Augmented Pla2g4c/Ptgs2/Hpgds axis in bronchial smooth muscle tissues of experimental asthma

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.

Sustained exposure to prostaglandin D₂ augments the contraction induced by acetylcholine via a DP₁ receptor-mediated activation of p38 in bronchial smooth muscle of naive mice

“…Consistently with the previous report ( 8 ), the mRNA expressions for Pla2g4c , Ptgs2 and Hpgds were significantly increased in the bronchial smooth muscle (BSM) tissues ( Fig. 1 ), indicating that arachidonic acid metabolism is shifted towards prostaglandin D 2 (PGD 2 ) production in mice with allergic asthma.…”

“…In allergic asthma, an involvement of prostaglandin D 2 (PGD 2 ), one of the cyclooxygenase (COX) metabolites that released from mast cells in allergic reaction, has been suggested in its pathogenesis. In animal models of allergic asthma, the PGD 2 levels in bronchoalveolar lavage (BAL) fluids were increased ( 6 , 7 , 8 ). In people with asthma, an increase in PGD 2 in BAL fluids was observed after allergen challenge to the airways ( 9 , 10 ).…”

Therapeutic Potential of Hematopoietic Prostaglandin D2 Synthase in Allergic Inflammation

“…Smooth muscle cell hyper-contraction is a characteristic feature of asthmatic airways causing a limitation of gas exchange. In a mouse model of OVA-induced allergic pulmonary inflammation, the COX-2/hPGDS/PGD 2 cascade was suggested to be involved in the development of bronchial smooth muscle cell hyper-responsiveness [103]. Microarray, RT-qPCR and Western blot results of this study revealed an increased hPGDS expression in bronchial epithelial cells of allergen-challenged mice suggesting an autocrine pathway.…”

“…Severe asthma often involves airway remodelling including smooth muscle cell hyper-proliferation and activity. PGD 2 promotes smooth muscle cell proliferation via DP2/CRTH2 activation and contributes to a hyper-responsive phenotype seen in asthmatic patients [103,104]. In summary, therapeutically blocking hPGDS and PGD 2 biosynthesis could be beneficial to delay the onset of allergic asthma, reduce eosinophilic and Th2 type inflammation, alleviate symptoms including allergic rhinitis and cough as well as reduce airway remodelling.…”

“…Hematopoietic PGDS expression has been reported in many cell types involved in allergic inflammation. Elevated PGD 2 levels have been shown to induce DP2/CRTH2-mediated smooth muscle cell proliferation and hyperresponsiveness [103], macrophage activation [11], nasal blockage [10] as well as influx, activation and survival of eosinophils, ILC2s and Th2 cells. Inhibition of hPGDS-derived PGD 2 production would target all above-mentioned pathological phenomena.…”