Chronic obstructive pulmonary disease (COPD) is a global public health problem. It is projected that by 2020 it will be the third leading cause of dead worldwide, and the fifth leading cause of years of life lost due to disability coupled with years of life lost due to premature dead. The definition provides that, besides being preventable, treatable and characterized by a chronic and persistent airflow limitation (usually progressive), COPD is due to an increased chronic inflammatory response. It has an overwhelming prevalence, yet accepted therapies are ineffective in reducing disease progression. Bronchodilators, the mainstay of COPD treatment, only provide symptomatic relief. Therefore, in order to provide a superior approach, it is important to better understand the rationale behind therapy and the underlying mechanisms by which the inflammatory process, through various pathogenic pathways, leads to deterioration. Cigarette smoke and other pollutants/biomass fuels affect the lungs ability to counterbalance proteases and neutralize different types of stress. Even if the initial noxa is discontinued, inflammation, infection and autoimmunity promote a chronic lung inflammatory response; leading to the development of emphysema and small airway disease. This is due to continuous endogenous production of reactive oxygen species, nitrative and carbonyl stress. The process then continues into a harmful spiral and systemic disease. The objective of this paper is to offer an updated review of COPD, simplifying the integration of basic science research and introducing the concepts and evidence of therapeutic alternatives. This review discusses why some drugs have failed and which alternatives are emerging. Probably there is no unique effective therapy, but several combinations of drugs might be required to impact the different subcellular compartments and obtain a more effective therapy in COPD. High level of ROS initiates the inflammatory process in COPD, with a highly specific cellular and molecular profile. Through protease/anti-protease imbalance and diverse kinds of stress, the pathological phenomena involving the bronchopulmonary, vascular and systemic compartment is generated. Autoimmunity and repeated infections potentially perpetuate and amplify the inflammatory process, even if the initial stimulus is suspended. Failure of current bronchodilator and steroid therapies to attenuate natural evolution of the disease and progressive deterioration indicates the need to develop powerful new drugs with innovative effects. It is likely than drug combinations are required, instead of monotherapy, in order to improve the effectiveness and impact the progressive course and mortality of COPD.

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