The overall objective of this proposal is to test three novel treatments aimed at reducing the frequency and/or the severity of acute exacerbations of COPD. We describe two randomized placebo-controlled trials. The first will determine whether long-term administration of N-acetyl cysteine (a thiol compound that decreases mucus viscosity and also has anti-oxidant, anti-inflammatory and cytoprotective effects), or clarithromycin (a macrolide antibiotic having both anti-inflammatory and antibiotic effects) will reduce the frequency and severity of COPD exacerbations. The second will determine whether administering bronchodilators via nebulizers that are powered with heliox (a mixture of helium and oxygen), as opposed to air, will more rapidly reverse the physiologic abnormalities, and reduce the length of hospital stay, associated with severe acute exacerbations of COPD as a result of the lower density of heliox reducing turbulent flow, thereby increasing bronchodilator deposition in more distal airways. As a sub goal we also propose to use a number of biomarkers (i.e., levels of adenosine in exhaled air, levels of interleukins 6 and 8 in sputum, levels of interleukins 6 and 8, surfactant protein D, vascular endothelial growth factor, fibrinogen, C-reactive peptide, Factor VIII activity, and von Willebrand's factor antigen in blood), to identify and characterize those patients who are more likely to have acute exacerbations. This information will, at the same time, also provide information regarding the pathobiology of COPD exacerbations.