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1.  Just a Spoonful of Technology Makes the Protocol Go Down 
doi:10.1164/rccm.200607-933ED
PMCID: PMC2648053  PMID: 17021356
2.  Uteroglobin-related Protein 1 Expression Suppresses Allergic Airway Inflammation in Mice 
Rationale
Uteroglobin-related protein (UGRP) 1, which is highly expressed in the epithelial cells of the airways, has been suggested to play a role in lung inflammation.
Objectives
The aim of study was to understand the effect of overexpressed UGRP1 on lung inflammation in a mouse model of allergic airway inflammation.
Methods
Ovalbumin-sensitized and -challenged mice, a model for allergic airway inflammation, were used in conjunction with recombinant adenovirus expressing UGRP1.
Measurements and Main Results
We demonstrated that intranasal administration of adeno-UGRP1 successfully delivered UGRP1 to the epithelial cells of airways and markedly reduced the number of infiltrating inflammatory cells, particularly eosinophils, in lung tissue as well as the level of proinflammatory cytokines such as interleukin (IL)-4, IL-5, and IL-13 in bronchoalveolar lavage fluids. The healed phase of inflammation was clearly seen in the peripheral areas of adeno-UGRP1–treated mouse lungs.
Conclusion
These results demonstrate that UGRP1 can suppress inflammation in the mouse model of allergic airway inflammation. Based on this result, we propose UGRP1 as a novel therapeutic candidate for treating lung inflammation such as is found in asthma.
doi:10.1164/rccm.200503-456OC
PMCID: PMC2582904  PMID: 16456148
asthma; bronchoalveolar lavage; eosinophils; mouse model; ovalbumin
3.  Longitudinal monitoring of lung injury in children following chlorine exposure in a swimming pool 
Rationale: Acute exposure to chlorine gas results in respiratory impairment, but few data are available on the pathobiology of the underlying lung damage. Objectives: To assess lung function and potential lung damage pathways in the acute phase and longitudinally over a 15-month follow-up after chlorine exposure. Methods: Ten previously-healthy children were accidentally exposed to chlorine gas at a swimming pool due an erroneous servicing procedure. Exhaled nitric oxide (FENO), exhaled breath condensate (EBC) compounds and serum Clara cell protein (CC16) were repeatedly measured. Main results: In the acute phase, all patients had respiratory distress (one child required mechanical ventilation) and reduced lung function (median and IQR: FVC 51% pred. [43-60], FEV1 51% pred. [46-60]). This was accompanied by low FENO (4.7 [3.9-7.9] ppb), high EBC leukotriene B4 (LTB-4) levels (24.4 [22.5-24.9] pg/mL) and increased serum CC16 levels (mean ± SE 23.4 ± 2.5 μg/L). Lung function returned to normal in 15 days (FVC 97% pred. [82-108] and FEV1 92% pred. [77-102]). FENO reached normal values after 2 months (12.6 [11.4-15] ppb), while LTB-4 levels were still increased (12 [9.3-17.1] pg/mL). Conclusion: Children acutely exposed to chlorine in a swimming pool presented a substantial lung function impairment associated with biochemical exhaled breath alterations, mainly represented by an increase in LTB-4 and a reduction in FENO. While lung function and FENO improved within a few weeks, the increased levels of exhaled LTB-4 persisted for several months.
doi:10.1164/rccm.200509-1392OC
PMCID: PMC1555620  PMID: 16763216
Chlorine inhalation; Pulmonary function; Exhaled nitric oxide; Exhaled breath condensate; Pneumoproteinemia
4.  Spontaneous Airway Hyperresponsiveness in Estrogen Receptor-α–deficient Mice 
Rationale: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans.
Objectives: To examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor–deficient mice.
Methods: Lung function was assessed by a combination of whole-body barometric plethysmography, invasive measurement of airway resistance, and isometric force measurements in isolated bronchial rings. M2 muscarinic receptor expression was assessed by Western blotting, and function was assessed by electrical field stimulation of tracheas in the presence/absence of gallamine. Allergic airway disease was examined after ovalbumin sensitization and exposure.
Measurements and Main Results: Estrogen receptor-α knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine and serotonin under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-α also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge.
Conclusions: These data suggest that estrogen receptor-α is a critical regulator of airway hyperresponsiveness in mice.
doi:10.1164/rccm.200509-1493OC
PMCID: PMC1899278  PMID: 17095746
lung function; asthma; hyperreactivity; M2 muscarinic receptor; estrogen receptor
5.  Superoxide Dismutase Improves Oxygenation and Reduces Oxidation in Neonatal Pulmonary Hypertension 
Rationale: Hyperoxic ventilation in the management of persistent pulmonary hypertension of the newborn (PPHN) can result in the formation of reactive oxygen species, such as superoxide anions, which can inactivate nitric oxide (NO) and cause vasoconstriction and oxidation.
