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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/μL were pretreated with rBPI23 or the irrelevant 22 kDa protein thaumatin [3.3–6.6 mg/kg, i.v. in 0.9% NaCI (NS)] 5 min before graded i.v. infection with 5 ± 109 or 1 ± 1010 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 ± 109 EC rats and none of six thaumatin + 1010 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-α. Sepsis-induced severe neutropenia (< 50 PMNs/μL) evident in all EC rats by t = 1.5 h was reversed with rBPI23 by t = 8 h, but thrombocytopenia (<5 ± 104 platelets/μL) evident in all groups by t = 4.5 h was not altered. Although rBPI23 did not prevent EC-induced increases in microvascular permeability, it reduced pulmonary interstitial edema, microvascular congestion, and hepatocytic steatosis. Thus rBPI23 enhances host defense during neutropenic bacteremia, independent of circulating levels of endotoxin or of proinflammatory cytokines including TNF.