Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns

Speer, Esther M.; Dowling, David J.; Ozog, Lukasz S.; Xu, Jianjin; Yang, Jie; Kennady, Geetika; Levy, Ofer

doi:10.1038/pr.2017.6

Cited by 40 publications

(48 citation statements)

References 38 publications

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“…If D = 1: (HBV + BCG) act additively, if D > 1: (HBV + BCG) act antagonistically, and if D < 1: (HBV + BCG) act synergistically. Our laboratory has employed this interaction analysis method in other recently published studies ( 13 , 38 , 39 ).…”

Section: Methodsmentioning

confidence: 99%

Adjuvant Effect of Bacille Calmette–Guérin on Hepatitis B Vaccine Immunogenicity in the Preterm and Term Newborn

et al. 2018

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Immunization is key to protecting term and preterm infants from a heightened risk of infection. However, preterm immunity is distinct from that of the term, limiting its ability to effectively respond to vaccines routinely given at birth, such as hepatitis B vaccine (HBV). As part of the Expanded Program on Immunization, HBV is often given together with the live-attenuated vaccine Bacille Calmette–Guérin (BCG), known to activate multiple pattern-recognition receptors. Of note, some clinical studies suggest BCG can enhance efficacy of other vaccines in term newborns. However, little is known about whether BCG can shape Th-polarizing cytokine responses to HBV nor the age-dependency of such effects, including whether they may extend to the preterm. To characterize the effects of BCG on HBV immunogenicity, we studied individual and combined administration of these vaccines to cord newborn and adult human whole blood and mononuclear cells in vitro and to neonatal and adult mice in vivo. Compared to either BCG or HBV alone, (BCG + HBV) synergistically enhanced in vitro whole blood production of IL-1β, while (BCG + HBV) also promoted production of several cytokines/chemokines in all age groups, age-specific enhancement included IL-12p70 in the preterm and GM-CSF in the preterm and term. In human mononuclear cells, (BCG + HBV) enhanced mRNA expression of several genes including CSF2, which contributed to clustering of genes by vaccine treatment via principle component analysis. To assess the impact of BCG on HBV immunization, mice of three different age groups were immunized subcutaneously with, BCG, HBV, (BCG + HBV) into the same site; or BCG and HBV injected into separate sites. Whether injected into a separate site or at the same site, co-administration of BCG with HBV significantly enhanced anti-HBV IgG titers in mice immunized on day of life-0 or -7, respectively, but not in adult mice. In summary, our data demonstrate that innate and adaptive vaccine responses of preterm and term newborns are immunologically distinct. Furthermore, BCG or “BCG-like” adjuvants should be further studied as a promising adjuvantation approach to enhance immunogenicity of vaccines to protect these vulnerable populations.

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Section: Methodsmentioning

confidence: 99%

Adjuvant Effect of Bacille Calmette–Guérin on Hepatitis B Vaccine Immunogenicity in the Preterm and Term Newborn

et al. 2018

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“…In previous neonatal pilot studies, PTX improved endothelial cell function, reduced coagulopathy in sepsis and NEC and diminished intestinal permeability by reducing myeloperoxidase activity and oxygen free radical generation [4]. PTX also significantly reduces inflammatory host responses to various stimuli in neonatal blood in vitro and in vivo [5][6][7]. A recent Cochrane review concluded that PTX increases survival and shortens length of hospital stay in neonates with sepsis, and recommended appropriately powered clinical trials be undertaken to confirm these findings [8].…”

Section: Introductionmentioning

confidence: 96%

Effects of maturation and size on population pharmacokinetics of pentoxifylline and its metabolites in very preterm infants with suspected late‐onset sepsis or necrotizing enterocolitis: a pilot study incorporating clinical outcomes

Salman

Hibbert

Page‐Sharp

et al. 2018

Brit J Clinical Pharma

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Aims Infection‐induced inflammation is associated with adverse long‐term outcomes in preterm infants. Pentoxifylline (PTX) is a candidate for adjunct immunomodulatory therapy in preterm infants with late‐onset sepsis (LOS) and necrotizing enterocolitis (NEC), but pharmacokinetic data in this population are extremely limited. This study aims to characterize the pharmacokinetic properties of intravenous PTX and its metabolites in preterm infants. Method An open label pilot clinical study of intravenous PTX as an adjunct therapy in preterm infants (gestation <32 weeks) with suspected LOS or NEC was undertaken. PTX was infused for 12 h for two days (60 mg kg−1 per 12 h), and in infants with confirmed diagnosis of LOS or NEC, for 6 h for another 4 days (30 mg kg−1 per 6 h). Plasma concentrations of PTX and its principal metabolites from collected blood samples were measured using a validated LCMS assay. NONMEM was used to analyse the data using population pharmacokinetic modelling. Results The preterm infants (n = 26) had a median (range) gestation of 24.8 weeks (23.3–30.4) and birthweight of 689 g (370–1285). PTX was well tolerated and without treatment‐limiting adverse effects. Changes in size (weight) and maturation were successfully modelled for PTX and metabolites. After allometric scaling, clearance increased with postmenstrual age, increasing by approximately 30% per week for PTX and M1 (lisofylline) and simulations of current dosing demonstrated a six‐fold difference in exposure between 24 and 35 weeks postmenstrual age. Conclusions The developed model can be used to explore dosing strategies based on size and maturation for preterm infants.

