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Effect of tobacco smoke on lung airway surface liquid

Institution: Children's Hospital Oakland Research Institute
Investigator(s): Jacob Bastacky, M.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0133A Award: $115,658
Subject Area: Pulmonary Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
We propose to examine the effects of tobacco smoke on one of the primary mechanisms by which the lung protects itself from the harmful effects of tobacco smoke, namely the secretion of a protective liquid layer in the airways. This is an extension of our previous work on tobacco effects further down the conducting airways, in the air sacs (alveoli) where gas exchange takes place, and our studies of the normal physiology of the airways. The proposed work is also relevant to the treatment of patients with tobacco-related lung diseases and to understanding the biological pathways from smoke exposure to tobacco-related diseases. Our experiments will help in understanding the mechanisms of mucus secretion and formation of the liquid layer (which overlays the cells lining the airway surfaces), from trachea to bronchus to terminal bronchiole, as the airway branches to deliver fresh air to the alveoli. We will examine the effects of secondhand smoke on secretion of liquid, ions, and mucus to see whether smoke simply stimulates the system or whether the system can adapt to the insult and learn to protect itself in a more efficient manner. It may be that such an adaptation has a unforeseen consequence; for example, predisposing an individual to serious disease such as cancer, asthma, or bronchitis. The information we will obtain will help to devise future treatments for both asthma and chronic bronchitis, which can be caused and exacerbated by smoking, and for other serious lung diseases such as cystic fibrosis and pulmonary edema.

Final Report
The goal of this research is to determine the effects of tobacco smoke on the liquid that lines the airways in the lung. This liquid is important because it is one of the first compartments to interact with smoke in the lung. This layer traps the products of combustion of tobacco, airborne particles and gasses removing them from the airstream but concentrating them in the liquid layer. The liquid dissolves some of these noxious materials and presents them to the underlying epithelial cells.

We hypothesize that the lining layer increases in thickness by secretion in response to tobacco smoke. We test this with low-temperature scanning electron microscopy, a method that preserves water in the lung. We find that we can measure the thickness of the liquid lining layer in the trachea as well as in the smaller airways and alveoli. We find that the layer in normal mice averages 4pm thickness and that pools of thicker liquid alternate with relatively thin areas. We have examined the effect of stimulation of the vagus nerve on secretion and clearance of deposited materials by surface liquid, finding that stimulation results in a rapid increase in lining layer thickness. We have developed methods of gold labeling proteins, which allow us to find these important molecules in the lung and in model systems. These techniques allow us to evaluate changes in permeability of the airway wall in response to tobacco. These changes are due both to direct chemical irritation and the indirect stimulation of nerves that can cause a change in leakiness of the airway wall. We have begun studies of the sodium, chloride, and potassium content of airway surface liquid using x-ray microanalyis in the scanning electron microscope.

These studies will further understanding of the workings of normal airways and suggest ways we can treat tobacco-related diseases that result in abnormal airway surface liquid. Common and serious diseases such as chronic bronchitis, where bacteria and viruses interact with white blood cells in the liquid lining the airways, or asthma, where there is inflammation of the airway wall, and increased - mucus, may involve changes in airway surface liquid which could be ameliorated therapeutically.
Publications

Regulation of the depth of surface liquid in bovine trachea
Periodical: American Journal of Physiology Index Medicus:
Authors: Wu DX, Lee CY, Uyekubo SN, Choi HK, Bastacky SJ, Widdicombe JH ART
Yr: 1998 Vol: 173 Nbr: 3 Pt 1 Abs: Pg: L388-L395

High-pressure frozen mouse lung: cryo scanning electron microscopy
Periodical: Proceedings Microscopy and Microanalysis Index Medicus:
Authors: Bastacky J, Walther P, Goerke J, Clausnitzer E, Lee C, Muller M ART
Yr: 1999 Vol: Nbr: Abs: Pg:

Surface tension of biological liquid surfaces: measurement by low-temperature scanning electron microscopy of fluorocarbon microdroplets
Periodical: Journal of the American Chemistry Society Index Medicus:
Authors: Bastacky J, Goerke J, Clements JA, et al ART
Yr: 1998 Vol: Nbr: Abs: Pg: