Theophylline Attenuates the Neutrophil-Dependent Augmentation of Eosinophil Trans-Basement Membrane Migration

Abstract

Background: Recent evidence suggests that both neutrophilic and eosinophilic inflammation persist in the airways of patients with severe asthma. Neutrophils can secrete a variety of mediators which may augment the migration of eosinophils. We have reported that activated neutrophils augment the trans-basement membrane migration (TBM) of eosinophils in vitro. Theophylline has been shown to modulate some functions of both neutrophils and eosinophils. The objective of this study was to evaluate whether theophylline modulates the neutrophil-dependent augmentation of eosinophil TBM. Methods: Eosinophils and neutrophils were isolated from peripheral blood collected from healthy donors and were then preincubated with either 0.1 mM theophylline or the medium control. The TBM of eosinophils in response to IL-8 was evaluated in the presence or absence of neutrophils by using the chambers with a Matrigel®-coated Transwell® insert. The generation of O₂^– was evaluated by the cytochrome c reduction assay. Results: As previously reported, IL-8-stimulated neutrophils significantly augmented the TBM of eosinophils. Theophylline significantly attenuated the neutrophil-dependent augmentation of eosinophil TBM (p < 0.001) and did not directly modify the TBM of neutrophils in response to IL-8 or LTB4. Similarly, the LTB4-induced TBM of eosinophils was not modified by theophylline. Finally, theophylline attenuated the superoxide anion generation from IL-8-stimulated neutrophils on the Matrigel-coated plates. Conclusions: Our results show that theophylline can attenuate the neutrophil-dependent augmentation of eosinophil TBM. This effect is possibly attributable to the suppression of neutrophil activation provoked by the combination of basement membrane and IL-8.

Blocking the Leukotriene B4 Receptor 1 Inhibits Late-Phase Airway Responses in Established Disease

“…In human asthma, increased numbers of neutrophils were found in the lungs of patients with fatal asthma (40,41). Nagata and colleagues have shown that neutrophils enhance the transbasement membrane migration of eosinophils in vitro; therefore, activation of neutrophils may enhance the accumulation of eosinophils in the airways, sustaining allergic inflammation (42)(43)(44). LTB4 is thought to play an important role in the activation and recruitment of leukocytes, including neutrophils (45).…”

Neutrophilic Inflammation in Severe Asthma

“…IL-8 induces the generation of superoxide anion (O 2 – ) by neutrophils [16]. O 2 – is metabolized to H 2 O 2 , which enhances adhesion of eosinophils to intercellular adhesion molecule (ICAM)-1 [17].…”

“…We examined the effect of theophylline on the IL-8-stimulated neutrophil-enhanced transmigration of eosinophils. Theophylline attenuates the neutrophil-dependent augmentation of eosinophil migration [16], suggesting that it could suppress neutrophil-mediated eosinophilic airway inflammation in severe asthma. Furthermore, the use of D1-like-R antagonist or D2-like-R agonist therapy could be a promising new strategy for treating Th17-mediated severe asthma, for the reasons described above.…”

Effects of inhaled aminophylline on airway constriction and inflammation in ovalbumin-sensitized guinea pigs

“…Bronchodilating doses of theophylline (10-20 mg/mL) are also hazardous in the elderly (Reed, 2010). On the other hand, theophylline has a variety of favorable anti-inflammatory effects on eosinophils, including the suppression of superoxide production (Piacentini et al, 2005), migration (Kikuchi et al, 2007) and eosinophilopoiesis (Wang et al, 2003), and the induction of apoptosis (Chung et al, 2000). Theophylline has further been reported to increase the activity of histone deacetylase 2 (HDAC2) (Tamimi et al, 2012) and is expected to be effective in the treatment of smoking-induced asthma (Spears et al, 2009) and COPD (Cosio et al, 2009).…”