The respiratory burst response of macrophages and neutrophils is a major component of antibacterial defenses. The enzyme complex responsible for the burst response is present on the surface of the plasma membrane. It produces superoxide using a coupled reaction similar to other electron transport chains. The respiratory burst is stimulated by chemotactic agents, such as f-met-leu-phe, C5a, ConA and immunoglobulins among other stimuli. Activation of the burst response involves mechanisms involving the breakdown of phsophatidyl inositol (PI) with the generation of Ins 1,4,5-P, the second messenger responsible for calcium release. Other agents like phorbol esters also stimulate the burst response by directly activating protein kinase C. Preliminary data demonstrate that ethanol alone stimulates the respiratory burst in rat alveolar macrophages. On the surface this might appear to result in enhanced antibacterial defenses. However, we hypothesize that chronic stimulation by ethanol might induce a refractory state in the burst response elicited by normal stimuli such as bacteria. In support of this, we have found that ethanol preincubation for ten minutes partially inhibits phorbol 12-myristate 13-acetate (PMA) induced burst activity. Ethanol acts upon the sequence of steps the cells use to stimulate the burst response. This proposal will try to identify the site of action of ethanol. The approach will be to study interaction of ethanol with other known burst response agonists. Effects of long term ethanol treatment will be studied in macrophages isolated from rats chronically treated with ethanol in vivo. These studies are important to elucidate someof the mechanisms involved in alcohol associated pulmonary infections. In addition, the interference of ethanol in the phosphatidyl inositol-Ca2+ is of a more global interest since many stimulus-response systems in many cell types use this signaling system.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007312-03
Application #
3111086
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1987-02-01
Project End
1991-01-31
Budget Start
1989-02-01
Budget End
1991-01-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027