Inflammatory cell function in young rodents with experimental cholestasis: Investigations of functional deficits, their etiology, and their reversibility

Children with cholestasis are susceptible to infective complications. This may be attributable to impaired host defense. We postulated that cholestasis affects systemic polymorphonuclear leukocyte (PMN) function by impeding chemotaxis, phagocytosis, and superoxide release, which are all critical in eliciting an adequate immune response. Sprague Dawley rats (225 g) were assigned to three groups: bile duct ligated (BDL), sham (SH), and normal control (NC). On day 21 after operation, PMN and sera were isolated. Chemotactic response to C_5a and FMLP (formyl-methionyl-leucyl-phenylalanine), superoxide release, and phagocytic uptake of ¹⁴C-labeled Staphylococcus aureus were performed on pooled PMN samples. Results were expressed as mean ± SD. Serum bilirubin at day 21 was 6.3±2.9 v 0.1±0.1 and 0.1±0 mg/dL (P<.01) in BDL, SH, and NC groups, respectively. Kinetic studies of PMN phagocytosis demonstrated impaired ¹⁴C S aureus uptake by BDL neutrophils at 60 (P<.05), 90 (P<.05), and 120 minutes (P<.05) compared with SH and NC groups. No differences in PMN chemotactic response to C_5a and FMLP was observed in BDL, SH and NC groups (43±14 v 40±12 and 33±1, and 43±20 v 43±14 and 28±1 cell per field, respectively). Zymosan stimulated superoxide release did not differ between groups (14.3±3.6 (BDL) v 15.1±8.7 (SH) and 12±2.0 (NC) nmol/30 min/mg cell protein, respectively. Thus, cholestasis impairs neutrophil phagocytosis in vitro. Further studies evaluated the etiology and reversibility of this phenomenon by examining neutrophil suppressive activity in cholestatic sera and the efficacy of internal biliary drainage in reversing neutrophil dysfunction associated with cholestasis. Studies demonstrated no evidence of neutrophil inhibitory activity in BDL sera. However, internal biliary drainage for 28 days with concomitant reversal of hyperbilirubinemia (serum bilirubin: BDL v SH and NC 0.1±0 v 0.1±0 and 0.1 mg/dL) resulted in restoration of PMN phagocytosis to normal in BDL (BDL v Sham and NC not significant). This study demonstrates severe impairment of PMN phagocytosis in juvenile cholestatic animals, which is reversible by internal biliary drainage. Impaired PMN phagocytosis may be the critical immunological deficit in predisposing to infective complications in children with cholestasis-a deficit that may be reversible by internal biliary drainage and other therapeutic maneuvers.