Abstract
Surfactant proteins (SPs) are important lipoprotein complex components, expressed in alveolar epithelial cells type II (AEC-II), and playing an essential role in maintenance of alveolar integrity and host defence. Because expressions of SPs are regulated by cyclic adenosine monophosphate (cAMP), we hypothesized that phosphodiesterase (PDE) inhibitors, influence SP expression and release. Analysis of PDE activity of our AEC-II preparations revealed that PDE4 is the major cAMP hydrolysing PDE in human adult AEC-II. Thus, freshly isolated human AEC-II were stimulated with two different concentrations of the PDE4 inhibitor roflumilast-N-oxide (3 nM and 1 µM) to investigate the effect on SP expression. SP mRNA levels disclosed a large inter-individual variation. Therefore, the experiments were grouped by the basal SP expression in low and high expressing donors. AEC-II stimulated with Roflumilast-N-oxide showed a minor increase in SP-A1, SP-C and SP-D mRNA mainly in low expressing preparations. To overcome the effects of different basal levels of intracellular cAMP, cyclooxygenase was blocked by indomethacin and cAMP production was reconstituted by prostaglandin E2 (PGE2). Under these conditions SP-A1, SP-A2, SP-B and SP-D are increased by roflumilast-N-oxide in low expressing preparations. Roflumilast-N-oxide fosters the expression of SPs in human AEC-II via increase of intracellular cAMP levels potentially contributing to improved alveolar host defence and enhanced resolution of inflammation.
Highlights
Pulmonary surfactant is composed of a variety of different lipids and four surfactant associated proteins (SP-A, SP-B, SP-C and SPD) and is important for reduction of the surface tension at the airliquid interface of the lung and participates in immunomodulatory processes
First we addressed whether PDE4 is present in primary human AEC-II: To this end lysates of AEC-II from three different donors were analyzed for cyclic adenosine monophosphate (cAMP)- or cGMP-hydrolyzing phosphodiesterase activity in the presence or absence of selective inhibitors to dissect PDE 1–5
In freshly isolated cells SP-C and SP-D mRNA was found highest compared with SP-B, SP-A2 and SP-A1
Summary
Pulmonary surfactant is composed of a variety of different lipids and four surfactant associated proteins (SP-A, SP-B, SP-C and SPD) and is important for reduction of the surface tension at the airliquid interface of the lung and participates in immunomodulatory processes. Functional SP-A is important for secretion, synthesis and recycling of surfactant phospholipids and involved in innate immune reactions. SP-A and SP-D, bind to a variety of pathogens, acting as an opsonin to enhance phagocytosis and support pulmonary clearance. Besides these immune defence tasks, they disclose anti-inflammatory effects and play a role in the resolution of pulmonary inflammation [3]
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