Gelatinase B is required for alveolar bronchiolization after intratrachealbleomycin

Increased expression of matrix metalloproteinases, particularly gelatinase B (MMP-9), has been described in the lungs In pulmonary fibrosis. Intratrac heal bleomycin is often used experimentally to produce lesions resembling h uman fibrosing alveolitis. To assess the role of gelatinase B in bleomycin- induced fibrosing alveolitis, we instilled bleomycin intratracheally into g elatinase 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, w hereas 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 microsc opy. Some bronchiolized cells stained with antibody to helix transcription factor 4, a factor associated with the ciliated cell phenotype. Thus, fibro sing alveolitis develops after intratracheal bleomycin irrespective of gela tinase B. However, gelatinase B is required for alveolar bronchiolization, perhaps by facilitating migration of Clara cells and other bronchiolar cell s into the regions of alveolar injury.