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1.  A Web-based, Tailored Asthma Management Program for Urban African-American High School Students 
Rationale: Urban African-American youth, aged 15–19 years, have asthma fatality rates that are higher than in whites and younger children, yet few programs target this population. Traditionally, urban youth are believed to be difficult to engage in health-related programs, both in terms of connecting and convincing.
Objectives: Develop and evaluate a multimedia, web-based asthma management program to specifically target urban high school students. The program uses “tailoring,” in conjunction with theory-based models, to alter behavior through individualized health messages based on the user's beliefs, attitudes, and personal barriers to change.
Methods: High school students reporting asthma symptoms were randomized to receive the tailored program (treatment) or to access generic asthma websites (control). The program was made available on school computers.
Measurements and Main Results: Functional status and medical care use were measured at study initiation and 12 months postbaseline, as were selected management behaviors. The intervention period was 180 days (calculated from baseline). A total of 314 students were randomized (98% African American, 49% Medicaid enrollees; mean age, 15.2 yr). At 12 months, treatment students reported fewer symptom-days, symptom-nights, school days missed, restricted-activity days, and hospitalizations for asthma when compared with control students; adjusted relative risk and 95% confidence intervals were as follows: 0.5 (0.4–0.8), p = 0.003; 0.4 (0.2–0.8), p = 0.009; 0.3 (0.1–0.7), p = 0.006; 0.5 (0.3–0.8), p = 0.02; and 0.2 (0.2–0.9), p = 0.01, respectively. Positive behaviors were more frequently noted among treatment students compared with control students. Cost estimates for program delivery were $6.66 per participating treatment group student.
Conclusions: A web-based, tailored approach to changing negative asthma management behaviors is economical, feasible, and effective in improving asthma outcomes in a traditionally hard-to-reach population.
doi:10.1164/rccm.200608-1244OC
PMCID: PMC1899296  PMID: 17290041
asthma; urban; adolescents; school-based; web-based
2.  A Web-based, Tailored Asthma Management Program for Urban African-American High School Students 
Rationale
Urban African-American youth, aged 15–19 years, have asthma fatality rates that are higher than in whites and younger children, yet few programs target this population. Traditionally, urban youth are believed to be difficult to engage in health-related programs, both in terms of connecting and convincing.
Objectives
Develop and evaluate a multimedia, web-based asthma management program to specifically target urban high school students. The program uses “tailoring,” in conjunction with theory-based models, to alter behavior through individualized health messages based on the user’s beliefs, attitudes, and personal barriers to change.
Methods
High school students reporting asthma symptoms were randomized to receive the tailored program (treatment) or to access generic asthma websites (control). The program was made available on school computers.
Measurements and Main Results
Functional status and medical care use were measured at study initiation and 12 months postbaseline, as were selected management behaviors. The intervention period was 180 days (calculated from baseline). A total of 314 students were randomized (98% African American, 49% Medicaid enrollees; mean age, 15.2 yr). At 12 months, treatment students reported fewer symptom-days, symptom-nights, school days missed, restricted-activity days, and hospitalizations for asthma when compared with control students; adjusted relative risk and 95% confidence intervals were as follows: 0.5 (0.4–0.8), p = 0.003; 0.4 (0.2–0.8), p = 0.009; 0.3 (0.1–0.7), p = 0.006; 0.5 (0.3–0.8), p = 0.02; and 0.2 (0.2–0.9), p = 0.01, respectively. Positive behaviors were more frequently noted among treatment students compared with control students. Cost estimates for program delivery were $6.66 per participating treatment group student.
Conclusions
A web-based, tailored approach to changing negative asthma management behaviors is economical, feasible, and effective in improving asthma outcomes in a traditionally hard-to-reach population.
doi:10.1164/rccm.200608-1244OC
PMCID: PMC1899296  PMID: 17290041
asthma; urban; adolescents; school-based; web-based
3.  Development of Chronic Bronchitis and Emphysema in β-Epithelial Na+ Channel–Overexpressing Mice 
Rationale: Chronic obstructive pulmonary disease is a leading cause of death worldwide, but its pathogenesis is not well understood. Previous studies have shown that airway surface dehydration in β-epithelial Na+ channel (βENaC)–overexpressing mice caused a chronic lung disease with high neonatal pulmonary mortality and chronic bronchitis in adult survivors.
Objectives: The aim of this study was to identify the initiating lesions and investigate the natural progression of lung disease caused by airway surface dehydration.
Methods: Lung morphology, gene expression, bronchoalveolar lavage, and lung mechanics were studied at different ages in βENaC-overexpressing mice.
Measurements and Main Results: Mucus obstruction in βENaC-overexpressing mice originated in the trachea in the first days of life and was associated with hypoxia, airway epithelial necrosis, and death. In surviving βENaC-overexpressing mice, mucus obstruction extended into the lungs and was accompanied by goblet cell metaplasia, increased mucin expression, and airway inflammation with transient perinatal increases in tumor necrosis factor-α and macrophages, IL-13 and eosinophils, and persistent increases in keratinocyte-derived cytokine (KC), neutrophils, and chitinases in the lung. βENaC-overexpressing mice also developed emphysema with increased lung volumes, distal airspace enlargement, and increased lung compliance.
