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1.  IL-9 Governs Allergen-induced Mast Cell Numbers in the Lung and Chronic Remodeling of the Airways 
Rationale
IL-9 is a pleiotropic cytokine that has multiple effects on structural as well as numerous hematopoietic cells, which are central to the pathogenesis of asthma.
Objectives
The contribution of IL-9 to asthma pathogenesis has thus far been unclear, due to conflicting reports in the literature. These earlier studies focused on the role of IL-9 in acute inflammatory models; here we have investigated the effects of IL-9 blockade during chronic allergic inflammation.
Methods
Mice were exposed to either prolonged ovalbumin or house dust mite allergen challenge to induce chronic inflammation and airway remodeling.
Measurements and Main Results
We found that IL-9 governs allergen-induced mast cell (MC) numbers in the lung and has pronounced effects on chronic allergic inflammation. Anti–IL-9 antibody–treated mice were protected from airway remodeling with a concomitant reduction in mature MC numbers and activation, in addition to decreased expression of the profibrotic mediators transforming growth factor-β1, vascular endothelial growth factor, and fibroblast growth factor-2 in the lung. Airway remodeling was associated with impaired lung function in the peripheral airways and this was reversed by IL-9 neutralization. In human asthmatic lung tissue, we identified MCs as the main IL-9 receptor expressing population and found them to be sources of vascular endothelial growth factor and fibroblast growth factor-2.
Conclusions
Our data suggest an important role for an IL-9-MC axis in the pathology associated with chronic asthma and demonstrate that an impact on this axis could lead to a reduction in chronic inflammation and improved lung function in patients with asthma.
doi:10.1164/rccm.200909-1462OC
PMCID: PMC3385369  PMID: 20971830
IL-9; mast cells; asthma; airway remodeling; AHR
2.  Yin Yang 1 Is a Novel Regulator of Pulmonary Fibrosis 
Rationale: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The transcription factor Yin Yang 1 (YY1) plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known.
Objectives: To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis.
Methods: Lung fibroblasts were cultured with transforming growth factor (TGF)-β or tumor necrosis factor-α. Nuclear factor (NF)-κB, YY1, and α-smooth muscle actin (SMA) were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1f/f conditional knockout mouse after being exposed to silica or bleomycin.
Measurements and Main Results: TGF-β and tumor necrosis factor-α up-regulated YY1 expression in lung fibroblasts. TGF-β–induced YY1 expression was dramatically decreased by an inhibitor of NF-κB, which blocked I-κB degradation. YY1 is significantly overexpressed in both human IPF and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate α-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1+/−) mice were significantly protected from lung fibrosis, which was associated with attenuated α-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1f/f mice reduced lung fibrosis.
Conclusions: YY1 is overexpressed in fibroblasts in both human IPF and murine models in a NF-κB–dependent manner, and YY1 regulates fibrogenesis at least in part by increasing α-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for pulmonary fibrosis.
doi:10.1164/rccm.201002-0232OC
PMCID: PMC3136995  PMID: 21169469
nuclear factor-κB; α-smooth muscle actin; idiopathic pulmonary fibrosis
3.  Interferon-γ Production by Neutrophils during Bacterial Pneumonia in Mice 
Rationale: Neutrophils are usually the first circulating leukocytes to respond during bacterial pneumonia. Their expression of oxidants, proteases, and other mediators present in granules is well documented, but their ability to produce mediators through transcription and translation after migration to an inflammatory site has been appreciated only more recently. Interferon (IFN)-γ is a cytokine with many functions important in host defense and immunity.
Objectives: To examine the expression and function of IFN-γ in bacterial pneumonias.
Methods: IFN-γ mRNA and protein were measured in digests of mouse lungs with 24-hour bacterial pneumonia. Bacterial clearance was studied with IFN-γ–deficient mice.
Measurements and Main Results: Streptococcus pneumoniae and Staphylococcus aureus each induce expression of IFN-γ mRNA and protein by neutrophils by 24 hours. Only neutrophils that have migrated into pneumonic tissue produce IFN-γ. Deficiency of Hck/Fgr/Lyn, Rac2, or gp91phox prevents IFN-γ production. IFN-γ enhances bacterial clearance and is required for formation of neutrophil extracellular traps. In contrast, Pseudomonas aeruginosa and Escherichia coli induce production of IFN-γ mRNA but not protein. During pneumonia induced by E. coli but not S. pneumoniae, neutrophils produce microRNAs that target the 3′ untranslated region of the IFN-γ gene.
Conclusions: S. pneumoniae and S. aureus, but not P. aeruginosa and E. coli, induce emigrated neutrophils to produce IFN-γ within 24 hours. Hck/Fgr/Lyn, Rac2, and NADPH oxidase are required for IFN-γ production. IFN-γ facilitates bacterial clearance at least in part through regulating formation of neutrophil extracellular traps. Differential expression by neutrophils of microRNAs that target the 3′ untranslated region of the IFN-γ gene may contribute to the pathogen-specific regulation of translation.
doi:10.1164/rccm.201004-0592OC
PMCID: PMC3114063  PMID: 21169470
host defense; inflammation; innate immunity; infection
4.  Epithelial Cell Death Is an Important Contributor to Oxidant-mediated Acute Lung Injury 
Rationale: Acute lung injury and the acute respiratory distress syndrome are characterized by increased lung oxidant stress and apoptotic cell death. The contribution of epithelial cell apoptosis to the development of lung injury is unknown.
