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How do tobacco smoke compounds impair lung surfactant?

Institution: University of California, Santa Barbara
Investigator(s): Joseph Zasadzinski, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6IT-0140 Award: $74,961
Subject Area: Pulmonary Disease
Award Type: Inno Dev & Exp Awards (IDEAS)

Initial Award Abstract
The surface of human lungs where gas exchange occurs are lined by a unique mixture of soap-like molecules mixed with specific proteins. This mixture, called lung surfactant, forms a single molecular layer film that reduces the effort required to breathe by more than 90% (compared to the energy required without the layer). In other words, without functional lung surfactant, normal breathing is impossible. The surfactant layer is also one of the first lines of defense against lung injury and disease. Even though this surfactant layer is directly exposed during smoking, the effect of smoking on the essential chemical and mechanical properties of the lung surfactant layer are unknown.

In this project, we will use a simple model of the lung surface to see the effects of the most reactive components of tobacco smoke - called oxidizers. Using an artificial surfactant model system, we can see this single molecular layer using an optical microscope by adding a small amount of a fluorescent dye. Our previous studies have identified the normal chemical and mechanical properties of natural surfactant layers. We now will add oxidizing compounds to the surfactant layer to directly observe the effects of these components of tobacco smoke on the properties of surfactant necessary for lung function. We also plan to examine the effects of therapeutic anti-oxidant compounds on reversing the effects we find. We hope to be able to determine the chemical changes in surfactant that result in lung impairment and develop novel therapies to reverse these effects, as well as provide clinical markers for early lung damage due to smoking.

Final Report
The surfactant lining of the alveolus is essential to minimizing the work of breathing, insuring uniform inflation, and minimizing chemical or particulate damage to the deep lungs. Lung surfactant achieves these multiple goals by forming a monolayer at the fluid-air interface of the alveolus that is capable of altering the interfacial tension as the available interfacial area changes during respiration, lowering the tension to near zero on exhalation and rapidly respreading to cover the interace on inhalation. Normal lung surfactant consists of a complex mixture of saturated phosphatidylcholines, unsaturated phosphatidylcholines and phosphatidylglycerols, fatty acids, and surfactant specific proteins that interact synergistically to achieve these physiological functions. Damage to any of these components by oxidative or other components of tobacco smoke can compromise the function of the surfactant, even though only relatively minor fractions of the total surfactant are affected. The small changes can contribute significantly to the work necessary to breathe, even though there may be clinically indistiguishable changes in surfactant composition as measured by lavage or other methods.

Our experimental studies are designed to elucidate the function of each of the lipid and protein constituents of lung surfactant to first understand the roles of the minor components of normal surfactant, especially the unsaturated lipids and proteins that are most vulnerable to the oxidative component of smoke. We model the alveolar lining of the lung by a conventional Langmuir trough in which we can control and modify the available area per molecule and measure the surface tension as a function of molecular area. We study the monolayer morphology with a combination of fluorescence and Brewster angle optical microscopy and atomic force microscopy. With these probes, we have shown that the monolayer undergoes distinct three-dimensional structural transformations that depend on the presence of the SP-B and SP-C proteins and unsaturated lipids.. These interactions would be impossible to predict from the pure component phase behavior, and expose the monolayer components to theaqueous phase. We have also shown that strong oxidizers in the aqueous phase completely destroy the unsaturated lipids and that low fractions of ozone in the vapor phase substantially alter the SP-B protein, both of which disrupt the monolayer phase behaviors. We are designing a novel needle in a channel viscometer to measure the elastic properties of the monolayer which appear to be essential to the morphological transitions in lung surfactant.

The work of breathing is directly related to the efficiency with which the surfactant lining of the lung performs its functions. We have elucidated the role of the surfactant monolayer, its chemical components, and the consequences of inactivation or removal of specific proteins and lipids that are susceptible to smoking related damage. It is clear that very small changes induced by oxidation or other chemical effects can lead to dramatic differences in surfactant performance and the associated work of breathing. While the Langmuir trough is a good model of the lung alveolar interface, it is necessary to determine more completely what the main chemical compounds and concentrations of tobacco smoke reach the deep lung and how best to model these interactions.

From free-standing to transferred films: an apparatus for the continuous monitoring of surface morphology via fluorescence and AFM
Periodical: Langmuir Index Medicus:
Authors: Lee KYC, Lipp MM, Takamoto DY, Zasadzinski JA, Waring AJ ART
Yr: 0 Vol: Nbr: Abs: Pg:

Coexistence between buckled and flat monolayers
Periodical: Physical Review Letters Index Medicus:
Authors: Lipp MM, Lee KYC, Waring AJ, Zasadzinski JA ART
Yr: 1998 Vol: 81 Nbr: Abs: Pg: 1650-1653

Effects of lung surfactant specific protein SP-B and model SP-B peptide on lipid monolayers at the air-water interface
Periodical: Colloids and Surfaces Index Medicus:
Authors: Lee KYC, Lipp MM, Waring AJ, Zasadzinski JA ART
Yr: 1997 Vol: 128 Nbr: Abs: Pg: 225-242

Direct observation of morphology changes induced by lung surfactant protein SP-B
Periodical: Laser Techniques for Biological Systems Index Medicus:
Authors: Lee KYC, Lipp MM, Takamoto DY, Zasadzinski J ART
Yr: 1998 Vol: 3273 Nbr: Abs: Pg: 115-133