The role of cysteinyl leukotrienes in asthma: From the molecule to the bedside

Inhibition of Eosinophil Survival by a Selective Inhibitor of Phosphodiesterase 4 via the Induction of Apoptosis

“…15) The increased concentration of intracellular cAMP is known to suppress the functions of inflammatory cells. 14,16) With regard to eosinophils of which the PDE isoenzyme is exclusively type 4,17) selective inhibitors of PDE 4 and theophylline, a nonselective PDE inhibitor, have been shown to inhibit chemotaxis, adhesion, degranulation, and the release of active oxygen by an increase in the cAMP content. 14,16,18) Furthermore, PDE 4 inhibitors and theophylline, as well dibutyryl cAMP (d-cAMP), a cAMP analogue, have been also demonstrated to reduce eosinophil survival prolonged by GM-CSF or IL-5.…”

“…These mediators contribute to the formation of the pathological features of asthmatic airways such as bronchoconstriction, mucus hypersecretion, microvascular leakage, submucosal edema, and epithelial shedding, which lead to the clinical features of asthma, hyperresponsiveness, and airway narrowing. [1][2][3][4][5] Eosinophils cultured in the absence of hematopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-5 undergo apoptosis, which is physiologic cell death characterized by morphologic changes such as membrane blebbing and nuclear condensation, and by the degradation of DNA into oligonucleosomesized fragments showing a "ladder" pattern on agarose gel. [6][7][8] Apoptotic eosinophils have been shown to be removed from the tissue without releasing inflammatory mediators after ingestion by macrophages, 8) which is believed to be one of the important mechanisms in the resolution of inflammation.…”