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Antiproteases modulate bronchial epithelial cell responses to endotoxin
S Koyama1, S I Rennard, L Claassen
1First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
The American Journal of Pathology
|May 1, 1995
Summary
Escherichia coli endotoxin triggers neutrophil activity and bronchial epithelial cell damage. Protease inhibitors partially block these effects, suggesting endotoxin activates cellular proteolytic activity.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Immunology
Background:
- Escherichia coli endotoxin is a potent inflammatory stimulus.
- Bronchial epithelial cells (BECs) play a role in airway inflammation.
- Endotoxin's effects on BECs involve cytotoxicity and altered cell accumulation.
Purpose of the Study:
- To investigate the role of bronchial epithelial cell (BEC) proteolytic activity in response to endotoxin.
- To determine if antiproteases can modulate endotoxin-induced effects on BECs.
Main Methods:
- Stimulation of BECs with varying concentrations of Escherichia coli endotoxin.
- Assessment of neutrophil chemotactic activity and BEC cytotoxicity (lactate dehydrogenase release).
- Evaluation of BEC accumulation under endotoxin exposure.
- Treatment with various antiproteases and a neutrophil elastase inhibitor.
- Measurement of serine proteolytic activity using synthetic substrates and 14C-labeled casein.
Main Results:
- Endotoxin stimulated neutrophil chemotactic activity and BEC cytotoxicity.
- Endotoxin inhibited BEC accumulation.
- Antiproteases and a neutrophil elastase inhibitor attenuated endotoxin-induced neutrophil chemotactic activity and cytotoxicity.
- Specific antiproteases (alpha 1-protease inhibitor, N-tosyl-L-lysine chloromethyl ketone) reversed the inhibition of BEC accumulation by endotoxin.
- Endotoxin significantly increased serine proteolytic activity in BECs, evidenced by casein solubilization.
Conclusions:
- Bronchial epithelial cell (BEC) responses to endotoxin involve the activation of cellular proteolytic activity.
- Targeting proteolytic activity may offer a therapeutic strategy for endotoxin-induced airway inflammation.