Abstract
Human neutrophil elastase (HNE) has been shown to be involved on death of different cell types, including epithelial lung cells, which is related to several pulmonary diseases. Since HNE activity may be influenced by extracellular matrix (ECM) molecules such as glycosaminoglycans (GAGs), and fibroblasts are the most common ECM-producing cells of lung connective tissue, the aim of this work was to verify if HNE can induce fibroblast death and to study the enzyme modulation by GAGs. HNE-like activity was mimicked by using human neutrophils conditioned medium (NCM). Heparan sulfate and chondroitin 6-sulfate reduce the enzyme activity and modify its secondary structure. NCM reduced cell viability, and this effect was higher in the presence of those GAGs. NCM also increased DNA fragmentation, suggesting the occurrence of apoptosis, but without influence of GAGs. These results can contribute to the understanding of HNE modulation in physio- and pathological processes where this enzyme is involved.
Highlights
Human neutrophil elastase (HNE) is a serine protease able to cleave fibrous elastin and other extracellular matrix (ECM) molecules, which plays essential structural function in lungs, arteries, skin, and ligaments [1, 2]
The cell death promoted by HNE fits in the concept of anoıkis, which was defined as apoptosis resulting from the disruption of cell-matrix interactions, mainly induced by proteases, and whose integrity is essential for survival of adherent cells [10]
In addition to ECM components secreted by fibroblasts, we aimed to study the effect of exogenous GAGs on HNE activity using a simplified cell culture system
Summary
Human neutrophil elastase (HNE) is a serine protease able to cleave fibrous elastin and other extracellular matrix (ECM) molecules, which plays essential structural function in lungs, arteries, skin, and ligaments [1, 2] This enzyme is primarily located in the acidophilic granules of polymorphonuclear leucocytes, and its release is involved in tissue destruction and inflammation, despite the presence of potent endogenous inhibitors [3]. It has been implicated in several pulmonary diseases including emphysema, cystic fibrosis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and chronic obstructive disease [3,4,5,6]. The cell death promoted by HNE fits in the concept of anoıkis (from the Greek, homeless), which was defined as apoptosis resulting from the disruption of cell-matrix interactions, mainly induced by proteases, and whose integrity is essential for survival of adherent cells [10]
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