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Activation of mast cells by systemic hypoxia, but not by local hypoxia, mediates increased leukocyte-endothelial adherence in cremaster venules

Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160

Submitted 15 July 2003 ; accepted in final form 23 August 2003

Systemic hypoxia, produced by lowering inspired PO₂, induces a rapid inflammation in several microcirculations, including cremaster muscle. Mast cell activation is a necessary element of this response. Selective reduction of cremaster microvascular PO₂ (Pm_O2) with normal systemic arterial PO₂ (Pa_O2; cremaster hypoxia/systemic normoxia), however, does not elicit increased leukocyte-endothelial adherence (LEA) in cremaster venules. This could be due to a short time of leukocyte exposure to the hypoxic cremaster environment. Conversely, LEA increases when Pa_O2 is lowered, while cremaster Pm_O2 remains high (cremaster normoxia/systemic hypoxia). An alternative explanation of these results is that a mediator released from a central site during systemic hypoxia initiates the inflammatory cascade. We hypothesized that if this is the case, cremaster mast cells would be activated during cremaster normoxia/systemic hypoxia, but not during cremaster hypoxia/systemic normoxia. The microcirculation of rat cremaster muscles was visualized by using intravital microscopy. Cremaster Pm_O2 was measured with a phosphorescence quenching method. Cremaster hypoxia/systemic normoxia (Pm_O2 7 ± 1 Torr, Pa_O2 87 ± 2 Torr) did not increase LEA; however, topical application of the mast cell activator compound 48/80 under these conditions did increase LEA. The effect of compound 48/80 on LEA was blocked by topical cromolyn, a mast cell stabilizer. LEA increased during cremaster normoxia/systemic hypoxia, (Pm_O2 64 ± 5 Torr, Pa_O2 33 ± 2 Torr); this increase was blocked by topical cromolyn. The results suggest that mast cell stimulation occurs only when Pa_O2 is reduced, independent of cremaster Pm_O2, and support the idea of a mediator that is released during systemic hypoxia and initiates the inflammatory cascade.

microvascular inflammation; microvascular PO₂; muscle microcirculation; compound 48/80; cromolyn

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