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“…Placental cord blood was collected from healthy term newborns between 38 to 41 weeks gestation who delivered by Cesarean section without labor and without current infection, including documented intrauterine infection (i.e. absence of clinical chorioamnionitis, prolonged fetal membrane rupture over 12h, clinical or laboratory signs of early-onset sepsis, or culture-proven sepsis of the mother or the newborn) or HIV [ 20 ]. Peripheral venous blood was donated with consent from healthy adult donors between 18 to 55 years of age.…”

Section: Methodsmentioning

confidence: 99%

“…We hypothesized that PTX + DEX or AZI (DEX/AZI) may provide broader, more profound and/or synergistic blunting of neonatal Toll-like receptor (TLR)- and/or inflammasome-mediated inflammatory cytokine production. As a model for infection-induced neonatal inflammation, we stimulated blood with TLR agonists (TLRAs) that activate TLR4 (the endotoxin lipopolysaccharide (LPS)), TLR7/8 (R848, an imidazoquinoline that induces adult-level inflammatory cytokine production in newborn monocytes) [ 19 ], or both TLR pathways and the inflammasome including R848 [ 19 ] and the combination of LPS and adenosine triphosphate (ATP) [ 20 ]. Using these whole blood assays, which preserve the age-specific immunomodulatory soluble and cellular factors naturally present in the newborn [ 21 – 23 ], we compared the anti-inflammatory effects of (PTX+DEX/AZI).…”

Section: Introductionmentioning

confidence: 99%

Pentoxifylline, dexamethasone and azithromycin demonstrate distinct age-dependent and synergistic inhibition of TLR- and inflammasome-mediated cytokine production in human newborn and adult blood in vitro

Speer

Dowling

et al. 2018

PLoS ONE

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IntroductionNeonatal inflammation, mediated in part through Toll-like receptor (TLR) and inflammasome signaling, contributes to adverse outcomes including organ injury. Pentoxifylline (PTX), a phosphodiesterase inhibitor which potently suppresses cytokine production in newborn cord blood, is a candidate neonatal anti-inflammatory agent. We hypothesized that combinations of PTX with other anti-inflammatory agents, the steroid dexamethasone (DEX) or the macrolide azithromycin (AZI), may exert broader, more profound and/or synergistic anti-inflammatory activity towards neonatal TLR- and inflammasome-mediated cytokine production.MethodsWhole newborn and adult blood was treated with PTX (50–200 μM), DEX (10−10–10−7 M), or AZI (2.5–20 μM), alone or combined, and cultured with lipopolysaccharide (LPS) (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/adenosine triphosphate (ATP) (inflammasome induction). Supernatant and intracellular cytokines, signaling molecules and mRNA were measured by multiplex assay, flow cytometry and real-time PCR. Drug interactions were assessed based on Loewe's additivity.ResultsPTX, DEX and AZI inhibited TLR- and/or inflammasome-mediated cytokine production in newborn and adult blood, whether added before, simultaneously or after TLR stimulation. PTX preferentially inhibited pro-inflammatory cytokines especially TNF. DEX inhibited IL-10 in newborn, and TNF, IL-1β, IL-6 and interferon-α in newborn and adult blood. AZI inhibited R848-induced TNF, IL-1β, IL-6 and IL-10, and LPS-induced IL-1β and IL-10. (PTX+DEX) synergistically decreased LPS- and LPS/ATP-induced TNF, IL-1β, and IL-6, and R848-induced IL-1β and interferon-α, while (PTX+AZI) synergistically decreased induction of TNF, IL-1β, and IL-6. Synergistic inhibition of TNF production by (PTX+DEX) was especially pronounced in newborn vs. adult blood and was accompanied by reduction of TNF mRNA and enhancement of IL10 mRNA.ConclusionsAge, agent, and specific drug-drug combinations exert distinct anti-inflammatory effects towards TLR- and/or inflammasome-mediated cytokine production in human newborn blood in vitro. Synergistic combinations of PTX, DEX and AZI may offer benefit for prevention and/or treatment of neonatal inflammatory conditions while potentially limiting drug exposure and toxicity.

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Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns

Abstract: PTX is a potent and efficacious inhibitor of TLR-mediated inflammatory cytokines in newborn cord blood and a promising neonatal anti-inflammatory agent.

Cited by 40 publications

References 38 publications

Adjuvant Effect of Bacille Calmette–Guérin on Hepatitis B Vaccine Immunogenicity in the Preterm and Term Newborn

Adjuvant Effect of Bacille Calmette–Guérin on Hepatitis B Vaccine Immunogenicity in the Preterm and Term Newborn

Effects of maturation and size on population pharmacokinetics of pentoxifylline and its metabolites in very preterm infants with suspected late‐onset sepsis or necrotizing enterocolitis: a pilot study incorporating clinical outcomes

Pentoxifylline, dexamethasone and azithromycin demonstrate distinct age-dependent and synergistic inhibition of TLR- and inflammasome-mediated cytokine production in human newborn and adult blood in vitro

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