Objectives: To determine whether oxidant-mediated activation of the intrinsic or extrinsic apoptotic pathway contributes to the development of acute lung injury.
Methods: Exposure of tissue-specific or global knockout mice or cells lacking critical components of the apoptotic pathway to hyperoxia, a well-established mouse model of oxidant-induced lung injury, for measurement of cell death, lung injury, and survival.
Measurements and Main Results: We found that the overexpression of SOD2 prevents hyperoxia-induced BAX activation and cell death in primary alveolar epithelial cells and prolongs the survival of mice exposed to hyperoxia. The conditional loss of BAX and BAK in the lung epithelium prevented hyperoxia-induced cell death in alveolar epithelial cells, ameliorated hyperoxia-induced lung injury, and prolonged survival in mice. By contrast, Cyclophilin D–deficient mice were not protected from hyperoxia, indicating that opening of the mitochondrial permeability transition pore is dispensable for hyperoxia-induced lung injury. Mice globally deficient in the BH3-only proteins BIM, BID, PUMA, or NOXA, which are proximal upstream regulators of BAX and BAK, were not protected against hyperoxia-induced lung injury suggesting redundancy of these proteins in the activation of BAX or BAK.
Conclusions: Mitochondrial oxidant generation initiates BAX- or BAK-dependent alveolar epithelial cell death, which contributes to hyperoxia-induced lung injury.
doi:10.1164/rccm.201002-0181OC
PMCID: PMC3086743  PMID: 20959557
cell death; epithelium; Bcl-2 proteins; acute respiratory distress syndrome
5.  Mesenchymal Stromal Cells in Bronchoalveolar Lavage as Predictors of Bronchiolitis Obliterans Syndrome 
Rationale: Bronchoalveolar lavage fluid (BAL) from human lung allografts demonstrates the presence of a multipotent mesenchymal stromal cell population. However, the clinical relevance of this novel cellular component of BAL and its association with bronchiolitis obliterans syndrome (BOS), a disease marked by progressive airflow limitation secondary to fibrotic obliteration of the small airways, remains to be determined.
Objectives: In this study we investigate the association of number of mesenchymal stromal cells in BAL with development of BOS in human lung transplant recipients.
Methods: Mesenchymal colony-forming units (CFUs) were quantitated in a cohort of 405 BAL samples obtained from 162 lung transplant recipients. Poisson generalized estimating equations were used to determine the predictors of BAL mesenchymal CFU count.
Measurements and Main Results: Higher CFU counts were noted early post-transplantation; time from transplant to BAL of greater than 3 months predicted 0.4-fold lower CFU counts (P = 0.0001). BOS diagnosis less than or equal to 365 days before BAL was associated with a 2.11-fold higher CFU count (P = 0.02). There were 2.62- and 2.70-fold higher CFU counts noted in the presence of histologic diagnosis of bronchiolitis obliterans (P = 0.05) and organizing pneumonia (0.0003), respectively. In BAL samples obtained from BOS-free patients greater than 6 months post-transplantation (n = 173), higher mesenchymal CFU counts (≥10) significantly predicted BOS onset in both univariate (hazard ratio, 5.61; 95% CI, 3.03–10.38; P < 0.0001) and multivariate (hazard ratio, 5.02; 95% CI, 2.40–10.51; P < 0.0001) Cox regression analysis.
Conclusions: Measurement of mesenchymal CFUs in the BAL provides predictive information regarding future BOS onset.
doi:10.1164/rccm.201005-0742OC
PMCID: PMC3086744  PMID: 21169468
bronchiolitis obliterans syndrome; acute rejection; bronchoalveolar lavage
6.  A Central Role for CD68(+) Macrophages in Hepatopulmonary Syndrome 
Rationale: The etiology of hepatopulmonary syndrome (HPS), a common complication of cirrhosis, is unknown. Inflammation and macrophage accumulation occur in HPS; however, their importance is unclear. Common bile duct ligation (CBDL) creates an accepted model of HPS, allowing us to investigate the cause of HPS.
Objectives: We hypothesized that macrophages are central to HPS and investigated the therapeutic potential of macrophage depletion.
Methods: Hemodynamics, alveolar–arterial gradient, vascular reactivity, and histology were assessed in CBDL versus sham rats (n = 21 per group). The effects of plasma on smooth muscle cell proliferation and endothelial tube formation were measured. Macrophage depletion was used to prevent (gadolinium) or regress (clodronate) HPS. CD68(+) macrophages and capillary density were measured in the lungs of patients with cirrhosis versus control patients (n = 10 per group).
Measurements and Main Results: CBDL increased cardiac output and alveolar–arterial gradient by causing capillary dilatation and arteriovenous malformations. Activated CD68(+) macrophages (nuclear factor-κB+) accumulated in HPS pulmonary arteries, drawn by elevated levels of plasma endotoxin and lung monocyte chemoattractant protein-1. These macrophages expressed inducible nitric oxide synthase, vascular endothelial growth factor, and platelet-derived growth factor. HPS plasma increased endothelial tube formation and pulmonary artery smooth muscle cell proliferation. Macrophage depletion prevented and reversed the histological and hemodynamic features of HPS. CBDL lungs demonstrated increased medial thickness and obstruction of small pulmonary arteries. Nitric oxide synthase inhibition unmasked exaggerated pulmonary vasoconstrictor responses in HPS. Patients with cirrhosis had increased pulmonary intravascular macrophage accumulation and capillary density.
