Interactions of mechano-transduction and inflammatory pathways in asthmatic airway remodelling: in silico, in vivo and in vitro models.

哮喘气道重塑中机械传导和炎症途径的相互作用：计算机、体内和体外模型。

• 批准号: MR/M004643/1
• 负责人: Bindi Brook
• 金额: $ 81.08万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM004643%2F1
• 关键词: Interactions; mechano; transduction; inflammatory; pathways

Asthma is a chronic disease that affects the airways that carry air in and out of the lungs. It affects ~300m people worldwide, and in the UK costs the NHS £2.3billion a year with 80% of this expenditure spent on the 20% of patients with the most severe and poorly controlled asthma.During an asthma attack, triggered by irritants such as dust or smoke, the muscle cells that line the walls of the airways, contract so that the airway becomes narrower. This is called bronchoconstriction. The lining of the airways also becomes inflamed and sticky mucus or phlegm is produced. All these reactions cause the airways to become narrower and irritated, leading to the symptoms of asthma such as coughing and wheezing. Over time, repeated episodes of asthma attacks can cause the number of muscle cells and other cells in the airway wall to increase resulting in the airway wall getting thicker (called remodelling) thereby exacerbating asthma symptoms and causing a decline in lung function. Doctors are currently unable to prevent airway remodelling or reverse it once it has occurred. Although symptoms can be managed with regular medication, serious complications can still arise requiring hospitalisation. For a very long time inflammation was thought to be the main cause of remodelling. However, medication called corticosteroids, that keeps inflammation levels down, in many cases appear to have little effect in preventing remodelling. More recently, we and others have found that, instead, bronchoconstriction itself may cause remodelling. Given that bronchoconstriction and inflammation occur together in asthma, we suggest a new theory: while remodelling might be initiated by inflammation, the contraction of the airway during bronchoconstriction, generates forces that trigger cells to produce chemicals that cause the airway wall to become even thicker. The increased numbers of cells respond even more strongly to inflammation so that there is a worsening cycle. Our aim is to investigate the combined effect of both inflammation and bronchoconstriction (which occur over minutes to hours) on remodelling which occurs over longer periods of time (days to weeks). The problem is very complex because there are both mechanical and biochemical processes involved that probably feedback on each other, as well as many cell types contained in the airway wall that also interact. Much of the research so far has been carried out on these individual aspects but it is incredibly difficult to work out what the combined effect of these interactions are, just by looking at the individual measurements. This work will develop a new model that represents both the biochemical and mechanical processes involved, and their complex interactions. This will allow us to run computational simulations for many random asthma episodes to predict whether or not remodelling occurs. To develop this model we will combine cutting-edge physics, mathematics and biological information from experiments on both human and animal tissue, bridging the gaps between the different levels (cells to tissues). This work will require both theoretical and experimental scientists to work as a team to ensure that the experiments that are done are designed in such a way that the theoretical models can be developed with exactly the right kind of data. Once the models are developed, they will need testing to ensure that what the model predicts matches what happens in real airways. So other data from specially designed experiments will also used for model testing. This work will thus help us to understand how the processes involved in remodelling interact with each other, and so to understand what might happen if we could disrupt one of the processes. Ultimately, computational tools developed in this way will help scientists really understand the underlying biology and to find new, more effective, therapies to either stop or reverse airway remodelling, preventing further decline in lung functio

