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

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.

Conserved Amblyomma americanum tick Serpin19, an inhibitor of blood clotting factors Xa and XIa, trypsin and plasmin, has anti-haemostatic functions

“…Similarly, plasmin degrades and inactivates blood-clotting factors V, VIII, IX and X in vitro, suggesting plasmin has anti-coagulant functions (Hoover-Plow, 2010) and is thus beneficial to tick feeding. On the other hand, plasmin has been reported to participate in several processes such as pro-inflammatory cytokine release (Syrovets et al, 2001), inducing monocyte and dendritic cell chemotaxis (Li et al, 2010), modifying IL-8 and producing a potent attractant of neutrophils (Mortier et al, 2011), tissue remodeling and wound healing (Shen et al, 2012), all of which can negatively impact tick-feeding success. From this perspective, AAS19 inhibition of plasmin seems to contribute to feeding on blood.…”

Plasmin Induces In Vivo Monocyte Recruitment through Protease-Activated Receptor-1–, MEK/ERK-, and CCR2-Mediated Signaling

“…Although we did not investigate the in vivo migration of fibroblasts in the present study, our in vitro results provide evidence that Pla could participate in such an in vivo process. Accordingly, a recent work from Shen et al (39) has shown that Plg is a key proinflammatory regulator that accelerates the healing of acute diabetic wounds. Indeed, the importance of Plg to wound healing was previously shown in Plg 2/2 mice (6).…”

Searching for a rat model of chronic tympanic membrane perforation: Healing delayed by mitomycin C/dexamethasone but not paper implantation or iterative myringotomy

“…To assess TMP patency, all 40 rats underwent otoscopic observation under general anesthesia postoperatively on day 0, 1, 3,5,7,9,11,14,17,21,28,35,42,49 and 56 using an otomicroscope and digital video-otoscope. The TMPs were assessed for closure, infection, opacification, thickening and granulation tissue.…”

“…In order to fully examine the efficacy of a novel graft, a chronic TMP animal model that mimics the clinical condition of chronic TMPs in patients is paramount. In the current literature, various animal models have been reported, including rat [2], mouse [3], chinchilla [4], guinea pig [5] and dog [6]. However, these models are mostly of acute TMPs and not useful for assessment of materials for myringoplasty or tympanoplasty on chronic TMPs.…”