EFFECT OF PHOSPHODIESTERASE 4 (PDE4) INHIBITORS ON EOTAXIN EXPRESSION IN HUMAN BRONCHIAL EPITHELIAL CELLS

PDE4 inhibitors increase cyclic adenosine monophosphate (cAMP) level in cells and inhibit various stages of the inflammatory process. cAMP is a classical second messenger synthesized from adenosine triphosphate (ATP) with the participation of a group of enzymes named adenylyl cyclases (1). It's involved in the regulation of levels of numerous hormones, cytokines and cell-mediated response to signals from neurotransmitters (2). cAMP is the main indicator for protein kinase A (PKA) cAMP begins the cascade of reactions leading to changes in the cell function by modulating the activity of PKA (3). cAMP is decomposed to 5'nucleotidemonophosphoran by a specific phosphodiesterase (PDEs). The various isoforms of PDE4 are present in all mobile immune and structural cells of the respiratory tract (4-7). The clinical application of PDE4 inhibitors are limited by side effects of gastrointestinal nature (nausea, vomiting, diarrhea). Several multicenter clinical trials have been conducted on the treatment of non-infected airway inflammatory diseases using PDE4 inhibitors showing highly inconsistent results (8-11). Recently it has been shown that roflumilast can decrease the exacerbations of chronic obstructive pulmonary disease (COPD). Orally given roflumilast used alone improves FEV1 (forced expiratory volume in one second) by 48 mL (12), but it gives better results in combination with salmeterol 49 ml, and tiotropium 80 mL (13). Eotaxins (eotaxin-1/CCL11, eotaxin-2/CCL24, eotaxin3/CCL26) are the strongest chemotactic agents for eosinophils. They are small (74-93 aminoacids) cysteine-cysteine (CC) chemokines. Many lung structural cells such as epithelial cells, airway smooth muscle cells, vascular endothelial cells and fibroblasts produce eotaxins (14-18). Eotaxins are also synthesized by various mobile cells isolated by bronchial alveolar lavage (BAL) from the bronchoalveolar space: macrophages, monocytes, basophils, eosinophils and lymphocytes (19-22). All three eotaxins act through their specific CCR3 receptor present on eosinophils, macrophages, T lymphocytes, basophils and lung epithelial cells (23). The key players in eotaxin expression are: Th2 cytokines: interleukin-4 (IL-4) and interleukin-13 (IL-13) and tumor necrosis factor-α (TNF-α). Many authors suggest that eotaxins differ from each other in their biological role. They are secreted in the subsequent stages of the allergic reaction. Eotaxin-1 is expressed constitutively in both healthy and allergic patients. It is produced in early stages of the allergic response (24). Eotaxin-2 and eotaxin-3 seem to be responsible for the long lasting eosinophilia after late asthmatic response (LAR) (25). They are produced only after allergen stimulation. Berkman et al. showed that only expression of eotaxin-3 24 hours after allergen challenge distinguishes asthmatics from healthy subjects. They reported up to 100-fold increase in eotaxin-3 mRNA in the lung biopsy from patients with asthma (26). JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2011, 62, 3, 303-311 www.jpp.krakow.pl