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Role for the alternative complement pathway in ischemia/reperfusion injury
Gregory L Stahl1, Yuanyuan Xu, Liming Hao
1Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. gstahl@zeus.bwh.harvard.edu
The American Journal of Pathology
|January 28, 2003
Summary
The alternative complement pathway exacerbates tissue injury following gastrointestinal ischemia and reperfusion (GI/R). Factor D deficiency protects against GI/R injury, suggesting factor D inhibition as a potential therapy.
Area of Science:
- Immunology
- Complement System
- Ischemia-Reperfusion Injury
Background:
- Terminal complement components contribute to tissue damage after ischemia and reperfusion (I/R).
- The specific complement pathways implicated in I/R injury remain largely undefined.
- The alternative complement pathway's amplification role suggests its significance in I/R pathogenesis.
Purpose of the Study:
- To investigate the role of the alternative complement pathway in gastrointestinal ischemia and reperfusion (GI/R) injury.
- To evaluate the protective effects of factor D deficiency in a murine model of GI/R injury.
Main Methods:
- Induction of GI ischemia by mesenteric artery clamping followed by reperfusion in factor D-deficient (-/-) and heterozygote (+/-) mice.
- Assessment of intestinal and pulmonary tissue injury using lactate dehydrogenase and myeloperoxidase activity.
- Reversal of protective effects by addition of human factor D and blockade with an inhibitory antibody.
Main Results:
- Factor D-deficient mice exhibited significantly reduced intestinal and pulmonary injury markers compared to heterozygote controls after GI/R.
- Baseline intestinal lactate dehydrogenase activity was similar between groups.
- Restoration of injury in deficient mice upon human factor D addition, blocked by an inhibitory antibody.
Conclusions:
- The alternative complement pathway significantly contributes to both local and remote tissue injury following GI/R.
- Targeting factor D represents a promising therapeutic strategy for mitigating GI/R-induced tissue damage.