Objective: To compare the effect of intratracheal recombinant human superoxide dismutase (rhSOD) and/or inhaled NO (iNO) on systemic oxygenation, contractility of pulmonary arteries (PAs), and lung reactive oxygen species (isoprostane, 3-nitrotyrosine) levels in neonatal lambs with PPHN.
Methods: Six newborn lambs with PPHN (induced by antenatal ductal ligation) were killed at birth. Twenty-six PPHN lambs were ventilated for 24 h with 100% O2 alone (n = 6) or O2 combined with rhSOD (5 mg/kg intratracheally) at birth (n = 4), rhSOD at 4 h of age (n = 5), iNO (20 ppm, n = 5), or rhSOD + iNO (n = 6). Contraction responses of fifth-generation PAs to norepinephrine and KCl, lung isoprostane levels, and 3-nitrotyrosine fluorescent intensity were measured.
Results: Systemic oxygenation was impaired in PPHN lambs and significantly improved (up to threefold) in both rhSOD groups with or without iNO. Oxygenation improved more rapidly with the combination of rhSOD + iNO compared with either intervention alone. Norepinephrine- and KCl-induced contractions and lung isoprostane levels were significantly increased by 100% O2 compared with nonventilated newborn lambs with PPHN. Both rhSOD and iNO mitigated the increased PA contraction response and lung isoprostane levels. Intratracheal rhSOD decreased the enhanced lung 3-nitrotyrosine fluorescence observed with iNO therapy.
Conclusion: Intratracheal rhSOD and/or iNO rapidly increase oxygenation and reduce both vasoconstriction and oxidation in newborn lambs with PPHN. This has important implications for clinical trials of rhSOD and iNO in newborn infants with PPHN.
doi:10.1164/rccm.200605-676OC
PMCID: PMC2111046  PMID: 17008638
isoprostanes; nitric oxide; oxygen; pulmonary hypertension; superoxide dismutase
6.  Superoxide Dismutase Improves Oxygenation and Reduces Oxidation in Neonatal Pulmonary Hypertension 
Rationale
Hyperoxic ventilation in the management of persistent pulmonary hypertension of the newborn (PPHN) can result in the formation of reactive oxygen species, such as superoxide anions, which can inactivate nitric oxide (NO) and cause vasoconstriction and oxidation.
Objective
To compare the effect of intratracheal recombinant human superoxide dismutase (rhSOD) and/or inhaled NO (iNO) on systemic oxygenation, contractility of pulmonary arteries (PAs), and lung reactive oxygen species (isoprostane, 3-nitrotyrosine) levels in neonatal lambs with PPHN.
Methods
Six newborn lambs with PPHN (induced by antenatal ductal ligation) were killed at birth. Twenty-six PPHN lambs were ventilated for 24 h with 100% O2 alone (n = 6) or O2 combined with rhSOD (5 mg/kg intratracheally) at birth (n = 4), rhSOD at 4 h of age (n = 5), iNO (20 ppm, n = 5), or rhSOD + iNO (n = 6). Contraction responses of fifth-generation PAs to norepinephrine and KCl, lung isoprostane levels, and 3-nitrotyrosine fluorescent intensity were measured.
Results
Systemic oxygenation was impaired in PPHN lambs and significantly improved (up to threefold) in both rhSOD groups with or without iNO. Oxygenation improved more rapidly with the combination of rhSOD + iNO compared with either intervention alone. Norepinephrine- and KCl-induced contractions and lung isoprostane levels were significantly increased by 100% O2 compared with nonventilated newborn lambs with PPHN. Both rhSOD and iNO mitigated the increased PA contraction response and lung isoprostane levels. Intratracheal rhSOD decreased the enhanced lung 3-nitrotyrosine fluorescence observed with iNO therapy.
Conclusion
Intratracheal rhSOD and/or iNO rapidly increase oxygenation and reduce both vasoconstriction and oxidation in newborn lambs with PPHN. This has important implications for clinical trials of rhSOD and iNO in newborn infants with PPHN.
doi:10.1164/rccm.200605-676
PMCID: PMC2111046  PMID: 17008638
isoprostanes; nitric oxide; oxygen; pulmonary hypertension; superoxide dismutase
7.  Spontaneous Airway Hyperresponsiveness in Estrogen Receptor-α–deficient Mice 
Rationale
Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans.
Objectives
To examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor–deficient mice.
