Am. J. Respir. Crit. Care Med., Volume 159, Number 4, April 1999, 1138-1146

Human Neutrophil Elastase Augments Fibroblast-Mediated Contraction of Released Collagen Gels

C. MAGNUS SKÖLD, XIANGDE LIU, TAKESHI UMINO, YUNKUI ZHU, YOSHIHIRO OHKUNI, DEBRA J. ROMBERGER, JOHN R. SPURZEM, ARTHUR J. HEIRES, and STEPHEN I. RENNARD

Pulmonary and Critical Care Medicine Section, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Division of Respiratory Medicine, Department of Medicine, Karolinska Hospital, Stockholm, Sweden; and Division of Internal Medicine, Kameda Medical Center, Kamogawa, Japan

In the present study, we tested the hypothesis that neutrophil elastase (NE) might mediate remodeling of extracellular matrix by affecting fibroblast-mediated contraction of three-dimensional collagen gels. Human lung fibroblasts were cast into type I collagen gels containing NE. After gelation, the gels were released into medium and the area was measured by image analyzer. NE augmented gel contraction (p < 0.001). This was not due to cell proliferation or to degradation to soluble collagen fragments because the amounts of DNA and hydroxyproline were not altered. ₁-Protease inhibitor and the synthetic inhibitor of NE, L-680,833, when added in sufficient amount to inhibit free elastase activity, blocked the contraction induced by NE. Furthermore, neutrophil granulocytes (PMN) in coculture, as well as conditioned media from PMN, resulted in an increased contractility (p < 0.001 for both). Bronchoalveolar lavage fluid (BALF) from patients with increased PMN in their lower respiratory tract and free elastase activity had augmentive activity for gel contraction which could be partially blocked by the inhibitors. We conclude that NE augments fibroblast-mediated contraction of collagen gels. The findings support the notion that products secreted by PMN in inflammatory disorders may lead to rearrangement of extracellular matrix and could subsequently lead to tissue dysfunction.

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