Conclusions: Our studies demonstrate that airway surface dehydration is sufficient to initiate persistent neutrophilic airway inflammation with chronic airways mucus obstruction and to cause transient eosinophilic airway inflammation and emphysema. These results suggest that deficient airway surface hydration may play a critical role in the pathogenesis of chronic obstructive pulmonary diseases of different etiologies and serve as a target for novel therapies.
doi:10.1164/rccm.200708-1233OC
PMCID: PMC2277210  PMID: 18079494
chronic obstructive lung disease; epithelial Na+ channels; airway surface liquid; inflammation; mucus
4.  Derivation of Lung Epithelium from Human Cord Blood–derived Mesenchymal Stem Cells 
Rationale: Recent studies have suggested that both embryonic stem cells and adult bone marrow stem cells can participate in the regeneration and repair of diseased adult organs, including the lungs. However, the extent of airway epithelial remodeling with adult marrow stem cells is low, and there are no available in vivo data with embryonic stem cells. Human umbilical cord blood contains both hematopoietic and nonhematopoietic stem cells, which have been used clinically as an alternative to bone marrow transplantation for hematologic malignancies and other diseases.
Objectives: We hypothesized that human umbilical cord blood stem cells might be an effective alternative to adult bone marrow and embryonic stem cells for regeneration and repair of injured airway epithelium.
Methods: Human cord blood was obtained from normal deliveries at the University of Vermont. Cultured plastic adherent cells were characterized as mesenchymal stem cells (MSCs) by flow cytometry and differentiation assays. Cord blood–derived MSCs (CB-MSCs) were cultured in specialized airway growth media or with specific growth factors, including keratinocyte growth factor and retinoic acid. mRNA and protein expression were analyzed with PCR and immunofluorescent staining. CB-MSCs were systematically administered to immunotolerant, nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice. Lungs were analyzed for presence of human cells.
Measurements and Main Results: When cultured in specialized airway growth media or with specific growth factors, CB-MSCs differentially expressed Clara cell secretory protein (CCSP), cystic fibrosis transmembrane conductance regulator (CFTR), surfactant protein C, and thyroid transcription factor-1 mRNA, and CCSP and CFTR protein. Furthermore, CB-MSCs were easily transduced with recombinant lentiviral vectors to express human CFTR. After systemic administration to immunotolerant, NOD-SCID, mice, rare cells were found in the airway epithelium that had acquired cytokeratin and human CFTR expression.
Conclusions: CB-MSCs appear to be comparable to MSCs obtained from adult bone marrow in ability to express phenotypic markers of airway epithelium and to participate in airway remodeling in vivo.
doi:10.1164/rccm.200706-859OC
PMCID: PMC2277209  PMID: 18063840
cord blood stem cells; lung epithelium; lung remodeling; mesenchymal stem cells
5.  An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis 
Rationale: Tissue fibrosis is considered a dysregulated wound-healing response. Fibronectin containing extra type III domain A (EDA) is implicated in the regulation of wound healing. EDA-containing fibronectin is deposited during wound repair, and its presence precedes that of collagen.
Objectives: To investigate the role of EDA-containing fibronectin in lung fibrogenesis.
Methods: Primary lung fibroblasts from patients with idiopathic pulmonary fibrosis or from patients undergoing resection for lung cancer were assessed for EDA-containing fibronectin and α-smooth muscle actin (α-SMA) expression. Mice lacking the EDA domain of fibronectin and their wild-type littermates were challenged with the bleomycin model of lung fibrosis. Primary lung fibroblasts from these mice were assayed in vitro to determine the contribution of EDA-containing fibronectin to fibroblast phenotypes.
Measurements and Main Results: Idiopathic pulmonary fibrosis lung fibroblasts produced markedly more EDA-containing fibronectin and α-SMA than control fibroblasts. EDA-null mice failed to develop significant fibrosis 21 days after bleomycin challenge, whereas wild-type controls developed the expected increase in total lung collagen. Histologic analysis of EDA-null lungs after bleomycin showed less collagen and fewer α-SMA–expressing myofibroblasts compared with that observed in wild-type mice. Failure to develop lung fibrosis in EDA-null mice correlated with diminished activation of latent transforming growth factor (TGF)-β and decreased lung fibroblast responsiveness to active TGF-β in vitro.
Conclusions: The data show that EDA-containing fibronectin is essential for the fibrotic resolution of lung injury through TGF-β activation and responsiveness, and suggest that EDA-containing fibronectin plays a critical role in tissue fibrogenesis.
doi:10.1164/rccm.200708-1291OC
PMCID: PMC2267338  PMID: 18096707
fibrosis; fibronectin; TGF-β; myofibroblast
6.  Low-Level Fiber-induced Radiographic Changes Caused by Libby Vermiculite 
Rationale: From 1921 to 1990, vermiculite ore from Libby, Montana, was shipped worldwide for commercial and residential use. A 1980 study of a manufacturing facility using Libby vermiculite was the first to demonstrate a small but significant prevalence of pleural chest radiographic changes associated with amphibole fibers contained in the ore.
Objectives: This follow-up study of the original cohort evaluated the extent of radiographic changes and cumulative fiber exposure (CFE) 25 years after cessation of exposure.
Methods: From the original cohort of 513 workers, 431 (84%) were living and available for participation and exposure reconstruction. Of these, 280 (65%) completed both chest radiographs and interviews. Primary outcomes were pleural and/or interstitial changes.
Measurements and Main Results: Pleural and interstitial changes were demonstrated in 80 (28.7%) and 8 (2.9%) participants, respectively. Of those participants with low lifetime CFE of less than 2.21 fiber/cc-years, 42 (20%) had pleural changes. A significant (P < 0.001) exposure–response relationship of pleural changes with CFE was demonstrated, ranging from 7.1 to 54.3% from the lowest to highest exposure quartile. Removal of individuals with commercial asbestos exposure did not alter this trend.
