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Effects of tobacco on inflammatory cell responses

Institution: University of California, Davis
Investigator(s): Lisa Miller, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6KT-0411 Award: $223,585
Subject Area: Pulmonary Disease
Award Type: New Investigator Awards
Abstracts

Initial Award Abstract
The role of inflammation in promoting and perpetuating pulmonary disease states is profound. Indeed, the rate of morbidity and mortality ensued by chronic inflammatory conditions such as chronic obstructive pulmonary disease (COPD) outweighs that which results from lung cancer. Cigarette smoke is a common etiologic factor in chronic bronchitis and COPD, suggesting that the chemical components of tobacco have a specific effect on the cellular constituents of the lung. Although chronic bronchitis and airway obstruction appear to be discrete syndromes, histologic and clinical evidence implicate the inflammatory response as a common path. The overall goal of this project is to characterize the biology of white blood cell recruitment to the lung in response to tobacco smoke. In this proposal, we will test the hypothesis that exposure of pulmonary airways to tobacco smoke components can stimulate the production of proteins which specifically recruit white blood cells (leukocytes) into the lung. We will use a cell culture model to allow focused attention on the precise biochemical and molecular mechanisms of leukocyte movement into the lung. A clear understanding of the basic mechanisms by which leukocytes recirculate within the lung is imperative for the development of therapeutic treatments which specifically target the immunologic response to tobacco smoke exposure.

Final Report
The objective of this project was to understand the biology of inflammatory cell recruitment to the lung in response to tobacco smoke. This project has tested the hypothesis that exposure of airway epithelial cells to tobacco smoke components can stimulate production of proteins (chemokines) that specifically bring inflammatory cells into the lung. The specific aims of this project were the following: (1) determine the effect of human bronchial epithelium exposure to tobacco smoke on subsequent inflammatory cell migration; (2) characterize expression of chemokines by bronchial epithelium in response to tobacco smoke; (3) determine the role of chemokines on inflammatory cell migration across bronchial epithelium and (4) characterize functional changes on migrated inflammatory cells by immunological markers. Work to date has focused on the functional role of chemokine expression by human airway epithelium, particularly in the trafficking of inflammatory cells. The direct effect of environmental tobacco smoke (ETS), or “second-hand smoke” on the expression of chemokines by airway epithelial cells was examined by in vitro methodology. In addition, the effects of acrolein and acetaldehyde exposure (volatile components of ETS) were examined using this approach. ETS was simulated by extracts collected from aged and diluted sidestream cigarette smoke and added directly to human airway epithelial cell cultures. Following an overnight exposure to either ETS or acrolein/acetaldehyde, culture supernatants and RNA were collected for cellular and molecular analysis. Using functional assays for chemokines, we have found that ETS and acrolein/acetaldehyde induced the migration of inflammatory cells to culture supernatants. Further, ETS and acrolein/acetaldehyde-treated cultures expressed higher levels of chemokine messenger RNA . Cumulatively, these findings suggest that exposure of the airways to volatile components of ETS result in the enhanced expression of chemokines in the lung; this suggests a putative mechanism by which persistent inhalation of “second-hand smoke” can result in airway inflammation and chronic lung disease.
Publications

Expression of the HML-1 epitope on human monocytes is independent of alphaE integrin mRNA
Periodical: Inflammation Index Medicus:
Authors: Miller LA, Li C, Hyde DM ART
Yr: 2000 Vol: 24 Nbr: Abs: Pg: 195-205

Trafficking of neutrophils across airway epithelium is dependent upon both thioredoxin- and pertussis toxin-sensitive signaling mechanisms
Periodical: Journal of Leukocyte Biology Index Medicus:
Authors: Miller LA, Usachenko JL, McDonald RJ, Hyde DM ART
Yr: 2000 Vol: 68 Nbr: Abs: Pg: 201-208

Neutrophils accelerate clearance of necrotic epithelial cells following ozone-induced lung injury in rhesus monkeys
Periodical: American Journal of Physiology Index Medicus:
Authors: Hyde DM, Miller LA, McDonald RJ, et al ART
Yr: 1999 Vol: 277 Nbr: Abs: Pg: L1190-L1198

Expression of the beta6 integrin subunit is associated with sites of neutrophil influx within ozone-exposed airways
Periodical: Journal of Histochemistry and Cytochemistry Index Medicus:
Authors: Miller LA, Barnett NL, Sheppard D, Hyde DM ART
Yr: 2001 Vol: 49 Nbr: 1 Abs: Pg: 41-47

Monocyte chemokine expression by airway epithelium is enhanced following exposure to environmental tobacco smoke
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Miller LA, Li C, Pinkerton KE, Hyde DM ABS
Yr: 1999 Vol: 159 Nbr: 3 Abs: A510 Pg:

House dust mite-sensitized rhesus monkeys exhibit time dependent local and systemic activation of lymphocytes
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Miller LA, Gerriets JE, Hyde DM ABS
Yr: 2000 Vol: 161 Nbr: 3 Abs: A206 Pg:

Correlation of cytokine/chemokine expression with immune cell recruitment by airway generation in house dust mite-sensitized rhesus monkeys
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Miller LA, Hurst SD, Coffman L, et al ABS
Yr: 2000 Vol: 161 Nbr: 3 Abs: A836 Pg:

Neonatal pulmonary immune responses following episodic exposure to aerosolized house dust mite
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Miller LA, Plopper CG, Hyde JE, et al ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: A601 Pg:

Chemokine expression and accumulation of dendritic cells following exposure to environmental tobacco smoke
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Miller LA, Gurley E, Wang B, Gershwin LJ, Pinkerton KE, Hyde DM ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: A177 Pg:

Characterization of IL-4 and macrophage derived-chemokine expression in airways of house dust mite-sensitized rhesus monkeys
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Chou DL, Hyde DM, Hurst SD, Coffman RL, Gershwin LJ, Miller LA ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: A868 Pg:

local and systemic immune responses in neonatal house dust mite-sensitized rhesus monkeys following episodic exposure to ozone
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Gerriets JE, Miller LA, Gershwin LJ, Hyde DMM ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: A601 Pg:

Localization of immune cells in neonatal house dust mite-sensitized rhesus monkeys following episodic exposure to ozone
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Miller LA, Putney LF, Stovall MY, et al ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: A433 Pg: