New study confirms the fears of many in a work and social environment that exposure to second-hand smoke can lead to a deadly and debilitating disease.
July 13, 2003 — Bethesda, MD — Cigarette smoke is the major cause of pulmonary emphysema. This disease involves severe damage to the walls of the air sacs (alveoli), causing the lungs to lose their capacity to expand and contract (loss of elasticity). At that point, the air sacs are unable to completely deflate and are therefore unable to fill with fresh air for adequate ventilation.
Two of every 1,000 Americans develop this disease. Scientists know smokers are significantly more likely to develop emphysema compared with nonsmokers, and the seriousness of the disease is directly correlated with the amount of cigarette smoking.
But why cigarette smoke leads to this disease is still open to speculation. Now, a team of researchers from Italy has found that cigarette smoke is a potent source of oxidative stress, DNA damage, and apoptosis for HFL-1 (fibroblast) cells, and is most likely the trigger leading to the development of pulmonary emphysema in smokers’ lungs.
Their findings confirm the fears of many in a work and social environment that exposure to second-hand smoke can lead to a deadly and debilitating disease.
Among the different toxic effects of cigarette smoke on human tissues, oxidation of structural and functional molecules and modulation of cell turnover play a major role. One study has hypothesized that cigarette smoke may act by decreasing the expression of vascular endothelial growth factor (VEGF) and its type 2 receptor, thus resulting in lung septal endothelial cell death.
Because fibroblasts (stellate or spindle-shaped cells with cytoplasmic processes present in connective tissue) play a pivotal role in remodeling of pulmonary tissue, researchers have exposed fibroblasts to cigarette smoke and have studied two important processes: oxidative stress and apoptosis.
Oxidative stress is a disturbance in the oxidant-antioxidant balance, resulting in potential cell damage. It is involved in many biological and pathological processes, such as inflammation and carcinogenesis, and in the development of many pulmonary diseases. In response to oxidative stress, lung cells release inflammatory mediators and cytokines (TNF-, IL-1, and IL-8) that are able to induce neutrophil recruitment and activation of transcription factors such as activator protein-1 and nuclear factor-B.
Apoptosis is a form of cell death that occurs under several physiological and pathological situations, and it represents a common mechanism of cell replacement, tissue remodeling, and removal of damaged cells. It is characterized by cell shrinkage, chromatin condensation, internucleosomal DNA fragmentation, and formation of apoptotic bodies. Apoptosis may occur spontaneously or in response to specific stimuli such as heat stress, radiation, steroids, and oxidative stress.
A New Study
Because oxidative stress and apoptosis are implicated in numerous processes, including aging, inflammation, and carcinogenesis, it is reasonable to hypothesize a link between these two processes. The mechanisms by which oxidants can modulate the apoptotic pathways have been recently reviewed. The aim of a new study was was to evaluate the ability of cigarette smoke to induce fibroblast oxidation and apoptosis.
The authors of “Cigarette Smoke Extract Induces Oxidative Stress and Apoptosis in Human Lung Fibroblasts” are Stefano Carnevali, Stefano Petruzzelli, Biancamaria Longoni, Renato Vanacore, Roberto Barale, Monica Cipollini, Fabrizio Scatena, Pierluigi Paggiaro, Alessandro Celi, and Carlo Giuntini, all from the University of Pisa; and Cisanello Hospital, Pisa, Italy. Their findings appear in the June 2003 edition of the American Journal of Physiology–Lung Cellular and Molecular Physiology.
Human fibroblast cells were exposed to various concentrations (one, five, and ten percent) of cigarette smoke extract (CSE) for three hours and oxidative stress and apoptosis were assessed by fluorescence-activated cell sorting and confocal laser fluorescence microscopy.
Since fibroblasts are the main cell type in connective tissue, they therefore play a major role in the repair of pulmonary tissue. Previous studies support the idea that fibroblasts are targets for a wide variety of stimuli, including cigarette smoke. For instance, cigarette smoke was able to inhibit fibroblast recruitment and proliferation and to alter fibroblast-mediated collagen gel contraction in vitro. Using a human lung fibroblast cell line as a model to study some of the harmful effects of cigarette smoke, the researchers found:
Cigarette smoke is able to induce cellular oxidative stress and that the oxidation depends on the concentrations of cigarette smoke extract.
The tobacco by-product induces fibroblast apoptosis that parallels the oxidation, possibly because direct cigarette smoke oxidants and/or intracellular reactive oxygen species (ROS) generated by cigarette smoke can switch on apoptotic pathway(s) in fibroblasts.
The oxidative and proapoptotic effects of cigarette smoke exposure on HFL-1 cells begin at very low CSE concentrations (one percent) and reach statistical significance against controls at five percent concentration after just three hours of incubation.
Fibroblasts in the small area of the smokers’ lungs may be continuously challenged by compounds capable of interfering with their functions and/or lifespan. This leads to speculation that concomitant oxidation and apoptosis in human lung fibroblasts observed in vitro after short-term exposure to CSE may lead, when repeated thousands of times in a smoker’s life, to a defective tissue repair and contribute to the development of pulmonary emphysema. The negative effect of CSE on fibroblast functions due to oxidation may further hamper the efficacy of tissue repair.
In this experiment NAC was able to reduce the toxic effects of cigarette smoke with a significant and parallel decrease of both oxidative stress and apoptosis. These results lend further support to the hypothesis that cellular oxidative stress and apoptosis induced by cigarette smoke are closely related each other.
Summary of Observations
These results support recent findings on the importance of resident cells in the development of emphysema. In this study, the researchers demonstrated that fibroblasts undergo cell death after exposure to cigarette smoke, which parallels the increase in oxidative stress.
Additionally, the researchers found that development of pulmonary emphysema might be not only the result of an imbalance between oxidants and antioxidants, and/or between proteases and antiproteases, but also the consequence of fibroblast oxidation and apoptosis caused by cigarette smoke. Moreover, the protective effect of antioxidants such as NAC against the toxic effects of cigarette smoke underlines the importance of this class of molecules in the treatment of tobacco smoke-induced pulmonary diseases.
Source: the June 2003 edition of the American Journal of Physiology–Lung Cellular and Molecular Physiology.
The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.