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

Area of Science:

• Biochemistry
• Immunology
• Pathology

Background:

• Elevated levels of matrix metalloproteinase-8 (MMP-8) are observed in airway obstruction (OB).
• The precise biological function of MMP-8 in the pathogenesis of OB remains unclear.
• MMP-8, an interstitial collagenase, is highly expressed by polymorphonuclear leukocytes (PMNs), which are abundant in early OB.

Purpose of the Study:

• To investigate the role of MMP-8 in promoting PMN migration within the collagen-rich matrix during OB.
• To determine the impact of MMP-8 deficiency on PMN infiltration and airway obliteration in a mouse model of OB.

Main Methods:

• Utilized a mouse heterotopic airway transplant model to study OB.
• Compared PMN migration and infiltration in wild-type (WT) and MMP-8 knockout (MMP-8(-/-)) mice.
• Assessed PMN migration through 3D collagen gels in vitro and evaluated the effect of MMP inhibitor GM6001.

Main Results:

• MMP-8(-/-) mice exhibited significantly reduced PMN infiltration into the airway lumen at 2 and 14 days post-transplantation.
• A marked decrease in PMN traversal through the matrix to the lumen was observed in MMP-8(-/-) mice compared to WT mice at 14 days.
• In vitro studies showed significantly impaired migration of MMP-8(-/-) PMNs through collagen gels, suggesting pericollagenase activity of MMP-8 is crucial for migration.
• MMP-8(-/-) mice displayed reduced airway lumen obliteration and collagen deposition, indicating protection from OB.

Conclusions:

• MMP-8 plays a significant role in facilitating PMN migration through the extracellular matrix in the context of OB.
• The absence of MMP-8 confers protection against airway obstruction by limiting PMN infiltration and subsequent tissue remodeling.
• Targeting MMP-8 may represent a therapeutic strategy for managing airway obstruction.