The interleukin-1 receptor antagonist can either reduce or enhance the lethality of Klebsiella pneumoniae sepsis in newborn rats

Abstract

Kiebsiella pneumoniae, a worldwide cause of nosocomial infections, is one of the most common causes of death in newborns in nurseries. In this study, we investigated the role of interleukin-1 (IL-1) in an experimental animal model of neonatal sepsis, using a natural antagonist of IL-1 receptors, the IL-1 receptor antagonist (IL-iRa), to block IL-l's effects in neonatal Kiebsiella sepsis in the absence of antibiotic treatment. Newborn Wistar-Kyoto rats were injected intraperitoneally with a single dose (10 mg/kg) of either IL-lRa (n = 43) or human serum albumin as a control (n = 40). At the same time, a 50% lethal dose ofK. pneumoniae was injected subcutaneously. No antibiotics were given at any time. After 10 days, survival was 60% for the albumin group and 80%Yo for the IL-lRa group (P < 0.01). IL-lRa treatment also afforded protection when the dose of bacteria was increased sixfold (P < 0.01). There were two episodes of leukopenia in the control group, which were suppressed by IL-lRa (P < 0.01 and P < 0.001). IL-1 and IL-6 levels were lower in the IL-lRa-treated group (P < 0.05 and P < 0.001, respectively). No differences between the two groups were observed in the number of bacteria in cultures of the blood, lungs, liver, or spleen. When IL-lRa (10 mg/kg) was given both at time zero and 24 h after bacterial challenge, lethality was significantly increased (P < 0.01). Single doses of IL-lRa of from 20 to 40 mg/kg progressively increased lethality compared with controls (P < 0.01) in both Wistar-Kyoto

Functional immaturity of rat alveolar macrophages during postnatal development

“…Our data show impaired production of IL‐1β by rat AM during postnatal maturation and this may explain the decreased neutrophil influx, which is seen in neonatal rats 26 , 46 . Indeed, blockade of the IL‐1 receptor enhanced lethality to Klebsiella pneumoniae infection in newborn rats, whereas IL‐1β administration gave protection to lethal infection 47 . These data strongly suggest that reduced IL‐1β secretion by young AM plays an important role in increased susceptibility to infections in human newborns.…”

Cutting Edge: IL-1α and Not IL-1β Drives IL-1R1–Dependent Neonatal Murine Sepsis Lethality

“…None of these strategies modifed sepsis mortality(Figure 4A–B, Figure 6B) as compared to WT mice treated with or without an isotype control-antibody. Although excessive IL-1β production can be detrimental to the host, IL-1β can also enhance innate immune function(12, 13). To determine whether the IL-1β response was inadequate in neonates and could be enhanced, concurrent treatment with rIL-1β(10ng/g IP)(13–15) was performed but also did not modify subsequent sepsis survival(26%, n = 34) compared to septic WT mice treated with PBS(28%, n = 36)(Figure 4C).…”

Treatment of Disseminated Intravascular Coagulation (DIC) with All-transRetinoic Acid in an Endotoxin-Induced Rat Model

“…Their clinical efficacy in humans has not yet been established. [30][31][32][33][34][35] Some papers have reported that anticytokine agents, such as anti-TNF-α antibody, 31 platelet activating factor (PAF) an tagonist, 36 and polymorphonuclear elastase inhibitor 37 have a protective effect against organ damage and shock in an endotoxin-induced model of sepsis. However, the doses of these drugs required for inhibition of DIC were too large to be of clinical use.…”