Gene expression networks in COPD: microRNA and mRNA regulation.

BACKGROUND: The mechanisms underlying chronic obstructive pulmonary disease (COPD) remain unclear. MicroRNAs (miRNAs or miRs) are small non-coding RNA molecules that modulate the levels of specific genes and proteins. Identifying expression patterns of miRNAs in COPD may enhance our understanding of the mechanisms of disease. A study was undertaken to determine if miRNAs are differentially expressed in the lungs of smokers with and without COPD. miRNA and mRNA expression were compared to enrich for biological networks relevant to the pathogenesis of COPD. METHODS: Lung tissue from smokers with no evidence of obstructive lung disease (n=9) and smokers with COPD (n=26) was examined for miRNA and mRNA expression followed by validation. We then examined both miRNA and mRNA expression to enrich for relevant biological pathways. RESULTS: 70 miRNAs and 2667 mRNAs were differentially expressed between lung tissue from subjects with COPD and smokers without COPD. miRNA and mRNA expression profiles enriched for biological pathways that may be relevant to the pathogenesis of COPD including the transforming growth factor ß, Wnt and focal adhesion pathways. miR-223 and miR-1274a were the most affected miRNAs in subjects with COPD compared with smokers without obstruction. miR-15b was increased in COPD samples compared with smokers without obstruction and localised to both areas of emphysema and fibrosis. miR-15b was differentially expressed within GOLD classes of COPD. Expression of SMAD7, which was validated as a target for miR-15b, was decreased in bronchial epithelial cells in COPD. CONCLUSIONS: miRNA and mRNA are differentially expressed in individuals with COPD compared with smokers without obstruction. Investigating these relationships may further our understanding of the mechanisms of disease.

Thrombospondin-1-deficient mice are not protected from bleomycin-induced pulmonary fibrosis.

Thrombospondin-1 (TSP-1) is an extracellular protein critical to normal lung homeostasis, and is reported to activate latent transforming growth factor-ß (TGF-ß). Because active TGF-ß is causally involved in lung fibrosis after bleomycin challenge, alterations in TSP-1 may be relevant to pulmonary fibrosis. We sought to determine the effects of TSP-1 deficiency on the susceptibility to bleomycin-induced pulmonary fibrosis in a murine model. Age-matched and sex-matched C57BL/6 wild-type (WT) and TSP-1-deficient mice were treated twice weekly for 4 weeks with intraperitoneal bleomycin (0.035 U/g) or PBS, and were allowed to rest 1 week before being killed. Their lungs were inflated with PBS, fixed in formalin, paraffin-embedded, and sectioned. A certified veterinary pathologist blindly scored each slide for inflammation and fibrosis. Lungs were homogenized to obtain RNA and protein for the real-time RT-PCR analysis of connective tissue growth factor (CTGF) and collagen I, and for Western blotting to detect phospho-Smad2, or total Smad2/3, respectively. In response to bleomycin treatment, measures of fibrosis and inflammation, along with CTGF and collagen I mRNA concentrations, were increased in TSP-1-deficient mice compared with WT mice. Notably, Smad 2/3 signaling was of equal strength in WT and TSP-1 knockout mice treated with bleomycin, suggesting that TSP-1 is not required for the activation of TGF-ß. These results demonstrate that TSP-1 deficiency does not protect mice from systemic bleomycin challenge, and that TSP-1 deficiency is associated with increased expression of lung collagen and CTGF.

Considering an infectious etiology of sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown cause. An infectious etiology of sarcoidosis has long been suspected, but only recently has scientific evidence provided a strong link between infectious agents and sarcoidosis. Moreover, recent advances in our understanding of the relationships between sarcoidosis phenotype and host genetic factors may further illuminate the mechanisms linking infection and sarcoidosis.

Laboratory testing in the intensive care unit.

Laboratory testing is ubiquitous among hospitalized patients and is more common among patients in the intensive care unit (ICU). Despite its high cost and prevalence, there are few data to support the current practice of laboratory testing in most ICUs. Although testing offers considerable potential benefits, it is not without risk, including misleading results, iatrogenic anemia, and therapeutic actions of uncertain benefit. Laboratory testing should be conducted as part of a therapeutic approach to a clinical problem, mindful of pretest probability of disease, the performance of the selected test, and the relative benefits and risks of testing. Considering the indication for a particular test can lead to a more rational approach to laboratory testing and better use of available tests.

Update on obstructive sleep apnea and its relation to COPD.

Chronic obstructive pulmonary disease (COPD) is a common and preventable lung disease that affects millions of people in the United States. Sleep disorders including obstructive sleep apnea (OSA) are also common. It is not surprising that many people with COPD also suffer from OSA. This relationship, however, puts people at risk for more nocturnal desaturations and potential complications related to this, including pulmonary hypertension and heart rhythm disturbances. This update focuses on the physiology of sleep disturbances in COPD as well as the clinical implications of OSA in COPD.

Sleep and Obstructive Lung Diseases.

Asthma and chronic obstructive pulmonary disease (COPD) are common obstructive lung diseases affecting millions of people in the United States. As sleep disorders are also common, it is not surprising that many people with obstructive lung disease also suffer from sleep disorders. However, people with COPD and those with asthma have worse sleep quality and more sleep-related problems when compared to people with other chronic health problems. In addition, a pathologic relationship may exist between obstructive sleep apnea (OSA) and obstructive lung diseases. This review focuses on the epidemiology, pathogenesis, and clinical implications of sleep disturbances in asthma and COPD.

Optimizing bronchodilator therapy in emphysema.

The treatment objectives for chronic obstructive pulmonary disease (COPD) include relieving symptoms such as dyspnea and cough, slowing the accelerated decline in lung function, decreasing exacerbations, and improving quality of life. All major guidelines for COPD management recommend beginning treatment with bronchodilators. There are several classes of bronchodilators, including beta-agonists, anticholinergics, and phosphodiesterase inhibitors, each with a specific mechanism of action. The overall approach to managing stable COPD involves a stepwise increase in treatment. Because of the progressive nature of emphysema, such an approach often involves combining bronchodilators from different pharmacologic classes. This review focuses on the pharmacologic properties of various bronchodilators and on recent studies that have examined combination therapy as a means to optimize treatment.