Administration of human protein C improves survival in an experimental model of sepsis.
OBJECTIVE
Study the effect of human protein C (PC) concentrate administration on organ damage and survival in septic rats.


METHODS
Animal study.


METHODS
University laboratory.


METHODS
Male Wistar rats.


METHODS
Cecal ligation and puncture (CLP) was performed in 210 rats. Rats were randomly assigned to receive either human protein C (PC) IV 1, 7, and 13 hrs after CLP (CLP+PC) or placebo (CLP). Septic animals were again randomized in a survival group (CLP: n = 50 and CLP+PC: n = 40) that was monitored for 60 hrs and time groups (CLP: n = 60 and CLP+PC: n = 60) that were killed at 6, 12, 24, 36, 48, and 60 hrs after CLP. Brain, heart, lung, liver, kidney, gastric, and colon tissue were removed and postfixed in paraffin sections.


RESULTS
PC infusion increased PC serum levels in early sepsis (median 7.25) compared with late sepsis (median 2, p = .001). Activated protein C/a1-antitrypsin complex levels in the CLP+PC group were significantly increased in late sepsis (60 hrs after CLP) compared with early sepsis (6, 12, and 24 hrs after CLP, p = .009, p = .004, and p = .008, respectively) and to late septic CLP and normal rats (p = .005 and p = .007, respectively). Their IL-6 and tumor necrosis factor a plasma levels were decreased (by 27% and 25%, respectively) at 6 hrs compared with placebo (p = .008 and p = .016). Their serum PC levels were also decreased in CLP+PC survivors compared with nonsurvivors of the same group (median = 1.5 vs. median = 7, p = .001). Apoptosis was reduced in brain (10% vs. 77.8%, p < .001), stomach (66.7% vs. 100%, p < .002) and intestine (33.3% vs. 85.2%, p < .001) compared with placebo. Finally, the survival of septic rats treated with human PC was significantly increased compared with placebo (75% vs. 54%, p = .033).


CONCLUSIONS
Human Protein C administration increased survival in septic rats, decreased plasma inflammatory cytokines levels and tissue injury in vital organs.
Messaris
Evangelos
E
Laboratory of Surgical Research, First Department of Propaedeutic Surgery, Athens University Medical School, Hippokratio General Hospital, Athens, Greece.
Betrosian
Alex P
AP
Memos
Nikolaos
N
Chatzigianni
Emmy
E
Boutsikou
Maria
M
Economou
Venetia
V
Dontas
Ismene
I
Theodossiades
George
G
Konstadoulakis
Manousos M
MM
Douzinas
Emmanuel E
EE
D000818:Animals; D002432:Cecum / Q000601:surgery; D016009:Chi-Square Distribution; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D053208:Kaplan-Meier Estimate; D008026:Ligation; D008297:Male; D011336:Probability; D011486:Protein C / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D018709:Statistics, Nonparametric; D015996:Survival Rate
D016207:Cytokines; D011486:Protein C