Conclusions: HPS results from intravascular accumulation of CD68(+) macrophages. An occult proliferative vasculopathy may explain the occasional transition to portopulmonary hypertension. Macrophage depletion may have therapeutic potential in HPS.
doi:10.1164/rccm.201008-1303OC
PMCID: PMC3086745  PMID: 21148721
liver transplantation; arteriovenous malformations; clodronate; cirrhosis; portopulmonary hypertension
7.  Novel Developments in the Epidemic of Human Immunodeficiency Virus and Tuberculosis Coinfection 
Tuberculosis (TB) disease remains one of the highest causes of mortality in HIV-infected individuals, and HIV–TB coinfection continues to grow at alarming rates, especially in sub-Saharan Africa. Surprisingly, a number of important areas regarding coinfection remain unclear. For example, increased risk of TB disease begins early in the course of HIV infection; however, the mechanism by which HIV increases this risk is not well understood. In addition, there is lack of consensus on the optimal way to diagnose latent TB infection and to manage active disease in those who are HIV infected. Furthermore, effective point-of-care testing for TB disease remains elusive. This review discusses key areas in the epidemiology, pathogenesis, diagnosis, and management of active and latent TB in those infected with HIV, focusing attention on issues related to high- and low-burden areas. Particular emphasis is placed on controversial areas where there are gaps in knowledge and on future directions of study.
doi:10.1164/rccm.201008-1246CI
PMCID: PMC3086746  PMID: 21177884
tuberculosis; HIV; diagnosis; management; epidemiology
8.  Effects of a School-based Intervention for Urban Adolescents with Asthma 
Rationale: Asthma prevalence and morbidity are especially elevated in adolescents, yet few interventions target this population.
Objectives: To test the efficacy of Asthma Self-Management for Adolescents (ASMA), a school-based intervention for adolescents and medical providers.
Methods: Three hundred forty-five primarily Latino/a (46%) and African American (31%) high school students (mean age = 15.1 yr; 70% female) reporting an asthma diagnosis, symptoms of moderate to severe persistent asthma, and asthma medication use in the last 12 months were randomized to ASMA, an 8-week school-based intervention, or a wait-list control group. They were followed for 12 months.
Measurements and Main Results: Students completed bimonthly assessments. Baseline, 6-month, and 12-month assessments were comprehensive; the others assessed interim health outcomes and urgent health care use. Primary outcomes were asthma self-management, symptom frequency, and quality of life (QOL); secondary outcomes were asthma medical management, school absences, days with activity limitations, and urgent health care use. Relative to control subjects, ASMA students reported significantly: more confidence to manage their asthma; taking more steps to prevent symptoms; greater use of controller medication and written treatment plans; fewer night awakenings, days with activity limitation, and school absences due to asthma; improved QOL; and fewer acute care visits, emergency department visits, and hospitalizations. In contrast, steps to manage asthma episodes, daytime symptom frequency, and school-reported absences did not differentiate the two groups. Most results were sustained over the 12 months.
Conclusions: ASMA is efficacious in improving asthma self-management and reducing asthma morbidity and urgent health care use in low-income urban minority adolescents.
doi:10.1164/rccm.201003-0429OC
PMCID: PMC3086747  PMID: 21139088
asthma; urban; adolescents; school-based; intervention
9.  Disability among Elderly Survivors of Mechanical Ventilation 
Rationale: Studies of long-term functional outcomes of elderly survivors of mechanical ventilation (MV) are limited to local samples and biased retrospective, proxy-reported preadmission functional status.
Objectives: To assess the impact on disability of hospitalization with MV, compared with hospitalization without MV, accounting for prospectively assessed prior functional status.
Methods: Retrospective population-based longitudinal cohort study of Medicare beneficiaries age 65 and older enrolled in the Medicare Current Beneficiary Survey, 1996–2003.
Measurements and Main Results: Premeasures and postmeasures of disability included mobility difficulty and weighted activities of daily living disability scores ranging from 0 (not disabled) to 100 (completely disabled) based on self-reported health and functional status collected 1 year apart. Among 54,771 person-years (PY) of observation over 7 calendar years of data, 42,890 PY involved no hospitalization, 11,347 PY involved a hospitalization without MV, and 534 PY included a hospitalization with MV. Mortality at 1 year was 8.9%, 23.9%, and 72.5%, respectively. The level of disability at the postassessment was substantially higher for a prototypical patient who survived after hospitalization with MV (adjusted activities of daily living disability score [95% confidence interval] 14.9 [12.2–17.7]; adjusted mobility difficulty score [95% confidence interval] 25.4 [22.4–28.4]) compared with an otherwise identical patient who survived hospitalization without MV (11.5 [11.1–11.9] and 22.3 [21.8–22.9]) or who was not hospitalized (8.0 [7.9–8.1] and 13.4 [13.3–13.6]).
