The hysteretic properties of lung parenchyma including tissue and surface film are the primary determinants of lung tissue resistance (Rt) which is a major component of total lung resistance at breathing frequencies. In most lung diseases, Rt and lung tissue elastance (Et) increase. These functional changes are invariably accompanied by thickening of alveolar walls. Recent studies suggest that increases in Rt and Et are due to thickening of alveolar walls. However, the actual mechanisms at the fiber, cellular or molecular level that produce Rt and Et are far from clear. These findings led them to formulate the following testable hypothesis: 1) The primary locus of parenchymal tissue resistance is the fiber network of the alveolar wall, and 2) changes in Rt and Et are directly related to alterations in fiber content and structure. They noted that tissue resistance is related to viscous energy dissipation which, in turn, must originate from internal motion of certain elements with respect to each other within the alveolar wall. What are those elements and what kind of motion takes place in the alveolar wall during breathing? How do alterations in the composition of the alveolar wall change this motion to increase viscous energy dissipation and stiffness? In this proposal, they intend to clarify the fundamental mechanisms that determine the elastic and hysteretic properties of the parenchyma and their role in the normal lung, in emphysema and fibrosis, two lung diseases that affect primarily the interstitium or the collagen-elastin fiber network. Their preliminary data provide direct experimental evidence that fibers carry out slow motion during stress relaxation implying that fibers are important contributors to Rt. Thus, they propose testing lung tissue properties at three different scales: 1) They will carry out whole lung experiments to identify organ level consequences of alterations in the composition of the alveolar wall such as digesting elastin fibers or producing pulmonary fibrosis; 2) To eliminate the influences of airways and surfactant, they will make macroscopic mechanical measurements on tissue strips while directly changing the composition of the extracellular matrix which will provide information on the contribution of collagen and elastin fiber network, and proteoglycan ground substance to Rt and Et; 3) To reveal the fundamental mechanism responsible for tissue hysteretic behavior, they will carry out stress relaxation measurements in the alveolar wall combined with immunofluorescent visualization of the dynamic events occurring at the level of a single collagen or elastin fiber. These mechanical measurements will be complemented with image analysis of the fluorescently labeled fiber network to quantify the alterations in the composition of the alveolar wall. The proposed research will greatly enhance their understanding of the origins of the macroscopic rheological behavior of lung parenchyma and create an opportunity to bridge the gap between the organ level function and the biophysical properties of the components of the extracellular matrix.
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