Published online before print October 2, 2009
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,1
* Department of Medicine, Division of Respiratory Diseases, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA;
University Duisburg-Essen, Essen, Germany; and
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
2. Correspondence: Children’s Hospital Boston, Respiratory Disease, 300 Longwood Ave., Hunnewell 2, Boston, MA 02115; E-mail: meera.subramaniam{at}childrens.harvard.edu
ABSTRACT
Increased levels of MMP-8 (neutrophil collagenase) have been reported in OB, but the biological role of MMP-8 in OB is not known. MMP-8 is an interstitial collagenase highly expressed by polymorphonuclear leukocytes, which are prominent in early OB. Here, we show that MMP-8 promotes migration of PMNs through the collagen-rich matrix in a mouse heterotopic airway transplant model of OB. Overall, MMP-8–/– mice had significantly fewer PMNs in the airway lumen 2 and 14 days post-transplantation, and the percentage of PMNs traversing the matrix to the lumen was decreased markedly in the MMP-8–/– compared with WT mice at 14 days. There were significantly more PMNs outside of the lumen in the ECM in the MMP-8–/– mice compared with WT mice. In vitro, significantly fewer MMP-8–/– PMNs migrated through 3D cross-linked collagen gels than WT PMNs. MMP inhibitor GM6001 was also able to impede migration of WT PMNs through collagen gels. The decreased migration was likely a result of pericollagenase activity of MMP-8, as WT PMNs expressing MMP-8 were not able to migrate effectively through collagen that was resistant to the collagenase. Protection from OB was seen in the MMP-8–/– mice, as the airway lumen had significantly less obliteration and collagen deposition, suggesting that MMP-8 plays an important role in the pathogenesis of OB.
Key Words: cell trafficking • inflammation • neutrophils
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