Conclusions: The greater marginal increase in disability among survivors of MV compared with survivors of hospitalization without MV is larger than would be predicted from prior functional status.
doi:10.1164/rccm.201002-0301OC
PMCID: PMC3159078  PMID: 21057004
Medicare; intensive care; mechanical ventilation; quality of life; functional status
10.  Costs and Consequences of Additional Chest X-Ray in a Tuberculosis Prevention Program in Botswana 
Rationale: Isoniazid preventive therapy is effective in reducing the risk of tuberculosis (TB) in persons living with HIV (PLWH); however, screening must exclude TB disease before initiating therapy. Symptom screening alone may be insufficient to exclude TB disease in PLWH because some PLWH with TB disease have no symptoms. The addition of chest radiography (CXR) may improve disease detection.
Objectives: The objective of the present analysis was to compare the costs and effects of the addition of CXR to the symptom screening process against the costs and effects of symptom screening alone.
Methods: Using data from Botswana, a decision analytic model was used to compare a “Symptom only” policy against a “Symptom+CXR” policy. The outcomes of interest were cost, death, and isoniazid- and multidrug-resistant TB in a hypothetical cohort of 10,000 PLWH.
Measurements and Main Results: The Symptom+CXR policy prevented 16 isoniazid- and 0.3 multidrug-resistant TB cases; however, because of attrition from the screening process, there were 98 excess cases of TB, 15 excess deaths, and an additional cost of U.S. $127,100. The Symptom+CXR policy reduced deaths only if attrition was close to zero; however, to eliminate attrition the cost would be U.S. $2.8 million per death averted. These findings did not change in best- and worst-case scenario analyses.
Conclusions: In Botswana, a policy with symptom screening only preceding isoniazid-preventive therapy initiation prevents more TB and TB-related deaths, and uses fewer resources, than a policy that uses both CXR and symptom screening.
doi:10.1164/rccm.201004-0620OC
PMCID: PMC3159079  PMID: 21148723
tuberculosis; isoniazid preventive therapy; cost-effectiveness; human immunodeficiency virus; chest X-ray
11.  Segmental Allergen Challenge Alters Multimeric Structure and Function of Surfactant Protein D in Humans 
Rationale: Surfactant protein D (SP-D), a 43-kD collectin, is synthesized and secreted by airway epithelia as a dodecamer formed by assembly of four trimeric subunits. We have previously shown that the quaternary structure of SP-D can be altered during inflammatory lung injury through its modification by S-nitrosylation, which in turn alters its functional behavior producing a proinflammatory response in effector cells.
Objectives: We hypothesized that alterations in structure and function of SP-D may occur in humans with acute allergic inflammation.
Methods: Bronchoalveolar lavage (BAL) fluid was collected from 15 nonsmoking patients with mild intermittent allergic asthma before and 24 hours after segmental provocation with saline, allergen, LPS, and mixtures of allergen and LPS. Structural modifications of SP-D were analyzed by native and sodium dodecyl sulfate gel electrophoresis.
Measurements and Main Results: The multimeric structure of native SP-D was found to be disrupted after provocation with allergen or a mixture of allergen and LPS. Interestingly, under reducing conditions, sodium dodecyl sulfate–polyacrylamide gel electrophoresis demonstrated that 7 of 15 patients with asthma developed an abnormal cross-linked SP-D band after segmental challenge with either allergen or a mixture of allergen with LPS but not LPS alone. Importantly, patients with asthma with cross-linked SP-D demonstrated significantly higher levels of BAL eosinophils, nitrogen oxides, IL-4, IL-5, IL-13, and S-nitrosothiol–SP-D compared with patients without cross-linked SP-D.
Conclusions: We conclude that segmental allergen challenge results in changes of SP-D multimeric structure and that these modifications are associated with an altered local inflammatory response in the distal airways.
doi:10.1164/rccm.201004-0654OC
PMCID: PMC3086753  PMID: 21131470
human asthma; pulmonary collectins; nitric oxide; surfactant proteins; biomarker
12.  The Role of Matrix Metalloproteinase-9 in Cigarette Smoke–induced Emphysema 
Rationale: Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction.
Objectives: To determine if MMP-9 causes cigarette smoke–induced emphysema using MMP-9 knockout mice and human samples.
Methods: Mouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury.
Measurements and Main Results: Mice deficient in MMP-9 develop the same degree of cigarette smoke–induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage.
Conclusions: These results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke–induced emphysema.
Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).
doi:10.1164/rccm.201005-0718OC
PMCID: PMC3086754  PMID: 21057003
pulmonary disease, chronic obstructive; laser capture microdissection; mice, knockout
13.  Radiographic Emphysema Predicts Low Bone Mineral Density in a Tobacco-exposed Cohort 
Rationale: Studies demonstrating an association between chronic obstructive pulmonary disease and low bone mineral density (BMD) implicate factors distinct from treatments and severity of lung disease in the pathogenesis of osteoporosis. Whereas emphysema has been independently associated with vascular disease and other comorbidities, its association with BMD has not been well studied.
Objectives: We explored the associations of BMD with computed tomography (CT) measures of emphysema and other risk factors in current and former smokers.
Methods: One hundred ninety subjects completed a CT scan, pulmonary function testing, questionnaires, and dual x-ray absorptiometry measurements of hip and lumbar spine BMD. Subjects were classified as having normal BMD, osteopenia, or osteoporosis. Demographic, physiologic, and radiographic characteristics were compared and the association of BMD with radiographic emphysema, airflow obstruction, and osteoporosis risk factors was assessed.