Conclusions: This study indicates that exposure within an industrial process to Libby vermiculite ore is associated with pleural thickening at low lifetime CFE levels. The propensity of the Libby amphibole fibers to dramatically increase the prevalence of pleural changes 25 years after cessation of exposure at low CFE levels is a concern in view of the wide national distribution of this ore for commercial and residential use.
doi:10.1164/rccm.200706-841OC
PMCID: PMC2267337  PMID: 18063841
vermiculite; pleural disease; amphiboles; fibrosis; mineral fiber
7.  Long-Term Use of Supplemental Multivitamins, Vitamin C, Vitamin E, and Folate Does Not Reduce the Risk of Lung Cancer 
Rationale: Lung cancer is the leading cause of cancer-related mortality in the United States. Although supplements are used by half the population, limited information is available about their specific effect on lung cancer risk.
Objectives: To explore the association of supplemental multivitamins, vitamin C, vitamin E, and folate with incident lung cancer.
Methods: Prospective cohort of 77,721 men and women aged 50–76 years from Washington State in the VITAL (VITamins And Lifestyle) study. Cases were identified through the Seattle–Puget Sound SEER (Surveillance, Epidemiology, and End Results) cancer registry.
Measurements and Main Results: Hazard ratios (HRs) for incident lung cancer according to 10-year average daily use of supplemental multivitamins, vitamin C, vitamin E, and folate. A total of 521 cases of lung cancer were identified. Adjusting for smoking, age, and sex, there was no inverse association with any supplement. Supplemental vitamin E was associated with a small increased risk of lung cancer (HR, 1.05 for every 100-mg/d increase in dose; 95% confidence interval [CI], 1.00–1.09; P = 0.033). This risk of supplemental vitamin E was largely confined to current smokers (HR, 1.11 for every 100-mg/d increase; 95% CI, 1.03–1.19; P < 0.01) and was greatest for non–small cell lung cancer (HR, 1.07 for every 100-mg/d increase; 95% CI, 1.02–1.12; P = 0.004).
Conclusions: Supplemental multivitamins, vitamin C, vitamin E, and folate were not associated with a decreased risk of lung cancer. Supplemental vitamin E was associated with a small increased risk. Patients should be counseled against using these supplements to prevent lung cancer.
doi:10.1164/rccm.200709-1398OC
PMCID: PMC2258445  PMID: 17989343
bronchial neoplasm; diet; dietary supplements; public health
8.  Survival after Surgery in Stage IA and IB Non–Small Cell Lung Cancer 
Rationale: Whether histologic subtype of non–small cell lung cancer (NSCLC) has an important effect on prognosis after surgery is unknown.
Objectives: We hypothesized that we could predict mortality more effectively by integrating precise tumor size and histology rather than relying on conventional staging.
Methods: We used the SEER (Surveillance, Epidemiology, and End Results) registry. Inclusion criteria were as follows: (1) primary squamous cell or adenocarcinoma; (2) potentially curative surgery, defined as a lobectomy or bilobectomy; (3) lymph node dissection performed; and (4) pathologic stage IA or IB.
Measurements and Main Results: From 1988 to 2000, 7,965 patients were included. For both all-cause and lung cancer–associated mortality, tumor size demonstrated the strongest association (log-rank P < 0.0001 for each). When tumors were small (⩽2 cm), lung cancer–associated mortality was similar for adenocarcinoma when compared with squamous cell carcinoma. When tumors were 3 cm or larger in size, lung cancer–associated mortality was higher for adenocarcinoma. The increased risk of lung cancer–associated mortality with adenocarcinoma was more pronounced in those younger than 65 years. Survival prediction using precise size and histology had much better discriminatory power than conventional TNM (tumor-node-metastasis) staging (P = 0.005).
Conclusions: Staging that takes into account size, histology, late recurrence risk, and patient age is more accurate than the current TNM system and is clinically relevant because improved prediction can facilitate better decisions on the use of adjuvant chemotherapy.
doi:10.1164/rccm.200706-815OC
PMCID: PMC2258444  PMID: 18006887
lung cancer; lung cancer staging; adenocarcinoma; lung cancer epidemiology
9.  Interaction between Smoking and Genetic Factors in the Development of Chronic Bronchitis 
Rationale: Smoking is a primary risk factor for chronic bronchitis, emphysema, and chronic obstructive pulmonary disease, but since not all smokers develop disease, it has been suggested that some individuals may be more susceptible to exogenous factors, such as smoking, and that this susceptibility could be genetically determined.
Objectives: The aim of the present study was to assess, in a population-based sample of twins, the following: (1) to what extent genetic factors contribute to the development of chronic bronchitis, including emphysema, taking sex into consideration, and (2) whether the genetic influences on chronic bronchitis, including emphysema, are separate from those for smoking behavior.
Methods: Disease cases and smoking habits were identified in 44,919 twins older than 40 years from the Swedish Twin Registry. Disease was defined as self-reported chronic bronchitis or emphysema, or recurrent cough with phlegm. Individuals who had smoked 10 pack-years or more were defined as smokers. Univariate and bivariate structural equation models were used to estimate the heritability specific for chronic bronchitis and that in common with smoking.
Measurements and Main Results: The heritability estimate for chronic bronchitis was a moderate 40% and only 14% of the genetic influences were shared with smoking.
