The recombinant 23-kDa N-terminal fragment of bactericidal/permeability-increasing protein (rBPI23) decreases Escherichia coli-induced mortality and organ injury during immunosuppression-related neutropenia.
Cyclophosphamide-induced neutropenia exacerbates septic shock and multiple organ injury in conscious rats during Escherichia coli (EC) bacteremia despite antibiotics and fluid administration. We hypothesized that such shock and inflammatory organ injury would be mitigated by rBPI23's microbicidal activity and/or binding of EC endotoxins. Four days after 100 mg cyclophosphamide/kg, catheterized rats with < 300 PMNs/microL were pretreated with rBPI23 or the irrelevant 22 kDa protein thaumatin [3.3-6.6 mg/kg, i.v. in 0.9% NaCl (NS)] 5 min before graded i.v. infection with 5 x 10(9) or 1 x 10(10) cfu of EC serotype 055:B5 ending at t = 0. Posttreatment with each protein continued (3.3-6.6 mg/kg in 1 mL NS/h) through 8 h, in addition to penicillin plus amikacin sulfate at t = 1.5 and 8 h. Arterial samples were obtained before pretreatment and at t = 1.5, 4.5, 8, and 24 h when animals were necropsied. One of eight thaumatin + 5 x 10(9) EC rats and none of six thaumatin + 10(10) EC rats survived 24 h. In contrast, rBPI23 significantly reduced mortality after either inoculum, improved bacterial clearance, and led to renormalization of early EC-induced hypotension, hypothermia, tachypnea, hyperoxemia, and hypocarbia. Compared with thaumatin, however, rBPI23 did not reduce circulating endotoxin or bioactive and antigenic tumor necrosis factor-alpha. Sepsis-induced severe neutropenia (< 50 PMNs/microL) evident in all EC rats by t = 1.5 h was reversed with rBPI23 by t = 8 h, but thrombocytopenia (< 5 x 10(4) platelets/microL) evident in all groups by t = 4.5 h was not altered.(ABSTRACT TRUNCATED AT 250 WORDS)
Lechner
A J
AJ
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Missouri 63104-1028, USA.
Lamprech
K E
KE
Johanns
C A
CA
Matuschak
G M
GM
D000818:Animals; D023181:Antimicrobial Cationic Peptides; D016470:Bacteremia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D003520:Cyclophosphamide / Q000633:toxicity; D004731:Endotoxins / Q000097:blood; D004927:Escherichia coli Infections / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity; D066298:In Vitro Techniques; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D009503:Neutropenia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D010446:Peptide Fragments / Q000494:pharmacology*; D010940:Plant Proteins / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013549:Sweetening Agents; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D004731:Endotoxins; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D010446:Peptide Fragments; D010940:Plant Proteins; D011994:Recombinant Proteins; D013549:Sweetening Agents; D014409:Tumor Necrosis Factor-alpha; C021623:bactericidal permeability increasing protein; C003427:thaumatin protein, plant; D003520:Cyclophosphamide