Measurements and Main Results: No difference existed in age, tobacco exposure, oral steroid use, or physical activity across BMD categories. Both osteopenia and osteoporosis were associated with the presence of airflow obstruction, inhaled corticosteroid use, and female sex, and demonstrated a significant relationship with the presence of visual emphysema (P = 0.0003). Quantitative emphysema, but not CT-measured indices of airway wall thickness, was inversely associated with BMD. Visual emphysema alone was a significant predictor of osteopenia/osteoporosis (odds ratio = 2.55; 95% confidence interval, 1.24–5.25) in a model including obstruction severity, age, sex, and inhaled and oral steroid use.
Conclusions: Radiographic emphysema is a strong, independent predictor of low BMD in current and former smokers. This relationship suggests a common mechanistic link between emphysema and osteopenia/osteoporosis.
doi:10.1164/rccm.201004-0666OC
PMCID: PMC3086755  PMID: 20935108
pulmonary disease, chronic obstructive; emphysema; osteoporosis
14.  An Empirical Study of Surrogates' Preferred Level of Control over Value-laden Life Support Decisions in Intensive Care Units 
Rationale: Despite ongoing ethical debate concerning who should control decisions to discontinue life support for incapacitated, critically ill patients, the perspectives of surrogate decision makers are poorly understood.
Objectives: To determine (1) what degree of decisional authority surrogates prefer for value-sensitive life support decisions compared with more technical biomedical decisions, and (2) what predicts surrogates' preferences for more control over life support decisions.
Methods: This was a prospective study of 230 surrogate decision makers for incapacitated, mechanically ventilated patients at high risk of death. Surrogates reported their preferred degree of decisional authority using the Degner Control Preferences Scale for two types of decisions: a value-sensitive decision about whether to discontinue life support and a decision regarding which antibiotic to prescribe for an infection.
Measurements and Main Results: The majority of surrogates (55%, 127/230; 95% confidence interval, 49–62%) preferred to have final control over the value-sensitive life support decision; 40% (91/230) wished to share control equally with the physician; 5% (12/230) of surrogates wanted the physician to make the decision. Surrogates preferred significantly more control over the value-sensitive life support decision compared with the technical decision about choice of antibiotics (P < 0.0001). Factors independently associated with surrogates' preference for more control over the life support decision were: less trust in the intensive care unit physician, male sex, and non-Catholic religious affiliation.
Conclusions: Surrogates vary in their desire for decisional authority for value-sensitive life support decisions, but prefer substantially more authority for this type of decision compared with technical, medical judgments. Low trust in physicians is associated with surrogates preferring more control of life support decisions.
doi:10.1164/rccm.201008-1214OC
PMCID: PMC3086756  PMID: 21037019
surrogate decision making; critical care; ethics; decisions; end-of-life care
15.  Upper Airway Structure and Body Fat Composition in Obese Children with Obstructive Sleep Apnea Syndrome 
Rationale: Mechanisms leading to obstructive sleep apnea syndrome (OSAS) in obese children are not well understood.
Objectives: The aim of the study was to determine anatomical risk factors associated with OSAS in obese children as compared with obese control subjects without OSAS.
Methods: Magnetic resonance imaging was used to determine the size of upper airway structure, and body fat composition. Paired analysis was used to compare between groups. Mixed effects regression models and conditional multiple logistic regression models were used to determine whether body mass index (BMI) Z-score was an effect modifier of each anatomic characteristic as it relates to OSAS.
Measurements and Main Results: We studied 22 obese subjects with OSAS (12.5 ± 2.8 yr; BMI Z-score, 2.4 ± 0.4) and 22 obese control subjects (12.3 ± 2.9 yr; BMI Z-score, 2.3 ± 0.3). As compared with control subjects, subjects with OSAS had a smaller oropharynx (P < 0.05) and larger adenoid (P < 0.01), tonsils (P < 0.05), and retropharyngeal nodes (P < 0.05). The size of lymphoid tissues correlated with severity of OSAS whereas BMI Z-score did not have a modifier effect on these tissues. Subjects with OSAS demonstrated increased size of parapharyngeal fat pads (P < 0.05) and abdominal visceral fat (P < 0.05). The size of these tissues did not correlate with severity of OSAS and BMI Z-score did not have a modifier effect on these tissues.
Conclusions: Upper airway lymphoid hypertrophy is significant in obese children with OSAS. The lack of correlation of lymphoid tissue size with obesity suggests that this hypertrophy is caused by other mechanisms. Although the parapharyngeal fat pads and abdominal visceral fat are larger in obese children with OSAS we could not find a direct association with severity of OSAS or with obesity.
doi:10.1164/rccm.201008-1249OC
PMCID: PMC3081285  PMID: 20935105
lymphoid hypertrophy; MRI; obese children
16.  Glycan Shielding of the Influenza Virus Hemagglutinin Contributes to Immunopathology in Mice 
Rationale: Pandemic influenza viruses historically have had few potential sites for N-linked glycosylation on the globular head of the hemagglutinin (HA) on emergence from the avian reservoir. Gain of glycans within antigenic sites of the HA during adaptation to the mammalian lung facilitates immune evasion.
Objectives: In this study, we sought to determine in mice how exposure to highly glycosylated viruses affects immunity to poorly glycosylated variants to model the emergence of a novel pandemic strain of a circulating subtype.
Methods: We engineered the 1968 H3N2 pandemic strain to express an additional two or four potential sites for glycosylation on the globular head of the HA. Mice were infected sequentially with highly glycosylated variants followed by poorly glycosylated variants and monitored for immune responses and disease.
