Complement depletion enhances pulmonary inflammatory response after liver injury.
Hepatic cryoablation can produce acute lung injury, with activation of nuclear factor (NF)-kappaB in the remnant liver and lungs, production of C-X-C chemokines, and neutrophil infiltration of the lungs. Activated complement stimulates NF-kappaB and cytokine secretion from Kupffer cells. The role of complement in the development of acute lung injury after cryoablation was examined using HLL transgenic mice (5'HIV-LTR-Luciferase gene; 5' HIV-LTR is an NF-kappaB-dependent promoter). Total complement depletion was achieved with preoperative administration of cobra venom factor (CVF). After hepatic cryoablation, bioluminescent NF-kappaB activity increased in the nonablated liver remnant by 4 hours in both control (119,093 +/- 22,808 net RLU/mg protein) and CVF-treated mice (117,722 +/- 14,932) from cumulative baseline (657 +/- 90, P < 0.0001). In the lung, complement-depletion induced significantly greater increases in NF-kappaB activation at both early and later times. Likewise, chemokines were higher in complement-depleted mice relative to controls (KC: 493 +/- 43 versus 269 +/- 29 pg/mg protein, P < 0.001; MIP-2: 171 +/- 29 versus 64 +/- 13 pg/mg protein, P < 0.0001). Pulmonary myeloperoxidase activity was equivalent at 24 hours, but complement-depletion caused a significantly more rapid influx of neutrophils. Complement depletion results in increased pulmonary inflammation following liver cryo injury via relative upregulation of NF-kappaB activity. Activated complement is not the initiator of the systemic inflammatory response; in fact, downstream components of the complement cascade may diminish subsequent inflammation.
Glasgow
Sean C
SC
Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Kanakasabai
Sathyabama
S
Ramachandran
Sabarinathan
S
Mohanakumar
T
T
Chapman
William C
WC
D000704:Analysis of Variance; D000818:Animals; D018925:Chemokines / Q000276:immunology; D003165:Complement System Proteins / Q000378:metabolism*; D003452:Cryosurgery; D008107:Liver Diseases / Q000601:surgery*; D008163:Luminescent Measurements; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D016328:NF-kappa B / Q000276:immunology; D011014:Pneumonia / Q000276:immunology*
D018925:Chemokines; D016328:NF-kappa B; D003165:Complement System Proteins