Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin.
Increased expression of matrix metalloproteinases, particularly gelatinase B (MMP-9), has been described in the lungs in pulmonary fibrosis. Intratracheal bleomycin is often used experimentally to produce lesions resembling human fibrosing alveolitis. To assess the role of gelatinase B in bleomycin-induced fibrosing alveolitis, we instilled bleomycin intratracheally into gelatinase B-deficient mice and gelatinase B+/+ littermates. Twenty-one days after bleomycin the two groups of mice were indistinguishable in terms of pulmonary histology and total lung collagen and elastin. However, the lungs of gelatinase B-deficient mice showed minimal alveolar bronchiolization, whereas bronchiolization was prominent in the lungs of gelatinase B+/+ mice. Gelatinase B was identified immunohistochemically in terminal bronchiolar cells and bronchiolized cells 7 and 14 days after bleomycin in gelatinase B+/+ mice, and whole lung gelatinase B mRNA was increased at the same times. Many bronchiolized cells displayed Clara cell features by electron microscopy. Some bronchiolized cells stained with antibody to helix transcription factor 4, a factor associated with the ciliated cell phenotype. Thus, fibrosing alveolitis develops after intratracheal bleomycin irrespective of gelatinase B. However, gelatinase B is required for alveolar bronchiolization, perhaps by facilitating migration of Clara cells and other bronchiolar cells into the regions of alveolar injury.
Betsuyaku
T
T
Departments of Medicine, Pediatrics, and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Fukuda
Y
Y
Parks
W C
WC
Shipley
J M
JM
Senior
R M
RM
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count / Q000187:drug effects; D003895:Desmosine / Q000378:metabolism; D005838:Genotype; D006909:Hydroxyproline / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007322:Instillation, Drug; D007442:Intubation, Intratracheal; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D020783:Matrix Metalloproteinase 7 / Q000172:deficiency / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology
D003895:Desmosine; D001761:Bleomycin; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9; D006909:Hydroxyproline