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Role of iron in postischemic microvascular injury
J K Smith1, D L Carden, M B Grisham
1Department of Physiology and Biophysics, School of Medicine, Louisiana State University Medical Center, Shreveport 71130.
Abstract:
Iron-catalyzed formation of hydroxyl radicals has been postulated to occur during reperfusion of ischemic tissues. To assess the role of iron-catalyzed oxidant production in ischemia/reperfusion (I/R) injury to skeletal muscle, we examined the effects of deferoxamine (an iron chelator) and apotransferrin (an iron-binding protein) on the increased vascular permeability produced by I/R in isolated, pump-perfused rat hindquarters. Solvent drag reflection coefficients (sigma) were measured in hindquarters subjected to 2 h of ischemia and 30 min of reperfusion with either no pretreatment, pretreatment with 50 mg/kg deferoxamine, 200 mg/kg apotransferrin, or iron-loaded deferoxamine (50 mg/kg). I/R alone was associated with an increase in vascular permeability as indicated by the significantly lower estimates of sigma obtained after I/R (0.68 +/- 0.03) compared with those obtained in nonischemic preparations (0.82 +/- 0.02). Pretreatment with deferoxamine or apotransferrin attenuated this permeability increase (sigma = 0.83 +/- 0.03 and 0.86 +/- 0.02, respectively), whereas pretreatment with iron-loaded deferoxamine afforded no protection (sigma = 0.71 +/- 0.02). These findings are consistent with the hypothesis that iron-catalyzed oxidant production is important in the genesis of microvascular injury following I/R. Since the enzyme xanthine oxidase has been implicated as a major source of oxidants generated during reperfusion, we also measured tissue levels of xanthine oxidase and xanthine dehydrogenase in muscle samples obtained from the same hindquarters in which we measured permeability changes.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Deferoxamine and apotransferrin reduced skeletal muscle vascular permeability during reperfusion injury, suggesting iron-catalyzed oxidant production contributes to microvascular damage. Iron-loaded deferoxamine offered no protection.
Area of Science:
- Biochemistry
- Physiology
- Pathology
Background:
- Ischemia/reperfusion (I/R) injury to skeletal muscle involves oxidant production.
- Iron-catalyzed formation of hydroxyl radicals is a proposed mechanism during reperfusion.
Purpose of the Study:
- To investigate the role of iron-catalyzed oxidant production in skeletal muscle I/R injury.
- To assess the protective effects of iron chelators against I/R-induced vascular permeability.
Main Methods:
- Isolated, pump-perfused rat hindquarters subjected to 2 hours of ischemia and 30 minutes of reperfusion.
- Measurement of solvent drag reflection coefficients (sigma) to assess vascular permeability.
- Administration of deferoxamine, apotransferrin, or iron-loaded deferoxamine as pretreatment.
Main Results:
- I/R significantly increased vascular permeability (sigma decreased from 0.82 to 0.68).
- Deferoxamine and apotransferrin pretreatment attenuated the permeability increase (sigma = 0.83 and 0.86, respectively).
- Iron-loaded deferoxamine did not provide protection (sigma = 0.71).
Conclusions:
- Iron-catalyzed oxidant production plays a significant role in skeletal muscle microvascular injury following I/R.
- Iron chelation therapy may be beneficial in mitigating I/R injury.
- Further investigation into the sources of oxidants, such as xanthine oxidase, is warranted.