## 5 Discussion  
Glucocorticoid treatments for inner ear pathologies is a challenging field, especially regarding post-surgical hearing preservation. Presently, there is a lack of uniform clinical guidelines instructing on the timing of treatment, the route of delivery or the dosing. This may be the result of a futile assortment of clinical evidence that focuses on treatment efficacy whilst employing a large variety of medications, dosages and regimens along with different methodological protocols. At the very least, the results do depict limited long-term hearing preservation by glucocorticoid therapies. This highlights the claim by which glucocorticoids are indeed anti-inflammatory, but they are not tissue-protective or tissue-restorative. Enter AAT, a molecule that is physiologically programmed to promote tissue repair and immune tolerance throughout life. It rises in the circulation during an infection as well as during the third trimester of a healthy pregnancy and with an advanced age; it is lost during protein-losing enteropathies in a manner that correlates with the gastrointestinal disease severity [73; 74] and has recently been shown to protect patients with steroid-refractory gut GVHD [75; 76]. In perilymph samples from patients undergoing cochlear implantations, the levels of endogenous perilymph AAT were inversely associated with cochlear hearing loss [77]; [PERSON] et al. described a relationship between AAT and the enzymatic concept of otsopgniosis in cases of cochlear otsclerosis [78]. AAT is not anti-inflammatory per se; it is pro-resolution. Whether an endogenous AAT insufficiency plays a role in a suboptimal recovery from inner ear disruptions is an important topic of ongoing and future exploration. Is there a direct relationship between AAT and the physiology of the glucocorticoid pathway? AAT was found to prevent the enzymatic degradation of corticosteroid-binding globulin in the blood [79] and to bind to the cytoplasmic glucocorticoid receptor (GR) [80]; conversely, the activation of the GR by glucocorticoids increased AAT production [81]. This receptor is, fundamentally, the channel by which endogenous cortisol generates its responses; it is tempting to suggest, therefore, that stressful conditions in the whole animal may apply this molecular bridge between cortisol delivery to the sites of inflammation and the production of tissue-protective AAT. These data invite further investigations into the pathways that may connect the favorable biological activities of both AAT and glucocorticoids in the context of a whole organism. Does a decision have to be made between AAT and glucocorticoids, or can the two be used in synergy? Very few studies address an AAT-augmented steroid therapy. In an in vitro study, LPS-stimulated macrophages were exposed to a concentration gradient of either AAT, dexamethasone, or both. The IL-6 and IL-1 Ra levels were determined in supernatants; the ratio these largely signified the inflammatory versus anti-inflammatory outcomes. Consistent with the literature, LPS-stimulated AAT-treated cells exhibited low IL-6 levels and high IL-1 Ra levels and LPS-stimulated dexamethasone-treated cells exhibited both low IL-6 and low IL-1 Ra levels [82]. According to the outcomes, the highest IL-1 Ra/IL-6 ratio was achieved by a combination of low concentrations of dexamethasone and high, yet clinically relevant, concentrations of AAT [83]. In contrast, lower concentrations of AAT were blocked by the addition of dexamethasone. This suggests that a low-dose glucocorticoidoid treatment still allows for an inflammatory modulation by AAT whilst carrying the desired immunosuppressive effects of glucocorticoids.