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Rapid mast cell activation causes leukocyte-dependent and -independent permeability alterations
1Immunology Research Group, University of Calgary Medical Centre, Alberta, Canada.
Abstract:
The major objective of this study was to systematically elucidate the mechanisms underlying microvascular permeability in rat mesenteric venules after the activation of perivascular mast cells. Intravital microscopy was used to assess polymorphonuclear leukocyte (PMN) infiltration and microvascular permeability alterations in single 25- to 40-micron diameter venules. Ruthenium red was used to detect mast cell activation on-line. Exposure of mast cells to compound 48/80 (CMP 48/80) caused a rapid mast cell activation and increase in microvascular permeability (within 15 min) that was maintained for the duration of the experiment. CMP 48/80 also increased PMN adhesion to the microvascular endothelium. Anti-PMN serum, as well as various antiadhesion therapies, including CL26 (anti-CD18 antibody) and fucoidan (selectin-immunoneutralizing carbohydrate), revealed that the early microvascular permeability was PMN independent. However, these regimens significantly reduced plasma protein leakage out of venules between 30 and 60 min. Methysergide (serotonin receptor antagonist), but not diphenhydramine (histamine receptor antagonist), inhibited the early PMN-independent microvascular permeability. Finally, a platelet-activating factor (PAF)-receptor antagonist did not affect the early phase of microvascular permeability but reversed the later phase, consistent with PAF's role as a proadhesive molecule for PMN during mast cell activation. These data demonstrate that, within the first hour of mast cell activation, a biphasic PMN-independent and -dependent response in microvascular permeability is observed. The data also raise the possibility that histamine's physiological role in this model may be unrelated to alterations in microvascular permeability.
Insights
Mast cell activation causes rapid, biphasic changes in microvascular permeability, initially independent of polymorphonuclear leukocytes (PMNs) and later dependent. This study clarifies early vascular responses to mast cell mediators.
Area of Science:
- Vascular Biology
- Immunology
- Cell Biology
Background:
- Perivascular mast cell activation is a key event in inflammatory responses.
- Understanding the mechanisms of microvascular permeability is crucial for treating inflammatory diseases.
Purpose of the Study:
- To elucidate the mechanisms of microvascular permeability following mast cell activation.
- To differentiate between polymorphonuclear leukocyte (PMN)-dependent and -independent pathways.
- To investigate the roles of specific mediators in mast cell-induced vascular changes.
Main Methods:
- Intravital microscopy of rat mesenteric venules.
- On-line detection of mast cell activation using Ruthenium red.
- Assessment of PMN infiltration and plasma protein leakage.
- Pharmacological inhibition using anti-PMN serum, antiadhesion therapies, receptor antagonists, and a platelet-activating factor (PAF)-receptor antagonist.
Main Results:
- Compound 48/80 (CMP 48/80) rapidly activated mast cells, increasing microvascular permeability and PMN adhesion.
- Early microvascular permeability (within 15 min) was PMN-independent but inhibited by methysergide (serotonin antagonist).
- Later microvascular permeability (30-60 min) was reduced by antiadhesion therapies and reversed by a PAF-receptor antagonist, indicating PMN dependence.
Conclusions:
- Mast cell activation induces a biphasic microvascular permeability response: early PMN-independent and later PMN-dependent phases.
- Serotonin plays a role in the early PMN-independent permeability, while PAF is involved in the later PMN-dependent phase.
- Histamine's role in microvascular permeability in this model may be limited.