Elastin Degradation by Human Alveolar Macrophages: A Prominent Role of Metalloproteinase Activity

Abstract

Macrophages are thought to play an important role in the turnover of extracellular matrix, but the capacity of human macrophages to degrade elastin, and the elastolytic mechanisms of these cells, have been controversial. Particular difficulty has been encountered in efforts to establish whether human macrophages secrete a metalloelastase that is analogous to the enzyme secreted by rodent macrophages. We studied elastin degradation by human alveolar macrophages cultured directly in contact with radiolabeled elastin using media containing 10% fetal bovine serum, and for comparison performed parallel studies of P388D1 murine macrophagelike cells that are known to secrete metalloelastase. With both cell types, we observed elastin degradation and the following: (1) direct contact between the cells and elastin substrate was required for elastin degradation; (2) elastin degradation was inhibited by the tissue inhibitor of metalloproteinases, but minimally or not at all by inhibitors of cysteine proteinases (E-64, CBZ-phe-phe-CHN2, CBZ-phe-ala-CHN2, and cystatin C), or by the serine proteinase inhibitor eglin-c; (3) elastin degradation increased sharply after the cells were in contact with elastin for 24 h, and required new protein synthesis as indicated by sensitivity to cycloheximide; (4) inclusion of dexamethasone (10(-6) to 10(-8) M) in the cultures led to decreased elastin degradation. Also, with both cell types, elastin degradation occurred despite the finding that cell-conditioned media did not contain elastase activity and could inhibit P388D1-derived metalloproteinase elastase. These results indicate a prominent role for metalloproteinase activity in elastin degradation by both human and murine macrophages and support the concept that events at the cell-substrate interface are critically important to macrophage-mediated elastin degradation.

Asthma: a disease remodeling the airways

“…Moreover, mechanical stretch during breathing further amplified by edema and distension may lead to the fragmentation of fibers in asthmatie airways. The reasons for these abnormalities in elastic fibers are not known but it has been found that alveolar maerophages synthesize elastase and other metalloproteinases eapable of digestitig elastic fibers (31,32).…”

Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases

“…The cellular sources of these enzymes include neutrophils, macrophages, and bronchial epithelial cells (23,39,41,44). In COPD there is an increase in the number of neutrophils in sputum and upper airway secretions compared with normal subjects.…”

Altered allergen-induced eosinophil trafficking and physiological dysfunction in airways with preexisting virus-induced injury

“…One proposed mechanism for reduced elastic recoil is disruption of elastin in lung parenchyma (3,28), and elevated levels of neutrophil elastase have been detected in asthmatics who have increased neutrophils in their sputum (52). Alveolar macrophages also produce elastases (41), and in a rat model of tobacco smoke-induced emphysema the pathogenetic elastolysis is dependent on macrophages (33,34). Desmin is another cytoskeletal protein that contributes to lung elastic recoil (42), although it is not known whether this protein is altered by inflammatory processes.…”