Identifying the mechanisms by which secondhand, also known as environmental tobacco smoke (ETS), might affect lung function, especially among children, is an important public health and policy concern. There are strong epidemiological correlations between long-term exposure to ETS and lung cancer in never-smoking adults. In addition to cancer, there are strong associations between workplace exposure to ETS and respiratory conditions including asthma, wheezing, coughing, etc., the severity of which depends on the extent of exposure. Childhood and/or continuing exposure to ETS is correlated to asthma and/or wheezing and increased respiratory illness in children. However, recognizing the negative effects of ETS in large populations does not explain the origin of these effects in individuals, especially at the cellular or molecular scale. This limits the interventions to control or reverse these effects. In this continuation proposal, we will examine the effects of ETS, or secondhand smoke, on the adsorption and distribution of lung surfactants.
Our work under this proposal has been and will continue to be based on an in vitro model - a temperature and surface tension controlled trough, filled with an aqueous “subphase”, onto which we spread monolayers of natural or synthetic human lung surfactant. This allows us to simulate the epithelial lining fluid (ELF) of the lungs. The saline subphase is similar in composition to the ELF that lines the alveolar and bronchial spaces within the lungs. To determine the effects of various levels of environmental tobacco smoke on surfactant, we have exposed the surfactant to a saline subphase conditioned by exposure to aged and diluted sidestream cigarette smoke (a model for environmental tobacco smoke, ETS) for various times and various concentrations. In parallel, we have studied the structure and function of the various components of surfactant to determine the “normal” function of each component and the synergistic interactions between these components that lead to proper lung function. The minimum surface tension of model lung surfactant monolayers and the morphology of the monolayer are significantly different depending on the level of exposure to ETS. ETS exposed surfactants do not adsorb to the interface as efficiently as normal surfactant, which causes increased minimum surface tensions. Increased minimum surface tension means breathing is more difficult, which can result in damage to the alveoli and bronchial tubes. This change in adsorption is likely due to degradation of the unsaturated lipids and/or the surfactant specific protein SP-C. both of which we believe play an important role in surfactant adsorption to the ELF-air interface.
This decrease in surfactant adsorption may be important to the development of chronic obstructive lung disease (COPD). In many lung diseases including COPD, there is an increase in serum and inflammatory proteins in the lung alveoli and airways. Our work under the previous grant has shown that surface-active proteins and other contaminants also inhibit the adsorption of lung surfactant to the interface, resulting in higher surface tensions. Such high tensions are detrimental to both alveolar and small airway function. Surface active compounds, be they the result of direct adsorption from smoking, from the proteins arising from inflammation, or serum proteins leaking from the pulmonary capillaries, decrease the rate of lung surfactant adsorption, resulting in damage to the lung, including increased work of breathing, increased leakage from the pulmonary capillaries, a reduction in the surface tension driven flow of particulates from the alveoli to the bronchial tubes, etc. Thus, dysfunction of surfactant in obstructive lung disease can contribute to increased airway resistance. Our second aim under this proposal is to shown how surfactant adsorption is inhibited by surface-active serum and inflammatory proteins present in the alveoli and airways due to smoking, and how certain simple water-soluble polymers can restore surfactant adsorption to normal levels. Such therapies may prove beneficial to obstructive lung diseases. |