Inter-alpha inhibitor protein administration improves survival from neonatal sepsis in mice.
Inter-alpha inhibitor proteins (IaIp) are serine proteases inhibitors that modulate endogenous protease activity and have been shown to improve survival in adult models of sepsis. We evaluated the effect of IaIp on survival and systemic responses to sepsis in neonatal mice. Sepsis was induced in 2-d-old mice with lipopolysaccharide (LPS), Escherichia coli, and group B Streptococci. Sepsis was associated with 75% mortality. IaIp, given by i.p. administration at doses between 15 and 45 mg/kg from 1 to 6 h after the onset of sepsis, improved survival to approximately 90% (p = 0.0159) in both LPS-induced sepsis and with live bacterial infections. The greatest effect was on reversal of hemorrhagic pneumonitis. The effects were dose and time dependent. Systemic cytokine profile and tissue histology were examined. Survival was compared in IL-10 knock out animals. Systemic cytokine levels including TNF-[alpha] and IL-10 were increased after induction of sepsis and modulated significantly after IaIp administration. Because the effect of IaIp was still demonstrable in IL-10 deficient mice, we conclude the beneficial effects of IaIp is because of suppression of proinflammatory cytokines such as TNF-[alpha] rather than augmentation of IL-10. IaIp may offer significant benefits as a therapeutic
Department of Pediatrics, Women & Infants' Hospital, Brown Medical School, Providence, RI 02905, USA.
Kultar
K
Singh
Ling Xiu
LX
Zhang
Kreso
K
Bendelja
Ryan
R
Heath
Shaun
S
Murphy
Surendra
S
Sharma
James F
JF
Padbury
Yow-Pin
YP
Lim
D000510:Alpha-Globulins / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D008070:Lipopolysaccharides; D051379:Mice; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D013292:Streptococcus agalactiae; D016019:Survival Analysis; D013997:Time Factors
D000510:Alpha-Globulins; D016207:Cytokines; D008070:Lipopolysaccharides; D015842:Serine Proteinase Inhibitors; C011877:inter-alpha-inhibitor