Molecular Biology of Chronic Obstructive Pulmonary Disease: Basic Research and Clinical Application

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.