Conclusions: Genetic factors independent of those related to smoking habits play a role in the development of chronic bronchitis.
doi:10.1164/rccm.200704-565OC
PMCID: PMC2258443  PMID: 18048810
chronic bronchitis; smoking; chronic obstructive pulmonary disease; twin study; genes
10.  Chronic Obstructive Pulmonary Disease in Hispanics 
Hispanics are individuals whose ancestry can be traced to Spain and/or areas previously under Spanish control (e.g., Mexico, Puerto Rico). They are a rapidly growing subset of the population of the United States and are quite diverse in their racial ancestry, country of origin, area of residence, socioeconomic status, tobacco use, and access to health care. Current evidence suggests that the prevalence and morbidity of chronic obstructive pulmonary disease (COPD) vary widely among Hispanic-American nations, with similar but limited findings among Hispanic subgroups in the United States. Potential reasons for such variation include differences in racial ancestry and genetic susceptibility, exposure to tobacco smoke and/or biomass smoke, access to health care, and disease management. Future studies of COPD in Hispanics should include large samples of subgroups that are well defined with regard to self-reported ethnicity, country of origin, area of residence, tobacco use, and socioeconomic status. Areas that need to be carefully examined include validation of COPD diagnoses for epidemiologic studies (e.g., by radiologic assessment), COPD in high-risk groups (e.g., Puerto Ricans), impact of biomass smoke (in rural areas) and air pollution (in urban areas) on COPD morbidity, effects of migration and acculturation on COPD prevalence and morbidity among Hispanic subgroups in the United States, development of reference values for spirometry, smoking cessation, and overcoming barriers to management. Public health measures, such as effective smoking prevention and cessation programs, reduction of air pollution and exposure to biomass smoke, and improved access to health care, would help reduce the burden of COPD among Hispanics in the United States and Latin America.
doi:10.1164/rccm.200708-1274PP
PMCID: PMC2258442  PMID: 18029789
chronic obstructive pulmonary disease; genetics; Hispanics; risk factors
11.  Racial Differences in Waiting List Outcomes in Chronic Obstructive Pulmonary Disease 
Rationale: Blacks with chronic illness have poorer outcomes than whites in the United States. The health outcomes of minorities with chronic obstructive pulmonary disease (COPD) on the lung transplant waiting list have not been studied.
Objectives: To compare outcomes of black and white patients with COPD after listing for lung transplantation in the United States.
Methods: Retrospective cohort study of all 280 non-Hispanic black and 5,272 non-Hispanic white adults 40 years and older with COPD listed for lung transplantation in the United States between 1995 and 2004.
Measurements and Main Results: Blacks with COPD were more likely to have pulmonary hypertension, obesity, and diabetes; to lack private health insurance; and to live in poorer neighborhoods than whites. Blacks were less likely to undergo transplantation after listing compared with whites, despite adjustment for age, lung function, pulmonary hypertension, cardiovascular risk factors, insurance coverage, and poverty level (adjusted hazard ratio, 0.83; 95% confidence interval, 0.70–0.98; P = 0.03). This was accompanied by a greater risk of dying or being removed from the list among blacks (unadjusted hazard ratio, 1.31; 95% confidence interval, 1.05–1.63; P = 0.02).
Conclusions: After listing for lung transplantation, black patients with COPD were less likely to undergo transplantation and more likely to die or be removed from the list compared with white patients. Unequal access to care may have contributed to these differences.
doi:10.1164/rccm.200708-1260OC
PMCID: PMC2258441  PMID: 18006881
racial disparities; lung transplantation; survival; competing risks; black or African American
12.  Ozone, Oxidant Defense Genes, and Risk of Asthma during Adolescence 
Rationale: Although oxidative stress is a cardinal feature of asthma, the roles of oxidant air pollutants and antioxidant genes heme oxygenase 1 (HMOX-1), catalase (CAT), and manganese superoxide dismutase (MNSOD) in asthma pathogenesis have yet to be determined.
Objectives: We hypothesized that the functional polymorphisms of HMOX-1 ([GT]n repeat), CAT (−262C>T −844C>T), and MNSOD (Ala-9Val) are associated with new-onset asthma, and the effects of these variants vary by exposure to ozone, a potent oxidant air pollutant.
Methods: We assessed this hypothesis in a population-based cohort of non-Hispanic (n = 1,125) and Hispanic white (n = 586) children who resided in 12 California communities and who were followed annually for 8 years to ascertain new-onset asthma.
Measurements and Main Results: Air pollutants were continuously measured in each of the study communities during the 8 years of study follow-up. HMOX-1 “short” alleles (<23 repeats) were associated with a reduced risk for new-onset asthma among non-Hispanic whites (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.41–0.99). This protective effect was largest in children residing in low-ozone communities (HR, 0.48; 95% CI, 0.25–0.91) (interaction P value = 0.003). Little evidence for an association with HMOX-1 was observed among Hispanic children. In contrast, Hispanic children with a variant of the CAT-262 “T” allele (CT or TT) had an increased risk for asthma (HR, 1.78; P value = 0.01). The effects of these polymorphisms were not modified by personal smoking or secondhand-smoke exposure.
Conclusions: Functional promoter variants in CAT and HMOX-1 showed ethnicity-specific associations with new-onset asthma. Oxidant gene protection was restricted to children living in low-ozone communities.
doi:10.1164/rccm.200706-863OC
PMCID: PMC2258440  PMID: 18048809
asthma; catalase; heme oxygenase-1; MnSOD; oxidative stress; ozone
13.  Disease-Specific Gene Expression Profiling in Multiple Models of Lung Disease 
Rationale: Microarray technology is widely employed for studying the molecular mechanisms underlying complex diseases. However, analyses of individual diseases or models of diseases frequently yield extensive lists of differentially expressed genes with uncertain relationships to disease pathogenesis.
