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Tobacco, Bacteria-Binding and Ca Signaling in Lung Epithelia

Institution: University of California, Berkeley
Investigator(s): Kevin Hybiske,
Award Cycle: 1999 (Cycle 8) Grant #: 8DT-0166 Award: $49,426
Subject Area: Pulmonary Disease
Award Type: Dissertation Awards
Abstracts

Initial Award Abstract
The lung airways use various defense mechanisms to prevent bacterial infections, including the beating of cilia to move mucus upwards toward the mouth (mucociliary escalator), maintenance of intact cell membranes and intercellular junctions to prevent bacterial entry, and secretion of antibacterial factors. Alteration of any of these critical factors allows binding of Pseudomonas aeruginosa (Pa) and other airway bacteria to airway cells. The bacterial binding causes the airway cells to release factors (interleukins, particularly interleukin-8, IL-8) into the blood stream to signal immune cells to leave the blood stream and invade the airways to fight the bacteria. The bacteria in turn can kill the epithelial cells and the PMN's, which kill bacteria by releasing a variety of antibacterial agents and, in the process, also kill some epithelial cells. This inflammatory response damages the airways, and if left unchecked can lead to destruction of lung tissue, emphysema and cancer. In addition to generating lung damage on its own, smoking also alters the lung's defense mechanisms, which then leads to the bacterial binding-epithelial cell signaling-PMN invasion sequence described above. The first goal of this project is to determine the effects of tobacco extracts on the location and function of Pa-binding proteins in airway epithelia. A biochemical approach will be used to identify the Pa-binding protein(s), and antibodies will then be generated and used to determine the position of these critical Pa-binding proteins in the airways. This set of experiments will allow us to determine where the critical Pa-binding proteins are located in the airway cells, and to determine whether smoking increases availability of these sites for Pa-binding. A second set of experiments will determine the effects of tobacco extracts on Pa-induced epithelial calcium signaling and IL-8 secretion. Imaging methods involving the use of a microscope, camera and computer allow us to measure the concentrations of calcium, a critical signaling ion in airway cells. We will determine the effects of Pa and smoking on cell calcium concentration, which is likely a key early event involved in the release of the PMN-attracting molecule IL-8, which will also be measured using a biochemical method. Increases in cell calcium are likely also involved in the events preceding killing of the epithelial cells. These experiments will determine the role of smoking in the initial stages of bacterial infection, epithelial cell killing and PMN-induced inflammation. These experiments will yield information relevant to the earliest stages of emphysema and cancer.
Publications

Pseudomonas aeruginosa induce NFkB-dependent and -independent changes in gene expression in airway epithelial cells
Periodical: Pediatric Pulmonology. Supplement Index Medicus:
Authors: Hybiske K, Huang J, Ichikawa S, Machen TE ART
Yr: 0 Vol: Nbr: Abs: Pg:

Cystic fibrosis airway epithelial cell polarity and bacterial flagellin determine host response to P. aeruginosa.
Periodical: Cellular Microbiology Index Medicus:
Authors: Hybiske K, Ichikawa J, Huang V, Lory SJ, Machen TE ART
Yr: 2004 Vol: 6 Nbr: Abs: Pg: 49-63

Airway epithelial cell polarity determines NF-kB-dependent gene regulation in response to Pseudomonas aeruginosa.
Periodical: Pediatric Pulmonology. Supplement Index Medicus:
Authors: Hybiske KJ, Huang V, Ichikawa J, Lory S, Machen T ABS
Yr: 2001 Vol: 23 Nbr: Abs: Pg: 284

Airway epithelial cell polarity and NF-kB-dependent gene r3egulation in response to Pseudomonas aeruginosa.
Periodical: FASEB Journal Index Medicus:
Authors: Hybiske KJ, Huang V, Ichikawa J, Lory S, Machen T ABS
Yr: 2002 Vol: Nbr: Abs: Pg:

P. aeruginosa flagellin and epithelial polarity but not cftr determine airway epithelial innate responses.
Periodical: Pediatric Pulmonology. Supplement Index Medicus:
Authors: Hybiske K, Illek B, Do J, Huang N, Ichikawa J, Lory S, Machen TE ABS
Yr: 2003 Vol: 25 Nbr: Abs: Pg: 287