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(Chest. 2001;120:S34.)
© 2001 American College of Chest Physicians

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 and Robert M. Senior, MD

* 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

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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