Objectives: To compare gene expression changes in a heterogeneous set of lung disease models in order to identify common gene expression changes seen in diverse forms of lung pathology, as well as relatively small subsets of genes likely to be involved in specific pathophysiological processes.
Methods: We profiled lung gene expression in 12 mouse models of infection, allergy, and lung injury. A linear model was used to estimate transcript expression changes for each model, and hierarchical clustering was used to compare expression patterns between models. Selected expression changes were verified by quantitative polymerase chain reaction.
Measurements and Main Results: A total of 24 transcripts, including many involved in inflammation and immune activation, were differentially expressed in a substantial majority (9 or more) of the models. Expression patterns distinguished three groups of models: (1) bacterial infection (n = 5), with changes in 89 transcripts, including many related to nuclear factor-κB signaling, cytokines, chemokines, and their receptors; (2) bleomycin-induced diseases (n = 2), with changes in 53 transcripts, including many related to matrix remodeling and Wnt signaling; and (3) T helper cell type 2 (allergic) inflammation (n = 5), with changes in 26 transcripts, including many encoding epithelial secreted molecules, ion channels, and transporters.
Conclusions: This multimodel dataset highlights novel genes likely involved in various pathophysiological processes and will be a valuable resource for the investigation of molecular mechanisms underlying lung disease pathogenesis.
doi:10.1164/rccm.200702-333OC
PMCID: PMC2258439  PMID: 18029791
gene expression; infection; asthma; fibrosis
14.  Cardiovascular Morbidity in Obstructive Sleep Apnea 
Sleep-disordered breathing and obstructive sleep apnea (OSA) are highly prevalent disorders throughout the lifespan, which may affect up to 2–10% of the population, and have now been firmly associated with an increased risk for cardiovascular and neurobehavioral complications. Nevertheless, the overall pathophysiologic mechanisms mediating end-organ injury in OSA remain undefined, particularly due to the very frequent coexistence of other disease states, such as obesity, that clearly complicate the potential cause–effect relationships. Two major, and to some extent overlapping, mechanisms have been proposed to explain the morbid consequences of OSA, namely increased generation and propagation of reactive oxygen species and initiation and amplification of inflammatory processes. The evidence supporting the validity of these concepts as well as that detracting from such mechanisms will be critically reviewed in the context of clinical and laboratory-based approaches. In addition, some of the contradictory issues raised by such evaluation of the literature will be interpreted in the context of putative modifications of the individual responses to OSA, as determined by genetic variants among susceptibility-related genes, and also by potential environmental modulators of the phenotypic expression of any particular end-organ morbidity associated with OSA.
doi:10.1164/rccm.200608-1190PP
PMCID: PMC2258438  PMID: 17975198
inflammation; oxidative stress; reactive oxygen species; intermittent hypoxia; sleep fragmentation
15.  Relation between Shunt, Aeration, and Perfusion in Experimental Acute Lung Injury 
Rationale: In a pulmonary process characterized by spatially heterogeneous loss of aeration, the impairment of gas exchange is expected to depend on the regional distribution of perfusion relative to that of aeration.
Objectives: To investigate how regional aeration, shunt, and perfusion are interrelated at different levels of end-expiratory pressure and how their interplay relates to global shunt fraction in acute lung injury.
Methods: Regional shunt and perfusion were assessed by imaging with positron emission tomography the pulmonary kinetics of [13N]nitrogen infused in saline solution in five sheep after lung lavage. The lung field was divided in six horizontal regions.
Measurements and Main Results: Each animal showed an inverse relation between regional shunt (Fs) and gas (Fg) fractions: Fs = −m · Fg + Fs0. This relation was similar among animals (m = 1.25 ± 0.14, Fs0 = 0.75 ± 0.15) and invariant with end-expiratory pressure, despite lack of correlation between global shunt and gas fractions and large interanimal variability in global shunt fraction. When this relation was used to estimate global shunt fraction as a perfusion-weighted average of the estimates of regional shunt fraction derived from regional gas fraction, 72% of the interanimal variability in global shunt fraction could be explained.
Conclusions: Despite large interanimal variability in global shunt fraction, there was a consistent inverse relation between regional shunt and gas fractions, independent of end-expiratory pressure. Most of the interanimal variability in global shunt fraction could be explained by the combined effect of this relation and the distribution of perfusion on regional shunt, rather than by differences in global aeration.
doi:10.1164/rccm.200703-484OC
PMCID: PMC2218852  PMID: 17932380
artificial respiration; adult respiratory distress syndrome; positron emission tomography; mechanical ventilators; X-ray computed tomography
16.  Gremlin-mediated Decrease in Bone Morphogenetic Protein Signaling Promotes Pulmonary Fibrosis 
Rationale: Members of the transforming growth factor (TGF)-β superfamily, including TGF-βs and bone morphogenetic proteins (BMPs), are essential for the maintenance of tissue homeostasis and regeneration after injury. We have observed that the BMP antagonist, gremlin, is highly up-regulated in idiopathic pulmonary fibrosis (IPF).
Objectives: To investigate the role of gremlin in the regulation of BMP signaling in pulmonary fibrosis.
Methods: Progressive asbestos-induced fibrosis in the mouse was used as a model of human IPF. TGF-β and BMP expression and signaling activities were measured from murine and human fibrotic lungs. The mechanism of gremlin induction was analyzed in cultured lung epithelial cells. In addition, the possible therapeutic role of gremlin inhibition was tested by administration of BMP-7 to mice after asbestos exposure.
