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Effect of sidestream smoke on lung injury and repair

Institution: University of California, Davis
Investigator(s): Laura Van Winkle, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6KT-0306 Award: $214,070
Subject Area: Pulmonary Disease
Award Type: New Investigator Awards
Abstracts

Initial Award Abstract
Environmental tobacco smoke (ETS) is a substantial public health hazard because of the large number of smokers and the widespread presence of ETS, a known human carcinogen. Many people are involuntarily exposed to ETS. ETS exposure has been shown to be causally associated with lung cancer in adults and decreased lung function in children. While studies of humans previously exposed to ETS unequivocally show that it has a negative effect on the lung, there are gaps in our understanding of the biology of this effect. How does ETS change lung structure and function? Why does ETS appear to affect children more severely than adults? The proposed studies are designed to address these questions.

In humans, the lung continues to develop for up to 8 years after birth. Animal studies have shown that developing lungs are particularly susceptible to injury by a class of compounds that are present in large abundance in tobacco smoke. These studies have also shown that once the developing lung is injured, it takes longer to repair than an adult lung and, in some regions, does not repair at all. This results in an alteration in lung structure. It is not known if ETS causes these same changes. The proposed studies will evaluate the effects of ETS on developing vs. adult lungs of mice. These studies will use methods that look at specific regions within the lung that are on the preceding studies. The hypothesis that will be tested is that ETS exposure predisposes the lung to further injury and if it alters the repair pattern. We also hypothesize that developing lungs will be more susceptible to injury and will have more failure of repair than adult lungs. Our aim is that these studies will give insight into the impact of ETS on both adults and children and that they will define whether exposure to ETS renders the lung more sensitive to further injury. The long term goal is to determine the mechanisms by which ETS causes lung diseases (including bronchitis and cancer).

Final Report
Our lungs are exposed to many pollutants in our environment over our lifetime. These pollutants include a mixture of toxic agents including ozone, car and truck exhaust and tobacco smoke. While numerous epidemiologic studies in people have linked tobacco smoke exposure to negative outcomes, such as cancer in adults and reactive airway diseases in children, there are few experimental models to evaluate how smoke exposure causes these effects. Environmental tobacco smoke, the smoke a nonsmoker breathes in a room full of smokers, is composed of 85% sidestream smoke off the burning end of the cigarette and 15% mainstream smoke exhaled by the smoker. Our studies use a surrogate for environmental tobacco smoke, called ADSS, that is entirely composed of sidestream smoke. We use ADSS at concentrations that approximate occupational exposures to study the effects of environmental tobacco smoke on lung tissue from adult animals (acute exposure) and from animals that were exposed from birth through adulthood (chronic exposure). The main hypothesis is that exposure of nonsmokers to environmental tobacco smoke either predisposes their lungs to further injury from other pollutants in the air or that smoke exposure compromises the ability of the lung to repair when further injured. A second hypothesis tested in these studies is that the effect of ADSS on lung tissue will vary by gender. There are four specific aims that address the effects of both acute and chronic ADSS exposures on: 1) The site-specificpattern of cellular changes, 2) the extent of injury, 3) the pattern of repair and 4) the pattern of repairduring a continuing exposure.

During the term of this grant all the specific aims were addressed. The first set of experiments involved mice exposed acutely to ADSS for one week. A key finding of these studies is. that even a short term prior exposure (6 hrs/day, 5 days/wk) in adult animals impairs the ability of the lung to repair an acute injury. This is an important finding because it indicates that a small amount of prior tobacco smoke exposure in combination with other air pollutants, such as naphthalene, which is a byproduct of fossil fuel combustion, impedes the lungs ability to repair. However, prior exposure to ADSS does not increase lung injury. These two findings suggest that tobacco smoke exposure causes a persistent change in lung epithelial cells that is manifest as altered ability to repair wounds in the deep lung. Our preliminary studies indicate that failure of repair is related to both a lack of proliferation and an inability of a certain cell type, called Clara cells, to redifferentiate. Further work is needed to identify the genetic mechanisms that underlie this change.

