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.
Departments of Medicine, Pediatrics, and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
T
T
Betsuyaku
Y
Y
Fukuda
W C
WC
Parks
J M
JM
Shipley
R M
RM
Senior
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