MMP-8 promotes polymorphonuclear cell migration through collagen barriers in obliterative bronchiolitis.
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.
Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston,Massachusetts, USA.
Umakanth A
UA
Khatwa
Bjoern E
BE
Kleibrink
Steven D
SD
Shapiro
Meera
M
Subramaniam
D000818:Animals; D001773:Blood Cells / Q000502:physiology; D001854:Bone Marrow Cells / Q000502:physiology; D001989:Bronchiolitis Obliterans / Q000201:enzymology / Q000276:immunology*; D002478:Cells, Cultured / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003094:Collagen; D005109:Extracellular Matrix; D005260:Female; D005782:Gels; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D014132:Trachea / Q000637:transplantation; D016042:Transplantation, Heterotopic
D005782:Gels; D003094:Collagen; D020784:Matrix Metalloproteinase 8