Pentoxifylline modulates LPS-induced hyperinflammation in monocytes of preterm infants in vitro

  title={Pentoxifylline modulates LPS-induced hyperinflammation in monocytes of preterm infants in vitro},
  author={Simone S Sch{\"u}ller and Lukas Wisgrill and Elisabeth Herndl and Andreas Spittler and Elisabeth F{\"o}rster-Waldl and Kambis Sadeghi and Boris W Kramer and Angelika Berger},
  journal={Pediatric Research},
BackgroundPentoxifylline (PTX), a methylxanthine derivate with immunomodulating properties, has been used as adjunctive treatment in severe neonatal sepsis. The aim of the study was to investigate the anti-inflammatory effects of PTX on Lipopolysaccharides (LPS)-stimulated monocytes of preterm neonates in vitro compared with monocytes of term infants and adult controls.MethodsWhole cord blood samples and control adult blood samples were incubated with LPS and PTX. The expression of surface… 

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

Age, 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.

Pentoxifylline Alone or in Combination with Gentamicin or Vancomycin Inhibits Live Microbe-Induced Proinflammatory Cytokine Production in Human Cord Blood and Cord Blood Monocytes In Vitro

It is 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.

Efficacy of Melatonin and Pentoxifylline combination therapy in treatment of endotoxin induced hepatic dysfunction in white albino mice

Melatonin and pentoxifylline alone and as combination therapy as effective in countering LPS induced hepatotoxicity is evaluated, however the combination therapy did not yield synergistic effects.

Detrimental Effects of an Inhaled Phosphodiesterase-4 Inhibitor on Lung Inflammation in Ventilated Preterm Lambs Exposed to Chorioamnionitis Are Dose Dependent.

The findings indicate the narrow therapeutic range of inhaled PDE4 inhibitors in the preterm population and find a dose-dependent proinflammatory effect of an inhaled highly selective PDE 4 inhibitor in the lung.

Immunomodulation to Prevent or Treat Neonatal Sepsis: Past, Present, and Future

A summary of studies that characterize immune ontogeny and neonatal sepsis is presented, followed by discussion of clinical trials assessing interventions such as breast milk, lactoferrin, probiotics, and pentoxifylline.

Compatibility of intravenous pentoxifylline with other medications infused concurrently in preterm infants with late‐onset sepsis

Systematic reviews suggest PTX is safe and potentially beneficial in this context and based on clinical trials, it has been using PTX for the past 20 years in neonatal sepsis.

Protocol: Pentoxifylline optimal dose finding trial in preterm neonates with suspected late onset sepsis (PTX-trial)

The optimal dose of PTX is defined as the ED75 (i.e., clinically and chemically effective dose for 75% of patients) in preterm neonates with late onset sepsis in a prospective open label sequential dose-optimization study with an adapted continual reassessment method.

Intravenous pentoxifylline is well tolerated in critically ill preterm infants with sepsis or necrotizing enterocolitis

Intravenous PTX is compatible with standard NICU drugs and well tolerated in critically ill preterm infants and there was no evidence of incompatibility.

Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives?

The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay, and preliminary data suggesting their potential benefit are suggested.



Pentoxifylline in vivo and in vitro down‐regulates the expression of the intercellular adhesion molecule‐1 in monocytes

The observed suppressive in vivo and in vitro effects ofPTX on ICAM‐1 expression in monocytes may contribute to the recently described antiinflammatory effects of PTX, e.g. in sepsis or allergic contact dermatitis.

Phosphodiesterase inhibition decreases nuclear factor-kappaB activation and shifts the cytokine response toward anti-inflammatory activity in acute endotoxemia.

PTX enhances anti-inflammatory activity and decreases mortality in acute endotoxemia and may be an important adjunct to therapies aiming to modulate the inflammatory response in sepsis.

Reduced TNF‐α response in preterm neonates is associated with impaired nonclassic monocyte function

The reduced functional response of nonclassic monocytes of preterm neonates appears to be part of the diminished early immune response to bacterial cell wall components and is likely to contribute to their susceptibility to bacterial infection.


In human PMN leukocytes and T cells, clinically relevant anti-inflammatory effects of PTX can be achieved only in the presence of sufficient adenosine concentrations, which might be a prerequisite for the accessibility of sepsis patients to treatment with PTX.

Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling.

The reduced functional response to bacterial cell wall components appears to be part of the functional immaturity of the neonatal immune system and might predispose premature newborns to bacterial infection.

Pentoxifylline, a phosphodiesterase inhibitor, induces immune deviation in patients with multiple sclerosis

The Adenosine System Selectively Inhibits TLR-Mediated TNF-α Production in the Human Newborn1

It is concluded that the distinct adenosine system of newborns polarizes TLR-mediated cytokine production during the perinatal period and may thereby modulate their innate and adaptive immune responses.

Monocyte Toll-Like Receptor 4 Expression and LPS-Induced Cytokine Production Increase during Gestational Aging

It is concluded that the minimized expression of TLR4 contributes to the susceptibility of VLBWI to infections with Gram-negative bacteria due to the lack of cytokines to boost initial immune response.

Effect of the immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered infants: a placebo-controlled, double-blind trial.

The dosage and schedule of drug administration in this study attenuated the severity of the clinical course of sepsis in this group of patients and significantly affects the synthesis of TNF and IL-6 as well as reduces the mortality rate in premature infants withSepsis.