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Effects of mechanical forces on lung injury and repair

机械力对肺损伤和修复的影响

基本信息

批准号：
7851200
负责人：
BELA SUKI
金额：
$ 49.49万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7851200
关键词：
Affect Airway Resistance Alveolar Alveolar wall Alveolus Biochemical Biological Assay Breathing Cause of Death Cell Culture Techniques Cell physiology Cells Cellular Mechanotransduction Chronic Chronic Obstructive Airway Disease Collagen Collagen Type I Connective Tissue Cells Data Deterioration Development Digestion Disease Disease Progression Elastases Elasticity Elastin Enzyme Activation Enzymes Epithelial Epithelial Cells Event Extracellular Matrix Failure Fibroblasts Fibrosis Future Gelatinase A Heterogeneity Histologic Human Immunohistochemistry In Vitro Inflammation Injury Interstitial Collagenase Lead Light Literature Lung Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Mechanical ventilation Mechanics Modeling Mus Nature Organ Pharmaceutical Preparations Physiological Play Property Publishing Pulmonary Emphysema Rattus Reporting Research Respiratory physiology Risk Rodent Model Role Rupture Signal Transduction Slide Spatial Distribution Staging Stimulus Stress Stretching Structure Structure of parenchyma of lung System Testing Tissues Transgenic Mice Type II Epithelial Receptor Cell Up-Regulation Weight-Bearing state Work base cigarette smoking collagenase cytokine disability enzyme activity experience in vivo indexing inhibitor/antagonist injury and repair lung injury mouse model network models overexpression pressure prevent protective effect research study surfactant

项目摘要

DESCRIPTION (provided by applicant): The lung is constantly under a pre-existing tensile stress or prestress generated by transpulmonary pressure which changes cyclically with breathing. This prestress is transmitted through the alveolar walls to the extracellular matrix (ECM) in the form of mechanical force. Our previous studies have shown that such mechanical forces in the emphysematous lung are able to rupture the collagen. Since the normal lung does not fail mechanically due to the protection of collagen, the failure of emphysematous tissue suggests that the collagen is remodeled so that it is prone to failure. Once the collagen fails, the alveolar wall can also rupture. The failure of alveoli will expose nearby regions to higher stresses and more alveoli would be at risk of failure, a sequence of events consistent with the progressive nature of emphysema. It has also been reported that in human late stage emphysema, there is a strong collagenase activity. This results in remodeling of collagen that eventually leads to collagen failure followed by airspace enlargement. Thus, our central hypothesis is that: The functional deterioration of the lung during the progression of emphysema is primarily determined by how mechanical forces modulate the remodeling and subsequent failure of collagen. We will investigate how mechanical forces modulate the ability of fibroblasts to secrete collagens (types I and III) and the ability of both fibroblasts and type II alveolar epithelial (type II) cells to secrete collagen remodeling enzymes such as the matrix metalloproteinases, MMP-1 and MMP-2. We will evaluate whether mechanical forces can accelerate enzyme activity during the degradation of collagens and the results will be correlated with alveolar structure and organ level function. We will utilize cells and tissues from two rodent models of emphysema: elastase-treatment, a standard model not directly related to collagen, and MMP-1 transgenic mice which develop emphysema without the involvement of elastin or inflammation. Our specific aims are to: 1) Determine the extent to which mechanical forces modulate the ability of fibroblasts and type II cells to express and secrete collagens and MMPs in tissue strips and cell culture. 2) Evaluate the effects of mechanical forces on the progression of injury by determining the dynamic interaction between enzyme activity and mechanical forces. 3) Determine the relationship among organ level function, cellular events and mechanical forces in the normal and emphysematous mouse lungs. This aim will confirm the physiological relevance of the in vitro studies in Aims 1 and 2. Should these experiments support our hypothesis, the consequences are important with a possible paradigm shift in the understanding and treatment of emphysema. First, if mechanotransduction plays an important role in emphysema, then any future attempt to prevent the development, or stop the progression of emphysema will have to incorporate the influence of mechanical forces at the cellular level. Second, drugs could not possibly stop the progression of emphysema, unless they also provide some form of protection of collagen from mechanical failure. PROJECT NARRATIVE: By 2020, chronic obstructive pulmonary disease will become the third most common cause of death and the fifth most common cause of disability in the world. Currently, it is not known how this disease develops or why it progresses. The research proposed here involves investigating how cells and connective tissue stretch in the lung during breathing and may open a new direction in understanding the disease with high potential to develop new treatments.