Measurements and Main Results: Gremlin mRNA levels were up-regulated in the asbestos-exposed mouse lungs, which is in agreement with the human IPF biopsy data. Down-regulation of BMP signaling was demonstrated by reduced levels of Smad1/5/8 and enhanced Smad2 phosphorylation in asbestos-treated lungs. Accordingly, analyses of cultured human bronchial epithelial cells indicated that asbestos-induced gremlin expression could be prevented by inhibitors of the TGF-β receptor and also by inhibitors of the mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase pathways. BMP-7 treatment significantly reduced hydroxyproline contents in the asbestos-treated mice.
Conclusions: The TGF-β and BMP signaling balance is important for lung regenerative events and is significantly perturbed in pulmonary fibrosis. Rescue of BMP signaling activity may represent a potential beneficial strategy for treating human pulmonary fibrosis.
doi:10.1164/rccm.200706-945OC
PMCID: PMC2218851  PMID: 17975199
gremlin; pulmonary fibrosis; bone morphogenetic protein; transforming growth factor-β
17.  Airway Smooth Muscle in Bronchial Tone, Inflammation, and Remodeling 
Airway smooth muscle (ASM) plays a pivotal role in modulating bronchomotor tone but also orchestrates and perpetuates airway inflammation and remodeling. Despite substantial research, there remain important unanswered questions. In 2006, the National Heart, Lung, and Blood Institute sponsored a workshop to define new directions in ASM biology. Important questions concerning the key functions of ASM include the following: Does developmental dysregulation of ASM function promote airway disease, what key signaling pathways in ASM evoke airway hyperresponsiveness in vivo, do alterations in ASM mass affect excitation–contraction coupling, and can ASM modulate airway inflammation and remodeling in a physiologically relevant manner? This workshop identified critical issues in ASM biology to delineate areas for scientific investigation in the identification of new therapeutic and diagnostic approaches in asthma, chronic obstructive pulmonary disease, and cystic fibrosis.
doi:10.1164/rccm.200708-1217PP
PMCID: PMC2218850  PMID: 18006883
myocyte; signal transduction; force generation; migration; remodeling
18.  Chromosomal Aneusomy in Bronchial High-Grade Lesions Is Associated with Invasive Lung Cancer 
Rationale: The development of lung cancer (LC) is accompanied by field changes in the airway mucosa that may have prognostic importance.
Objectives: To compare patients with prevalent LC to control subjects regarding their histologic dysplasia scores and chromosomal aneusomy as measured by fluorescence in situ hybridization (FISH).
Methods: The most advanced bronchial histology lesion was assessed from each of 44 LC cases and 90 cancer-free control subjects using a four-color FISH probe set encompassing the chromosome 6 centromere, 5p15.2, 7p12 (epidermal growth factor receptor), and 8q24 v-myc myelocytomatosis viral oncogene homolog (MYC) sequences. Histology grades were coded as dysplasia (moderate or severe) or carcinoma in situ (CIS).
Measurements and Main Results: CIS was the highest histologic grade for 32 subjects, and dysplasia was the highest grade for 102 subjects (54 moderate, 48 severe). Chromosomal aneusomy was seen in 64% of the LC cases, but in only 31% of the control subjects (odds ratio [OR], 4.68; 95% confidence interval [CI]. 1.97–11.04). Among those with any level of dysplasia, the OR for positive FISH and LC was 2.28 (95% CI, 0.75–6.86). Among those with CIS, the OR for positive FISH and LC was 5.84 (95% CI, 1.31–26.01).
Conclusions: Chromosomal aneusomy is associated with LC. Prospective examination of aneusomy as a precursor lesion that predicts LC is needed.
doi:10.1164/rccm.200708-1142OC
PMCID: PMC2218849  PMID: 17989344
chromosomal aneusomy; fluorescence in situ hybridization; carcinoma in situ; premalignancy
19.  The Synergistic Interactions of Allergic Lung Inflammation and Intratracheal Cationic Protein 
Rationale: Airways hyperresponsiveness (AHR) is a hallmark feature of asthma, and can be caused by various disparate mechanisms. Mouse models of AHR have been useful for studying these mechanisms in isolation, but such models still typically do not exhibit the same degree of AHR as seen in severe human asthma. We hypothesized that more severe AHR in mice could be achieved by imbuing them with more than one mechanism of AHR.
Objectives: We sought to determine if the airway wall thickening accompanying allergic inflammation and the exaggerated smooth muscle shortening induced by intratracheal cationic protein could act together to produce a severe form of AHR.
Methods: We used the forced oscillation technique to measure methacholine responsiveness in BALB/c mice that had been sensitized and challenged with ovalbumin followed by an intratracheal instillation of poly-l-lysine.
Measurements and Main Results: We found that both ovalbumin and poly-l-lysine treatment alone caused moderate levels of AHR. When the two treatments were combined, however, they synergized in terms of their effect on lung stiffness to an extent that could even be fatal, reflecting a significantly enhanced level of airway closure.
Conclusions: Our results suggest that mechanistic synergy between airway wall thickening and exaggerated smooth muscle shortening produces a more germane mouse model of asthma that may have particular relevance to the pathophysiology of the acute severe asthma exacerbation.
doi:10.1164/rccm.200706-832OC
PMCID: PMC2218848  PMID: 17962637
airway hyperresponsiveness; methacholine; mouse model; asthma exacerbation
20.  CD40 and CD80/86 Act Synergistically to Regulate Inflammation and Mortality in Polymicrobial Sepsis 
Rationale: Costimulatory molecules, including the CD40–CD154 and CD80/86–CD28 dyads, play a prominent role in regulating inflammation in the adaptive immune response. Studies from our group and others suggest a potentially important role for these costimulatory cascades in innate immunity as well.
