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Activated neutrophils increase microvascular permeability in skeletal muscle: role of xanthine oxidase
J K Smith1, D L Carden, R J Korthuis
1Department of Physiology and Biophysics, Louisiana State University Medical Center, School of Medicine, Shreveport 71130.
Abstract:
To determine the role of xanthine oxidase in the microvascular dysfunction produced by activated granulocytes, we examined the effect of xanthine oxidase depletion or inhibition on the increase in microvascular permeability produced by infusion of the neutrophil activator phorbol myristate acetate (PMA). Changes in vascular permeability were assessed by measurement of the solvent drag reflection coefficient for total plasma proteins (sigma) in rat hindquarters subjected to PMA infusion in xanthine oxidase-replete and -depleted animals, in animals pretreated with the xanthine oxidase inhibitor oxypurinol, and in animals depleted of circulating neutrophils by pretreatment with antineutrophil serum (ANS). Xanthine oxidase depletion was accomplished by administration of a tungsten-supplemented (0.7 g/kg diet) molybdenum-deficient diet. In animals fed the tungsten diet, muscle total xanthine dehydrogenase plus xanthine oxidase activity was decreased to less than 10% of control values. Estimates of sigma averaged 0.84 +/- 0.04 in control hindquarters, whereas PMA infusion was associated with a marked increase in microvascular permeability (decrease in sigma to 0.68 +/- 0.03). PMA infusion also caused an increase in the amount of the radical-producing oxidase form of xanthine oxidase (from 3.9 +/- 0.05 to 5.6 +/- 0.4 mU/g wet wt). ANS pretreatment attenuated this permeability increase (sigma = 0.77 +/- 0.04) and diminished the rise in xanthine oxidase activity (4.9 +/- 0.5 mU/g wet wt). Xanthine oxidase depletion with the tungsten diet or pretreatment with oxypurinol had no effect on this neutrophil-mediated microvascular injury (sigma = 0.69 +/- 0.06 and 0.67 +/- 0.03, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Xanthine oxidase does not cause microvascular dysfunction from activated neutrophils. Depleting or inhibiting this enzyme did not prevent increased vascular permeability caused by phorbol myristate acetate (PMA).
Area of Science:
- Biochemistry
- Physiology
- Immunology
Background:
- Activated granulocytes, such as neutrophils, can cause microvascular dysfunction.
- Xanthine oxidase is an enzyme implicated in oxidative stress and inflammation.
- The specific role of xanthine oxidase in neutrophil-mediated microvascular injury requires clarification.
Purpose of the Study:
- To investigate the role of xanthine oxidase in microvascular dysfunction induced by activated granulocytes.
- To determine if xanthine oxidase depletion or inhibition affects microvascular permeability changes caused by phorbol myristate acetate (PMA).
Main Methods:
- Vascular permeability was assessed using the solvent drag reflection coefficient (sigma) in rat hindquarters.
- Xanthine oxidase was depleted using a tungsten-supplemented, molybdenum-deficient diet.
- Xanthine oxidase inhibition was achieved with oxypurinol.
- Neutrophils were depleted using antineutrophil serum (ANS).
- PMA was infused to activate granulocytes.
Main Results:
- PMA infusion significantly increased microvascular permeability (decreased sigma) and xanthine oxidase activity.
- Neutrophil depletion (ANS) attenuated the PMA-induced permeability increase and the rise in xanthine oxidase activity.
- Xanthine oxidase depletion (tungsten diet) or inhibition (oxypurinol) did not affect the neutrophil-mediated microvascular injury.
Conclusions:
- Xanthine oxidase is not the primary mediator of microvascular dysfunction caused by activated neutrophils.
- Neutrophils, not xanthine oxidase, are responsible for the observed increase in microvascular permeability following PMA infusion.