Prophylactic uses of integrin CD18-betaA peptide in a murine polymicrobial peritonitis model.
OBJECTIVE
To evaluate the prophylactic properties of integrin CD18-betaA peptide in a murine model of abdominal polymicrobial peritonitis and sepsis.


METHODS
Bacterial sepsis was induced in Institute of Cancer Research (ICR) mice by cecal ligation and puncture (CLP) surgery. Inflicted mice were then injected with either sterile saline or CD18-betaA peptide intraperitoneally at 2 h after surgery, and were sacrificed at 12 and 24 h after surgery. Blood samples were immediately collected, and analyzed for endotoxin activity and tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. Lungs and liver were studied for CD45+ leukocyte and CD3 mRNA content. Pulmonary expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM) and E-selectin was also determined.


RESULTS
Intraperitoneal injection of CD18-betaA peptide significantly suppressed circulating endotoxin activity (P < 0.01) at 24 h, as well as serum levels of TNF-alpha (P < 0.05 at 12 and 24 h) and IL-6 (P < 0.01 at 12 h, P < 0.05 at 24 h) in CLP-inflicted mice. CD18-betaA peptide also abrogated leukocyte infiltration into liver and lungs as unveiled by reduced CD45+ leukocyte and CD3 mRNA contents. Furthermore, the peptide significantly reduced pulmonary expression of VCAM (P < 0.01 at 12 h, P < 0.001 at 24 h), E-selectin (P < 0.01 at 12 and 24 h), and ICAM-1 (P < 0.01 at 12 h, P < 0.001 at 24 h). These actions of CD18-betaA peptide collectively protected septic mice against lethality (P < 0.01).


CONCLUSIONS
CD18-betaA peptide is a potent endotoxin antagonist that can protect surgical patients against sepsis-associated lethality.
Department of Pharmacology and Surgery, National University Hospital System, National University of Singapore, Singapore 117597, Singapore. tonywkf@hku.hk
Kwong-Fai
KF
Wong
Jana
J
Wo
David
D
Ho
Ronnie T
RT
Poon
José M
JM
Casasnovas
John M
JM
Luk
D000595:Amino Acid Sequence; D000818:Animals; D018821:CD18 Antigens / Q000627:therapeutic use*; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000097:blood; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000627:therapeutic use*; D010538:Peritonitis / Q000097:blood / Q000382:microbiology* / Q000401:mortality / Q000517:prevention & control*; D018805:Sepsis / Q000097:blood / Q000382:microbiology* / Q000401:mortality / Q000517:prevention & control*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D018821:CD18 Antigens; D017252:CD3 Complex; D019040:E-Selectin; D004731:Endotoxins; D015850:Interleukin-6; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D017493:Leukocyte Common Antigens