Effects of mechanical forces on lung injury and repair

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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.