Protease-activated receptors as potential drug targets in allergic airways disease

哮喘是一种肺部疾病，每年造成约700名澳大利亚人死亡，并在我们的社区造成广泛的发病率。对于过敏性哮喘患者来说，吸入过敏原（如室内灰尘中所含的过敏原）会引发免疫反应，导致气道壁肿胀、粘液分泌过多和支气管平滑肌收缩。这些影响导致气道变窄，使哮喘患者呼吸更加困难。我们的研究小组一直在研究一组新的蛋白质，称为蛋白酶激活受体（PAR），并在一个令人兴奋的发展中发现，刺激PAR的物质抑制小鼠的过敏性气道炎症，这是一种成熟的过敏性哮喘动物模型。这增加了PAR兴奋剂将来可能被开发为抗哮喘药物的可能性。然而，在我们对气道PAR的理解中存在许多巨大的空白，在考虑将其用作抗哮喘药物之前需要填补这些空白。因此，目前的研究将解决许多重要的问题：PAR兴奋剂是否总是改善过敏性炎症，或者是否有一些剂量或次数的给药会恶化过敏性炎症？一种称为PAR2的PAR的刺激物可以改善过敏性炎症，但是存在于气道中的其他三种PAR（PAR1，PAR3和PAR4）的刺激物呢？PAR如何改善过敏性炎症，以及涉及哪些物质和细胞？PAR兴奋剂是否在更复杂的过敏性炎症动物模型中也有效，例如涉及蛋白水解过敏原（例如来自屋尘螨的Der p1）、呼吸道病毒和更好地反映人类疾病过敏性哮喘的长时间过敏原暴露（慢性模型）的动物模型？这些问题的答案和一系列其他问题将显着提高我们的理解的潜在效用的PAR兴奋剂在治疗过敏性气道疾病。

Asthma is a lung disease that kills about 700 Australians each year and causes widespread morbidity in our community. For people with allergic asthma inhalation of allergens such as those contained in house dust triggers an immune response that causes swelling of the airway wall, overproduction of mucus and bronchial smooth muscle contraction. These effects lead to the narrowing of the airways that makes breathing more difficult in people with asthma. Our research groups have been investigating a novel group of proteins, called protease-activated receptors (PARs), and in an exciting development have found that substances that stimulate PARs inhibit allergic airways inflammation in mice, which is a well-established animal model of allergic asthma. This raises the possibility that PAR stimulants may in the future be developed as anti-asthma drugs. However, there are many large gaps in our understanding of airway PARs that need to be filled before their use as anti-asthma drugs can be contemplated. Thus, the current study will address many important questions: Do PAR stimulants always improve allergic inflammation, or are there some doses or times of dosing that worsen allergic inflammation? Stimulants of one PAR, called PAR2, improve allergic inflammation, but what about stimulants of the three other PARs (PAR1, PAR3 and PAR4) that exist in the airways? How do PARs improve allergic inflammation, and which substances and cells are involved? Are PAR stimulants also effective in more complex animal models of allergic inflammation, such as those involving proteolytic allergens (e.g. Der p1 from the house dust mite), respiratory tract viruses, and extended periods of allergen exposure (chronic models) that better reflect the human disease allergic asthma? The answers to these and a range of other questions will significantly improve our understanding of the potential utility of PAR stimulants in the treatment of allergic airways disease.