Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q.
Complement activation plays an important role in local and remote tissue injury associated with gastrointestinal ischemia-reperfusion (GI/R). The role of the classical and lectin complement pathways in GI/R injury was evaluated using C1q-deficient (C1q KO), MBL-A/C-deficient (MBL-null), complement factor 2- and factor B-deficient (C2/fB KO), and wild-type (WT) mice. Gastrointestinal ischemia (20 min), followed by 3-h reperfusion, induced intestinal and lung injury in C1q KO and WT mice, but not in C2/fB KO mice. Addition of human C2 to C2/fB KO mice significantly restored GI/R injury, demonstrating that GI/R injury is mediated via the lectin and/or classical pathway. Tissue C3 deposition in C1q KO and WT, but not C2/fB KO, mice after GI/R demonstrated that complement was activated in C1q KO mice. GI/R significantly increased serum alanine aminotransferase, gastrointestinal barrier dysfunction, and neutrophil infiltration into the lung and gut in C1q KO and WT, but not C2/fB KO, mice. MBL-null mice displayed little gut injury after GI/R, but lung injury was present. Addition of recombinant human MBL (rhuMBL) to MBL-null mice significantly increased injury compared with MBL-null mice after GI/R and was reversed by anti-MBL mAb treatment. However, MBL-null mice were not protected from secondary lung injury after GI/R. These data demonstrate that C2 and MBL, but not C1q, are necessary for gut injury after GI/R. Lung injury in mice after GI/R is MBL and C1q independent, but C2 dependent, suggesting a potential role for ficolins in this model.
Hart
Melanie L
ML
Center for Experimental Therapeutics and Reperfusion Injury, Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ceonzo
Kathleen A
KA
Shaffer
Lisa A
LA
Takahashi
Kazue
K
Rother
Russell P
RP
Reenstra
Wende R
WR
Buras
Jon A
JA
Stahl
Gregory L
GL
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015922:Complement C1q / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003175:Complement C2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D003176:Complement C3 / Q000378:metabolism; D003171:Complement Pathway, Classical / Q000235:genetics / Q000276:immunology; D037582:Complement Pathway, Mannose-Binding Lectin / Q000235:genetics / Q000276:immunology*; D003911:Dextrans / Q000097:blood; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives*; D041981:Gastrointestinal Tract / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007422:Intestines / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D008297:Male; D037241:Mannose-Binding Lectins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology
D003175:Complement C2; D003176:Complement C3; D003911:Dextrans; D037241:Mannose-Binding Lectins; C015219:fluorescein isothiocyanate dextran; D015922:Complement C1q; D009195:Peroxidase; D000410:Alanine Transaminase; D016650:Fluorescein-5-isothiocyanate