Abstract
Neonatal sepsis and its accompanying inflammatory response contribute to substantial morbidity and mortality. Pentoxifylline (PTX), a phosphodiesterase inhibitor which suppresses transcription and production of proinflammatory cytokines, is a candidate adjunctive therapy for newborn sepsis. We hypothesized that PTX decreases live microbe-induced inflammatory cytokine production in newborn blood. Cord blood was stimulated with live microorganisms commonly encountered in newborn sepsis (Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, or Candida albicans) and simultaneously treated with antimicrobial agents (gentamicin, vancomycin, or amphotericin B) and/or clinically relevant concentrations of PTX. Microbial colony counts were enumerated by plating, supernatant cytokines were measured by multiplex assay, intracellular cytokines and signaling molecules were measured by flow cytometry, and mRNA levels were measured by quantitative reverse transcription-PCR. PTX inhibited concentration-dependent E. coli-, S. aureus-, S. epidermidis-, and C. albicans-induced tumor necrosis factor (TNF) and E. coli-induced interleukin-1β (IL-1β) production in whole blood, with greater suppression of proinflammatory cytokines in combination with antimicrobial agents. Likewise, PTX suppressed E. coli-induced monocytic TNF and IL-1β, whereby combined PTX and gentamicin led to significantly greater reduction of TNF and IL-1β. The anti-inflammatory effect of PTX on microbe-induced proinflammatory cytokine production was accompanied by inhibition of TNF mRNA expression and was achieved without suppressing the production of the anti-inflammatory IL-10. Of note, microbial colony counts in newborn blood were not increased by PTX. Our findings demonstrated that PTX inhibited microbe-induced proinflammatory cytokine production, especially when combined with antimicrobial agents, without enhancing microbial proliferation in human cord blood in vitro, thus supporting its utility as candidate adjunctive agent for newborn sepsis.
Highlights
An estimated 1 million newborns die annually worldwide during the first 4 weeks of life due to severe infections such as sepsis and pneumonia [1], with a high risk among preterm newborns, who represent ϳ11% of all live births globally [1, 2]
Based on the cytokine-inhibiting actions of PTX in conjunction with potential increased bacterial clearance [20], we hypothesized that PTX decreases live microbe-induced proinflammatory cytokine production in newborn blood and blood-derived monocytes without enhancing microbial proliferation
Aac.asm.org newborn cord blood by PTX [13], improved bacterial clearance [20], and survival in septic newborn animals [27], we hypothesized that PTX decreases live bacteriuminduced inflammatory cytokine production in newborn blood without enhancing bacterial proliferation in vitro
Summary
An estimated 1 million newborns die annually worldwide during the first 4 weeks of life due to severe infections such as sepsis and pneumonia [1], with a high risk among preterm newborns, who represent ϳ11% of all live births globally [1, 2]. In order to optimally mirror physiological conditions encountered in neonatal sepsis in vitro, we stimulated whole newborn cord blood, which contains a multitude of anti-inflammatory humoral and cellular factors [21, 22], with live microorganisms that are commonly encountered in newborn sepsis [23], including Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, and Candida albicans, and treated blood samples with clinically relevant concentrations of conventional antimicrobial agents and PTX [24, 25]. Enhanced suppression of proinflammatory cytokines, but no effect on pathogen burden, was observed in vitro when PTX was administered in combination with antimicrobial agents, supporting the potential utility of PTX as an adjunctive anti-inflammatory agent for newborn sepsis
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