Measurements and Main Results: The mutant with four additional glycosylation sites (+4 virus) elicited significantly lower antibody responses than the wild-type or +2 virus and was unable to elicit neutralizing antibodies. Mice infected with the +4 virus and then challenged with wild-type virus were not protected from infection and experienced significant T-cell–mediated immunopathology. Infection with a recent seasonal H1N1 virus followed by infection with the 2009 pandemic H1N1 elicited similar responses.
Conclusions: These data suggest that sequential infection with viral strains with different surface glycosylation can prime the host for immunopathology if a neutralizing antibody response matching the T-cell response is not present. This mechanism may have contributed to severe disease in young adults infected with the 2009 pandemic virus.
doi:10.1164/rccm.201007-1184OC
PMCID: PMC3159075  PMID: 20935106
influenza virus; glycosylation; pandemic; immunopathology; pneumonia
17.  A Concise Review of Pulmonary Sarcoidosis 
This is an update on sarcoidosis, focusing on etiology, diagnosis, and treatment. In the area of etiopathogenesis, we now have a better understanding of the immune response that leads to the disease as well as genetic factors that modify both the risk for the disease and its clinical outcome. Several groups have also identified possible agents as a cause for sarcoidosis. Although none of these potential causes has been definitely confirmed, there is increasing evidence to support that one or more infectious agents may cause sarcoidosis, although this organism may no longer be viable in the patient. The diagnosis of sarcoidosis has been significantly aided by new technology. This includes the endobronchial ultrasound, which has been shown to increase the yield of needle aspiration of mediastinal and hilar lymph nodes. The positive emission tomography scan has proven useful for selecting possible biopsy sites by identifying organ involvement not appreciated by routine methodology. It has also helped in assessing cardiac involvement. The biologic agents, such as the anti–tumor necrosis factor antibodies, have changed the approach to refractory sarcoidosis. There is increasing evidence that the clinician can identify which patient is most likely to benefit from such therapy. As new and more potent antiinflammatory agents have been developed, it is clear that there are other factors that burden the patient with sarcoidosis, including fatigue and sarcoidosis-associated pulmonary hypertension. There have been several recent studies demonstrating treatment options for these problems.
doi:10.1164/rccm.201006-0865CI
PMCID: PMC3081278  PMID: 21037016
mycobacterium; HLA; Löfgren syndrome; infliximab; pulmonary hypertension
18.  Ethnic Differences in the Effect of Asthma on Pulmonary Function in Children 
Rationale: The impact of asthma on chronic lung function deficits is well known. However, there has been little study of ethnic differences in these asthma-associated deficits.
Objectives: To examine whether there are ethnic differences in the effects of asthma on children's lung function.
Methods: We evaluated the impact of asthma on lung function in 3,245 Hispanic and non-Hispanic white school children (age 10–18 yr) in a longitudinal analysis of the Southern California Children's Health Study. Sex-specific mixed-effects regression spline models were fitted separately for each ethnic group.
Measurements and Main Results: Large deficits in flows were observed among children with asthma diagnosed before age 4 years regardless of ethnicity. Hispanic girls with asthma had greater deficits in flows than non-Hispanic girls and were largest for maximal midexpiratory flow (−5.13% compared with −0.58%, respectively). A bigger impact of asthma in Hispanic girls was also found for FEV1, FEF75, and PEF (P value 0.04, 0.07, and 0.005, respectively). These ethnic differences were limited to girls diagnosed after age 4 years. In boys, asthma was also associated with greater deficits in flows among Hispanic than in non-Hispanic white children (differences that were not statistically significant). Ethnic differences in prevalence of pets and pests in the home, health insurance coverage, parental education, and smoking did not explain the pattern of lung function differences.
Conclusions: Larger asthma-associated lung function deficits in Hispanics, especially among girls, merit further investigation to determine public health implications and to identify causes amenable to intervention.
doi:10.1164/rccm.200912-1863OC
PMCID: PMC3081280  PMID: 20889910
Hispanics; non-Hispanic whites; pulmonary function; asthma
19.  Autophagic Protein LC3B Confers Resistance against Hypoxia-induced Pulmonary Hypertension 
Rationale: Pulmonary hypertension (PH) is a progressive disease with unclear etiology. The significance of autophagy in PH remains unknown.
Objectives: To determine the mechanisms by which autophagic proteins regulate tissue responses during PH.
Methods: Lungs from patients with PH, lungs from mice exposed to chronic hypoxia, and human pulmonary vascular cells were examined for autophagy using electron microscopy and Western analysis. Mice deficient in microtubule-associated protein-1 light chain-3B (LC3B−/−), or early growth response-1 (Egr-1−/−), were evaluated for vascular morphology and hemodynamics.
Measurements and Main Results: Human PH lungs displayed elevated lipid-conjugated LC3B, and autophagosomes relative to normal lungs. These autophagic markers increased in hypoxic mice, and in human pulmonary vascular cells exposed to hypoxia. Egr-1, which regulates LC3B expression, was elevated in PH, and increased by hypoxia in vivo and in vitro. LC3B−/− or Egr-1−/−, but not Beclin 1+/−, mice displayed exaggerated PH during hypoxia. In vitro, LC3B knockdown increased reactive oxygen species production, hypoxia-inducible factor-1α stabilization, and hypoxic cell proliferation. LC3B and Egr-1 localized to caveolae, associated with caveolin-1, and trafficked to the cytosol during hypoxia.
