Rethinking chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a complex polygenic disease characterized by an abnormal inflammatory response to smoke, and results in a progressive and debilitating condition with declining lung function. The reasons why some smokers get COPD are not known. We suggest that corticosteroid resistance, which derives from oxidative stress, might actually be the cause of COPD and represent the starting point of the pathology. The absence of response to corticosteroids would let the disease develop, impairing the organism capacity to suppress any kind of inflammatory process. Corticosteroid resistance may derive from smoke induced oxidative stress and plausibly impairs the organism capacity to suppress inflammation. Many factors may contribute to the development and persistence of corticosteroid resistance: inefficient antioxidant defences, a corticosteroid response less efficient or more sensitive to oxidative conditions, and also any other concomitant factor, environmental, genetic or intercurrent, which would contribute to amplify inflammation and hence oxidative stress. One or more of these factors might represent the variable component of the disease, which gives origin to COPD heterogeneity. This hypotheses may also explain why the disease persists after quitting smoking, as an inflammatory process severe enough to generate a strong oxidative stress may support itself by maintenance of corticosteroid resistance.