The monoterpene 1,8-Cineol is a natural plant-based therapeutic agent that is commonly applied to treat different inflammatory diseases due to its mucolytic, anti-microbial and anti-inflammatory properties. It has become increasingly clear in the recent years that 1,8-Cineol spreads almost everywhere in the human body after its oral administration, from the gut to the blood to the brain. Its anti-microbial potential and even its anti-viral effects have been observed to include numerous bacteria and fungi species. Many recent studies help to better understand the cellular and molecular immunological consequences of 1,8-Cineol treatment in inflammatory diseases and further provide information concerning the mechanistic modes of action in the regulation of distinct inflammatory biosynthetic pathways. This review aims to present a holistic and understandable overview of the different aspects of 1,8-Cineol in infections and inflammation.

Introduction: Major features of the pathogenesis in otitis media, the most common disease in childhood, include hyperplasia of the middle ear mucosa and infiltration by leukocytes, both of which typically resolve upon bacterial clearanceviaapoptosis. Activation of innate immune receptors during the inflammatory process leads to the activation of intracellular transcription factors (such as NF-κB, AP-1), which regulate both the inflammatory response and tissue growth. We investigated these leading signaling pathways in otitis media using mouse models, human samples, and human middle ear epithelial cell (HMEEC) lines for therapeutic immunomodulation.Methods: A stable otitis media model in wild-type mice and immunodeficient KO-mice, as well as human tissue samples from chronic otitis media, skin from the external auditory canal and middle ear mucosa removed from patients undergoing ear surgery, were studied. Gene and protein expression of innate immune signaling molecules were evaluated using microarray, qPCR and IHC.In situapoptosis detection determined the apoptotic rate. The influence of bacterial infection on immunomodulating molecules (TNFα, MDP, Tri-DAP, SB203580, Cycloheximide) in HMEEC was evaluated. HMEEC cells were examined after bacterial stimulation/inhibition for gene expression and cellular growth.Results: Persistent mucosal hyperplasia of the middle ear mucosa in chronic otitis media resulted from gene and protein expression of inflammatory and apoptotic genes, including NODs, TNFα, Casp3 and cleaved Casp3. In clinical chronic middle ear samples, these molecules were modulated after a specific stimulation. They also induced a hyposensitive response after bacterial/NOD-/TLR-pathway double stimulation of HMEEC cellsin vitro. Hence, they might be suitable targets for immunological therapeutic approaches.Conclusion: Uncontrolled middle ear mucosal hyperplasia is triggered by TLRs/NLRs immunoreceptor activation of downstream inflammatory and apoptotic molecules.

Introduction: Patients with otitis media (OM) encounter significant functional hearing impairment with conductive, or a combined hearing loss and long-term sequelae involving impaired speech/language development in children, reduced academic achievement and irreversible disorders of middle and inner ear requiring a long time therapy and/or multiple surgeries. In its persistent chronic form, Otitis media (COM) can often only be treated by undergoing ear surgery for hearing restoration. The persistent inflammatory reaction plays a major role, often caused by multi-resistant pathogens in the ear. Herein, we present outcomes of patients implanted with currently the only FDA approved active Middle Ear Implant Vibrant Soundbridge (VSB), suffering from persistent COM. Methods: The study enrolled 42 patients, treated by performing middle ear (ME) surgery to different extents and implanted with the VSB to various structures in the ME. Included were 17 children and 25 adults that had recurrent and/or persisting OM and significant hearing loss. Preoperative and postoperative patients' audiometric data were evaluated and the benefit with VSB assessed using the Glasgow Benefit Inventory for adults and pediatric cohorts. The microbial spectrum of pathogens was assessed before and after surgery, exploring the colonization of the otopathogens, as well as the intestinal microbiome from individually burdened patients. Results: The mean functional gain is 29.7 dB HL (range from 10 to 56.2 dB HL) with a significant improvement in speech intelligibility in quiet. Following VSB implantation, no significant differences in coupling were observed at low complication rates. Postoperatively patients showed significantly increased benefit with VSB compared to the untreated situation, including less otorrhea, pain, medical visits, and medication intake, with no recurrent OM and significant bacterial shift in otopathogens. The analysis of the intestinal microbiome displayed a high abundance of bacterial strains that might be linked to chronic and persistent inflammation. Conclusions: Functional ear surgery including rehabilitation with a VSB in patients suffering from COM present to be safe and effective. The successful acceptance accompanied by the improved audiological performance resulted in significant benefit with VSB, with a shift in the ear pathogens and altered microbiome and thus is a great opportunity to be treated.

Hypothesis: Otitis media (OM) can be successfully visualized and diagnosed by dynamic microscopic optical coherence tomography (dmOCT). Background: OM is one of the most common infectious diseases and, according to the WHO, one of the leading health problems with high mortality in developing countries. Despite intensive research, the only definitive treatment of therapy-refractory OM for decades has been the surgical removal of inflamed tissue. Thereby, the intra-operative diagnosis is limited to the surgeon’s visual impression. Supportive imaging modalities have been little explored and have not found their way into clinical application. Finding imaging techniques capable of identifying inflamed tissue intraoperatively, therefore, is of significant clinical relevance. Methods: This work investigated a modified version of optical coherence tomography with a microscopic resolution (mOCT) regarding its ability to differentiate between healthy and inflamed tissue. Despite its high resolution, the differentiation of single cells with mOCT is often impossible. A new form of mOCT termed dynamic mOCT (dmOCT) achieves cellular contrast using micro-movements within cells based on their metabolism. It was used in this study to establish correlative measurements with histology. Results: Using dmOCT, images with microscopic resolution were acquired on ex vivo tissue samples of chronic otitis media and cholesteatoma. Imaging with dmOCT allowed the visualization of specific and characteristic cellular and subcellular structures in the cross-sectional images, which can be identified only to a limited extent in native mOCT. Conclusion: We demonstrated for the first time a new marker-free visualization in otitis media based on intracellular motion using dmOCT.

Zusammenfassung: Einleitung Die Ätiopathogenese der chronischen Otitis media epitympanalis bzw. des Cholesteatoms und ihr proliferierender destruierender Verlauf mit möglichen Komplikationen wie Destruktion der knöchernen Strukturen mit Hörverlust, vestibulärer Dysfunktion, Gesichtsnervenlähmung und intrakraniellen Komplikationen sind immer noch ungeklärt. Die Therapie der Wahl ist nach wie vor die operative Sanierung. Aktuelle Studien befassen sich immer mehr mit dem angeborenen Immunsystem.Methoden Unsere Untersuchungen erfolgten im Mausmodell an WT-Mäusen und immundefizienten KO-Mäusen sowie an Gewebeproben vom Cholesteatom, gesunder Gehörgangshaut und gesunder Mittelohrschleimhaut, die während sanierenden Ohroperationen entnommen wurden. Die Expressionsanalysen erfolgten auf Gen- und Proteinebene mit TNF als Major Target zur Therapieevaluation. Mittels TUNEL-Färbung und Immunhistochemie an Kryoschnitten wurde die Apoptose-Rate durch TNF bestimmt.Ergebnisse Das ungerichtet-expansive Cholesteatomwachstum zeigt ein immunmodulatorisches Profil mit Hoch- und Runterregulation von verschiedenen Gen-Netzwerken, vor allem Molekülen der TNF-Down- und -Upstream-Signalwege. Dabei wird TNF sowohl inflammatorisch als auch apoptotisch moduliert und eignet sich als möglicher Therapieansatz in verschiedenen Modellen.Schlussfolgerungen Es gibt Hinweise auf eine immunmodulatorische Regulation im Cholesteatom.