Objectives: To determine the role of CD80/86 alone and in combination with CD40 in lethal polymicrobial sepsis in mice and humans.
Methods: The murine cecal ligation and puncture (CLP) model was used to determine the role of CD80/86 alone and in combination with CD40 using wild-type mice, CD80/86−/− mice, and novel CD40/80/86−/− mice. Expression of cell-bound and soluble costimulatory molecules was assessed in humans via ELISA and flow cytometry.
Measurements and Main Results: Lethal CLP was associated with up-regulation of CD40 and CD80/86 and their respective ligands CD28 and CD154 on innate effector cells. Blockade or deletion of CD80/86 attenuated mortality and inflammatory cytokine production during CLP. CD40/80/86−/− mice exhibited further reductions in mortality, lung injury, and inflammatory cytokine production compared with CD80/86−/− mice. Finally, humans with sepsis had increased monocyte expression of CD40 and CD80 compared with healthy control subjects; with higher levels in subjects requiring vasopressor support. Levels of soluble CD28 and CD154 were significantly higher in patients who died compared with those who lived.
Conclusions: These data demonstrate a central role for CD40 and CD80/86 in the innate immune response and suggest that combined inhibition of CD40 and CD80/86 may improve mortality in sepsis. Expression of costimulatory molecules may serve as biomarkers for outcome in septic patients.
doi:10.1164/rccm.200703-515OC
PMCID: PMC2218847  PMID: 17989345
costimulation; innate immunity; sepsis
21.  Potential Value of Regionalized Intensive Care for Mechanically Ventilated Medical Patients 
Rationale: Regionalization has been proposed as a method to improve outcomes for medical patients receiving mechanical ventilation in the intensive care unit.
Objectives: To determine the number of patients who would be affected by regionalization and the potential mortality reduction under a regionalized system of care.
Methods: We performed a retrospective cohort study with Monte Carlo simulation, using 2001 state discharge data from eight states representing 42% of the U.S. population. Adult medical patients undergoing invasive mechanical ventilation were identified. Patient location and hospital mortality rates were obtained from the discharge data; estimates of the relative risk reduction in hospital mortality for high-volume hospitals compared with low-volume hospitals were obtained from the published literature and applied to the cohort.
Measurements and Main Results: Of 180,976 adult medical patients who underwent mechanical ventilation at 1,170 nonfederal hospitals, 83,050 (46%) received mechanical ventilation at 887 (76%) hospitals with low annual volumes (fewer than 275 patients per year). Using published risk estimates, approximately 4,720 lives per year (95% range, 2,522–6,744) could potentially be saved in the 8 states by routinely transferring patients from low- to high-volume hospitals, representing a number needed to treat of 15.7. The median distance that patients would need to travel to reach a high-volume hospital was 8.5 miles (interquartile range, 4.0–21.2 mi).
Conclusions: Regionalization of intensive care could potentially improve survival for patients undergoing mechanical ventilation. Transfer distances are modest for most patients.
doi:10.1164/rccm.200708-1214OC
PMCID: PMC2218846  PMID: 18006884
mechanical ventilation; triage; transportation of patients; critical care; Monte Carlo method
22.  Cross-shift Airway Responses and Long-Term Decline in FEV1 in Cotton Textile Workers 
Rationale: Acute airway response, measured as cross-shift change in FEV1, to cotton dust may lead to subsequent chronic loss of lung function in exposed workers.
Objectives: To explore the association between the magnitude and frequency of cross-shift change and chronic loss of FEV1.
Methods: Four hundred eight cotton workers and 417 silk workers from Shanghai textile mills were observed prospectively for 20 years, with cross-shift measurements at baseline and follow-up surveys at approximate 5-year intervals. To account for repeated measures of 5-year change, generalized estimating equations were used to estimate the relationship between the magnitude of cross-shift change in FEV1 (ΔFEV1) and subsequent 5-year annualized change. Linear regression models were used to examine the association between the number of drops in cross-shift FEV1 (ΔFEV1 < 0) and annualized change over the entire study period.
Measurements and Main Results: Exposure to cotton dust was associated with a 10 ml/year decrement in 5-year annualized FEV1 decline. In addition, every 10 ml in ΔFEV1 drop was associated with an additional 1.5 ml/year loss in annualized FEV1 decline. The association between the frequency of drops and annualized decline was stronger for cotton workers than for silk workers over the entire study period.
Conclusions: Cotton workers had larger and more frequent drops, as well as excessive chronic declines in FEV1, than did silk workers. The magnitude and frequency of cross-shift drops were associated with chronic loss in FEV1 over the entire 20-year period examined.
doi:10.1164/rccm.200702-318OC
PMCID: PMC2720104  PMID: 17975204
cross-shift FEV1 change; chronic changes in lung function; cotton textile workers; cotton dust; occupational lung disease
23.  Racial Variation in the Incidence, Care, and Outcomes of Severe Sepsis 
Rationale: Higher rates of sepsis have been reported in minorities.
Objectives: To explore racial differences in the incidence and associated case fatality of severe sepsis, accounting for clinical, social, health care service delivery, and geographic characteristics.
Methods: Retrospective population-based cohort study using hospital discharge and U.S. Census data for all persons (n = 71,102,655) living in 68 hospital referral regions in six states.
