Gelatinase B Is Required for Alveolar Bronchiolization after Intratracheal Bleomycin

• Published in: The American journal of pathology Vol. 157; no. 2; pp. 525 - 535
• Main Authors: Betsuyaku, Tomoko, Fukuda, Yuh, Parks, William C., Shipley, J. Michael, Senior, Robert M.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.08.2000; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Biological and medical sciences; Bleomycin - pharmacology; Bronchi - drug effects; Bronchi - pathology; Bronchi - ultrastructure; Bronchoalveolar Lavage Fluid - cytology; Cell Count - drug effects; Desmosine - metabolism; Genotype; Hydroxyproline - drug effects; Hydroxyproline - metabolism; Immunohistochemistry; Instillation, Drug; Intubation, Intratracheal; Lung - enzymology; Lung - metabolism; Lung - pathology; Lymphocytes - cytology; Lymphocytes - drug effects; Macrophages - cytology; Macrophages - drug effects; Matrix Metalloproteinase 7 - deficiency; Matrix Metalloproteinase 7 - genetics; Matrix Metalloproteinase 9 - deficiency; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Mice; Mice, Inbred Strains; Mice, Knockout; Microscopy, Electron; Neutrophils - cytology; Neutrophils - drug effects; Pneumology; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - pathology; Pulmonary Alveoli - ultrastructure; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - enzymology; Pulmonary Fibrosis - pathology; Regular; Respiratory system : syndromes and miscellaneous diseases; Bronchiole; Immunohistochemistry; Pathogenesis; Lung; Reverse transcription; Metalloendopeptidases; Bleomycin; Glycopeptide; Lung disease; Respiratory disease; Enzyme; Rodentia; Gelatinase B; Polymerase chain reaction; Pathology; Peptidases; Vertebrata; Experimental disease; Mammalia; Transmission electron microscopy; Mouse; Pulmonary alveolus; Animal; Fibrosis; Hydrolases; Molecular biology; Intratracheal administration
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)64563-4

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.