title: Mechanical failure, stress redistribution, elastase activity and binding site availability on elastin during the progression of emphysema.
abstract: Emphysema is a disease of the lung parenchyma with progressive alveolar tissue destruction that leads to peripheral airspace enlargement. In this review, we discuss how mechanical forces can contribute to disease progression at various length scales. Airspace enlargement requires mechanical failure of alveolar walls. Because the lung tissue is under a pre-existing tensile stress, called prestress, the failure of a single wall results in a redistribution of the local prestress. During this process, the prestress increases on neighboring alveolar walls which in turn increases the probability that these walls also undergo mechanical failure. There are several mechanisms that can contribute to this increased probability: exceeding the failure threshold of the ECM, triggering local mechanotransduction to release enzymes, altering enzymatic reactions on ECM molecules. Next, we specifically discuss recent findings that stretching of elastin induces an increase in the binding off rate of elastase to elastin as well as unfolds hidden binding sites along the fiber. We argue that these events can initiate a positive feedback loop which generates slow avalanches of breakdown that eventually give rise to the relentless progression of emphysema. We propose that combining modeling at various length scales with corresponding biological assays, imaging and mechanics data will provide new insight into the progressive nature of emphysema. Such approaches will have the potential to contribute to resolving many of the outstanding issues which in turn may lead to the amelioration or perhaps the treatment of emphysema in the future.
authors.affiliation: Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215, USA.
authors.forename: Béla
authors.initials: B
authors.lastname: Suki
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jesudason
authors.forename: Susumu
authors.initials: S
authors.lastname: Sato
authors.forename: Harikrishnan
authors.initials: H
authors.lastname: Parameswaran
authors.forename: Ascanio D
authors.initials: AD
authors.lastname: Araujo
authors.forename: Arnab
authors.initials: A
authors.lastname: Majumdar
authors.forename: Philip G
authors.initials: PG
authors.lastname: Allen
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Bartolák-Suki
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology*; D001696:Biomechanical Phenomena; D003094:Collagen; D018450:Disease Progression; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000201:enzymology; D040542:Mechanotransduction, Cellular; D010196:Pancreatic Elastase / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000201:enzymology*; D013552:Swine / Q000378:metabolism
chemical_list: D003094:Collagen; D004549:Elastin; D010196:Pancreatic Elastase