Methods
Lung function was assessed by a combination of whole-body barometric plethysmography, invasive measurement of airway resistance, and isometric force measurements in isolated bronchial rings. M2 muscarinic receptor expression was assessed by Western blotting, and function was assessed by electrical field stimulation of tracheas in the presence/absence of gallamine. Allergic airway disease was examined after ovalbumin sensitization and exposure.
Measurements and Main Results
Estrogen receptor-α knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine and serotonin under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-α also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge.
Conclusions
These data suggest that estrogen receptor-α is a critical regulator of airway hyperresponsiveness in mice.
doi:10.1164/rccm.200509-1493OC
PMCID: PMC1899278  PMID: 17095746
lung function; asthma; hyperreactivity; M2 muscarinic receptor; estrogen receptor
8.  Longitudinal Monitoring of Lung Injury in Children after Acute Chlorine Exposure in a Swimming Pool 
Rationale: Acute exposure to chlorine gas results in respiratory impairment, but few data are available on the pathobiology of the underlying lung damage.
Objectives: To assess lung function and potential lung damage pathways in the acute phase and longitudinally over a 15-mo follow-up after acute chlorine exposure.
Methods: Ten previously healthy children were accidentally exposed to chlorine gas at a swimming pool because of an erroneous servicing procedure. The fraction of nitric oxide in exhaled air (FeNO), exhaled breath condensate compounds, and serum Clara cell–specific protein CC16 were repeatedly measured.
Main results: In the acute phase, all patients had respiratory distress (one child required mechanical ventilation) and reduced lung function (median and interquartile range: FVC, 51 [43–60]% predicted; FEV1, 51 [46–60]% predicted). This was accompanied by low FeNO (4.7 [3.9–7.9] ppb), high exhaled breath condensate leukotriene B4 (LTB4) levels (24.4 [22.5–24.9] pg/ml), and increased serum CC16 levels (mean ± SEM, 23.4 ± 2.5 μg/L). Lung function returned to normal in 15 d (FVC, 97% predicted [82–108], and FEV1, 92% predicted [77–102]). FeNO reached normal values after 2 mo (12.6 [11.4–15] ppb), whereas LTB4 levels were still increased (12 [9.3–17.1] pg/ml).
Conclusion: Children acutely exposed to chlorine in a swimming pool presented a substantial lung function impairment associated with biochemical exhaled breath alterations, represented mainly by an increase in LTB4 and a reduction in FeNO. Although lung function and FeNO improved within a few weeks, the increased levels of exhaled LTB4 persisted for several months.
doi:10.1164/rccm.200509-1392OC
PMCID: PMC1555620  PMID: 16763216
chlorine inhalation; exhaled breath condensate; exhaled nitric oxide; pneumoproteinemia; pulmonary function
9.  Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis 
Rationale: Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin.
Methods: To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single- and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined.
Results: After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg).
Conclusions: By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation.
doi:10.1164/rccm.200602-280OC
PMCID: PMC1862756  PMID: 16574936
moxifloxacin; rifampin; rifapentine; tuberculosis; treatment
10.  Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis 
Rationale
Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin.
Methods
To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single- and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined.
Results
After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg).
Conclusions
By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation.
doi:10.1164/rccm.200602-280OC
PMCID: PMC1862756  PMID: 16574936
moxifloxacin; rifampin; rifapentine; tuberculosis; treatment
11.  Uteroglobin-related Protein 1 Expression Suppresses Allergic Airway Inflammation in Mice 
Rationale: Uteroglobin-related protein (UGRP) 1, which is highly expressed in the epithelial cells of the airways, has been suggested to play a role in lung inflammation.
Objectives: The aim of study was to understand the effect of overexpressed UGRP1 on lung inflammation in a mouse model of allergic airway inflammation.
Methods: Ovalbumin-sensitized and -challenged mice, a model for allergic airway inflammation, were used in conjunction with recombinant adenovirus expressing UGRP1.
Measurements and Main Results: We demonstrated that intranasal administration of adeno-UGRP1 successfully delivered UGRP1 to the epithelial cells of airways and markedly reduced the number of infiltrating inflammatory cells, particularly eosinophils, in lung tissue as well as the level of proinflammatory cytokines such as interleukin (IL)-4, IL-5, and IL-13 in bronchoalveolar lavage fluids. The healed phase of inflammation was clearly seen in the peripheral areas of adeno-UGRP1–treated mouse lungs.
Conclusion: These results demonstrate that UGRP1 can suppress inflammation in the mouse model of allergic airway inflammation. Based on this result, we propose UGRP1 as a novel therapeutic candidate for treating lung inflammation such as is found in asthma.
doi:10.1164/rccm.200503-456OC
PMCID: PMC2582904  PMID: 16456148
asthma; bronchoalveolar lavage; eosinophils; mouse model; ovalbumin
12.  Occupational Risk Factors and Asthma among Health Care Professionals 
Rationale: Recent U.S. data suggest an increased risk of work-related asthma among health care workers, yet only a few specific determinants have been elucidated.
