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Gut phospholipase A2 mediates neutrophil priming and lung injury after mesenteric ischemia-reperfusion
Abstract:
Intestinal ischemia-reperfusion (I/R) provokes polymorphonuclear neutrophil (PMN)-mediated lung injury via a process characterized by circulating PMN priming, pulmonary PMN sequestration, and increased microvascular leak in the lung. We found in rats subjected to intestinal I/R (ischemia 45 min and reperfusion 6 h) that 1) intestinal phospholipase A2 (PLA2) was activated during ischemia, 2) circulating PMN priming (assessed by superoxide production with N-formyl-Met-Leu-Phe) occurred after 1 h reperfusion, and 3) exaggerated 125I-labeled albumin lung leak occurred after 2 h reperfusion, compared with sham-treated animals (P < 0.05). Treatment with a PLA2 inhibitor, quinacrine, within 15 min of reperfusion reversed the exaggerated gut PLA2 activity and abrogated subsequent PMN priming and lung leak (P < 0.05). However, when quinacrine was administered after 2 h of reperfusion, circulating PMN priming and lung leak continued to evolve despite suppression of intestinal PLA2 activity. We conclude that intestinal PLA2 activation may be a prerequisite for the sequelae of circulating PMN priming and pulmonary microvascular leak observed after intestinal I/R.
Insights
Intestinal ischemia-reperfusion injury activates phospholipase A2 (PLA2), leading to neutrophil priming and lung damage. Inhibiting PLA2 early prevents this lung injury, highlighting PLA2
Area of Science:
- Gastroenterology
- Pulmonology
- Inflammation Research
Background:
- Intestinal ischemia-reperfusion (I/R) causes lung injury mediated by neutrophils.
- This injury involves neutrophil priming, sequestration, and increased lung vascular permeability.
Purpose of the Study:
- To investigate the role of intestinal phospholipase A2 (PLA2) in mediating lung injury following intestinal I/R.
- To determine if early inhibition of PLA2 can prevent I/R-induced lung injury.
Main Methods:
- Rats underwent intestinal I/R (45 min ischemia, 6 h reperfusion).
- Intestinal PLA2 activity, circulating neutrophil priming, and lung microvascular leak were assessed.
- PLA2 inhibitor quinacrine was administered at different time points post-reperfusion.
Main Results:
- Intestinal I/R activated PLA2, primed neutrophils, and increased lung leak.
- Early quinacrine treatment (within 15 min) reversed these effects.
- Late quinacrine treatment (after 2 h) did not prevent ongoing neutrophil priming and lung leak.
Conclusions:
- Intestinal PLA2 activation is a critical early event in the cascade leading to I/R-induced lung injury.
- Targeting PLA2 early after reperfusion may be a therapeutic strategy to mitigate lung damage.