### Alpha1-Antitrypsin Is Tissue-Protective  
Alpha1-antitrypsin (AAT) is a circulating tissue-protective glycoprotein that is elevated in response to the molecular signs of tissue damage. Its production is triggered by hypoxia and by inflammatory cytokines. At elevated levels, AAT diverts unwanted inflammation towards an inflammatory resolution, decreases the levels of destructive reactive oxygen species (ROS) and interferes with the apoptosis of several cell types, including neutrophils, which better facilitate a bacterial burden reduction. Together with these more enduring active neutrophils, AAT has been shown to acquire direct antibacterial attributes in the presence of elevated tissue-derived nitric oxide [10]. Unlike in the case of resting cells, in the context of an inflammatory trigger AAT enhances the production of resolution-phase mediators, including IL-10, IL-1 receptor antagonist (IL-1 Ra), TGF\(\beta\) and VEGF, all the while inhibiting the production of IL-1b, IL-6 and TNF\(\alpha\) alongside interfering with local cytokine-activating enzymes [11]. This is achieved, in part, by modifying the nuclear translocation profile of selected NF-kB family members in a way that, in response to an inflammatory surge, inflammation-driven resolution genes are preferentially induced. In cell culture experiments, both AAT and dexamethasone were shown to achieve anti-inflammatory outcomes, yet only the AAT treatment increased the production of the anti-inflammatory cytokine, IL-1 Ra (Table 1) [12]. Importantly, upon a co-treatment with both AAT and dexamethasone, the production of IL-1 Ra was diminished by dexamethasone, presumably as the result of an inability of NF-kB family members to reach the gene promoter of IL-1 Ra.  
\begin{table}
\begin{tabular}{c c c} \hline \hline  & **Glucocorticoids** & **\(\alpha\)I-Antitrypsin** \\ \hline \multirow{4}{*}{**Mechanism of action**} & Comprehensive inhibition of inflammatory-associated molecules & Immune modulation diverting excessive inflammation towards an anti-inflammatory resolution and tissue repair \\  & & \\ \cline{1-1}  & & \\ \cline{1-1}  & & \\ \cline{1-1}  & & \\ \cline{1-1}  & & \\ \hline \multirow{4}{*}{**Clinical indication**} & Ear surgery (e.g., cochlear implants, stapes and inner ear fistulas), inner ear disease (e.g., vestibular neuronitis and sudden sensorineural hearing loss) & Genetic AAT deficiency \\ \cline{1-1}  & & \\ \hline \multirow{2}{*}{**Dosage**} & The protocols vary & Lifelong weekly 60–80 mg/kg slow drip i.v. infusions \\ \cline{1-1}  & & \\ \hline \multirow{2}{*}{**Potential benefit to hearing system**} & Inhibition of excessive inflammatory damage and minimization of damage to hair cells & Facilitation of early inner ear tissue repair, inhibition of excessive inflammatory damage and preservation of hair cell viability \\ \cline{1-1}  & & \\ \hline \hline \end{tabular}
\end{table}
Table 1: _Comparison between glucocorticoids and AAT. Mechanism of action, clinical indication, dose and relevance to hearing._In alignment with the protective attributes of AAT, patients with a genetic AAT deficiency exhibit signs of poor tissue repair, most typically in the form of lung alveolar wall degradation; for these individuals, human plasma-derived affinity-purified AAT is administered by weekly intravenous slow drip perfusion sessions. In recent years, interest in the potential benefits of a clinical-grade AAT therapy for enhancing tissue repair outside a genetic AAT deficiency has gained attention [13; 14; 15; 16].  
In this review, the anatomically minuscule inner ear compartment serves as an archetype for the detrimental intersection between a standard of care glucocorticoid therapy, tissue damage to the point of functional failure and presumed insufficient liver-derived circulating AAT. For scope considerations, focus is placed on iatrogenic surgical damage to the inner ear as the underpinning of inner ear tissue damage.