Overexpression of MMP9 in macrophages attenuates pulmonary fibrosis induced by bleomycin.
Pulmonary fibrosis is a common response to a variety of lung injuries, characterized by fibroblast/myofibroblast expansion and abnormal accumulation of extracellular matrix. An increased expression of matrix metalloprotease 9 (MMP9) in human and experimental lung fibrosis has been documented, but its role in the fibrotic response is unclear. We studied the effect of MMP9 overexpression in bleomycin-driven lung fibrosis using transgenic mice expressing human MMP9 in alveolar macrophages (hMMP9-TG). At 8 weeks post-bleomycin, the extent of fibrotic lesions and OH-proline content were significantly decreased in the TG mice compared to the WT mice. The decreased fibrosis in hMMP9-TG mice was preceded by a significant reduction of neutrophils and lymphocytes in bronchoalveolar lavage (BAL) at 1 and 4 weeks post-bleomycin, respectively, as well as by significantly less TIMP-1 than the WT mice. From a variety of cytokines/chemokines investigated, we found that BAL levels of insulin-like growth factor binding protein-3 (IGFBP3) as well as the immunoreactive protein in the lungs were significantly lower in hMMP9-TG mice compared with WT mice despite similar levels of gene expression. Using IGFBP-3 substrate zymography we found that BAL from TG mice at 1 week after bleomycin cleaved IGFBP-3. Further, we demonstrated that MMP9 degraded IGFBP-3 into lower molecular mass fragments. These findings suggest that increased activity of MMP9 secreted by alveolar macrophages in the lung microenvironment may have an antifibrotic effect and provide a potential mechanism involving IGFBP3 degradation.
Cabrera
Sandra
S
Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico.
Gaxiola
Miguel
M
Arreola
José Luis
JL
Ramírez
Remedios
R
Jara
Paul
P
D'Armiento
Jeanine
J
Richards
Thomas
T
Selman
Moisés
M
Pardo
Annie
A
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009504:Neutrophils / Q000166:cytology; D009195:Peroxidase / Q000032:analysis / Q000378:metabolism; D040081:Protein Array Analysis; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D016207:Cytokines; D018972:Insulin-Like Growth Factor Binding Protein 3; D001761:Bleomycin; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9; D006909:Hydroxyproline