Environmental tobacco smoke effects on lung surfactant
Abstracts
Initial Award Abstract |
|
Quantifying the risks that environmental tobacco smoke (ETS) might pose to non-smokers is an important public health and policy concern. A causal association between ETS exposure and lung cancer appears to exist; in fact, nonsmokers married to smokers have a statistically significant risk of developing lung cancer. In addition to lung cancer, associations have been found between passive smoking at the workplace and chronic respiratory symptoms such as wheezing and cough. Respiratory effects of ETS are especially significant in infants and children exposed to parental smoking. For instance, epidemiological studies have clearly shown that children raised in homes with smokers have more coughing, wheezing, and respiratory illness compared with children raised in homes without smoking. However, epidemiological studies cannot provide a detailed explanation for the actual physiological effects, of ETS on specific organs, tissues, etc. in a systematic and controlled fashion.
This proposal is designed to determine the effects of controlled exposure to environmental tobacco smoke on the mechanical and morphological features of human lung surfactants. The surfactant lining of the alveolus plays an important part in proper lung function including minimizing the work of breathing, ensuring uniform lung inflation, and reducing chemical and particulate damage to the deep lungs. Lung surfactant achieves these multiple goals by forming a single molecule layer thick film at the fluid-air interface of the alveolus which lowers the surface tension as the available interfacial area changes during respiration. The surfactant monolayer must be capable of maintaining a near zero surface tension at the contracting alveolus interface during exhalation to minimize the work of breathing. The surfactant monolayer must also respread quickly to cover the expanding interface during inhalation in order to prepare for the next breath; this requires that monolayer viscosity sit in a suitable range. Normal lung surfactant consists of a complex mixture of saturated phosphatidylcholines, unsaturated phosphatidy1cholines and phosphatidylglycerols, fatty acids and surfactant specific proteins that act synergistically to achieve these necessary physiological functions.
We have found that removing or inactivating the protein and unsaturated lipid components of lung surfactants leads to poor surfactant performance in vitro, and correlates very well with poor lung performance in animal models. In addition, we have recently begun systematic studies of the dependence of monolayer morphology and viscosity on the details of the lung surfactant composition. Too viscous monolayer can not repread quickly to cover exposed area, while monolayers with excessively low viscosity can not achieve sufficiently low surface tensions. The monolayer viscosity is thus a material parameter equal in importance to the lipid composition, surfactant proteins and fluid composition. We plan to use in vitro measurements of surfactant performance such as minimum surface tension, monolayer morphology and monolayer viscosity to determine the effects of ETS on lung surfactants. To do this, we will expose a buffered saline solution (similar to the alveolar lining fluid) to various concentrations of side-stream smoke using a system developed at the Institute of Toxicology and Environmental Health at UC Davis. Lung surfactant monolayers will be spread over this "smoke-conditioned" fluid and the surface tension, viscosity, phase behavior, and morphology of the monolayers will be compared to control monolayers. Variations in these parameters will be quantified and related to changes in the chemical composition and concentrations of the components of lung surfactant. These alterations can then be related to the physiological effects known to occur in passive smoking. We hope to be able to provide direct information on the effects of ETS on the lung surfactant system, and how these changes can lead to changes in respiratory health. |
Final Report |
|
Quantifying the risks that environmental tobacco smoke (ETS) might pose to non-smokers is an important public health and policy concern. A causal association between ETS exposure and lung cancer and other diseases appears to exist. Respiratory effects of ETS are especially significant in infants and children exposed to parental smoking. However, epidemiological studies cannot provide a detailed explanation for the actual physiological effects, of ETS on specific organs, tissues, etc. in a systematic and controlled fashion; this type of information is needed in order to design effective treatments.
The awarded project is designed to determine the effects of controlled exposure to environmental tobacco smoke on the mechanical and morphological features of human lung surfactants. The surfactant lining of the alveolus plays an important part in proper lung function including minimizing the work of breathing, ensuring uniform lung inflation, and reducing chemical and particulate damage to the deep lungs. Lung surfactant achieves these multiple goals by forming a single molecule layer thick film at the fluid-air interface of the alveolus which controls the surface tension as the available interfacial area changes during respiration. The surfactant monolayer must be capable of maintaining a near zero surface tension at the contracting alveolus interface during exhalation to minimize the work of breathing. The surfactant monolayer must also respread quickly to cover the expanding interface during inhalation in order to prepare for the next breath; this requires that monolayer viscosity sit in a suitable range. Normal lung surfactant consists of a complex mixture of saturated phosphatidylcholines, unsaturated phosphatidy1cholines and phosphatidylglycerols, fatty acids and surfactant specific proteins that act synergistically to achieve these necessary physiological functions.
Under the support of the dissertation award from the Tobacco-Related Disease Program, we were able to use a combination of Langmuir trough, atomic force microscopy, gracing incident X-ray diffraction, fluorescence microscopy and magnetic needle viscometry to study model lung surfactant systems. Identifying the function of lung surfactant proteins and lipids is essential to the effects of ETS to each individual component in lung surfactants. We found that the major function of palmitic acid and hexadecanol to lung surfactant is to adjust monolayer viscosity for high viscosity during exhalation and low viscosity during inhalation, that is, palmitic acid or hexadecanol adjusts the viscosity of lung surfactant to the right range for its proper function. Palmitic acid, as well as n-hexadecanol, makes the monolayer rigid at low surface tension and fluid at high surface tension and modifies SP-C function, and decreases the tilt angle of monoalyer at a certain surface pressure. Shear viscosity of model lung surfactant mixtures strongly relates to the morphology of monolayer and particularly to the fraction of solid domain. This scaling relationship is directly analogous to that derived for three-dimensional colloidal dispersions in a solvent with long-range repulsive interactions between the solids (with area fraction replacing volume fraction). The repulsion between solid domains is consistent with the known repulsive dipole-dipole interaction between solid phase domains in monolayers.
Lung surfactant protein SP-B and peptides based on SP-B induce a reversible folding transition at monolayer collapse that allows all components of surfactant to be retained at the interface during respreading. SP-B also interacts with POPG specifically and induces a 3-D aggregation in fluid phase above certain surface pressure.
We also applied tobacco exposed side stream solution to simulate the ETS exposed solution and used this solution for subphase in lung surfactant monolayer study. Our data show that ETS degrades lung surfactant more rapidly compared to the system without ETS. The minimum surface tension for the lung surfactant monolayer increases much faster in the system with ETS exposure. Since surface tension is proportional to the work required to expand lungs, this implies that people with ETS exposure need more energy to breathe or need to produce more lung surfactant to maintain lung function. Our microscopy images show that the degraded function is accompanied by altered lung surfactant morphology. |
Publications
| The role of lung surfactant proteins and lipids in monolayer stability |
| Periodical: Biophysical Journal |
Index Medicus: |
| Authors: Ding J, Takamoto DY, von Nahmen A, et al |
ART |
| Yr: 0 |
Vol: |
Nbr: |
Abs: |
Pg: |
| The role of lung surfactant proteins and lipids in monolayer stability |
| Periodical: Biophysical Journal |
Index Medicus: |
| Authors: Ding J, Takamoto DY, von Nahmen A, et al |
ART |
| Yr: 0 |
Vol: |
Nbr: |
Abs: |
Pg: |
