MMP-8 promotes polymorphonuclear cell migration through collagen barriers in obliterative bronchiolitis

Abstract

MMP-8 promotes migration of polymorphonuclear cells through collagen-rich matrices and protection is seen in MMP-8−/− mice in a heterotopic airway transplant model of OB.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.