Few smokers develop COPD. Why?

Abstract

COPD is a common disease and its major risk factor, cigarette smoking, has been identified. However, only a minority of smokers develop clinically relevant disease. Although, the current understanding of the pathogenesis includes an "abnormal inflammation" as a response to various noxious agents, its various pathways are not clear. Oxidative stress, inflammation, tissue damage and tissue repair (remodeling) are parts of the complex procedure leading to COPD. This is a review of the available literature concerning the "susceptible" smoker. An epidemiological model is discussed, putting emphasis on the timing of the exposure to cigarette smoke. There are evidences that respiratory adenoviral infection in early life could be also an important factor. Differences in nutrition could also play a role in protecting against the oxidative stress. Airway hyperresponsiveness failed to clarify the whole picture and is still open for debate. Genetic differences are the most likely explanations to describe the "susceptible" smoker. However, the only well-established genetic risk factor is the alpha-l-antitrypsin. Other candidate genes were reviewed, alpha-l-antichymotrypsin, blood group antigens, vitamin-D binding protein, a2-macroglobulin, immunoglobulin deficiency, extracellular superoxide dismutase, secretory leukocyte proteinase inhibitor, cathepsin G, tumor necrosis factor-a gene and others. Microsatellite DNA instability in COPD could be a useful tool to identify the locus of genetic alterations leading to COPD. Thus, in addition to exposure to exogenous factors, host factors, most likely several genes, are involved and affect various pathways of the pathogenesis of COPD.

Blunted ventilatory response to hypoxia/hypercapnia in mice with cigarette smoke-induced emphysema

“…Nevertheless, the appearance of hypoxemic hypercapnia and the substantial AVR to hypoxia and hypoxic hypercapnia in C3H/HeN emphysematous mice has built a solid basis for further mechanistically studying AVR genesis. In addition, although emphysema can be modeled in other ways, such as exogenous administration of proteinases, chemicals, and particulate materials (Mahadeva et al 2002), CS-induced emphysema was chosen in the present study because ~ 85% of patients with COPD result from smoking (Anto et al 2001;Siafakas et al 2002). Second, we recognized that it would be optimal if the cardiorespiratory (arterial blood gases) variables under room air and in response to chemical challenges could be measured in conscious mice.…”

“…Chronic obstructive pulmonary disease (COPD), ~ 85% of it resulting from mainstream and second hand cigarette smoke (CS) (Anto et al 2001;Siafakas et al 2002), kills 2.5 million people worldwide every year (Barnes 2000). Chronic hypercapnia often complicates severe COPD and is associated with a worse prognosis (Burrows et al 1969;Cooper et al 1991).…”

Mechanisms of Lung Development: Contribution to Adult Lung Disease and Relevance to Chronic Obstructive Pulmonary Disease

“…Although there is clearly a role for environmental factors in the pathogenesis of COPD, there is also accumulated evidence of a major genetic component influencing disease susceptibility and severity. For example, COPD is associated with cigarette smoke, but the disease is manifested in a relatively small fraction of the overall population of smokers (1)(2)(3).…”

Transcription Factor Nrf2 Plays a Pivotal Role in Protection against Elastase-Induced Pulmonary Inflammation and Emphysema

“…Importantly, however, not all smokers develop clinically significant emphysema, and this observation suggests that some additional factors may be involved in determining individual susceptibility to emphysema (5). A well-documented host factor is a hereditary deficiency of ␣1-antitrypsin, a major circulating inhibitor of serine protease that is synthesized in the liver (6,7).…”