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Gelatinase B Is Required for Alveolar Bronchiolization After Intratracheal Bleomycin Instillation*

Tomoko Betsuyaku, MD, PhD; Yuh Fukuda, MD; William C. Parks, PhD; J. Michael Shipley, PhD; Robert M. Senior, MD
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*From the Washington University School of Medicine (Drs. Betsuyaku, Parks, Shipley, and Senior), St. Louis, MO; and Nippon Medical School (Dr. Fukuda), Tokyo, Japan.

Correspondence to: Tomoko Betsuyoku, MD, PhD, Pulmonary and Critical Care Medicine, The Jewish Hospital of St. Louis, Washington University School of Medicine, 216 South Kingshighway Blvd, St. Louis, MO 63110



Chest. 2001;120(1_suppl):S34. doi:10.1378/chest.120.1_suppl.S34
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Increased expression of matrix metalloproteinases, particularly gelatinase B (matrix metalloproteinase-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 instillation, the two groups of mice were indistinguishable in terms of pulmonary fibrosis histologically and total lung collagen and elastin. However, the lungs of gelatinase B-deficient mice showed minimal alveolar bronchiolization, while bronchiolization was prominent in the lungs of gelatinase B +/+ mice. Gelatinase B was identified immunohistochemically in terminal bronchiolar cells and bronchiolized cells 7 days and 14 days after bleomycin instillation in gelatinase B +/+ mice, and whole-lung gelatinase B messenger RNA was increased at the same time. Many bronchiolized cells displayed Clara cell features by electron microscopy and by immunostaining with antibody to Clara cell-specific protein. Some bronchiolized cells stained with antibody to forkhead/winged helix transcription factor 4, a factor associated with the ciliated cell phenotype, but none stained for an alveolar type-II cell marker, surfactant protein C. Thus, fibrosing alveolitis develops after intratracheal bleomycin instillation irrespective of gelatinase B. However, gelatinase B is required for alveolar bronchiolization, perhaps by facilitating migration of Clara cells and other bronchiolar cells into regions of alveolar injury.

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