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Cytotoxic response of sinusoidal endothelial cells to polymorphonuclear leukocytes and its potential implication in
E Lasnier1, M C Blanc, C Housset
1Service de Biochimie A, INSERM U 402, Hôpital Saint-Antoine, AP-HP, Paris, Service de Biochimie A, Hôtel Dieu, AP-HP, Paris, CNRS URA 1534, Hôpital Cochin, Paris, France. elisabeth.lasnier@sat.ap-hop-paris.fr
Aims:
Interactions between polymorphonuclear leukocytes (PMN) and sinusoidal endothelial cells (SEC) may contribute to ischemia-reperfusion injury. The aim of the study was to determine the influence of PMN hypoxia-reoxygenation and degranulation, on SEC toxic response.
Methods:
PMNs collected from rat pleural cavity underwent hypoxia- reoxygenation or N-formyl-methionyl-leucyl-phenylalanine (fMLP) degranulation treatment, and were then separated from their conditioned medium. Rat SECs were incubated either with PMNs in coculture or with their conditioned medium, for 210 min. Oxidative metabolism in PMNs was measured by chemiluminescence. LDH release and elastase activity were measured in SEC supernatants.
Results:
PMN-conditioned medium induced an increase in LDH release in SECs. Hypoxia-reoxygenation of PMNs induced an increase in their chemiluminescent response without increasing the cytotoxic effect of their conditioned medium. By contrast, the cytotoxic effect of conditioned medium was increased following PMN treatment with fMLP. In the latter case, cytotoxicity was combined with a rise in the elastase activity released in the supernatants, but was not reduced by inhibitors of elastase or of other proteases.
Conclusions:
The results indicate that toxic products are released, at least in part through degranulation, by PMNs, and induce cytotoxicity in SECs. This mechanism may contribute to SEC injury during hypoxia-reoxygenation.
Insights
Polymorphonuclear leukocytes (PMNs) release toxic products via degranulation, causing damage to sinusoidal endothelial cells (SECs). This process may contribute to cell injury during hypoxia-reoxygenation events.
Area of Science:
- Cellular and Molecular Biology
- Immunology
- Pathophysiology
Background:
- Polymorphonuclear leukocytes (PMNs) and sinusoidal endothelial cells (SECs) interactions are implicated in ischemia-reperfusion injury.
- Understanding the specific mechanisms of PMN-induced SEC damage is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the impact of PMN hypoxia-reoxygenation and degranulation on SECs.
- To elucidate the role of PMN-derived factors in SEC cytotoxicity.
Main Methods:
- Rat PMNs were subjected to hypoxia-reoxygenation or N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation.
- SECs were exposed to conditioned medium from treated PMNs or co-cultured with PMNs.
- LDH release and elastase activity in SEC supernatants were measured.
Main Results:
- PMN-conditioned medium increased LDH release in SECs, indicating cytotoxicity.
- fMLP-induced PMN degranulation significantly enhanced the cytotoxic effect of their conditioned medium.
- This enhanced cytotoxicity correlated with increased elastase activity but was not inhibited by protease inhibitors.
Conclusions:
- PMN degranulation releases toxic products that induce SEC cytotoxicity.
- This PMN-mediated SEC injury mechanism may play a role in ischemia-reperfusion injury.
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