We also investigated the impact of chronic ADSS exposure during lung development. In male and female littermates exposed to ADSS, there were differences in responses by gender. Certain cell types that are associated with lung cancer in women were increased in the female mice. In addition, it is apparent that female mice are more sensitive to injury and that ADSS exposure increases enzymes in the lungs of female mice that would make them even more susceptible to injury. Future work will examine the biochemical basis for the elevated susceptibility to injury in female mice.

The potential impact of our studies are that exposure to environmental tobacco smoke concurrent with another toxic agent (many of which are present in our daily environment as air pollution) results in an inability of the lung to repair from injury. Another key finding is that chronic exposure during lung development and lung injury may affect females differently than males. These studies and their results are relevant to two sensitive subpopulations, women and children.
Publications

Expression of Endothelin-1 during Clara cell injury and bronchiolar epithelial repair
Periodical: FASEB Journal Index Medicus:
Authors: Van Winkle LS, Brown CD, Johnson ZA, Plopper CG ART
Yr: 1998 Vol: 12 Nbr: 4 Abs: pA314 Pg: 1829

Effect of aged and diluted sidestream cigarette smoke (ADSS) on lung injury and repair in the adult mouse
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Van Winkle LS, Brown CD, O'Donnell KJ, Pinkerton KE, Plopper CG ABS
Yr: 1999 Vol: 159 Nbr: 3 Abs: A437 Pg:

The attenuated fibroblast sheath of the respiratory tract epithelial-mesenchymal trophic unit
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Evans MJ, Van Winkle LS, Fanucchi MV, Plopper CG ART
Yr: 1999 Vol: 21 Nbr: Abs: Pg: 655-657

Three dimensional organization of the lamina reticularis in the rat tracheal basement membrane zone
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Evans MJ, Van Winkle LS, Fanucchi MV, et al ART
Yr: 2000 Vol: 22 Nbr: Abs: Pg: 393-397

Sidestream smoke exposure impairs lung repair from injury
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Van Winkle LS, Evans MJ, Brown CD, et al ART
Yr: 2001 Vol: 161 Nbr: 3 Abs: A174 Pg:

Prior exposure to aged and diluted sidestream cigarette smoke impairs bronchiolar injury and repair
Periodical: Journal of Toxicological Sciences Index Medicus:
Authors: Van Winkle LS, Evans MJ, Brown CD, Willits NH, Pinkerton KE, Plopper CG ART
Yr: 2001 Vol: 60 Nbr: Abs: Pg: 152-164

Early events in naphthalene-induced acute Clara cell toxicity: II. Comparison of glutathione depletion and histopathology by airway location
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Plopper CG, Van Winkle LS, Fanucchi MV, et al ART
Yr: 2001 Vol: 24 Nbr: Abs: Pg: 272-281

Cellular and molecular characteristics of basal cells in airway epithelium
Periodical: Experimental Lung Research Index Medicus:
Authors: Evans MJ, Van Winkle LS, Fanucchi MV, Plopper CG ART
Yr: 2001 Vol: 27 Nbr: 5 Abs: Pg: 401-415

Effect of aged and diluted sidestream cigarette smoke (ADSS) on lung injury and repair in the adult mouse
Periodical: Proceedings of the TRDRP Annual Investigator's Meeting Index Medicus:
Authors: Van Winkle LS, Brown CD, O'Donnell KJ, Pinkerton KE, Plopper CG ABS
Yr: 1998 Vol: Nbr: Abs: Pg:

Cigarette smoke exposure impairs lung repair from injury
Periodical: Molecular and Cellular Biology Index Medicus:
Authors: Van Winkle LS, Evans MJ, Brown CD, Shimizu JA, Pinkerton KE, Plopper CG ABS
Yr: 2000 Vol: 11 Nbr: Abs: 231a Pg:

Impaired bronchiolar epithelial repair after environmental tobacco smoke exposure
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Van Winkle LS, Evans MJ, Brown CD, Shimizu JA, Pinkerton KE, Plopper CG ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: A363 Pg:

Gender differences in naphthalene-induced acute lung injury and metabolism
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Van Winkle LS, Plopper CG, Brown CD, Gunderson AD, Shimizu JA ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: A465 Pg: