How anti-inflammatory drugs differentially affect the bronchoprotective signalling of Protease-Activated Receptor-2

哮喘对澳大利亚社区的健康状况不佳和生活质量受损的负担有很大影响，与其他国家相比，澳大利亚的哮喘患病率最高。此外，有证据表明，哮喘的患病率在世纪后半叶有所增加。目前还没有治愈哮喘的方法，通过发现药物开发的新靶点来更好地治疗哮喘的需求从未如此迫切。PAR 2是一种位于呼吸道中许多细胞类型表面的受体，包括衬在气道导管上的上皮细胞。当PAR 2被刺激时，它会导致上皮细胞产生和释放大量的PGE 2（前列腺素E2）。然后，从上皮细胞释放的PGE 2与其他蛋白质结合，例如位于平滑肌细胞上的前列腺素EP 2受体。这导致气道平滑肌细胞放松。导致气道平滑肌细胞放松的药物-称为支气管扩张剂-使呼吸更容易，通常在哮喘发作期间用于缓解支气管收缩。PPP轴的激活似乎也抑制了气道壁肿胀（即具有抗炎作用）。因此，激活PPP轴的药物可能通过减少气道肿胀和产生平滑肌松弛而有益于哮喘的治疗。因此，我们正在研究最佳刺激PAR 2-PGE 2-前列腺素EP 2受体轴（PPP轴）的方法，作为开发哮喘新疗法的手段。

Asthma contributes significantly to the burden of ill health and impaired quality of life in Australian communities, and for many measures of asthma, Australia has amongst the highest prevalence when compared with other countries. Furthermore, there is evidence that the prevalence of asthma has increased during the latter part of the 20th century. There is currently no cure for asthma, and the need for better asthma therapies through the discovery of novel targets for drug development has never been more acute. PAR2 is a receptor that is located on the surface of many cell types in the respiratory tract, including the epithelial cells that line the airway tubes. When PAR2 is stimulated it causes the epithelial cells to produce and release large amounts of PGE2 (prostaglandin E2). PGE2 released from epithelial cells then binds to other proteins such as the prostanoid EP2 receptor located on smooth muscle cells. This causes the airway smooth muscle cells to relax. Drugs that cause airway smooth muscle cells to relax - called bronchodilators - make breathing easier, and are often used during an asthma attack to relieve bronchoconstriction. It also appears that activation of the PPP axis inhibits airway wall swelling (that is, has anti-inflammatory actions). Thus, drugs that activate the PPP axis may be beneficial in the treatment of asthma by reducing airway sweeling and producing smooth muscle relaxation. Thus, we we are investigating ways of optimally stimulating the PAR2-PGE2-prostanoid EP2 receptor axis (the PPP axis), as a means of develeping novel treatments for asthma.