Measurements and Main Results: Age-, sex- and race-standardized severe sepsis incidence and inpatient case fatality rates, adjusted incidence rate ratios, and adjusted intensive care unit (ICU) admission and case fatality rate differences. Of 8,938,111 nonfederal hospitalizations, 282,292 had severe sepsis. Overall, blacks had the highest age- and sex-standardized population-based incidence (6.08/1,000 vs. 4.06/1,000 for Hispanics and 3.58/1,000 for whites) and ICU case fatality (32.1 vs. 30.4% for Hispanics and 29.3% for whites, P < 0.0001). Adjusting for differences in poverty in their region of residence, blacks still had a higher population-based incidence of severe sepsis (adjusted rate ratio, 1.44 [95% CI, 1.42–1.46]) than whites, but Hispanics had a lower incidence (adjusted rate ratio, 0.91 [0.90–0.92]). Among patients with severe sepsis admitted to the ICU, adjustments for clinical characteristics and the treating hospital fully explained blacks' higher ICU case fatality.
Conclusions: Higher adjusted black incidence and the lower Hispanic incidence may reflect residual confounding, or it could signal biologic differences in susceptibility. Focused interventions to improve processes and outcomes of care at the hospitals that disproportionately treat blacks could narrow disparities in overall mortality from severe sepsis.
doi:10.1164/rccm.200703-480OC
PMCID: PMC2720103  PMID: 17975201
severe sepsis; epidemiology; race; clinical practice variations
24.  Autoantibodies in Patients with Chronic Obstructive Pulmonary Disease 
Rationale: Adaptive immune responses are present in patients with chronic obstructive pulmonary disease (COPD), and it has been postulated that these processes could be autoreactive.
Objectives: To ascertain if humoral autoimmunity could play a role in COPD pathogenesis.
Methods: Circulating IgG autoantibodies were detected by immunofluorescence and immunoprecipitation. Immunohistochemistry and immunofluorescence were used to evaluate intrapulmonary IgG and complement (C3) deposition in human lung explants. Autoantibody pathogenicity was also investigated with an antibody-dependent cell-mediated cytotoxicity assay.
Measurements and Main Results: The prevalence of anti–HEp-2 epithelial cell autoantibodies in 47 smokers/former smokers with COPD (GOLD stages 1–4) was greater than among 8 subjects with a smoking history but normal spirometry and 21 healthy control subjects who had never smoked (68 vs. 13 vs. 10%, respectively; P < 0.0001). Antibodies against primary pulmonary epithelial cells were found in 12 of 12 patients with COPD versus 3 of 12 never-smoked control subjects (P < 0.001). Self-antigens immunoprecipitated from 34 of 35 (97%) of COPD plasmas (vs. 0/12 never-smoked controls). Antibodies against a particular 130-kD autoantigen (n = 7) were associated with decreased body mass index (23.2 ± 2.1 vs. 29.5 ± 1.0 kg/m2, P = 0.007). Intrapulmonary immune complexes were present in six of six and C3 was seen in five of six COPD lung explants, unlike zero of six and one of six normals, respectively. Cytotoxicity of pulmonary epithelial cells by allogeneic mononuclear cells also increased 46% after incubation with COPD plasmas (n = 10), compared with identical treatments with eight normal specimens (P = 0.03).
Conclusions: IgG autoantibodies with avidity for pulmonary epithelium, and the potential to mediate cytotoxicity, are prevalent in patients with COPD. Autoreactive adaptive immune responses may be important in the etiology of this disease.
doi:10.1164/rccm.200701-014OC
PMCID: PMC2204079  PMID: 17975205
autoimmunity; humoral immunity; B cells; emphysema
25.  IFN-γ Production during Initial Infection Determines the Outcome of Reinfection with Respiratory Syncytial Virus 
Rationale: Severe respiratory syncytial virus (RSV) bronchiolitis has been associated with deficient IFN-γ production in humans, but the role of this cytokine in determining the outcome of reinfection is unknown.
Objectives: To define the role of IFN-γ in the development of RSV-mediated airway hyperresponsiveness (AHR) and lung histopathology in mice.
Methods: Wild-type (WT) and IFN-γ knockout mice were infected with RSV in the newborn or weaning stages and reinfected 5 weeks later. Airway responses were assessed on Day 6 after the primary or secondary infection.
Measurements and Main Results: Both WT and IFN-γ knockout mice developed similar levels of AHR and airway inflammation after primary infection. After reinfection, IFN-γ knockout mice, but not WT mice, developed AHR, airway eosinophilia, and mucus hyperproduction. Intranasal administration of IFN-γ during primary infection but not during reinfection prevented the development of these altered airway responses on reinfection in IFN-γ knockout mice. Adoptive transfer of WT T cells into IFN-γ knockout mice before primary infection restored IFN-γ production in the lungs and prevented the development of altered airway responses on reinfection. Treatment of mice with IFN-γ during primary neonatal infection prevented the enhancement of AHR and the development of airway eosinophilia and mucus hyperproduction on reinfection.
Conclusions: IFN-γ production during primary RSV infection is critical to the development of protection against AHR and lung histopathology on reinfection. Provision of IFN-γ during primary infection in infancy may be a potential therapeutic approach to alter the course of RSV-mediated long-term sequelae.
doi:10.1164/rccm.200612-1890OC
PMCID: PMC2204078  PMID: 17962634
respiratory syncytial virus; interferon-γ; asthma; airway hyperresponsiveness; mice

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