Objectives: To evaluate associations of asthma prevalence with occupational exposures in a cross-sectional survey of health care professionals.
Methods: A detailed questionnaire was mailed to a random sample (n = 5,600) of all Texas physicians, nurses, respiratory therapists, and occupational therapists with active licenses in 2003. Information on asthma symptoms and nonoccupational asthma risk factors obtained from the questionnaire was linked to occupational exposures derived through an industry-specific job-exposure matrix.
Measurements: There were two a priori defined outcomes: (1) physician-diagnosed asthma with onset after entry into health care (“reported asthma”) and (2) “bronchial hyperresponsiveness–related symptoms,” defined through an 8-item symptom-based predictor.
Main Results: Overall response rate was 66%. The final study population consisted of 862 physicians, 941 nurses, 968 occupational therapists, and 879 respiratory therapists (n = 3,650). Reported asthma was associated with medical instrument cleaning (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.34–3.67), general cleaning (OR, 2.02; 95% CI, 1.20–3.40), use of powdered latex gloves between 1992 and 2000 (OR, 2.17; 95% CI, 1.27–3.73), and administration of aerosolized medications (OR, 1.72; 95% CI, 1.05–2.83). The risk associated with latex glove use was not apparent after 2000. Bronchial hyperresponsiveness–related symptoms were associated with general cleaning (OR, 1.63; 95% CI, 1.21–2.19), aerosolized medication administration (OR, 1.40; 95% CI, 1.06–1.84), use of adhesives on patients (OR, 1.65; 95% CI, 1.22–2.24), and exposure to a chemical spill (OR, 2.02; 95% CI, 1.28–3.21).
Conclusions: The contribution of occupational exposures to asthma in health care professionals is not trivial, meriting both implementation of appropriate controls and further study.
doi:10.1164/rccm.200609-1331OC
PMCID: PMC1899286  PMID: 17185646
work-related asthma; health care workers
13.  Inhaled Corticosteroids and Risk of Lung Cancer among Patients with Chronic Obstructive Pulmonary Disease 
Rationale and Objectives: Lung cancer is a frequent cause of death among patients with chronic obstructive pulmonary disease (COPD). We examined whether the use of inhaled corticosteroids among patients with COPD was associated with a decreased risk of lung cancer.
Methods: We performed a cohort study of United States veterans enrolled in primary care clinics between December 1996 and May 2001. Participants had received treatment for, had an International Classification of Disease, 9th edition, diagnosis of, or a self-reported diagnosis of COPD. Patients with a history of lung cancer were excluded. To be exposed, patients must have been at least 80% adherent to inhaled corticosteroids. We used Cox regression models to estimate the risk of cancer and adjust for potential confounding factors.
Findings: We identified 10,474 patients with a median follow-up of 3.8 years. In comparison to nonusers of inhaled corticosteroids, adjusting for age, smoking status, smoking intensity, previous history of non–lung cancer malignancy, coexisting illnesses, and bronchodilator use, there was a dose-dependent decreased risk of lung cancer associated with inhaled corticosteroids (ICS dose < 1,200 μg/d: adjusted HR, 1.3; 95% confidence interval, 0.67–1.90; ICS dose ⩾ 1,200 μg/d: adjusted HR, 0.39; 95% confidence interval, 0.16–0.96). Changes in cohort definitions had minimal effects on the estimated risk. Analyses examining confounding by indication suggest biases in the opposite direction of the described effects.
Interpretation: Results suggest that inhaled corticosteroids may have a potential role in lung cancer prevention among patients with COPD. These initial findings require confirmation in separate and larger cohorts.
doi:10.1164/rccm.200608-1125OC
PMCID: PMC1899285  PMID: 17185647
chronic obstructive pulmonary disease; pharmacoepidemiology; lung cancer; adherence
14.  Leptin Resistance Protects Mice from Hyperoxia-induced Acute Lung Injury 
Rationale: Human data suggest that the incidence of acute lung injury is reduced in patients with type II diabetes mellitus. However, the mechanisms by which diabetes confers protection from lung injury are unknown.
Objectives: To determine whether leptin resistance, which is seen in humans with diabetes, protects mice from hyperoxic lung injury.
Methods: Wild-type (leptin responsive) and db/db (leptin resistant) mice were used in these studies. Mice were exposed to hyperoxia (100% O2) for 84 hours to induce lung injury and up to 168 hours for survival studies. Alveolar fluid clearance was measured in vivo.