Conclusions: The results demonstrate elevated LC3B in the lungs of humans with PH, and of mice with hypoxic PH. The increased susceptibility of LC3B−/− and Egr-1−/− mice to hypoxia-induced PH and increased hypoxic proliferation of LC3B knockdown cells suggest adaptive functions of these proteins during hypoxic vascular remodeling. The results suggest that autophagic protein LC3B exerts a protective function during the pathogenesis of PH, through the regulation of hypoxic cell proliferation.
doi:10.1164/rccm.201005-0746OC
PMCID: PMC3081281  PMID: 20889906
autophagy; hypoxia; hypertension, pulmonary
20.  Sex Hormones Are Associated with Right Ventricular Structure and Function 
Rationale: Sex hormones have effects on the left ventricle, but hormonal influences on the right ventricle (RV) are unknown.
Objectives: We hypothesized that sex hormones would be associated with RV morphology in a large cohort free of cardiovascular disease.
Methods: Sex hormones were measured by immunoassay and RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume, and end-systolic volume (RVESV) were measured by cardiac magnetic resonance imaging in 1,957 men and 1,738 postmenopausal women. The relationship between each hormone and RV parameter was assessed by multivariate linear regression.
Measurements and Main Results: Higher estradiol levels were associated with higher RVEF (β per 1 ln[nmol/L], 0.88; 95% confidence interval [CI], 0.32 to 1.43; P = 0.002) and lower RVESV (β per 1 ln[nmol/L], −0.87; 95% CI, −1.67 to −0.08; P = 0.03) in women using hormone therapy. In men, higher bioavailable testosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.97; 95% CI, 0.20 to 3.73; P = 0.03) and greater RV mass and volumes (P ≤ 0.01). Higher dehydroepiandrosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.37; 95% CI, 0.15 to 2.59; P = 0.03) and greater RV mass (β per 1 ln[nmol/L], 0.25; 95% CI, 0.00 to 0.49; P = 0.05) and volumes (P ≤ 0.001) in women.
Conclusions: Higher estradiol levels were associated with better RV systolic function in women using hormone therapy. Higher levels of androgens were associated with greater RV mass and volumes in both sexes.
doi:10.1164/rccm.201007-1027OC
PMCID: PMC3081282  PMID: 20889903
sex; sex hormones; right ventricle
21.  Metabolic Abnormalities in Children with Asthma 
Rationale: Childhood asthma and obesity have reached epidemic proportions worldwide, and the latter is also contributing to increasing rates of related metabolic disorders, such as diabetes. Yet, the relationship between asthma, obesity, and abnormal lipid and glucose metabolism is not well understood, nor has it been adequately explored in children.
Objectives: To analyze the relationship between asthma diagnosis and body mass in children across the entire range of weight percentile categories, and to test the hypothesis that early derangement in lipid and glucose metabolism is independently associated with increased risk for asthma.
Methods: Cross-sectional analysis of a representative sample of public school children from a statewide community-based screening program, including a total of 17,994 children, 4 to 12 years old, living in predominantly rural West Virginia, and enrolled in kindergarten, second, or fifth grade classrooms.
Measurements and Main Results: We analyzed demographics; family history; smoke exposure; parent-reported asthma diagnosis; body mass index; evidence of acanthosis nigricans as a marker for developing insulin resistance; and fasting serum lipid profile including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. Regardless of their body mass index percentile, children diagnosed with asthma were more likely than children without asthma to have higher triglyceride levels and acanthosis nigricans after controlling for sex differences and smoke exposure.
Conclusions: This study provides the first set of community-based data linking asthma, body mass, and metabolic variables in children. In particular, these findings uniquely describe a statistically significant association between asthma and abnormal lipid and glucose metabolism beyond body mass index associations.
doi:10.1164/rccm.201004-0603OC
PMCID: PMC3056222  PMID: 20851922
body mass index; cardiovascular risk; diabetes; insulin resistance; obesity
22.  Regulatory Haplotypes in ARG1 Are Associated with Altered Bronchodilator Response 
Rationale: β2-agonists, the most common treatment for asthma, have a wide interindividual variability in response, which is partially attributed to genetic factors. We previously identified single nucleotide polymorphisms in the arginase 1 (ARG1) gene, which are associated with β2-agonist bronchodilator response (BDR).
Objectives: To identify cis-acting haplotypes in the ARG1 locus that are associated with BDR in patients with asthma and regulate gene expression in vitro.
Methods: We resequenced ARG1 in 96 individuals and identified three common, 5′ haplotypes (denoted 1, 2, and 3). A haplotype-based association analysis of BDR was performed in three independent, adult asthma drug trial populations. Next, each haplotype was cloned into vectors containing a luciferase reporter gene and transfected into human airway epithelial cells (BEAS-2B) to ascertain its effect on gene expression.
Measurements and Main Results: BDR varied by haplotype in each of the three populations with asthma. Individuals with haplotype 1 were more likely to have higher BDR, compared to those with haplotypes 2 and 3, which is supported by odds ratios of 1.25 (95% confidence interval, 1.03–1.71) and 2.18 (95% confidence interval, 1.34–2.52), respectively. Luciferase expression was 50% greater in cells transfected with haplotype 1 compared to haplotypes 2 and 3.