描述(申请人提供)：肺一直处于预先存在的张应力或预应力下，由经肺压力产生，该压力随呼吸循环变化。这种预应力以机械力的形式通过肺泡壁传递到细胞外基质(ECM)。我们之前的研究表明，肺气肿肺中的这种机械力能够破坏胶原。由于正常肺不会因为胶原蛋白的保护而机械性衰竭，所以肺气肿组织的衰竭表明胶原蛋白被重塑，因此容易发生衰竭。一旦胶原蛋白失效，肺泡壁也可能破裂。肺泡的衰竭将使附近区域暴露在更高的压力下，更多的肺泡将面临衰竭的风险，这一系列事件与肺气肿的进展性质一致。也有报道称，在人类晚期肺气肿中，存在较强的胶原酶活性。这会导致胶原蛋白的重塑，最终导致胶原蛋白的丧失，继而导致间隙扩大。因此，我们的中心假设是：肺气肿进展过程中肺功能的恶化主要是由机械力如何调节胶原的重塑和随后的衰竭决定的。我们将研究机械力如何调节成纤维细胞分泌胶原蛋白(I型和III型)的能力，以及成纤维细胞和II型肺泡上皮(II型)细胞分泌胶原重塑酶的能力，如基质金属蛋白酶、基质金属蛋白酶-1和基质金属蛋白酶-2。我们将评估机械力是否可以加速胶原蛋白降解过程中的酶活性，结果将与肺泡结构和器官水平功能相关。我们将利用两种肺气肿啮齿动物模型的细胞和组织：弹性蛋白酶治疗，一种与胶原没有直接关系的标准模型，以及没有弹性蛋白或炎症参与的发生肺气肿的基质金属蛋白酶-1转基因小鼠。我们的具体目标是：1)确定机械力在多大程度上调节成纤维细胞和II型细胞在组织条和细胞培养中表达和分泌胶原蛋白和MMPs的能力。2)通过确定酶活性和机械力之间的动态相互作用来评价机械力对损伤进展的影响。3)确定正常小鼠和肺气肿小鼠肺组织器官水平功能、细胞事件和机械力之间的关系。这一目标将证实AIMS 1和AIMS 2中体外研究的生理学相关性。如果这些实验支持我们的假设，其结果将是重要的，可能会改变对肺气肿的理解和治疗。首先，如果机械转导在肺气肿中起重要作用，那么未来任何阻止肺气肿发展或进展的尝试都必须纳入细胞水平的机械力的影响。其次，药物不可能阻止肺气肿的发展，除非它们还能提供某种形式的胶原蛋白保护，使其免受机械故障的影响。项目简介：到2020年，慢性阻塞性肺病将成为世界上第三大常见死亡原因和第五大最常见的残疾原因。目前，还不知道这种疾病是如何发展的，也不知道为什么会发展。这里提出的研究涉及研究细胞和结缔组织在呼吸过程中如何在肺内伸展，并可能为理解这种疾病开辟一个新的方向，具有开发新治疗方法的巨大潜力。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional and morphological assessment of early impairment of airway function in a rat model of emphysema.

肺气肿大鼠模型气道功能早期损伤的功能和形态学评估。

DOI：
10.1152/japplphysiol.00587.2011
发表时间：
2012
期刊：
Journal of applied physiology (Bethesda, Md. : 1985)
影响因子：
0
作者：
Tolnai,J;Szabari,MV;Albu,G;Maar,BA;Parameswaran,H;Bartolak-Suki,E;Suki,B;Hantos,Z
通讯作者：
Hantos,Z

Acute mechanical forces cause deterioration in lung structure and function in elastase-induced emphysema.

急性机械力导致弹性蛋白酶诱导的肺气肿中肺结构和功能恶化。

DOI：
10.1152/ajplung.00217.2012
发表时间：
2012
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
Szabari,MV;Parameswaran,H;Sato,S;Hantos,Z;Bartolák-Suki,E;Suki,B
通讯作者：
Suki,B

Lung structure and function in elastase-treated rats: A follow-up study.

弹性蛋白酶治疗大鼠的肺结构和功能：一项后续研究。

DOI：
10.1016/j.resp.2015.04.005
发表时间：
2015
期刊：
Respiratory physiology & neurobiology
影响因子：
2.3
作者：
Szabari,MV;Tolnai,J;Maár,BA;Parameswaran,H;Bartolák-Suki,E;Suki,B;Hantos,Z
通讯作者：
Hantos,Z

Mechanical failure, stress redistribution, elastase activity and binding site availability on elastin during the progression of emphysema.

肺气肿进展过程中的机械故障、应力重新分布、弹性蛋白酶活性和弹性蛋白上的结合位点可用性。

DOI：
10.1016/j.pupt.2011.04.027
发表时间：
2012
期刊：
Pulmonary pharmacology & therapeutics
影响因子：
3.2
作者：
Suki,Bela;Jesudason,Rajiv;Sato,Susumu;Parameswaran,Harikrishnan;Araujo,AscanioD;Majumdar,Arnab;Allen,PhilipG;Bartolak-Suki,Erzsebet
通讯作者：
Bartolak-Suki,Erzsebet

Assessing the functional mechanical properties of bioengineered organs with emphasis on the lung.

评估生物工程器官的功能机械特性，重点是肺。