Is the cellular response to cigarette smoke predictive of the phenotypic variation of COPD?

Abstract

the adverse health consequences of cigarette smoking are not limited to the lung but also include effects on multiple other organ systems that are exposed directly or indirectly to the hazardous gaseous and soluble compounds generated by burning tobacco. Cigarette smoking (CS) is a risk factor for many major diseases including chronic obstructive pulmonary disease (COPD), atherosclerosis, cerebral and coronary vascular diseases, hypertension, and many types of cancer. Within the diagnosis category of COPD, it is widely recognized that there is substantial phenotypic heterogeneity with respect to both pulmonary and extrapulmonary manifestations. To understand the variability in responses to CS, it becomes essential to decipher the involved mechanisms at a cellular and molecular level that contribute to cigarette-related pathology. In this issue of the Journal, there are three papers (1, 4, 6) that provide insight regarding the molecular pathogenesis of CS-related COPD that could be related to phenotypic variation, by examining three classes of cell types of lung: endothelial cells, epithelial cells, and immune effector cells.

There are several general basic facts related to the molecular reaction to cigarette smoke (CS) that need to be addressed. Even a brief exposure to CS impairs mucociliary clearance and potentially initiates a cascade of events that result in airway inflammation and injury. Inflammation that results from exposure to CS is characterized by a fourfold or greater increase in the numbers of alveolar macrophages and neutrophils into the air space. Exposure to CS is associated with an enhanced susceptibility to respiratory infections, which probably contributes to the episodic exacerbations of COPD that are associated with deterioration in health status, and smokers have a higher incidence of pneumonia. CS contains a complicated mixture of over 4,700 different chemical compounds including a high concentration of various oxidants and free radicals. The aqueous phase of CS may undergo continuous redox cycling with lung lining fluid for a considerable period of time. Reactive oxygen species (ROS) are unstable molecules that oxidize various cellular components including DNA, proteins, and lipids that have profound effects on critical cellular machinery. Additionally, ROS regulates several important physiological and pathophysiological responses, such as oxygen sensing, angiogenesis, control of vascular tone, and regulation of cell growth, differentiation, and migration. Finally, ROS are also important in the intracellular signaling pathways engaged by various inflammatory conditions. For example, it is known that ROS production by the mitochondria or via Toll-like receptor signaling affects the nucleotide-binding oligomerization domain inflammasome, which recognizes tissue damage and injuries (3).

In this issue of the Journal, Wu et al. (6) show that CS inhibits retinoic acid-inducible gene I (RIG-I) activation and subsequent secretion of IP-10 from alveolar macrophages and IFN-β from epithelial cells in the clinically relevant setting of influenza infection. This effect was prevented by treatment with an antioxidant, which suggests that ROS originated from CS mediated the reaction. RIG-I is one of family members of pattern recognition receptors involved in sensing cytoplasmic viral RNAs (5). Inhibition of RIG-I could impair activation of a beneficial host defense against viral infection. Polymorphisms or other modifications of functional RIG-I or similar proteins could have a profound impact on the frequency of COPD exacerbations or incidence of pneumonia, which would have health consequences. However, there are unanswered questions: it is still unclear whether oxidants generated by CS are either directly sensed by RIG-I or indirectly sensed through cytoplasmic proteins that modulate inflammasome activity. Furthermore, it would be interesting to investigate whether alveolar macrophages or neutrophils that are exposed to CS are similarly affected.

Smoking-related diseases are the largest category of preventable medical conditions, and absolute smoking cessation is a general public health goal. However, identification of an especially susceptible population could be useful in preventing the most egregious harmful effects of CS that result in the highest morbidity, mortality, and health care costs. Furthermore some of these same risk factors may be related to the pathogenesis of other lung diseases, especially those that result from environmental exposures. It is very clear that the individual response to CS is considerably variable since only 20–30% of cigarette smokers develop COPD over a lifetime. This observation raised the idea of polygenetic susceptibility to CS, which has been strongly supported by epidemiological genetic studies that have been recently published (2). In this issue of the Journal, Henno et al. (4) reported that only a fraction of smokers had evidence of dysregulation of pulmonary vasorelaxation, which, potentially, could result in pulmonary artery hypertension. In this study, ∼24% of smokers exhibited marked endothelial dysfunction in response to acetylcholine, which appears to be mediated by overactivation of the endothelin-1- dependent pathway. This is a potentially important observation because there is a certain phenotype among COPD patients who have an unexpectedly elevated pulmonary artery systolic pressure that is out of proportion to spirometric deterioration of lung function. Henno et al.'s study suggests that endothelin-1-dependent vascular relaxation dysfunction may be the mechanism in this population of COPD patients, although future studies will be necessary to confirm this observation. The recently published genome-wide association study (8) indicated that there is variation in the identification of the genetic loci that correlates with various CS diseases, which supports the idea that there are many different phenotypic manifestations that are associated with exposure to a single common hazard, CS.

CS has profound effects on cellular biological function at multiple levels that range from effects on DNA to effects on the cell surface. Epigenetic modifications such as DNA methylation and histone phosphoacetylation are well documented in CS-related lung disease models that result from transcriptional and posttranslational activity of many genes that are altered by cigarette-related compounds (7). The cell surface is an active site for CS injury as well. Cigarette smoke upregulates sphingomyelinase, which hydrolyzes sphingomyelin to ceramide. Elevated ceramide enhances apoptosis of cells and lung injury. In this issue of Journal, Bodas et al. (1) show that membrane-CFTR controls apoptosis by regulating the expression of ceramide and lipid-raft proteins in CS-induced lung injury models. It is possible that this or a similar mechanism is related to the loss of alveolar structure in patients with severe emphysematous COPD.

These and other recently published articles that explore the molecular events related to exposure to cigarette smoke and important because they have “set the stage” for more to come. Smoking-related diseases such as COPD remain mostly preventable but unfortunately also incurable and there is no single therapy that can halt the decline in lung function or the progressive destruction of the lung. The smoking epidemic is worldwide and increasing in many locations. In our view, it is essential that research be focused on improving our understanding of the specific cellular and biochemical injuries induced by CS and relating this to the various types and subtypes of COPD and the extent and nature of the extrapulmonary manifestations. It is possible, if not likely, that the involved mechanisms would be involved in the molecular pathogenesis of many other lung diseases of known and unknown causes.

DISCLOSURES

No conflicts of interest, financial or otherwise are declared by the author(s).