Abstract
RationaleAugmented smooth muscle contractility of the airways is one of the causes of airway hyperresponsiveness in asthmatics. However, the mechanism of the altered properties of airway smooth muscle cells is not well understood.ObjectivesTo identify differentially expressed genes (DEGs) related to the bronchial smooth muscle (BSM) hyper-contractility in a murine asthma model.MethodsThe ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Transcriptomic profiles were generated by microarray analysis of BSM tissues from the OA-challenged and control animals, and KEGG (Kyoto Encyclopedia of Genes and Genomes) Pathway Analysis was applied.Measurements and main resultsTension study showed a BSM hyperresponsiveness to acetylcholine (ACh) in the OA-challenged mice. A total of 770 genes were differentially expressed between the OA-challenged and control animals. Pathway analysis showed a significant change in arachidonic acid (AA) metabolism pathway in BSM tissues of the OA-challenged mice. Validation of DEGs by quantitative RT-PCR showed a significant increase in PLA2 group 4c (Pla2g4c)/COX-2 (Ptgs2)/PGD2 synthase 2 (Hpgds) axis. PGD2 level in bronchoalveolar fluids of the OA-challenged mice was significantly increased. A 24-h incubation of BSM tissues with PGD2 caused a hyperresponsiveness to ACh in naive control mice.ConclusionsAA metabolism is shifted towards PGD2 production in BSM tissues of asthma. Increased PGD2 level in the airways might be a cause of the BSM hyperresponsiveness in asthma.
Highlights
Enhanced airway responsiveness to non-specific stimuli, called airway hyperresponsiveness (AHR), is a characteristic feature of bronchial asthma
Validation of differentially expressed gene (DEG) by quantitative RT-PCR showed a significant increase in phospholipase A2 (PLA2) group 4c (Pla2g4c)/COX-2 (Ptgs2)/prostaglandin D2 (PGD2) synthase 2 (Hpgds) axis
arachidonic acid (AA) metabolism is shifted towards PGD2 production in bronchial smooth muscle (BSM) tissues of asthma
Summary
Enhanced airway responsiveness to non-specific stimuli, called airway hyperresponsiveness (AHR), is a characteristic feature of bronchial asthma. Rapid relief from airway limitation in asthma attack by short-acting beta2-stimulant inhalation may suggest an involvement of augmented airway smooth muscle contraction in the airway obstruction. It is important for development of asthma therapy to understand the disease-related changes in the contractile signaling of airway smooth muscle cells. One possible explanation of the hyper-contraction of smooth muscle may be an up-regulation of these proteins associated with contraction In addition to their contractile function, smooth muscle cells of the airways have ability to generate/secrete various biologically active substances including interleukins, chemokines, and prostanoids [8,9,10,11,12,13].
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