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Possible Impedance of Luminal Reepithelialization by Tracheal Cartilage Metalloproteinases
Lynn Sigurdson, PhD;
Tuhina Sen, BSc;
Leon Hall III, BSc;
Ari Rubenfeld, MD;
Robert Hard, PhD;
Joseph Gardella, PhD;
Frank Bright, PhD;
Wesley L. Hicks, Jr, MD
Arch Otolaryngol Head Neck Surg. 2003;129:197-200.
Background Rapid reepithelialization of respiratory epithelium after injury to the large conducting airway (eg, trachea and bronchus) is poor. Our laboratory has developed an in vitro model of the trachea that allows us to examine reepithelialization in a complex culture system. We previously described how the presence of cartilage inhibited respiratory epithelial cell (REC) migration/proliferation. In the present study, we examined the effect of cartilage-conditioned medium (CCM) on REC proliferation. We hypothesized that a potential cause of delayed reepithelialization of the large conducting airway after injury could be excessive or aberrant secretion of matrix metalloproteinases (MMPs) by cartilage.
Design We assessed cartilage-derived MMP production and effects on REC proliferation by adding CCM to primary cultures of porcine RECs on type I collagen and determining the cell number and viability. Cartilage-conditioned medium–derived MMP activity was determined by means of gelatin zymography in pooled samples from different times during in vitro cartilage culture.
Results We detected MMP-2 and a small amount of MMP-9 in CCM. Enzyme activity was abolished by EDTA, confirming MMP identity. Cartilage-conditioned medium inhibited REC attachment and proliferation. Addition of the MMP inhibitor GM6001 to cartilage cultures yielded CCM that did not inhibit REC growth, indicating a role for cartilage-derived MMPs in modulating REC proliferation.
Conclusion Cartilage production and activity of MMP after injury to the large conducting airway may be a factor in the failure of luminal reepithelialization, resulting in aberrant repair.
From the Department of Head and Neck Surgery, Roswell Park Cancer Institute, Buffalo, NY (Drs Sigurdson, Rubenfeld, and Hicks, Ms Sen, and Mr Hall); and the Department of Anatomy and Cell Biology (Dr Hard), School of Medicine (Dr Rubenfeld), and the Department of Chemistry (Drs Gardella and Bright), State University of New York at Buffalo. Ms Sen was a participant in the Roswell Park Cancer Institute Summer Student Research Program. Dr Rubenfeld is now affiliated with the Department of Otolaryngology, Georgetown University, Washington, DC. Dr Hicks owns patent 6 312 952 for the composite coculture system; observations based in part on the model system generated the hypothesis for this study.
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