title: Neutrophil inhibition with L-selectin-directed MAb improves or worsens survival dependent on the route but not severity of infection in a rat sepsis model.
abstract: Both route and severity of infection may influence immunomodulator agents in sepsis. We studied the effect of each variable on HRL-3, an L-selectin-directed MAb that inhibits neutrophil function, in a rat sepsis model. Animals (n = 800) were randomized to be treated with either HRL-3 or placebo and to receive Escherichia coli either intravenously (IV) or intrabronchially (IB) in doses producing low or high mortality rates. Animals received antibiotics and were observed for 168 h. Route but not dose of E. coli altered the effects HRL-3 on mortality rate (mean hazards ratio +/- SE). With IV E. coli, compared with control, HRL-3 was beneficial and reduced the hazards ratio both early (0 to 6 h; -0.75 +/- 0.23) and late (6 to 168 h; -0.72 +/- 0.36) (P = 0.001 and 0.04, respectively, over all E. coli doses). In contrast, with IB E. coli HRL-3 reduced the hazards ratio early (-1.1 +/- 0.36) but worsened it late (0.87 +/- 0.23) (P = 0.002 for both effects over all E. coli doses) in patterns significantly different from IV E. coli (P < 0.0001). Compared with control, although HRL-3 did not alter lung neutrophil numbers or injury score at 6 or 168 h with IV E. coli (P = ns for all), it reduced both early and increased them late with IB E. coli (P </= 0.05 for all comparing 6 with 168 h). Thus immunomodulators inhibiting neutrophil function, although potentially beneficial with sepsis due to intravascular infection, may be harmful with extravascular infection regardless of severity.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bldg. 10, Rm. 7D43, Bethesda, MD 20892, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Haley
authors.forename: Chantal
authors.initials: C
authors.lastname: Parent
authors.forename: Xizhong
authors.initials: X
authors.lastname: Cui
authors.forename: Andre
authors.initials: A
authors.lastname: Kalil
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Fitz
authors.forename: Rosaly
authors.initials: R
authors.lastname: Correa-Araujo
authors.forename: Charles
authors.initials: C
authors.lastname: Natanson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
authors.forename: Steven M
authors.initials: SM
authors.lastname: Banks
authors.forename: Peter Q
authors.initials: PQ
authors.lastname: Eichacker
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004927:Escherichia coli Infections / Q000150:complications / Q000276:immunology* / Q000517:prevention & control*; D019041:L-Selectin / Q000008:administration & dosage / Q000276:immunology; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects*; D016016:Proportional Hazards Models; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000175:diagnosis / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control*; D012720:Severity of Illness Index; D013534:Survival; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C502937:HRL-3 monoclonal antibody; D019041:L-Selectin