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Neutrophil elastase induces mucus cell metaplasia in mouse lung

Departments of ¹Pediatrics and ³Medicine, Duke University Medical Center, Durham 27710; ²Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; ⁴Department of Cell and Analytical Biology, Bayer Biotechnology, Berkeley, California 94710; and ⁵Department of Medicine, Veterans Affairs Medical Center, University of Minnesota, Minneapolis, Minnesota, 55417

Submitted 14 April 2004 ; accepted in final form 20 July 2004

Goblet cell hyperplasia in the superficial airway epithelia is a signature pathological feature of chronic bronchitis and cystic fibrosis. In these chronic inflammatory airway diseases, neutrophil elastase (NE) is found in high concentrations in the epithelial lining fluid. NE has been reported to trigger mucin secretion and increase mucin gene expression in vitro. We hypothesized that chronic NE exposure to murine airways in vivo would induce goblet cell metaplasia. Human NE (50 µg) or PBS saline was aspirated intratracheally by male Balb/c (6 wk of age) mice on days 1, 4, and 7. On days 8, 11, and 14, lung tissues for histology and bronchoalveolar lavage (BAL) samples for cell counts and cytokine levels were obtained. NE induced Muc5ac mRNA and protein expression and goblet cell metaplasia on days 8, 11, and 14. These cellular changes were the result of proteolytic activity, since the addition of an elastase inhibitor, methoxysuccinyl Ala-Ala-Pro-Val chloromethylketone (AAPV-CMK), blocked NE-induced Muc5ac expression and goblet cell metaplasia. NE significantly increased keratinocyte-derived chemokine and IL-5 in BAL and increased lung tissue inflammation and BAL leukocyte counts. The addition of AAPV-CMK reduced these measures of inflammation to control levels. These experiments suggest that NE proteolytic activity initiates an inflammatory process leading to goblet cell metaplasia.

neutrophil elastase; goblet cell metaplasia; Muc5ac

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