Measurements and Main Results: Lung leptin levels were increased both in wild-type and leptin receptor–defective db/db mice after hyperoxia. Hyperoxia-induced lung injury was decreased in db/db compared with wild-type mice. Hyperoxia increased lung permeability in wild-type mice but not in db/db mice. Compared with wild-type control animals, db/db mice were resistant to hyperoxia-induced mortality (lethal dose for 50% of mice, 152 vs. 108 h). Intratracheal instillation of leptin at a dose that was observed in the bronchoalveolar lavage fluid during hyperoxia caused lung injury in wild-type but not in db/db mice. Intratracheal pretreatment with a leptin receptor inhibitor attenuated leptin-induced lung edema. The hyperoxia-induced release of proinflammatory cytokines was attenuated in db/db mice. Despite resistance to lung injury, db/db mice had diminished alveolar fluid clearance and reduced Na,K-ATPase function compared with wild-type mice.
Conclusions: These results indicate that leptin can induce and that resistance to leptin attenuates hyperoxia-induced lung injury and hyperoxia-induced inflammatory cytokines in the lung.
doi:10.1164/rccm.200603-312OC
PMCID: PMC1899284  PMID: 17185651
alveolar fluid clearance; pulmonary edema; Na,K-ATPase; diabetes mellitus; oxygen
15.  IL4Rα Mutations Are Associated with Asthma Exacerbations and Mast Cell/IgE Expression 
Background: Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor α (IL4Rα) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown.
Hypothesis: Allelic substitutions in IL4Rα are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE.
Methods: Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4Rα. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE.
Results: In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately.
Conclusions: SNPs in IL4Rα, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell–related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.
doi:10.1164/rccm.200607-909OC
PMCID: PMC1899282  PMID: 17170387
asthma; genetics; IL4Rα; exacerbations; mast cells; IgE
16.  Pediatric Sleep Apnea 
Over the last 30 years, the prevalence of overweight across all pediatric age groups and ethnicities has increased substantially, with the current prevalence of overweight among adolescents estimated to be approximately 30%. Current evidence suggests that overweight is modestly associated with obstructive sleep apnea syndrome (OSAS) among young children, but strongly associated with OSAS in older children and adolescents. The rising incidence of pediatric overweight likely will impact the prevalence, presentation, and treatment of childhood OSAS. The subgroup of children who may be especially susceptible include ethnic minorities and those from households with caregivers from low socioeconomic groups. OSAS, by exposing children to recurrent intermittent hypoxemia or oxidative stress, may amplify the adverse effects of adiposity on systemic inflammation and metabolic perturbations associated with vascular disease and diabetes. When these conditions manifest early in life, they have the potential to alter physiology at critical developmental stages, or, if persistent, provide cumulative exposures that may powerfully alter long-term health profiles. An increased prevalence of overweight also may impact the response to adenotonsillectomy as a primary treatment for childhood OSAS. The high and anticipated increased prevalence of pediatric OSAS mandates assessment of optimal approaches for preventing and treating both OSAS and overweight across the pediatric age range. In this Pulmonary Perspective, the interrelationships between pediatric OSAS and overweight are reviewed, and the implications of the overweight epidemic on childhood OSAS are discussed.
doi:10.1164/rccm.200606-790PP
PMCID: PMC2176093  PMID: 17158283
sleep apnea; childhood obesity; childhood overweight
17.  The Confounding Effects of Thoracic Gas Compression on Measurement of Acute Bronchodilator Response 
Rationale: Improvement in FEV1 is a main endpoint in clinical trials assessing the efficacy of bronchodilators. However, the effect of bronchodilators on maximal expiratory flow may be confounded by thoracic gas compression (TGC).
Objective: To determine whether TGC confounds effect of albuterol on FEV1.
Methods: We evaluated the response to albuterol inhalation in 10 healthy subjects, 9 subjects with asthma, and 15 subjects with chronic obstructive pulmonary disease (COPD) with mean (SD) age in years of 38 (SD, 11), 45 (SD, 11), and 64 (SD, 8), respectively. Lung mechanics were measured at baseline and 20 minutes after inhalation of 180 μg of albuterol. We then applied a novel method to calculate FEV1 corrected for the effect of TGC (NFEV1).
Results: Prior to albuterol administration, NFEV1 was significantly higher than FEV1. However, post–albuterol inhalation, FEV1 increased more than NFEV1 because of reduced TGC. In multiple regression analysis, the changes in TGC, inspiratory lung resistance, and ratio of residual volume to total lung capacity postalbuterol predicted more than 75% of FEV1 improvement in patients with COPD.
