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TCV-309, a novel platelet activating factor antagonist, inhibits leukocyte accumulation and protects against
P Canale1, F Squadrito, D Altavilla
1Institute of Pharmacology, School of Medicine, University of Messina, Italy.
Abstract:
The aim of this study was to evaluate: (1) the accumulation of leukocytes in the ileum and the lung during splanchnic artery occlusion (SAO) shock; (2) the role of platelet-activating factor (PAF) and tumor necrosis factor (TNF-alpha) in this phenomenon. Untreated anesthesized rats subjected to total occlusion of the celiac, superior and inferior mesenteric arteries for 45 min, followed by reperfusion, uniformly died within 90 min after reperfusion. The mean survival time was 93 +/- 7 min. The neutrophilic infiltrate was quantitated in the ileum and in the lung using a myeloperoxidase (MPO) assay. MPO activity in the ileum and in the lung averaged 0.05 +/- 0.03 and 0.4 +/- 0.02 U x 10(-3)/g protein in animals killed before occlusion. MPO activity did not change in rats killed immediately before reperfusion and was significantly elevated (0.11 +/- 0.02 and 1.7 +/- 0.6 U x 10(-3)/g protein in the ileum and the lung, respectively) in those killed 80 min after the beginning of the reperfusion. The histological examination confirmed the accumulation of leukocytes in the mucosa of the ileum and the lung over the 80 min. SAO shocked rats exhibited leukopenia and increased serum levels of TNF-alpha. In order to evaluate the role of PAF and TNF-alpha in SAO shock, a powerful PAF receptor antagonist, TCV-309 (5 micrograms/kg i.v.), was injected 5 min after reperfusion. TCV-309 increased survival time, lowered serum TNF-alpha, reduced MPO activity in both the ileum and the lung and ameliorated leukopenia induced by SAO shock.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Splanchnic artery occlusion (SAO) shock causes leukocyte accumulation in the ileum and lung, mediated by platelet-activating factor (PAF) and tumor necrosis factor-alpha (TNF-alpha). Blocking PAF receptors improved survival and reduced inflammation in SAO shock models.
Area of Science:
- Physiology
- Immunology
- Shock Pathophysiology
Background:
- Splanchnic artery occlusion (SAO) shock is a critical condition characterized by reduced blood flow to abdominal organs.
- Leukocyte infiltration into tissues contributes to organ damage during shock states.
- The roles of platelet-activating factor (PAF) and tumor necrosis factor-alpha (TNF-alpha) in SAO-induced inflammation require further elucidation.
Purpose of the Study:
- To investigate leukocyte accumulation in the ileum and lung during SAO shock.
- To determine the involvement of PAF and TNF-alpha in the inflammatory response to SAO shock.
- To evaluate the therapeutic potential of a PAF receptor antagonist in mitigating SAO shock pathology.
Main Methods:
- Rats were subjected to 45 minutes of splanchnic artery occlusion followed by reperfusion.
- Leukocyte infiltration was quantified using myeloperoxidase (MPO) assays in ileum and lung tissues.
- Serum levels of TNF-alpha were measured, and histological examinations were performed.
- A PAF receptor antagonist, TCV-309, was administered post-reperfusion to assess its effects on survival and inflammatory markers.
Main Results:
- SAO shock led to significant leukocyte accumulation in the ileum and lung, confirmed by elevated MPO activity and histology.
- SAO-induced shock resulted in leukopenia and increased serum TNF-alpha levels.
- Administration of TCV-309 significantly improved survival time, reduced MPO activity, lowered serum TNF-alpha, and ameliorated leukopenia.
Conclusions:
- Leukocyte accumulation in the ileum and lung is a key feature of SAO shock.
- PAF and TNF-alpha play crucial roles in the pathogenesis of SAO shock.
- Targeting the PAF receptor with antagonists like TCV-309 offers a promising therapeutic strategy for managing SAO shock.