哮喘是一种慢性疾病，它会影响将空气送入和送出肺部的气道。它影响着全球约3亿人，在英国，NHS每年花费23亿英镑，其中80%的支出用于20%的最严重和控制不佳的哮喘患者。在哮喘发作期间，由灰尘或烟雾等刺激物引发，气道壁的肌肉细胞收缩，使气道变得更窄。这就是所谓的支气管收缩。呼吸道内壁也会发炎，产生粘性粘液或痰。所有这些反应导致气道变窄和刺激，导致哮喘的症状，如咳嗽和喘息。随着时间的推移，哮喘发作的反复发作会导致气道壁中的肌肉细胞和其他细胞的数量增加，导致气道壁变厚（称为重塑），从而加剧哮喘症状并导致肺功能下降。医生目前无法阻止气道重塑或逆转它一旦发生。虽然症状可以通过常规药物治疗，但仍可能出现严重并发症，需要住院治疗。长期以来，炎症被认为是重塑的主要原因。然而，一种叫做皮质类固醇的药物，可以降低炎症水平，在许多情况下，似乎对预防重塑没有什么作用。最近，我们和其他人发现，支气管收缩本身可能导致重塑。鉴于支气管收缩和炎症在哮喘中同时发生，我们提出了一个新的理论：虽然重塑可能是由炎症引发的，但支气管收缩期间气道的收缩产生了触发细胞产生化学物质的力量，导致气道壁变得更厚。细胞数量的增加对炎症的反应更加强烈，因此有一个恶化的周期。我们的目的是研究炎症和支气管收缩（发生在几分钟到几小时内）对重塑的综合影响，重塑发生在更长的时间内（几天到几周）。这个问题是非常复杂的，因为有机械和生化过程参与，可能相互反馈，以及许多细胞类型包含在气道壁，也相互作用。到目前为止，大部分研究都是在这些单独的方面进行的，但是仅仅通过观察单独的测量结果，很难确定这些相互作用的综合效果是什么。这项工作将开发一个新的模型，代表所涉及的生物化学和机械过程，以及它们之间复杂的相互作用。这将使我们能够对许多随机哮喘发作进行计算模拟，以预测是否发生重塑。为了开发这个模型，我们将结合联合收割机尖端的物理学，数学和生物学信息，从人类和动物组织的实验，弥合不同层次（细胞到组织）之间的差距。这项工作将需要理论和实验科学家作为一个团队工作，以确保所做的实验是以这样一种方式设计的，即理论模型可以用正确的数据来开发。一旦模型被开发出来，他们将需要测试，以确保模型预测的与真实的气道中发生的情况相匹配。因此，从专门设计的实验中获得的其他数据也将用于模型测试。因此，这项工作将帮助我们了解重塑过程中涉及的过程如何相互作用，从而了解如果我们破坏其中一个过程会发生什么。最终，以这种方式开发的计算工具将帮助科学家真正了解潜在的生物学，并找到新的，更有效的治疗方法来阻止或逆转气道重塑，防止肺功能进一步下降。

项目成果

Biomechanical Model Of Inflammation-Induced Airway Smooth Muscle Mass Accumulation And Extracellular Matrix Deposition In An Ovalbumin Murine Model Of Asthma

卵白蛋白小鼠哮喘模型中炎症诱导的气道平滑肌质量积累和细胞外基质沉积的生物力学模型

• 发表时间: 2016
• 期刊: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
• 影响因子: 24.7
• 作者: Hill M. R.

Airway and Parenchymal Strains during Bronchoconstriction in the Precision Cut Lung Slice.

• DOI: 10.3389/fphys.2016.00309
• 发表时间: 2016
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Hiorns JE;Bidan CM;Jensen OE;Gosens R;Kistemaker LE;Fredberg JJ;Butler JP;Krishnan R;Brook BS
• 通讯作者: Brook BS

In vitro, in silico and in vivo study challenges the impact of bronchial thermoplasty on acute airway smooth muscle mass loss.

• DOI: 10.1183/13993003.01680-2017
• 发表时间: 2018-05
• 期刊: The European respiratory journal
• 作者: Chernyavsky IL;Russell RJ;Saunders RM;Morris GE;Berair R;Singapuri A;Chachi L;Mansur AH;Howarth PH;Dennison P;Chaudhuri R;Bicknell S;Rose FRAJ;Siddiqui S;Brook BS;Brightling CE
• 通讯作者: Brightling CE

The Impact Of Bronchial Thermoplasty On Airway Epithelial And Smooth Muscle Cells: An In Vitro And In Silico Study

支气管热成形术对气道上皮和平滑肌细胞的影响：体外和计算机研究

• 发表时间: 2016
• 期刊: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
• 影响因子: 24.7
• 作者: Brook B. S.

Corrigendum: Airway and Parenchymal Strains during Bronchoconstriction in the Precision Cut Lung Slice

勘误表：精密切割肺切片中支气管收缩期间的气道和实质应变

• DOI: 10.3389/fphys.2017.00117
• 发表时间: 2017
• 期刊: Frontiers in Physiology
• 影响因子: 4
• 作者: Hiorns J