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Oxidant-mediated, CD18-dependent microvascular dysfunction induced by complement-activated granulocytes
D L Carden1, J K Smith, R J Korthuis
1Department of Physiology, Louisiana State University Medical Center, School of Medicine, Shreveport 71130.
Insights
Complement-activated granulocytes cause microvascular dysfunction in skeletal muscle. Neutrophil depletion and adherence inhibition prevent this, but xanthine oxidase does not.
Area of Science:
- Physiology
- Immunology
- Vascular Biology
Background:
- Complement activation leads to granulocyte recruitment and microvascular dysfunction.
- Neutrophil adherence plays a critical role in inflammatory processes.
- Skeletal muscle microvasculature is susceptible to inflammatory damage.
Purpose of the Study:
- To elucidate the mechanisms by which complement-activated granulocytes induce microvascular dysfunction in skeletal muscle.
- To investigate the role of neutrophil adherence and reactive oxygen species in ZAP-induced microvascular permeability.
Main Methods:
- Assessment of microvascular permeability using the solvent drag reflection coefficient (sigma) in canine gracilis muscle.
- Measurement of neutrophil infiltration via myeloperoxidase activity.
- Intervention with antineutrophil serum (ANS), IB4 antibody, xanthine oxidase inhibitors, deferoxamine, and catalase.
Main Results:
- Zymosan-activated plasma (ZAP) significantly increased vascular permeability (sigma = 0.51).
- Neutropenia (ANS) and inhibition of neutrophil adherence (IB4) normalized ZAP-induced permeability (sigma ≈ 0.9).
- Deferoxamine and catalase also reduced ZAP-induced permeability, while xanthine oxidase inhibition did not.
Conclusions:
- Complement-induced microvascular dysfunction in skeletal muscle is primarily mediated by granulocyte infiltration and adherence.
- Inhibition of neutrophil adherence is a key therapeutic target for mitigating ZAP-induced microvascular injury.
- The role of xanthine oxidase in this specific model of microvascular dysfunction appears limited.
Abstract:
To determine the mechanisms whereby complement-activated granulocytes induce microvascular dysfunction in skeletal muscle, we examined the effect of antineutrophil serum (ANS), IB4 (a monoclonal antibody that inhibits CD18-dependent neutrophil adherence), xanthine oxidase inhibition or inactivation, deferoxamine, and catalase on the increase in canine gracilis muscle microvascular permeability induced by intravascular administration of zymosan-activated plasma (ZAP). Changes in vascular permeability were assessed by measurement of the solvent drag reflection coefficient (sigma) for total plasma proteins, and the extent of neutrophil infiltration was estimated by assessing muscle myeloperoxidase activity. ZAP infusion was associated with a marked increase in vascular permeability compared with control muscles that received no treatment or to muscles treated with zymosan heat-inactivated plasma (ZIP) (sigma = 0.51 +/- 0.04, 0.89 +/- 0.02, and 0.90 +/- 0.01, respectively). Estimates of sigma in animals rendered neutropenic with ANS, or treated with IB4, deferoxamine, or catalase before ZAP infusion were not significantly different from values obtained in control or ZIP-treated muscles (sigma = 0.96 +/- 0.02, 0.88 +/- 0.03, 0.85 +/- 0.02, and 0.79 +/- 0.01, respectively). However, xanthine oxidase inactivation or inhibition provided no protection from this ZAP-induced microvascular dysfunction (sigma = 0.58 +/- 0.02 and 0.58 +/- 0.01, respectively). In addition, neutropenia and inhibition of neutrophil adherence also prevented ZAP-induced increases in vascular resistance and tissue neutrophil infiltration.(ABSTRACT TRUNCATED AT 250 WORDS)