title: Plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  Plg(-/-) 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.
  
  
  RESULTS
  Daily 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.
  
  
  CONCLUSIONS
  Our data suggests that plg is a promising drug candidate for the treatment of chronic TM perforations in humans.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Guo
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wilczynska
authors.forename: Jinan
authors.initials: J
authors.lastname: Li
authors.forename: Sten
authors.initials: S
authors.lastname: Hellström
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden. tor.ny@medchem.umu.se.
authors.forename: Tor
authors.initials: T
authors.lastname: Ny
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007633:Keratins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010958:Plasminogen / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D018058:Tympanic Membrane Perforation / Q000188:drug therapy* / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects
chemical_list: D007633:Keratins; D010958:Plasminogen