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Antiinflammatory agents inhibit microvascular permeability induced by leukotrienes and by stimulated human
Abstract:
One pathologic change common to the inflammatory process is loss of microvessel membrane integrity which results in edema. Polymorphonuclear leukocytes (PMN) are primary contributors to the development of edema because they cause tissue injury which alters vascular permeability and hemodynamics. The aim of this study was to assess the influence of arachidonic acid metabolites generated by activation of human PMN on the in vivo microvascular preparation of the hamster cheek pouch. Fluorescein-labeled dextran MW: 150,000 was used to assess microvascular permeability. Human PMN were activated with arachidonic acid (AA) and the calcium ionophore A23187, and the supernatant retained for testing. Topical application of the PMN supernatant, purified LTD4 or LTB4 resulted in marked extravasation of macromolecules from post-capillary venules of control hamsters. The extravasation was reduced when hamsters were pretreated with indomethacin (5 mg/kg), imidazole (25 mg/kg), ketoconazole (10 mg/kg), 13-azaprostanoic acid (30 mg/kg), FPL 55712 (1 mg/kg) and dimethylthiourea (500 mg/kg). The interpretation of the results suggests that the increased vascular permeability induced by PMN secretions may be mediated in part by the thromboxane pathway.
Insights
Inflammation causes edema by increasing microvessel permeability. Human polymorphonuclear leukocytes (PMN) secretions, particularly thromboxane, contribute to this vascular leakage, exacerbating inflammatory responses.
Area of Science:
- Inflammation and Immunology
- Vascular Biology
- Biochemistry
Background:
- Inflammatory processes often lead to edema due to compromised microvessel integrity.
- Polymorphonuclear leukocytes (PMN) play a key role in tissue injury and altered vascular permeability during inflammation.
Purpose of the Study:
- To investigate the impact of arachidonic acid metabolites from activated human PMN on microvascular permeability in vivo.
- To identify specific mediators involved in PMN-induced vascular leakage.
Main Methods:
- Utilized a hamster cheek pouch model with fluorescein-labeled dextran to measure macromolecule extravasation.
- Activated human PMN with arachidonic acid and A23187, collecting supernatant for topical application.
- Administered various inhibitors (indomethacin, imidazole, ketoconazole, etc.) to assess their effects on vascular permeability.
Main Results:
- PMN supernatant, LTD4, and LTB4 significantly increased macromolecule extravasation from post-capillary venules.
- Pretreatment with inhibitors targeting cyclooxygenase, lipoxygenase, and thromboxane pathways reduced this extravasation.
- Dimethylthiourea also attenuated the vascular leakage, suggesting a role for reactive oxygen species.
Conclusions:
- Human PMN secretions can induce significant increases in vascular permeability.
- The thromboxane pathway is implicated as a major mediator of PMN-induced vascular leakage.
- These findings highlight potential therapeutic targets for managing inflammatory edema.