Conclusion: Improvements in FEV1 after albuterol in patients with COPD are due to reduction of lung resistance, hyperinflation, and TGC. The latter is negligible during tidal breathing. Thus, although reduction of lung resistance and hyperinflation may result in improved dyspnea with a bronchodilator, the contribution of TGC reduction to improvement of FEV1 may not exert any meaningful clinical effect during tidal breathing. This fact has to be taken into consideration when assessing the efficacy of new bronchodilators.
doi:10.1164/rccm.200602-255OC
PMCID: PMC1899266  PMID: 17110648
FEV1; chronic obstructive pulmonary disease; asthma; lung mechanics; albuterol
18.  Lethal and Edema Toxins in the Pathogenesis of Bacillus anthracis Septic Shock 
Recent research regarding the structure and function of Bacillus anthracis lethal (LeTx) and edema (ETx) toxins provides growing insights into the pathophysiology and treatment of shock with this lethal bacteria. These are both binary-type toxins composed of protective antigen necessary for their cellular uptake and either lethal or edema factors, the toxigenic moieties. The primary cellular receptors for protective antigen have been identified and constructed and key steps in the extracellular processing and internalization of the toxins clarified. Consistent with the lethal factor's primary action as an intracellular endopeptidase targeting mitogen-activated protein kinase kinases, growing evidence indicates that shock with this toxin does not result from an excessive inflammatory response. In fact, the potent immunosuppressive effects of LeTx may actually contribute to the establishment and persistence of infection. Instead, shock with LeTx may be related to the direct injurious effects of lethal factor on endothelial cell function. Despite the importance of LeTx, very recent studies show that edema factor, a potent adenyl cyclase, has the ability to make a substantial contribution to shock caused by B. anthracis and works additively with LeTx. Furthermore, ETx may contribute to the immunosuppressive effects of LeTx. Therapies under development that target several different steps in the cellular uptake and function of these two toxins have been effective in in vitro and in vivo systems. Understanding how best to apply these agents clinically and how they interact with conventional treatments should be goals for future research.
doi:10.1164/rccm.200608-1239CP
PMCID: PMC2176088  PMID: 17095744
anthrax; toxin; shock; treatment
19.  The Chemokine Receptor D6 Has Opposing Effects on Allergic Inflammation and Airway Reactivity 
Rationale: The D6 chemokine receptor can bind and scavenge several chemokines, including the T-helper 2 (Th2)–associated chemokines CCL17 and CCL22. Although D6 is constitutively expressed in the lung, its pulmonary function is unknown.
Objectives: This study tested whether D6 regulates pulmonary chemokine levels, inflammation, or airway responsiveness during allergen-induced airway disease.
Methods: D6-deficient and genetically matched C57BL/6 mice were sensitized and challenged with ovalbumin. ELISA and flow cytometry were used to measure levels of cytokines and leukocytes, respectively. Mechanical ventilation was used to measure airway reactivity.
Results: The ability of D6 to diminish chemokine levels in the lung was chemokine concentration dependent. CCL17 and CCL22 were abundant in the airway, and their levels were attenuated by D6 when they were within a defined concentration range. By contrast, airway concentrations of CCL3, CCL5, and CCL11 were low and unaffected by D6. Allergen-challenged D6-deficient mice had more dendritic cells, T cells, and eosinophils in the lung parenchyma and more eosinophils in the airway than similarly challenged C57BL/6 mice. By contrast, D6-deficient mice had reduced airway responses to methacholine compared with C57BL/6 mice. Thus, D6 has opposing effects on inflammation and airway reactivity.
Conclusions: The ability of D6 to scavenge chemokines in the lung is dependent on chemokine concentration. The absence of D6 increases inflammation, but reduces airway reactivity. These findings suggest that inhibiting D6 function might be a novel means to attenuate airway responses in individuals with allergic asthma.
doi:10.1164/rccm.200606-839OC
PMCID: PMC1899265  PMID: 17095748
chemokines; lung; D6; allergic; transforming growth factor–; β
20.  Combination Therapy with a Long-Acting β-Agonist and a Leukotriene Antagonist in Moderate Asthma 
Rationale: Long-acting β-agonists (LABAs) and inhaled corticosteroids administered together appear to be complementary in terms of effects on asthma control. The elements of asthma control achieved by LABAs (improved lung function) and leukotriene receptor antagonists (LTRAs; protection against exacerbations) may be complementary as well.
Objective: We sought to determine whether the combination of the LTRA montelukast and the LABA salmeterol could provide an effective therapeutic strategy for asthma.
Methods and Measurements: In a randomized, placebo-controlled, crossover study of 192 subjects with moderate asthma, we compared the clinical efficacy of regular treatment over 14 weeks with the combination of montelukast and salmeterol to that with the combination of beclomethasone and salmeterol in moderate asthma. The primary efficacy outcome was time to treatment failure.
