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Abstract
Chronic obstructive pulmonary disease (COPD) is defined as airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with the inhalation of noxious gases, typically cigarette smoke. The protease-antiprotease paradigm suggests that the pathogenesis ofCOPDand emphysema is the result of an imbalance between enzymes that degrade the extracellular matrix within the lung and proteins that oppose this proteolytic activity. This reviewassesses the genetic evidence in support of protease-antiprotease imbalance in the pathogenesis of COPD. It also articulates why suppression of protease activity in alpha-1 antitrypsin deficiencymaybe insufficient to prevent the progression of COPD. Rather, alpha-1 antitrypsin deficiencymay be better treated by small-molecules so reads molecules, RNA-silencing, and other strategies that target the protein misfolding and polymerization that cause the disease.
Keywords: alpha-1 antitrypsin deficiency; polymers; genetics
Chronic obstructive pulmonary disease (COPD) is defined as airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases (1), typically cigarette smoke. The syndrome of COPD is composed of inflammation in the large and small airways (bronchitis and bronchiolitis, respectively) and alveolar destruction (emphysema). These three components vary in proportion between affected individuals and may be associated with systemic features such as cardiovascular disease, fatigue, depression, and osteoporosis. COPD is classically defined by spirometry, with individuals being affected when they have an FEV1 less than 80% predicted and airflow obstruction defined by an FEV1/FVC ratio less than 0.7.
The protease-antiprotease theory for the pathogenesis of COPD has its roots in experimental models of emphysema from the 1960s (2) and the observation that individuals with genetic deficiency of the antiprotease alpha-1 antitrypsin are particularly susceptible to COPD (3). This theory suggests that the pathogenesis of COPD and emphysema is the result of an imbalance between enzymes that degrade the extracellular matrix within the lung and proteins that oppose this proteolytic activity (4). This review assesses the genetic evidence in support of protease-antiprotease imbalance in the pathogenesis of COPD and articulates why suppression of protease activity in alpha-1 antitrypsin deficiency may be insufficient to prevent the progression of disease.
Epidemiology of COPD
Because COPD is diagnosed spirometrically, it is difficult and expensive to obtain...