Lung volume indices predict morbidity in smokers with preserved spirometry.

BACKGROUND: Abnormal lung volumes that reflect air trapping are common in COPD. However, their significance in smokers with preserved spirometry (normal FEV1 to FVC ratio) is unclear. METHODS: Using the Veterans Administration Informatics and Computing Infrastructure database, we identified 7479 patients at risk for COPD (ever smokers >40 years of age without restrictive lung disease) who had preserved spirometry and concomitant lung volume measurements, and examined their subsequent health records for clinical diagnoses of COPD, healthcare utilisation, follow-up spirometry and mortality. RESULTS: Air trapping was prevalent, with 31% of patients having residual volume to total lung capacity ratio (RV:TLC) greater than the upper limit of normal (ULN). RV:TLC varied widely from 14% to 77% (51% to 204% of predicted) across the normal ranges of FEV1:FVC and FEV1. Patients with RV:TLC greater than the ULN were more likely to receive subsequent clinical diagnoses of COPD (HR (95% CI)=1.55 (1.42 to 1.70), p<0.001) and had higher all-cause mortality (HR (95% CI)=1.41 (1.29 to 1.54), p<0.001). They had higher rates of respiratory medication prescriptions and hospital and intensive care unit admissions. Other air trapping and static hyperinflation indices showed similar associations with health outcomes. Additionally, high-normal RV:TLC was associated with intermediate adverse health outcomes compared with low-normal and abnormal RV:TLC. Abnormal RV:TLC predicted higher likelihood of progression to spirometric COPD (OR (95% CI)=1.30 (1.03 to 1.65), p=0.027). CONCLUSION: In this study of the Veterans Affairs electronic health records, air trapping was common in smokers with preserved spirometry and predicted adverse respiratory outcomes and progression to overt COPD.

Modeling vascular inflammation and atherogenicity after inhalation of ambient levels of ozone: exploratory lessons from transcriptomics.

BACKGROUND: Epidemiologic studies have linked inhalation of air pollutants such as ozone to cardiovascular mortality. Human exposure studies have shown that inhalation of ambient levels of ozone causes airway and systemic inflammation and an imbalance in sympathetic/parasympathetic tone. METHODS: To explore molecular mechanisms through which ozone inhalation contributes to cardiovascular mortality, we compared transcriptomics data previously obtained from bronchoalveolar lavage (BAL) cells obtained from healthy subjects after inhalational exposure to ozone (200 ppb for 4 h) to those of various cell samples from 11 published studies of patients with atherosclerotic disease using the Nextbio genomic data platform. Overlapping gene ontologies that may be involved in the transition from pulmonary to systemic vascular inflammation after ozone inhalation were explored. Local and systemic enzymatic activity of an overlapping upregulated gene, matrix metalloproteinase-9 (MMP-9), was measured by zymography after ozone exposure. RESULTS: A set of differentially expressed genes involved in response to stimulus, stress, and wounding were in common between the ozone and most of the atherosclerosis studies. Many of these genes contribute to biological processes such as cholesterol metabolism dysfunction, increased monocyte adherence, endothelial cell lesions, and matrix remodeling, and to diseases such as heart failure, ischemia, and atherosclerotic occlusive disease. Inhalation of ozone increased MMP-9 enzymatic activity in both BAL fluid and serum. CONCLUSIONS: Comparison of transcriptomics between BAL cells after ozone exposure and various cell types from patients with atherosclerotic disease reveals commonly regulated processes and potential mechanisms by which ozone inhalation may contribute to progression of pre-existent atherosclerotic lesions.

Inflammatory and repair pathways induced in human bronchoalveolar lavage cells with ozone inhalation.

BACKGROUND: Inhalation of ambient levels of ozone causes airway inflammation and epithelial injury. METHODS: To examine the responses of airway cells to ozone-induced oxidative injury, 19 subjects (7 with asthma) were exposed to clean air (0ppb), medium (100ppb), and high (200ppb) ambient levels of ozone for 4h on three separate occasions in a climate-controlled chamber followed by bronchoscopy with bronchoalveolar lavage (BAL) 24h later. BAL cell mRNA expression was examined using Affymetrix GeneChip Microarray. The role of a differentially expressed gene (DEG) in epithelial injury was evaluated in an in vitro model of injury [16HBE14o- cell line scratch assay]. RESULTS: Ozone exposure caused a dose-dependent up-regulation of several biologic pathways involved in inflammation and repair including chemokine and cytokine secretion, activity, and receptor binding; metalloproteinase and endopeptidase activity; adhesion, locomotion, and migration; and cell growth and tumorigenesis regulation. Asthmatic subjects had 1.7- to 3.8-fold higher expression of many DEGs suggestive of increased proinflammatory and matrix degradation and remodeling signals. The most highly up-regulated gene was osteopontin, the protein level of which in BAL fluid increased in a dose-dependent manner after ozone exposure. Asthmatic subjects had a disproportionate increase in non-polymerized osteopontin with increasing exposure to ozone. Treatment with polymeric, but not monomeric, osteopontin enhanced the migration of epithelial cells and wound closure in an α9ß1 integrin-dependent manner. CONCLUSIONS: Expression profiling of BAL cells after ozone exposure reveals potential regulatory genes and pathways activated by oxidative stress. One DEG, osteopontin, promotes epithelial wound healing in an in vitro model of injury.

Regenerative capacity of old muscle stem cells declines without significant accumulation of DNA damage.

The performance of adult stem cells is crucial for tissue homeostasis but their regenerative capacity declines with age, leading to failure of multiple organs. In skeletal muscle this failure is manifested by the loss of functional tissue, the accumulation of fibrosis, and reduced satellite cell-mediated myogenesis in response to injury. While recent studies have shown that changes in the composition of the satellite cell niche are at least in part responsible for the impaired function observed with aging, little is known about the effects of aging on the intrinsic properties of satellite cells. For instance, their ability to repair DNA damage and the effects of a potential accumulation of DNA double strand breaks (DSBs) on their regenerative performance remain unclear. This work demonstrates that old muscle stem cells display no significant accumulation of DNA DSBs when compared to those of young, as assayed after cell isolation and in tissue sections, either in uninjured muscle or at multiple time points after injury. Additionally, there is no significant difference in the expression of DNA DSB repair proteins or globally assayed DNA damage response genes, suggesting that not only DNA DSBs, but also other types of DNA damage, do not significantly mark aged muscle stem cells. Satellite cells from DNA DSB-repair-deficient SCID mice do have an unsurprisingly higher level of innate DNA DSBs and a weakened recovery from gamma-radiation-induced DNA damage. Interestingly, they are as myogenic in vitro and in vivo as satellite cells from young wild type mice, suggesting that the inefficiency in DNA DSB repair does not directly correlate with the ability to regenerate muscle after injury. Overall, our findings suggest that a DNA DSB-repair deficiency is unlikely to be a key factor in the decline in muscle regeneration observed upon aging.