Main Results: Three months after the randomization of the last subject, the Data and Safety Monitoring Board determined that the primary research question had been answered and terminated the trial. The combination of montelukast and salmeterol was inferior to the combination of beclomethasone and salmeterol as judged by protection against asthma treatment failures (p = 0.0008), lung function (26 L/min difference in a.m. peak expiratory flow rate, p = 0.011), asthma control score (0.22 difference in Asthma Control Questionnaire score, p = 0.038), and markers of inflammation and airway reactivity.
Conclusions: Patients with moderate asthma similar to those we studied should not substitute the combination of an LTRA and an LABA for the combination of inhaled corticosteroid and an LABA.
doi:10.1164/rccm.200601-112OC
PMCID: PMC1899264  PMID: 16973987
combination therapy; leukotriene; beta-agonists; inhaled corticosteroids
21.  Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury 
Rationale: Nitrogen oxide (NO) species are markers for oxidative stress that may be pathogenic in acute lung injury (ALI).
Objectives: We tested two hypotheses in patients with ALI: (1) higher levels of urine NO would be associated with worse clinical outcomes, and (2) ventilation with lower Vt would reduce urine NO as a result of less stretch injury.
Methods: Urine NO levels were measured by chemiluminescence in 566 patients enrolled in the National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Network trial of 6 ml/kg versus 12 ml/kg Vt ventilation. The data were expressed corrected and uncorrected for urine creatinine (Cr).
Results: Higher baseline levels of urine NO to Cr were associated with lower mortality (odds ratio, 0.43 per log(10) increase in the ratio), more ventilator-free days (mean increase, 1.9 d), and more organ-failure–free days (mean increase, 2.3 d) on multivariate analysis (p < 0.05 for all analyses). Similar results were obtained using urine NO alone. NO to Cr levels were higher on Day 3 in the 6 ml/kg than in the 12 ml/kg Vt group (p = 0.04).
Conclusions: Contrary to our hypothesis, higher urine NO was associated with improved outcomes in ALI at baseline and after treatment with the 6 ml/kg Vt strategy. Higher endogenous NO may reflect less severe lung injury and better preservation of the pulmonary and systemic endothelium or may serve a protective function in patients with ALI.
doi:10.1164/rccm.200607-947OC
PMCID: PMC1899263  PMID: 17082495
acute respiratory distress syndrome; nitrogen oxide species; pulmonary endothelium; tidal volume; pulmonary edema
22.  Aspirin and Decreased Adult-Onset Asthma 
Rationale: In an observational cohort study, women who self-selected for frequent aspirin use developed less newly diagnosed asthma than women who did not take aspirin.
Objective: To explore whether low-dose aspirin decreased the risk of newly diagnosed asthma in a randomized, double-blind, placebo-controlled trial.
Methods: The Physicians' Health Study randomized 22,071 apparently healthy male physicians, aged 40–84 yr at baseline and tolerant of aspirin, over an 18-wk run-in period, to 325 mg aspirin or placebo on alternate days. The aspirin component was terminated after 4.9 yr due principally to the emergence of a statistically extreme 44% reduction in risk of first myocardial infarction among those randomly assigned to aspirin.
Measurements: Physicians could self-report an asthma diagnosis on questionnaires at baseline, 6 mo, and annually thereafter. Asthma was not an a priori endpoint of the trial.
Results: Among 22,040 physicians without reported asthma at randomization, there were 113 new asthma diagnoses in the aspirin group and 145 in the placebo group. The hazard ratio was 0.78 (95% confidence interval, 0.61–1.00; p = 0.045). This apparent 22% lower risk of newly diagnosed asthma among those assigned to aspirin was not modified by baseline characteristics including smoking, body mass index, or age.
Conclusions: Aspirin reduced the risk of newly diagnosed adult-onset asthma in a large, randomized clinical trial of apparently healthy, aspirin-tolerant men. This result requires replication in randomized trials designed a priori to test this hypothesis; it does not imply that aspirin improves symptoms in patients with asthma.
doi:10.1164/rccm.200603-411OC
PMCID: PMC1899281  PMID: 17068328
asthma; aspirin; NSAIDs; analgesics; obstructive airways disease
23.  Informal Caregiver Burden among Survivors of Prolonged Mechanical Ventilation 
Rationale: Although caregiver burden is well described in chronic illness, few studies have examined burden among caregivers of survivors of critical illness. In existing studies, it is unclear whether the observed burden is a consequence of critical illness or of preexisting patient illness.
Objectives: To describe 1-yr longitudinal outcomes for caregivers of patients who survived critical illness, and to compare depression risk between caregivers of patients with and without pre–intensive care unit (ICU) functional dependency.
