapeutic intervention. The intracellular viral sensor protein melanoma differentiation–associated protein 5 (MDA5) sustains the acute immune response to Sendai virus, a mouse pathogen that causes chronic lung inflammation, but its role in the development of postviral chronic lung disease is unknown.
Objectives: To establish the role of MDA5 in the development of chronic lung disease.
Methods: MDA5-deficient or control mice were infected with Sendai virus. The acute inflammatory response was evaluated by profiling chemokine and cytokine expression and by characterizing the composition of the cellular infiltrate. The impact of MDA5 on chronic lung pathology and function was evaluated through histological studies, degree of oxygen saturation, and responsiveness to carbachol.
Measurements and Main Results: MDA5 deficiency resulted in normal virus replication and in a distinct profile of chemokines and cytokines that associated with acute lung neutropenia and enhanced accumulation of alternatively activated macrophages. Diminished expression of neutrophil-recruiting chemokines was also observed in cells infected with influenza virus, suggesting a key role of MDA5 in driving the early accumulation of neutrophils at the infection site. The biased acute inflammatory response of MDA5-deficient mice led to an enhanced chronic lung inflammation, epithelial cell hyperplasia, airway hyperreactivity, and diminished blood oxygen saturation.
Conclusions: MDA5 modulates the development of chronic lung inflammation by regulating the early inflammatory response in the lung.
doi:10.1164/rccm.201307-1338OC
PMCID: PMC3977719  PMID: 24417465
respiratory virus; chronic lung disease; innate immunity; paramyxovirus
46.  Mucosal Immune Responses Predict Clinical Outcomes during Influenza Infection Independently of Age and Viral Load 
Rationale: Children are an at-risk population for developing complications following influenza infection, but immunologic correlates of disease severity are not understood. We hypothesized that innate cellular immune responses at the site of infection would correlate with disease outcome.
Objectives: To test the immunologic basis of severe illness during natural influenza virus infection of children and adults at the site of infection.
Methods: An observational cohort study with longitudinal sampling of peripheral and mucosal sites in 84 naturally influenza-infected individuals, including infants. Cellular responses, viral loads, and cytokines were quantified from nasal lavages and blood, and correlated to clinical severity.
Measurements and Main Results: We show for the first time that although viral loads in children and adults were similar, innate responses in the airways were stronger in children and varied considerably between plasma and site of infection. Adjusting for age and viral load, an innate immune profile characterized by increased nasal lavage monocyte chemotactic protein-3, IFN-α2, and plasma IL-10 levels at enrollment predicted progression to severe disease. Increased plasma IL-10, monocyte chemotactic protein-3, and IL-6 levels predicted hospitalization. This inflammatory cytokine production correlated significantly with monocyte localization from the blood to the site of infection, with conventional monocytes positively correlating with inflammation. Increased frequencies of CD14lo monocytes were in the airways of participants with lower inflammatory cytokine levels.
Conclusions: An innate profile was identified that correlated with disease progression independent of viral dynamics and age. The airways and blood displayed dramatically different immune profiles emphasizing the importance of cellular migration and localized immune phenotypes.
doi:10.1164/rccm.201309-1616OC
PMCID: PMC3977720  PMID: 24308446
natural influenza virus infection; human; cytokine; innate immune response; monocyte
47.  Glutaredoxin-1 Attenuates S-Glutathionylation of the Death Receptor Fas and Decreases Resolution of Pseudomonas aeruginosa Pneumonia 
Rationale: The death receptor Fas is critical for bacterial clearance and survival of mice after Pseudomonas aeruginosa infection.
Objectives: Fas ligand (FasL)–induced apoptosis is augmented by S-glutathionylation of Fas (Fas-SSG), which can be reversed by glutaredoxin-1 (Grx1). Therefore, the objective of this study was to investigate the interplay between Grx1 and Fas in regulating the clearance of P. aeruginosa infection.
Methods: Lung samples from patients with bronchopneumonia were analyzed by immunofluorescence. Primary tracheal epithelial cells, mice lacking the gene for Grx1 (Glrx1−/−), Glrx1−/− mice treated with caspase inhibitor, or transgenic mice overexpressing Grx1 in the airway epithelium were analyzed after infection with P. aeruginosa.
Measurements and Main Results: Patient lung samples positive for P. aeruginosa infection demonstrated increased Fas-SSG compared with normal lung samples. Compared with wild-type primary lung epithelial cells, infection of Glrx1−/− cells with P. aeruginosa showed enhanced caspase 8 and 3 activities and cell death in association with increases in Fas-SSG. Infection of Glrx1−/− mice with P. aeruginosa resulted in enhanced caspase activity and increased Fas-SSG as compared with wild-type littermates. Absence of Glrx1 significantly enhanced bacterial clearance, and decreased mortality postinfection with P. aeruginosa. Inhibition of caspases significantly decreased bacterial clearance postinfection with P. aeruginosa, in association with decreased Fas-SSG. In contrast, transgenic mice that overexpress Grx1 in lung epithelial cells had significantly higher lung bacterial loads, enhanced mortality, decreased caspase activation, and Fas-SSG in the lung after infection with P. aeruginosa, compared with wild-type control animals.
Conclusions: These results suggest that S-glutathionylation of Fas within the lung epithelium enhances epithelial apoptosis and promotes clearance of P. aeruginosa and that glutaredoxin-1 impairs bacterial clearance and increases the severity of pneumonia in association with deglutathionylation of Fas.
doi:10.1164/rccm.201310-1905OC
PMCID: PMC3977722  PMID: 24325366
Pseudomonas; glutaredoxin-1; protein S-glutathionylation; Fas; apoptosis
50.  Is Chronic Asthma Associated with Shorter Leukocyte Telomere Length at Midlife? 
Rationale: Asthma is prospectively associated with age-related chronic diseases and mortality, suggesting the hypothesis that asthma may relate to a general, multisystem phenotype of accelerated aging.
Objectives: To test whether chronic asthma is associated with a proposed biomarker of accelerated aging, leukocyte telomere length.
Methods: Asthma was ascertained prospectively in the Dunedin Multidisciplinary Health and Development Study cohort (n = 1,037) at nine in-person assessments spanning ages 9–38 years. Leukocyte telomere length was measured at ages 26 and 38 years. Asthma was classified as life-course-persistent, childhood-onset not meeting criteria for persistence, and adolescent/adult-onset. We tested associations between asthma and leukocyte telomere length using regression models. We tested for confounding of asthma-leukocyte telomere length associations using covariate adjustment. We tested serum C-reactive protein and white blood cell counts as potential mediators of asthma-leukocyte telomere length associations.
Measurements and Main Results: Study members with life-course-persistent asthma had shorter leukocyte telomere length as compared with sex- and age-matched peers with no reported asthma. In contrast, leukocyte telomere length in study members with childhood-onset and adolescent/adult-onset asthma was not different from leukocyte telomere length in peers with no reported asthma. Adjustment for life histories of obesity and smoking did not change results. Study members with life-course-persistent asthma had elevated blood eosinophil counts. Blood eosinophil count mediated 29% of the life-course-persistent asthma-leukocyte telomere length association.
Conclusions: Life-course-persistent asthma is related to a proposed biomarker of accelerated aging, possibly via systemic eosinophilic inflammation. Life histories of asthma can inform studies of aging.
doi:10.1164/rccm.201402-0370OC
PMCID: PMC4214127  PMID: 24956257
asthma; telomere; aging; longitudinal; developmental phenotype

Results 26-50 (1247)