THE RECOMBINANT 23-KDA N-TERMINAL FRAGMENT OF BACTERICIDAL PERMEABILITY-INCREASING PROTEIN (RBPI(23)) DECREASES ESCHERICHIA COLI-INDUCED MORTALITY AND ORGAN INJURY DURING IMMUNOSUPPRESSION-RELATED NEUTROPENIA

Cyclophosphamide-induced neutropenia exacerbates septic shock and mult iple organ injury in conscious rats during Escherichia coil (EC) bacte remia despite antibiotics and fluid administration. We hypothesized th at such shock and inflammatory organ injury would be mitigated by rBPI (23)'s microbicidal activity and/or binding of EC endotoxins. Four day s after 100 mg cyclophosphamide/kg, catheterized rats with <300 PMNs/m u L were pretreated with rBPI(23) or the irrelevant 22 kDa protein tha umatin [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 end ing 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 su lfate at t = 1.5 and 8 h. Arterial samples were obtained before pretre atment 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, rBPI(23) significantly red uced mortality after either inoculum, improved bacterial clearance, an d led to renormalization of early EC-induced hypotension, hypothermia, tachypnea, hyperoxemia, and hypocarbia. Compared with thaumatin, howe ver, rBPI(23) did not reduce circulating endotoxin or bioactive and an tigenic tumor necrosis factor-alpha. Sepsis-induced severe neutropenia (<50 PMNs/mu L) evident in all EC rats by t = 1.5 h was reversed with rBPI(23) by t = 8 h, but thrombocytopenia (<5 x 10(4) platelets/mu L) evident in all groups by t = 4.5 h was not altered. Although rBPI(23) did not prevent EC-induced increases in microvascular permeability, i t reduced pulmonary interstitial edema, microvascular congestion, and hepatocytic steatosis. Thus rBPI(23) enhances host defense during neut ropenic bacteremia, independent of circulating levels of endotoxin or of proinflammatory cytokines including TNF.