Protection against endotoxic shock by bactericidal/permeability-increasing protein in rats.
Bactericidal/permeability-increasing protein (BPI) is a neutrophil primary granule protein that inhibits effects of LPS in vitro. The current study examined the effects of BPI on hemodynamics, mortality, and circulating endotoxin and cytokines in conscious rats with endotoxic shock. Catheters were implanted into the right femoral artery and vein. 1 d later, human recombinant BPI (10 mg/kg) or vehicle was intravenously injected immediately, 30 min, or 2 h after intravenous injection of LPS (7.5 mg/kg). Mean arterial pressure (MAP) and heart rate were monitored and blood was collected before and after injection. BPI given immediately or 30 min after LPS prevented the LPS-induced reduction in MAP at 4-8 h and markedly reduced mortality. BPI given 2 h after LPS injection had no protective effect. BPI treated immediately after LPS reduced the circulating levels of endotoxin and IL-6 but increased the circulating levels of TNF. We propose that BPI exerts its protective effect through a TNF-independent mechanism, by inhibiting endotoxin-stimulated production of IL-6.
Jin
H
H
Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.
Yang
R
R
Marsters
S
S
Ashkenazi
A
A
Bunting
S
S
Marra
M N
MN
Scott
R W
RW
Baker
J B
JB
D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides; D001794:Blood Pressure / Q000187:drug effects; D001798:Blood Proteins / Q000627:therapeutic use*; D004731:Endotoxins / Q000097:blood / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007022:Hypotension / Q000188:drug therapy; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use; D012772:Shock, Septic / Q000401:mortality / Q000628:therapy*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D004731:Endotoxins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C021623:bactericidal permeability increasing protein