Abstract
BackgroundMost tympanic membrane (TM) perforations heal spontaneously, but approximately 10-20% remain open as chronic TM perforations. Chronic perforations can lead to an impaired hearing ability and recurrent middle ear infections. Traditionally, these perforations must be surgically closed, which is costly and time consuming. Therefore, there is a need for simpler therapeutic strategies. Previous studies by us have shown that plasminogen (plg) is a potent pro-inflammatory regulator that accelerates cutaneous wound healing in mice. We have also shown that the healing of TM perforations is completely arrested in plg-deficient (plg-/-) mice and that these mice develop chronic TM perforations. In the present study, we investigated the therapeutic potential of local plg injection in acute and chronic TM perforation mice models.MethodsPlg-/- mice and wild-type mice were subjected to standardized TM perforations followed by local injection of plg into the soft tissue surrounding the TM. TM perforations with chronic characteristics were induced by leaving TM perforations in plg-/- mice untreated for 9 days before treatment. The healing process was observed through otomicroscope and finally confirmed by immunostaining. The quality of TM healing was evaluated based on the morphology of the TM.ResultDaily local injections of plg into the soft tissue surrounding the TM restored the ability to heal TM perforations in plg-/- mice in a dose-dependent manner, and potentiated the healing rate and quality in wild-type mice. A single local injection of plg initiated the healing of the chronic-like TM perforations in these mice, resulting in a closed TM with a continuous but rather thick outer keratinocyte layer. However, three plg injections led to a completely healed TM with a thin keratinizing squamous epithelium covering a connective tissue layer.ConclusionOur data suggests that plg is a promising drug candidate for the treatment of chronic TM perforations in humans.
Highlights
Most tympanic membrane (TM) perforations heal spontaneously, but approximately 10-20% remain open as chronic TM perforations
We have shown that active plasmin is important for TM healing and that urokinase-type plasminogen activators (PAs) (uPA), but not type PA (tPA), plays a central role in the activation of plg to plasmin [13]
To further investigate the role of plg in the healing of TM perforations, we studied whether local plg injection could restore the healing of TM perforations in plg−/− mice and if so whether plg stimulated healing in a dose-dependent manner
Summary
Most tympanic membrane (TM) perforations heal spontaneously, but approximately 10-20% remain open as chronic TM perforations. Chronic perforations can lead to an impaired hearing ability and recurrent middle ear infections. These perforations must be surgically closed, which is costly and time consuming. Previous studies by us have shown that plasminogen (plg) is a potent pro-inflammatory regulator that accelerates cutaneous wound healing in mice. Chronic perforations can lead to impaired hearing and recurrent middle ear infections [5]. In plg−/− mice, cutaneous wounds do not heal and become chronic, partially due to a disturbed inflammatory phase. In these mice, wounds can heal completely only after plg supplementation. Plg administration enhances the healing of acute cutaneous wounds in wild-type (WT) mice and initiates and allows the complete healing of chronic diabetic wounds in diabetic mice [11]
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