(From the author's abstract) This proposal seeks to investigate the molecular mechanisms of acute lung injury through the use of transgenic mice. Specifically, heterozygous SP-B deficient mice will be used to understand pulmonary responses to ozone, a common air pollutant. The investigators speculate that heterozygotes have an increased risk of developing complications from acute lung injury (e.g., acute respiratory distress). To address this hypothesis they have developed a transgenic mouse model that is heterozygous for SP-B deficiency. Heterozygotes possess half-normal levels of SP-B mRNA and protein, consistent with inactivation of a single SP-B allele. In these mice, pulmonary compliance is decreased, airway collapse is evident at low deflation pressures, and residual volume is increased. They present three specific aims to test their hypothesis: (1) To determine whether heterozygous mice are more susceptible to oxidant injury, pulmonary functions, injury, and inflammation will be measured after ozone exposure of SP-B (+/-) and (+/+) mice. Mice will be pretreated with recombinant SP-B and responses measured after ozone exposure to determine whether surfactant replacement can protect against injury. (2) To determine whether SP-B is a macromolecular target of ozone. SP-B and synthetic analogs will be exposed to ozone and changes in protein structure and physical surface activity of model membrane bilayers measured. (3) To determine the in vivo significance of the amino acid targets of ozone in the SP-B molecule identified in specific aim 2, the investigators will introduce mutant forms of SP-B with single amino acid substitutions into mice heterozygous for SP-B to produce mice that are null for normal murine SP-B and express only the introduced mutated form.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058275-02
Application #
2519620
Study Section
Special Emphasis Panel (ZES1-CKS-B (02))
Project Start
1996-09-01
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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