Interplay of the extracellular matrix and immune cells in lung pathology: key role for chitinase-like proteins

背景哮喘是一种复杂的炎症性疾病，其研究主要集中在对呼吸道炎症的认识和治疗上。在一些哮喘患者中，抗炎药很好地控制了症状和病情恶化。然而，这些药物并不总是改善肺功能，对于严重的哮喘，一些患者在抗炎治疗后看不到任何改善。哮喘的呼吸道也会经历病理变化，从而导致气道重塑。重塑导致细胞外基质成分(如胶原蛋白)在肺结构内沉积和重组，使肺僵硬，最终降低肺的功能能力。目前的研究表明，重塑可能与炎症分开发生，这解释了为什么抗炎药并不总是改善哮喘患者的肺功能。我们已经证明，几丁质酶样蛋白(CLP)是哮喘患者肺部高度产生的分子，有助于重塑反应。CLPs浓度越高，哮喘和重塑越严重。在小鼠模型上，我们已经证明抑制CLP可以逆转哮喘的重塑。然而，我们仍然需要了解CLP的工作原理和首先发生重塑的原因，以便提出成功治疗哮喘和改善肺功能的新疗法。在这个项目中，我们将提出以下问题：1)CLP、炎性细胞和组织结构细胞如何相互通信以触发重塑？2)抑制CLP对细胞/分子产生什么作用，从而破坏基质和逆转重塑？3)当重塑发生时，它是否改变了肺部对过敏原等炎症挑战的反应方式？我们将如何回答这些问题？其中一些工作将使用小鼠模型，给小鼠注射人类经常遇到的过敏原(尘螨、真菌、花粉)的鸡尾酒。重要的是，这种小鼠模型具有人类严重哮喘的共同特征，可以用人类无法完成的方式来研究疾病途径。我们将测量暴露于空气变应原后肺基质的变化，重点放在最初重塑事件的位置以及炎症或组织细胞在这些区域周围聚集的位置。由于CLP有助于重塑的启动，我们将调查干扰CLP是否会改变对启动肺重塑至关重要的细胞的行为。接下来，我们将研究如何逆转重塑，从而改善肺功能，询问CLP如何分解基质。利用小鼠变应原模型，除了分离的小鼠和人肺细胞外，我们还将确定当CLP被抑制时，哪些降解基质的途径、细胞和分子会发生变化。这项研究将使我们能够确定未来的靶点，以制造可以逆转哮喘重塑的药物。最后，我们将调查哮喘期间肺重塑的后果。炎症细胞需要在进入肺之前穿过基质。如果基质发生变化，就像哮喘一样，它将改变细胞进入肺部的方式。利用小鼠模型，以及人类和小鼠细胞的培养，我们可以操纵细胞/基质来确定哮喘重塑如何影响肺部炎症，并最终确定肺对触发炎症反应的过敏原和分子的反应方式。总体而言，我们希望实现什么？我们将了解肺基质蛋白是如何随着哮喘诱因(如过敏原)的变化而发生变化的，以及这些基质变化是否决定了一个人的呼吸道炎症类型或发生的哮喘类型。关键是，我们将确定可以逆转重塑的方法，并且已经有了一个独特的线索来通过操纵CLP来调查这一点。

BackgroundAsthma is a complex inflammatory disease, and as such research has focussed on understanding and treating airway inflammation. In some asthma sufferers, anti- inflammatory agents work well to control symptoms and exacerbations. However, these drugs don't always improve lung function and in severe asthma, some patients fail to see any improvement after anti-inflammatory treatments. The asthmatic airway also undergoes pathological changes that result in airway remodelling. Remodelling results in the extracellular matrix components (e.g. collagens) being deposited and reorganised within the lung architecture making the lungs stiff and rigid, ultimately reducing the ability of the lungs to function. Current research suggests remodelling may occur separately from inflammation, explaining why anti-inflammatories don't always improve lung function in asthma. We have shown that chitinase-like proteins (CLPs), molecules that are highly produced in the lungs of people with asthma, contribute to remodelling responses. The higher the concentration of CLPs, the more severe the asthma and remodelling. Using mouse models, we have shown that inhibiting CLPs can reverse asthma remodelling. However, we still need to understand how CLPs work and what causes remodelling to occur in the first place, in order to come up with new therapies that will successfully treat asthma and improve lung function.Questions we will ask during this project:1) How do CLPs, inflammatory cells and tissue structural cells communicate with each other to trigger remodelling? 2) What does inhibiting CLPs do to cells/molecules to breakdown the matrix and reverse remodelling?3) When remodelling occurs, does it change the way the lungs can respond to inflammatory challenges like allergens?How will we answer these questions?Some of the work will use a mouse model that involves giving mice a cocktail of allergens (dust mites, fungi, pollen) frequently encountered by people. Importantly, this mouse model shares common features with severe asthma in people and can be used to study disease pathways in ways that cannot be done in people. We will measure how the lung matrix changes after exposure to aero-allergens, focusing on the location of initial remodelling events and the inflammatory or tissue cells accumulate around these areas. As CLPs contribute to the initiation of remodelling, we will investigate whether interfering with CLPs changes the behaviour of cells important for initiating lung remodelling.Next, we will investigate how to reverse remodelling and hence improve lung function, asking questions about how CLPs breakdown the matrix. Using the mouse allergen model, in addition to isolated mouse and human lung cells, we will determine what pathways, cells and molecules that degrade the matrix are changed when CLPs are inhibited. This research will allow us to identify future targets for making drugs that can reverse remodelling in asthma.Lastly, we will investigate the consequences of lung remodelling during asthma. Inflammatory cells need to navigate their way through the matrix before entering the lung. If the matrix changes, like it does in asthma, it will alter the way cells get into the lung. Using mouse models, and cultures of human and mouse cells, we can manipulate cells/matrix to determine how asthma remodelling influences lung inflammation and ultimately the way the lungs can respond to allergens and molecules that trigger inflammatory responses. What do we hope to achieve overall?We will gain an understanding of how lung matrix proteins change in response to asthma triggers, like allergens, and whether these matrix changes dictate the type of airway inflammation a person has or the type of asthma that develops. Critically, we will determine ways in which remodelling can be reversed, and already have a unique lead to investigate this through manipulation of CLPs.