Effect of the Beige Mutation on Bleomycin-induced Pulmonary Fibrosis in Mice1,2

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Abstract
A single endotracheal administration of bleomycin causes pulmonary fibrosis in several animal species. In view of the functional deficits in neutrophil function as a result of the beige mouse (bg/bg) mutation, its effect on bleomycin-induced pulmonary fibrosis was examined to evaluate the role of the neutrophil in such a response. Neutrophils from beige mice showed a selective defect in the ability to degranulate in response to cytochalasin B and formyl-methionylleucyl-phenylalanine, without impairing their ability to produce superoxide anion and H2O2 in response to the same stimuli as well as phorbol myristate acetate. Despite this functional deficit, beige mice responded more intensely to bleomycin than did their heterozygote controls at both 2 wk and 1 month after drug instillation, as assessed by both lung collagen synthesis and deposition. This suggests that the inability to mobilize hydrolytic enzymes has no effect on the ability to mount a fibrogenic response, and it would even be detrimental by enhancing such a response caused by decreased connective tissue catabolism as a consequence of the inability to release the granule enzymes to the extracellular space.