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1 Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
2 Laboratory of Experimental Pathology, National Institutue of Environmental Health Sciences, Research Triangle Park, NC, USA
3 Department of Medicine, Duke University Medical Center, Durham, NC, USA
4 Department of Cell and Analytical Biology, Bayer Biotechnology, Berkeley, CA, USA
5 Department of Medicine, Veterans Affairs Medical Center, University of Minnesota, Minneapolis, MN, USA
* To whom correspondence should be addressed. E-mail: voyno001{at}mc.duke.edu.
Goblet cell hyperplasia in the superficial airway epithelia is a signature pathologic 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 phosphate buffered 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 due to 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 bronchoalveolar lavage (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.
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