Methods: Prospective, parallel, cohort study of survivors of prolonged (greater than 48 h) mechanical ventilation and their informal caregivers. Caregivers were divided into two cohorts on the basis of whether patients were functionally independent (n = 99, 59%), or dependent (n = 70, 41%) before admission. Functional dependency was defined as dependency in one or more activities of daily living or in three or more instrumental activities of daily living. Patient and caregiver outcomes were measured 2, 6, and 12 mo after mechanical ventilation initiation.
Measurements and Main Results: We studied three caregiver outcomes: depression risk, lifestyle disruption, and employment reduction. Most patients were male (59.8%), with a mean (SD) age of 56.6 (19.0) yr. Caregivers were mostly female (75.7%), with a mean (SD) age of 54.6 (14.7) yr. Prevalence of caregiver depression risk was high at all time points (33.9, 30.8, and 22.8%; p = 0.83) and did not vary by patient pre-ICU functional status. Lifestyle disruption and employment reduction were also common and persistent.
Conclusions: Depression symptoms, lifestyle disruption, and employment reduction were common among informal caregivers of critical illness survivors. Depression risk was high regardless of patient pre-ICU functional status.
doi:10.1164/rccm.200604-493OC
PMCID: PMC1899280  PMID: 17068327
caregivers; depression; mechanical ventilation; outcomes research; quality of life
24.  Caspase-3 Regulation of Diaphragm Myonuclear Domain during Mechanical Ventilation–induced Atrophy 
Rationale: Unloading the diaphragm via mechanical ventilation (MV) results in rapid diaphragmatic fiber atrophy. It is unknown whether the myonuclear domain (cytoplasmic myofiber volume/myonucleus) of diaphragm myofibers is altered during MV.
Objective: We tested the hypothesis that MV-induced diaphragmatic atrophy is associated with a loss of myonuclei via a caspase-3–mediated, apoptotic-like mechanism resulting in a constant myonuclear domain.
Methods: To test this postulate, Sprague-Dawley rats were randomly assigned to a control group or to experimental groups exposed to 6 or 12 h of MV with or without administration of a caspase-3 inhibitor.
Measurements and Main Results: After 12 h of MV, type I and type IIa diaphragm myofiber areas were decreased by 17 and 23%, respectively, and caspase-3 inhibition attenuated this decrease. Diaphragmatic myonuclear content decreased after 12 h of MV and resulted in the maintenance of a constant myonuclear domain in all fiber types. Both 6 and 12 h of MV resulted in caspase-3–dependent increases in apoptotic markers in the diaphragm (e.g., number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive nuclei and DNA fragmentation). Caspase-3–dependent increases in apoptotic markers occurred after 6 h of MV, before the onset of myofiber atrophy.
Conclusions: Collectively, these data support the hypothesis that the myonuclear domain of diaphragm myofibers is maintained during prolonged MV and that caspase-3–mediated myonuclear apoptosis contributes to this process.
doi:10.1164/rccm.200601-142OC
PMCID: PMC1899279  PMID: 17082496
muscle atrophy; respiratory muscle; apoptosis; ventilatory weaning
25.  Coagulation Factor Xa Modulates Airway Remodeling in a Murine Model of Asthma 
Rationale: Previous studies have demonstrated that dysregulated coagulation and fibrinolysis contribute to the pathogenesis of asthma.
Objective: The role of procoagulant factor X in a murine model of ovalbumin (OVA)-induced asthma was investigated.
Methods: Biochemical, cellular, and physiologic in vivo and in vitro approaches were used to determine effects of factor X on the asthmatic response in mice.
Measurements and Main Results: Factor X transcript levels and factor Xa activity were increased in lungs of asthmatic mice challenged with OVA, compared with controls treated with phosphate-buffered saline. Factor X was highly expressed in bronchoalveolar lavage fluid macrophages from asthmatic mice. Treatment of mice with the factor Xa inhibitor fondaparinux during the last 4 wk of OVA challenge resulted in the attenuation of airway hyperresponsiveness but did not alter infiltration of inflammatory cells into the lung. There was a significant decrease in the thickness of the mucosal layer and in lung collagen deposition in fondaparinux-treated mice. In vitro investigations using human mucus-producing NCI-H292 cells indicated that exogenous factor Xa enhanced mucin production in a dose-dependent manner. Levels of amphiregulin, a protein that induces mucin production, were also increased in cells stimulated by factor Xa.
Conclusions: The results of this study introduce a novel participant in the asthmatic response and indicate that factor Xa functions in airway remodeling in asthma by stimulating mucin production, through regulation of amphiregulin expression and collagen deposition.
doi:10.1164/rccm.200608-1097OC
PMCID: PMC1899277  PMID: 17082493
coagulation protein; airway hyperresponsiveness; mucus production; amphiregulin

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