Effects of C1 inhibitor on tissue damage in a porcine model of controlled hemorrhage.
Activation of the complement system has been associated with tissue injury after hemorrhage and resuscitation in animals. We investigated whether administration of recombinant human C1-esterase inhibitor (rhC1-INH), a regulator of complement and contact activation systems, reduces tissue damage and cytokine release and improves metabolic acidosis in a porcine model of hemorrhagic shock. Male Yorkshire swine were assigned to experimental groups and subjected to controlled, isobaric hemorrhage to a target mean arterial pressure of 35 mmHg. Hypotension was maintained for 20 min followed by a bolus intravenous injection of rhC1-INH or vehicle; animals were then observed for 3 h. Blood chemistry and physiologic parameters were recorded. Lung and small intestine tissue samples were subjected to histopathologic evaluation and immunohistochemistry to determine the extent of injury and deposition of complement proteins. Cytokine levels and quantitative assessment of renal and hepatic function were measured via enzyme-linked immunosorbent assay and chemistry analyzer, respectively. Pharmacokinetics of rhC1-INH revealed dose proportionality for maximum concentration, half-life, and the time span in which the functional C1-INH level was greater than 1 IU/mL. Recombinant human C1-INH significantly reduced renal, intestinal, and lung tissue damage in a dose-dependent manner (100 and 250 IU/kg). In addition, rhC1-INH (250 IU/kg) markedly improved hemorrhage-induced metabolic acidosis and circulating tumor necrosis factor α. The tissue-protective effects of rhC1-INH appear to be related to its ability to reduce tissue complement activation and deposition. Recombinant human C1-INH decreased tissue complement activation and deposition in hemorrhaged animals, improved metabolic acidosis, reduced circulating tumor necrosis factor α, and attenuated tissue damage in this model. The observed beneficial effects of rhC1-INH treatment on tissue injury 20 min into severe hypotension present an attractive model of low-volume resuscitation, particularly in situations with a restrictive medical logistical footprint.
ImmunoModulation of Trauma Program, US Army Institute of Surgical Research, Fort Sam Houston, Texas 78234, USA. jurandir.dallelucca@us.army.mil
Jurandir J
JJ
Dalle Lucca
Yansong
Y
Li
Milomir
M
Simovic
Anthony E
AE
Pusateri
Michael
M
Falabella
Michael A
MA
Dubick
George C
GC
Tsokos
D000138:Acidosis / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects; D050718:Complement C1 Inhibitor Protein / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051056:Complement Inactivating Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003165:Complement System Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D007262:Infusions, Intravenous; D007410:Intestinal Diseases / Q000209:etiology / Q000517:prevention & control; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008168:Lung / Q000378:metabolism; D008171:Lung Diseases / Q000209:etiology / Q000517:prevention & control; D008297:Male; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control; D012771:Shock, Hemorrhagic / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D034421:Sus scrofa; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D050718:Complement C1 Inhibitor Protein; D051056:Complement Inactivating Agents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003165:Complement System Proteins