Neutrophil elastase induces mucus cell metaplasia in mouse lung.

Abstract

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 microg) 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.

• Authors: Judith A Voynow, Bernard M Fischer, David E Malarkey, Lauranell H Burch, Teresa Wong, Malinda Longphre, Samuel B Ho, W Michael Foster
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 287 Issue 6 Pg. L1293-302 (Dec 2004) ISSN: 1040-0605 [Print] United States
• PMID: 15273079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Actins
• MUC5AC protein, human
• Muc5ac protein, mouse
• Mucin 5AC
• Mucins
• Leukocyte Elastase

Topics

• Actins (genetics)
• Animals
• Gene Expression Regulation (drug effects)
• Inflammation (chemically induced)
• Leukocyte Elastase (toxicity)
• Lung (drug effects, pathology)
• Male
• Metaplasia
• Mice
• Mice, Inbred BALB C
• Mucin 5AC
• Mucins (genetics)
• Respiratory Mucosa (drug effects, physiology)