Effect of activators and the phosphodiesterase inhibitors Pentoxifylline and Enoximone on the deformability of neutrophils in neonates and adults

Abstract

Background: Stimulated polymorphonuclear leukocytes (PMN) are extremely rigid compared to resting PMN. They may obstruct narrow vessels and contribute to ischaemic organ injury. Deformability is a prerequisite for both active and passive movement in the microcirculation. Aim: The investigation was designed to study whether stimulators and inhibitors of stimulation show different effects on deformability of neonatal and adult PMN. Methods: Deformability of PMN was assessed by complete aspiration of a PMN into a micropipette with an internal diameter of 5 μm. Blood samples from 20 neonates and 20 adults were studied before and after stimulation with N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP), interleukin‐8 (IL‐8) or tumour necrosis factor‐α (TNF‐α). Moreover, effects of the phosphodiesterase inhibitors Pentoxifylline (PTX) and Enoximone on the deformability of stimulated PMN were investigated. Results: fMLP, IL‐8 and TNF‐α significantly delayed aspiration times of PMN in relation to the concentrations of the stimulators. The addition of PTX or Enoximone to stimulated PMN increased the deformability up to 60% depending on the concentration of the inhibitors. No significant differences in the aspiration times were found between neonatal and adult PMN at any of the experimental conditions after activation with the three stimulators and treatment with the two inhibitors. Conclusion: Neonatal and adult PMN show similar reduction of passive deformability when stimulated with either fMLP, IL‐8 or TNF‐α compared to resting PMN and a similar improvement of deformability in response to PTX or Enoximone.

Isoforskolin pretreatment attenuates lipopolysaccharide-induced acute lung injury in animal models

“…Traditionally, this signal transduction cascade has been targeted by pharmacological inhibitors of phosphodiesterases. Although the beneficial effects of phosphodiesterase inhibitor on ALI have been widely investigated [12][13][14][15], less is known about the roles of AC activators, related AC isoforms and cAMP-protein kinase A pathway. AC isoforms 1 to 9 are differentially expressed in tissues and constitute an interesting drug target.…”

“…Pharmacological approaches to increase cAMP levels also block the injury of microvascular endothelial and alveolar epithelial barrier function caused by H 2 O 2 challenge [11]. Up-regulation of intracellular cAMP by phosphodiesterase inhibitors [12][13][14][15] or exogenous supplement of cAMP by dibutyryl cAMP [16][17][18] was reported to improve ALI in several models.…”

Deformability of passive and activated neutrophils in children with Gram‐negative septicemia

“…We speculate that inhibition of PMN activation by drugs (e.g. pentoxifylline [28]) may ameliorate the circulatory complications of septicemia.…”

“…Pseudopods are extremly rigid [13,26]. Since the activated peripheral neutrophils behaved in a similar way to neutrophils with chemotactic activation [20,[26][27][28][29], we assume that the activated peripheral neutrophils are representative of neutrophils that are sequestrated in vivo.…”

Effects of phosphodiesterase (III/IV)-inhibitors and cytokines on mechanical properties of neutrophilic granulocytes in neonates and adults

“…Despite the functional differences activated PMN from neonates and adults show similar loss in deformability compared to passive PMN when determined with the micropipette technique [42]. The advantages of this technique are the continuous microscopic observation during the deformation process and the assessment of the tested cells.…”