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Comparative Study
. 2012;7(12):e51303.
doi: 10.1371/journal.pone.0051303. Epub 2012 Dec 7.

Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations

Yue Shen  1 , Yongzhi Guo, Chun Du, Malgorzata Wilczynska, Sten Hellström, Tor Ny
Affiliations
Comparative Study

Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations

Yue Shen et al. PLoS One. 2012.

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Characterization of the quality of TM healing.
(A) The scoring system used to evaluate the healing quality of TM perforations. (B) The quality of TM healing for tPA−/− mice (square) and WT mice (circle) at various time points following TM perforation. (C) The quality of TM healing for uPA−/− mice (trangle), tPA−/− mice (square) and WT (circle) mice at day 9 after perforation. (D) The quality of TM healing for uPA−/− mice, tPA−/− mice and WT mice at day 12 after perforation. (E) The quality of TM healing for uPA−/− mice, tPA−/− mice and WT mice at day 15 after perforation. NS indicates not significant. P<0.05 was considered to be significant.
Figure 2
Figure 2. Immunohistochemistry for keratin in open TMs of WT (A), tPA−/− (B) and uPA−/− (C) mice at day 9 after perforation.
Arrows indicate the keratin spurs. Scale bar, 200 µm. EEC, external ear canal; MEC, middle ear cavity; TM, tympanic membrane.
Figure 3
Figure 3. Immunohistochemistry for keratin in the TMs of WT (A), tPA−/− (B) and uPA−/− (C) mice at day 15 after perforation.
Scale bar, 200 µm. EEC, external ear canal; MEC, middle ear cavity; TM, tympanic membrane.
Figure 4
Figure 4. Immunohistochemistry for fibrin in open TMs in WT (A), tPA−/− (B), uPA−/− (C) mice and the only closed TM in uPA−/− (D) mice at day 9 after perforation.
Arrows indicate fibrin deposition. Scale bar, 200 µm. EEC, external ear canal; MEC, middle ear cavity; TM, tympanic membrane.
Figure 5
Figure 5. The number of total leukocytes and neutrophils in the lavage at 6 hours of thioglycollate-induced peritonitis.
The results are expressed as mean ± SD. Data was analyzed by 1-way ANOVA. NS indicates not significant.
Figure 6
Figure 6. Immunohistochemistry for neutrophils in the open TMs in WT (A), tPA−/− (B), uPA−/− (C) mice and the only closed TM in uPA−/− (D) mice at day 9 after perforation.
Arrows indicate neutrophil staining. Scale bar, 200 µm. EEC, external ear canal; MEC, middle ear cavity; TM, tympanic membrane.
See this image and copyright information in PMC

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