Abstract
Acute respiratory distress syndrome and pulmonary fibrosis are progressive inflammatory lung diseases with high mortality rates. The disintegrin and metalloproteinase (ADAM) 8, expressed by leukocytes, endothelial cells and epithelial cells is upregulated in lungs during malignant and inflammatory processes. ADAM8 mediates the release of soluble factors by proteolytic cleavage as well as adhesive cell interactions and migratory processes. Here we analysed the involvement of ADAM8 in the development of lung fibrosis (bleomycin, 7 and 21 days) and endotoxin (LPS)-induced lung inflammation (4, 24, 48, 72 h) by comparing Adam8deficient and littermate control mice. Bronchoalveolar lavage (BAL) and blood were investigated by flow cytometry and ELISA. Lung tissue was subjected to mRNA expression analysis, edema and hydroxyproline determination, and histology. Underlying mechanisms were investigated in vitro using shRNA-mediated knockdown of ADAM8 in endothelial, epithelial, and leukocytic cells. Adam8-deficient mice were protected against leukocyte recruitment at all time points after LPS challenge compared to littermate mice, but did not show protection against edema formation or cytokine secretion. Moreover, Adam8-deficiency protected against development of severe fibrosis as indicated by reduced leukocyte recruitment and collagen deposition. In vitro, leukocytic ADAM8 was involved in leukocyte migration, adhesion and integrin-regulation. For transcellular migration, ADAM8 was also essential on endothelial but not on epithelial cells. Our results show that ADAM8 can be detrimental in inflammatory lung diseases and that this may be in part due to its involvement in leukocyte recruitment into the alveolar space.
- Copyright ©ERS 2015