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Effects of matrix metalloproteinase inhibitor on LPS-induced goblet cell metaplasia

¹Department of Internal Medicine, Korea University Ansan Hospital, Ansan, 425-707; ²Department of Internal Medicine, Korea University Guro Hospital, Seoul 152-703; ³Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University, Seoul 150-950; ⁵Department of Internal Medicine, Korea University Anam Hospital, Seoul 136-705; and ⁴Department of Clinical Pathology, College of Medicine, Kangwon National University, Chuncheon, Korea 200-947

Submitted 19 February 2003 ; accepted in final form 8 March 2004

Bacterial infections of the lung are known to induce inflammatory responses, which lead to mucus hypersecretion. Moreover, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and its activation. Furthermore, matrix metalloproteinases (MMPs), especially MMP-9, have been reported to promote the transmigration of activated neutrophils. In this study, we investigated the associations between lipopolysaccharide (LPS)-induced goblet cell (GC) metaplasia and EGFR expression and the effects of MMP inhibitor (MMPI). Various concentrations of LPS were instilled into the tracheas of pathogen-free Sprague-Dawley rats, and airways were examined at different times after LPS instillation. To examine the role of MMP-9, we treated rats 3 days before LPS instillation and daily thereafter with MMPI. Neutrophilic infiltration, Alcian blue/periodic acid-Schiff (AB/PAS) staining, and immunohistochemical staining for MUC5AC, EGFR, and MMP-9 were performed. The instillation of LPS increased AB/PAS and MUC5AC staining in time- and dose-dependent manners, and treatment with MMPI significantly prevented GC metaplasia. The instillation of LPS into the trachea also induced neutrophilic infiltration and EGFR and MMP-9 expression in the airway epithelium, and MMPI was found to significantly prevent neutrophil recruitment, GC metaplasia, and EGFR and MMP-9 expression. This study demonstrates that the MMP-9 and EGFR cascades are associated with LPS-induced mucus hypersecretion.

lipopolysaccharide; mucus hypersecretion

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