Role for the alternative complement pathway in ischemia/reperfusion injury.
The terminal complement components play an important role in mediating tissue injury after ischemia and reperfusion (I/R) injury in rats and mice. However, the specific complement pathways involved in I/R injury are unknown. The role of the alternative pathway in I/R injury may be particularly important, as it amplifies complement activation and deposition. In this study, the role of the alternative pathway in I/R injury was evaluated using factor D-deficient (-/-) and heterozygote (+/-) mice. Gastrointestinal ischemia (GI) was induced by clamping the mesenteric artery for 20 minutes and then reperfused for 3 hours. Sham-operated control mice (+/- versus -/-) had similar baseline intestinal lactate dehydrogenase activity (P = ns). Intestinal lactate dehydrogenase activity was greater in -/- mice compared to +/- mice after GI/R (P = 0.02) thus demonstrating protection in the -/- mice. Intestinal myeloperoxidase activity in +/- mice was significantly greater than -/- mice after GI/R (P < 0.001). Pulmonary myeloperoxidase activity after GI/R was significantly higher in +/- than -/- mice (P = 0.03). Addition of human factor D to -/- animals restored GI/R injury and was prevented by a functionally inhibitory antibody against human factor D. These data suggest that the alternative complement pathway plays an important role in local and remote tissue injury after GI/R. Inhibition of factor D may represent an effective therapeutic approach for GI/R injury.
Stahl
Gregory L
GL
Department 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
Xu
Yuanyuan
Y
Hao
Liming
L
Miller
Mendy
M
Buras
Jon A
JA
Fung
Michael
M
Zhao
Hui
H
D000818:Animals; D011416:Complement Factor D / Q000172:deficiency* / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000502:physiology*; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000097:blood* / Q000473:pathology*
D007770:L-Lactate Dehydrogenase; D009195:Peroxidase; C493488:CFD protein, human; D011416:Complement Factor D; C493491:complement factor D, mouse