ACETALDEHYDE-MEDIATED BRONCHIAL CILIA DYSFUNCTION

Project: Research project

Description

Alcoholics have an increased incidence of pulmonary
diseases that are in part due to altered lung host defense functions
related to alcohol toxicity and a strong tendency for alcoholics to smoke
heavily. A major airway defense function that is impaired during both
alcohol ingestion and cigarette smoking is the mucociliary clearance
system. One possible mechanism of mucociliary impairment common to both
alcohol ingestion and smoking is acetaldehyde exposure since acetaldehyde
is produced during the metabolism of ethanol both by the liver and locally
in the airways and is also found in significant amounts in the vapor phase
of cigarette smoke. This is important because acetaldehyde is a highly
reactive molecule that has been recognized as a significant toxin in
biologic systems related to its ability to covalently bind to reactive
protein residues. Preliminary experiments have demonstrated the influence
of acetaldehyde on bronchial epithelial cell cilia. These studies
established that acetaldehyde is directly toxic to ciliated airway
epithelial cells causing cilia slowing or paralysis, inhibits cilia dynein
ATPase activity, and binds to cilia proteins critical for motility
especially dynein and tubulin. It is hypothesized, therefore, that:
Acetaldehyde impairs airway cilia function by binding to critical cilia
proteins, including dynein and tubulin, in concentrations encountered
during alcohol ingestion and cigarette smoking. To test this hypothesis
the following specific aims are proposed: 1) Assess the ability of
acetaldehyde to bind to axonemal dynein and tubulin and impair the ATPase
activity of dynein. These experiments will measure stoichiometric and
competitive acetaldehyde binding to and functional impairment of purified
cilia dynein and tubulin. 2) Elucidate the mechanism(s) by which
acetaldehyde binding impairs the interaction of axonemal dynein with
tubulin and microtubules. These experiments will examine acetaldehyde's
effect on dynein's ability to enhance microtubule polymerization and
translocate microtubules in a cell-free system. 3) Assess the importance
of acetaldehyde exposure as a cause of cilia dysfunction in the setting of
alcohol and smoke exposure. These experiments will quantify
acetaldehyde-protein binding and dysfunction in the cilia of tissues
exposed to acetaldehyde vapor, cigarette smoke and ethanol both in vitro
and in vivo.
StatusFinished
Effective start/end date3/1/915/31/17

Funding

  • National Institutes of Health: $80,000.00
  • National Institutes of Health: $482,689.00
  • National Institutes of Health: $338,070.00
  • National Institutes of Health: $97,401.00
  • National Institutes of Health: $325,552.00
  • National Institutes of Health: $432,769.00
  • National Institutes of Health: $404,390.00
  • National Institutes of Health
  • National Institutes of Health: $473,525.00
  • National Institutes of Health: $191,539.00
  • National Institutes of Health: $521,792.00
  • National Institutes of Health: $506,137.00
  • National Institutes of Health: $419,499.00
  • National Institutes of Health: $77,524.00
  • National Institutes of Health: $176,689.00
  • National Institutes of Health
  • National Institutes of Health: $89,539.00
  • National Institutes of Health: $508,166.00
  • National Institutes of Health: $413,497.00
  • National Institutes of Health
  • National Institutes of Health: $417,652.00
  • National Institutes of Health: $435,246.00
  • National Institutes of Health: $439,516.00
  • National Institutes of Health: $33,169.00
  • National Institutes of Health
  • National Institutes of Health: $421,475.00
  • National Institutes of Health: $98,334.00

Fingerprint

Cilia
Ethanol
Alcohols
Acetaldehyde
Dyneins
Lung
Eating
Nitric Oxide
Mucociliary Clearance
Alcoholics
Tubulin
Smoke
Smoking
Aptitude
Axonemal Dyneins
Pneumonia
Bronchitis
Phosphotransferases
Microtubules
Tobacco Products

ASJC

  • Medicine(all)