Local Alpha1-Antitrypsin Accelerates the Healing of Tympanic Membrane Perforation in Mice

Background: Most tympanic membrane (TM) perforations heal spontaneously, but 10%–20% remain chronic and might lead to impaired hearing and recurrent middle ear infections. Alpha1-antitrypsin (AAT) is a circulating tissue-protective protein that is elevated under inflammatory conditions and is currently indicated for genetic AAT deficiency. Recently, AAT has been shown to promote tissue remodeling and inflammatory resolution. Objective: This study aimed to examine the effects of local clinical-grade AAT treatment on tissue repair in a mouse model of acute traumatic TM perforation. Methods: Wild-type mice underwent unilateral TM perforation and were either left untreated or treated locally with human AAT (9 × 10⁻³ mL at 20 mg/mL on days 0, 1, and 2; n = 15/group). The perforations were evaluated macroscopically on a serial basis. Mice were sacrificed on various days post-injury, and TMs were excised for gene analysis by RT-PCR. Results: There were no adverse reactions in hAAT-treated ears throughout the study period. Compared with untreated animals, TM closure occurred earlier in the treated group (days until full closure, median: 4 and 9, respectively). According to gene expression analysis, VEGF, TGFβ, and collagen-5A1 were induced earlier in AAT-treated mice (day 4–5 compared with day 9). Additionally, IL-10 expression levels were higher and IL-6 levels were lower in treated versus untreated mice. Conclusion: A local tissue environment rich in AAT promotes early tissue repair in a perforated TM model both macroscopically and molecularly. Studies are underway to examine TM functionality and recombinant AAT formulations for micro-dosing in the format of a single local application. Level of Evidence: NA Laryngoscope, 134:3802–3806, 2024.