During the two last decades, the profiling of miRNAs as biomarkers or prognostic factors in disease has become increasingly popular, as changes in tissue miRNA expression appear to manifest in the circulation. The ability to profile circulating miRNAs provides a noninvasive tool for investigating disease-specific miRNAs as novel biomarkers for diagnosis, prognosis, and therapeutic response in the blood. This chapter discusses circulating miRNAs, found in plasma, serum, and a host of other body fluids, as biomarkers and, possibly, as critical regulators of tissue remodeling and repair.

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.

Thrombospondin-1 (TSP-1) is an extracellular protein critical to normal lung homeostasis, and is reported to activate latent transforming growth factor-β (TGF-β). Because active TGF-β 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-β. 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.

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 β, 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.

Recent evidence demonstrates the importance of microRNAs (miRNAs) in several human diseases, including solid and hematological malignancies, diabetes and diseases of the nervous system. However, little is known about the role that miRNAs play in the development and pathogenesis of lung diseases. Murine models of disease suggest that the loss of specific miRNAs is vital to lung development and modulation of the immune system that consequently results in the development of uncontrolled inflammation in the lung. Other studies have found that bacterial challenges also upregulate the expression of specific miRNAs. In this article, we will focus on miRNA involvement in lung development and the possibility that dysregulation and/or reactivation of miRNAs may contribute to lung disease. We will also review the role of miRNAs in the pathogenesis of specific diseases, such as lung cancer, sepsis and smoking-related lung disease.

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.

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.

A 52-year-old man presented to his primary care physician with dyspnea and cough. For the past 15 years, he had had recurrent episodes of cough that were relieved only by intermittent courses of oral corticosteroids. In the past 3 weeks, his cough had increased in frequency, and severe dyspnea had developed. This time, 2 weeks of prednisone had not provided relief. He had occasional chills but no fever.

A 52-year-old man presented to his primary care physician with dyspnea and cough. For the past 15 years, he had had recurrent episodes of cough that were relieved only by intermittent courses of oral corticosteroids. In the past 3 weeks, his cough had increased in frequency, and severe dyspnea had developed. This time, 2 weeks of prednisone had not provided relief. He had occasional chills but no fever.

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.

INTRODUCTION:Pulmonary fibromas and granular cell tumors are rare benign tumors of the lung. Treatment of these endobronchial tumors has traditionally been by surgical resection. We report the first case of an endobronchial fibroma and granular cell tumor (GCT) in the same patient with successful resection of the fibroma using electrocautery snare.

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.

INTRODUCTION:There are multiple causes of hypoxia in patients with acute myeloid leukemia (AML).One of these is pulmonary leukostasis which is an oncologic emergency and can be difficult to diagnose and manage.We report a case of a patient with newly diagnosed AML and hypoxia secondary to pulmonary leukostasis that was successfully treated with chest irradiation. CASE PRESENTATION:A 71-year-old white male with no past medical history presented to our medical center with three weeks of progressive dyspnea, fatigue, and a ten pound weight loss.He denied chest pain, orthopnea, or fevers.His only medicines were over-the-counter vitamins and he was a lifelong nonsmoker.On examination, he was tachycardic to 120 beats per minute and his SpO2 was 92% on 3 liters nasal cannula.There were faint crackles bilaterally on lung exam with no jugular venous distention or lower extremity edema.Labs revealed a white count of 208.9 K/ul with 60% blasts, hemoglobin of 6.9 g/dl, and platelet count of 26 K/ul.Bone marrow biopsy was hypercellular with 94% blasts and the patient was given a diagnosis of AML.His ejection fraction by MUGA was 51%.Chest CT demonstrated diffuse ground glass infiltrates.Blood cultures were negative for infection.Cytoreduction was attempted with hydroxyurea and 2 cycles of leukapheresis.Despite these therapies, his oxygen requirement increased and on 100% FIO2 his PaO2 was 134, with an SpO2 of 90%.Chest irradiation was then given at 100 cGy with a marked improvement in his oxygenation, eventually weaning to room air in 48 hours.He was then initiated on induction chemotherapy for his AML. DISCUSSIONS:The differential diagnosis of hypoxia in patients with AML includes leukostasis, pneumonia, pulmonary emboli, congestive heart failure, alveolar hemorrhage, or spurious hypoxia.Spurious hypoxemia is found in patients with hyperleukocytosis and may be due to consumption of dissolved oxygen from the sample by the white cells or coating of the oxygen electrode by white cells.In these cases, pulse oximetry may be the most accurate method of assessing oxygenation.Leukostasis occurs due to an increased blast count that impedes blood flow in the microcirculation.In addition, there may be an adhesive interaction between the blasts and endothelium, and hypoxia due to leukostasis may be exacerbated by the high metabolic activity of the dividing cells.Making the diagnosis of pulmonary leukostasis can be difficult.A diffuse vascular occlusive pattern on perfusion lung scanning may be supportive.A bronchoalveolar lavage with a large number of blasts and no evidence of infection may also be supportive, but most diagnoses are retrospective after clinical improvement with cytoreduction.Cytoreduction is often initiated as, in some patients, leukostasis or other problems may lessen the response to chemotherapy or delay the initiation of chemotherapy.However, cytoreduction by leukapheresis or other means has not been shown to improve mortality.Rapid cytoreduction can be achieved with induction chemotherapy, hydroxyurea, leukapheresis, or less commonly, irradiation.The rationale for radiation is that it destroys established intravascular foci of blast cells.There are only a few case reports in the literature utilizing irradiation for pulmonary leukostasis with hypoxia.Three cases that have reported benefit were all in young patients ages 25-29.A case report of a 65-year-old patient cited no benefit.CONCLUSION: This is a case of 71-year-old patient with hypoxia due to pulmonary leukostasis that responded to chest irradiation after being refractory to other therapies.When instituted early, chest irradiation may be of benefit in treating severe pulmonary leukostasis.