Extra-cellular matrix inducible collagenase activity in asthma: a potential drug target against airway remodelling.

在英国，哮喘影响了500多万人，每年有7万人住院，1.3万人死亡。尽管接受了治疗，许多患者仍会出现明显的症状。慢性哮喘患者可发生称为气道重塑的结构性气道改变，从而增加其症状的频率和严重程度。目前的哮喘治疗方法没有很好地计算气道重构，迫切需要新的方法来治疗气道重构。细胞外基质蛋白包围所有细胞提供支持，但也影响细胞功能。在重塑过程中，过量的细胞外基质蛋白胶原- 1和腱蛋白- c沉积在气道中。我们已经证明，这些蛋白质可以导致一种叫做MMPs的酶的表达增加。我们认为，气道平滑肌细胞响应胶原蛋白1和腱蛋白c的信号而产生的MMP-1导致气道收缩加剧和哮喘症状。在这项研究中，我们将研究胶原蛋白1和腱蛋白c如何作用于平滑肌细胞以产生更多的MMP-1。接下来，我们将在哮喘实验模型中确定这些细胞外基质蛋白和MMP-1如何导致气道收缩增加。然后，我们将在人类哮喘中证实我们的发现：我们将使用来自没有肺部疾病的人的样本，并将它们与哮喘患者进行比较，哮喘患者对标准哮喘触发器的反应是轻微和强烈的气道狭窄。通过研究MMP-1、I型胶原和tenascin-C在这些患者肺部的表达，以及他们是否有更多的气道狭窄和更严重的哮喘症状。我们希望这项研究能为治疗气道重塑、减轻哮喘症状和改善哮喘患者的生活质量提供潜在的新靶点。

Asthma effects more than 5 million people in the UK and is responsible for 70,000 hospital admissions and 13,000 deaths each year. Despite treatment many patients still experience significant symptoms. Patients with chronic asthma can develop structural airway changes called airway remodelling which increase the frequency and severity of their symptoms. Airway remodelling is not well counted by current asthma therapies and new approaches to treat remodelling are urgently required. Extracellular matrix proteins surround all cells providing support but also effecting cell function. In remodelling, excessive amounts of the extracellular matrix proteins collagen 1 and tenascin-C are deposited in the airways. We have shown that these proteins can cause increased expression of enzymes called MMPs. We think that MMP-1, made by smooth muscle cells in the airways in response to signals from collagen 1 and tenascin-C leads to increased airway contraction and asthma symptoms. In this study, we will examine how collagen 1 and tenascin-C act on smooth muscle cells to produce more MMP-1. Next, we will determine how these extracellular matrix proteins and MMP-1 lead to increased airway contraction in an experimental model of asthma. We will then confirm our findings in human asthma: we will use samples from people with no lung disease and compare them with patients with asthma, with mild and stronger airway narrowing in response to a standard asthma trigger. By studying the expression of MMP-1, collagen I and tenascin-C in the lungs of these patients and if they have more airway narrowing and worse asthma symptoms. We hope this study will provide potential new targets for drugs to treat airway remodelling, reduce asthma symptoms and improve quality of life for those with asthma.