Role of Matrix Metalloprotease‐3 (MMP‐3) in Remodeling Following Bleomycin‐Induced Injury in Rats

Abstract

Tissue-repair after injury involves extracellular matrix remodeling in which damaged connective tissue and newly synthesized matrix components are further degraded and cleared. In the bleomycin model of pulmonary fibrosis there is a progressive increase in connective tissue production, leading to impaired lung function. Matrix metalloproteases (MMP) are thought to be important in removing damaged connective tissue elements so that normal structure and function can be reestablished. By day-21 after bleomycin challenge MMP-3 deficient (MMP-3-/-) mice demonstrated significantly greater airway thickening then C57bl/6 (MMP-3+/+) mice. By day-45 airway thickening had returned to pre-challenge levels in the MMP-3+/+ mice but was still significantly higher in the MMP-3−/ − mice, relative to day-21 levels. Hydroxyproline content mirrored the increase in airway thickness. At day-3 immunoreactive laminin in the BAL fluid was higher in MMP-3+/+ versus MMP-3−/ − mice. However, by day-21 laminin levels in the BAL fluid of MMP-3+/+ mice were seen to decline and by day-45 there was little detectable laminin in the BAL fluid. In contrast, immunoreactive laminin levels in the MMP-3−/ − animals continued to increase through day-45. Therefore, the higher level of laminin in the BAL fluid of MMP-3−/ − mice (in addition to elevated hydroxyproline and airway thickening, relative to MMP-3+/+ mice) suggest the continued accumulation of components in the alveolar basement membrane in the absence of functional MMP-3. Work supported by NIH RO1 HL07097