Mice Deficient in Urokinase-Type Plasminogen Activator Have Delayed Healing of Tympanic Membrane Perforations

Yue Shen,Malgorzata Wilczynska,Yongzhi Guo,Sten Hellström,Chun Du,Tor Ny

doi:10.1371/journal.pone.0051303

Yue Shen, Malgorzata Wilczynska + Show 4 more

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https://doi.org/10.1371/journal.pone.0051303

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Journal: PLoS ONE	Publication Date: Dec 7, 2012
Citations: 20	License type: CC BY 4.0

Affiliation: Karolinska University Hospital, Umeå University

Abstract

Mice deficient in plasminogen, the precursor of plasmin, show completely arrested healing of tympanic membrane (TM) perforations, indicating that plasmin plays an essential role in TM healing. The activation of plasminogen to plasmin is performed by two plasminogen activators (PAs), urokinase-type PA (uPA) and tissue-type PA (tPA). To elucidate the functional roles of PAs in the healing of TM perforations, we investigated the phenotypes of single gene-deficient mice lacking uPA (uPA−/−) or tPA (tPA−/−) after TM perforation. Delayed healing of TM perforations was observed in uPA−/− mice but not tPA−/− mice. The migration of keratinocytes was clearly delayed and seemed to be misoriented in uPA−/− mice. Furthermore, fibrin deposition and the inflammatory response were persistent in these mice. Our findings demonstrate that uPA plays a role in the healing of TM perforations. The observed phenotypes in uPA−/− mice are most likely due to the reduced generation of plasmin.

Highlights

The tympanic membrane (TM) or so-called eardrum is a thin, cone-shaped membrane that separates the middle ear cavity (MEC) from the external ear canal (EEC)
The delayed healing of uPA2/2 mice continued at day 12 after perforation, at which all 10 TM perforations were closed in WT mice and tPA2/2 mice, but only 8 out of 10 TM perforations were closed in uPA2/2 mice
In the present study we show that the healing of TM perforations is significantly delayed in uPA2/2 mice but normal in tPA2/2 mice

Summary

Introduction

The tympanic membrane (TM) or so-called eardrum is a thin, cone-shaped membrane that separates the middle ear cavity (MEC) from the external ear canal (EEC). Its main function is to receive sound vibrations from the outer air and transmit them to the auditory ossicles. It plays a protective role in preventing irritable and infectious agents from being transported from the EAC into the MEC [1]. The TM has three layers, including an outer keratinizing squamous epithelium facing toward the EEC, a middle connective tissue layer (the lamina propria), and an inner single-layered epithelium, the latter of which is continuous with the mucosal lining of the MEC. Chronic perforations usually lead to conductive hearing impairment, mild tinnitus and repeated infections of the middle ear [1]

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