Conclusions: The identified ARG1 haplotypes seem to alter BDR and differentially regulate gene expression with a concordance of decreased BDR and reporter activity from haplotypes 2 and 3. These findings may facilitate pharmacogenetic tests to predict individuals who may benefit from other therapeutic agents in addition to β2-agonists for optimal asthma management.
Clinical trial registered with www.clinicaltrials.gov (NCT00156819, NCT00046644, and NCT00073840).
doi:10.1164/rccm.201005-0758OC
PMCID: PMC3056223  PMID: 20851928
pharmacogenetics; asthma; β2-agonist
23.  Early Identification of Patients at Risk of Acute Lung Injury 
Rationale: Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies.
Objectives: To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS).
Methods: In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions.
Measurements and Main Results: Twenty-two hospitals enrolled 5,584 patients at risk. ALI developed a median of 2 (interquartile range 1–4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80 (95% confidence interval, 0.78–0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9–5.7).
Conclusions: ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies.
Clinical trial registered with www.clinicaltrials.gov (NCT00889772).
doi:10.1164/rccm.201004-0549OC
PMCID: PMC3056224  PMID: 20802164
respiratory distress syndrome, adult; prevention; prediction model; acute respiratory failure
24.  Increased Proteolysis, Myosin Depletion, and Atrophic AKT-FOXO Signaling in Human Diaphragm Disuse 
Rationale: Patients on mechanical ventilation who exhibit diaphragm inactivity for a prolonged time (case subjects) develop decreases in diaphragm force-generating capacity accompanied by diaphragm myofiber atrophy.
Objectives: Our objectives were to test the hypotheses that increased proteolysis by the ubiquitin-proteasome pathway, decreases in myosin heavy chain (MyHC) levels, and atrophic AKT-FOXO signaling play major roles in eliciting these pathological changes associated with diaphragm disuse.
Methods: Biopsy specimens were obtained from the costal diaphragms of 18 case subjects before harvest (cases) and compared with intraoperative specimens from the diaphragms of 11 patients undergoing surgery for benign lesions or localized lung cancer (control subjects). Case subjects had diaphragm inactivity and underwent mechanical ventilation for 18 to 72 hours, whereas this state in controls was limited to 2 to 4 hours.
Measurements and Main Results: With respect to proteolysis in cytoplasm fractions, case diaphragms exhibited greater levels of ubiquitinated-protein conjugates, increased activity of the 26S proteasome, and decreased levels of MyHCs and α-actin. With respect to atrophic signaling in nuclear fractions, case diaphragms exhibited decreases in phosphorylated AKT, phosphorylated FOXO1, increased binding to consensus DNA sequence for Atrogin-1 and MuRF-1, and increased supershift of DNA-FOXO1 complexes with specific antibodies against FOXO1, as well as increased Atrogin-1 and MuRF-1 transcripts in whole myofiber lysates.
Conclusions: Our findings suggest that increased activity of the ubiquitin-proteasome pathway, marked decreases in MyHCs, and atrophic AKT-FOXO signaling play important roles in eliciting the myofiber atrophy and decreases in diaphragm force generation associated with prolonged human diaphragm disuse.
doi:10.1164/rccm.200910-1487OC
PMCID: PMC3056225  PMID: 20833824
AKT; FOXO; ubiquitination; proteasome; myosin heavy chains
25.  Conditional Depletion of Airway Progenitor Cells Induces Peribronchiolar Fibrosis 
Rationale: The respiratory epithelium has a remarkable capacity to respond to acute injury. In contrast, repeated epithelial injury is often associated with abnormal repair, inflammation, and fibrosis. There is increasing evidence that nonciliated epithelial cells play important roles in the repair of the bronchiolar epithelium after acute injury. Cellular processes underlying the repair and remodeling of the lung after chronic epithelial injury are poorly understood.
Objectives: To identify cell processes mediating epithelial regeneration and remodeling after acute and chronic Clara cell depletion.
Methods: A transgenic mouse model was generated to conditionally express diphtheria toxin A to ablate Clara cells in the adult lung. Epithelial regeneration and peribronchiolar fibrosis were assessed after acute and chronic Clara cell depletion.
Measurements and Main Results: Acute Clara cell ablation caused squamous metaplasia of ciliated cells and induced proliferation of residual progenitor cells. Ciliated cells in the bronchioles and pro–surfactant protein C–expressing cells in the bronchiolar alveolar duct junctions did not proliferate. Epithelial cell proliferation occurred at multiple sites along the airways and was not selectively associated with regions around neuroepithelial bodies. Chronic Clara cell depletion resulted in ineffective repair and caused peribronchiolar fibrosis.
Conclusions: Colocalization of proliferation and cell type–specific markers demonstrate that Clara cells are critical airway progenitor cells. Continuous depletion of Clara cells resulted in persistent squamous metaplasia, lack of normal reepithelialization, and peribronchiolar fibrosis. Induction of proliferation in subepithelial fibroblasts supports the concept that chronic epithelial depletion caused peribronchiolar fibrosis.
doi:10.1164/rccm.201005-0744OC
PMCID: PMC3056226  PMID: 20870756
chronic obstructive pulmonary disease; bronchiolitis obliterans syndrome; squamous metaplasia; diphtheria toxin; progenitor cells

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