Background: Postviral olfactory dysfunction (PVOD) following a viral upper respiratory tract infection (URI) is one of the most common causes of olfactory disorders, often lasting for over a year. To date, the molecular pathology of PVOD has not been elucidated.Methods: A murine model of Toll-like receptor 3 (TLR3)-mediated upper respiratory tract inflammation was used to investigate the impact of URIs on the olfactory system. Inflammation was induced via the intranasal administration of polyinosinic–polycytidylic acid (poly(I:C), a TLR3 ligand) to the right nostril for 3 days. Peripheral olfactory sensory neurons (OSNs), immune cells in the olfactory mucosa, and glial cells in the olfactory bulb (OB) were analyzed histologically. Proinflammatory cytokines in the nasal tissue and OB were evaluated using the quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA).Results: In the treated mice, OSNs were markedly reduced in the olfactory mucosa, and T cell and neutrophil infiltration therein was observed 1 day after the end of poly(I:C) administration. Moreover, there was a considerable increase in microglial cells and slight increase in activated astrocytes in the OB. In addition, qPCR and ELISA revealed the elevated expression of interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma both in the OB and nasal tissue.Conclusions: Taken together, the decreased peripheral OSNs, OB microgliosis, and elevated proinflammatory cytokines suggest that immunological changes in the OB may be involved in the pathogenesis of PVOD.

To review the various basic research and treatments available to regenerate the vocal folds and to discuss the direction for future treatments. A comprehensive review was performed in PubMed database and Google Scholar utilizing search terms including combinations and variations of the following concepts: vocal fold anatomy, vocal fold disorders, and regenerative therapies. No particular inclusion or exclusion criteria were set due to the nature of this narrative review article. The regenerative treatments available for each vocal fold layer are the following: 1) epidermal growth factor and transforming growth factor-β1 for the epithelial layer, 2) autologous fibroblasts, autologous bone-marrow derived mesenchymal stem cells (MSCs), autologous adipose tissue-derived stromal vascular fraction (ADSVF), basic fibroblast growth factor (bFGF), collagen-hyaluronic acid nanofiber, pirfenidone, hepatocyte growth factor (HGF), pulsed dye laser (PDL), diode laser, and platelet-rich plasma (PRP) for the lamina propria, 3) bFGF and controlled-release bFGF with autologous fascia, HGF, c-Met agonistic antibody, and PRP for the muscular layer, 4) and bFGF and PRP-loaded nerve guidance conduit for the nerve. Treatments deemed clinically safe with sustained efficacy assessed up to 6 months are HGF and PDL, while bFGF, autologous fibroblasts, autologous bone marrow-derived MSCs, ADSVF, and PRP have been studied up to 12 months. An ideal regenerative treatment is one that restores the injured or lost components of the vocal fold. The layered structure of the vocal fold allows for several mechanisms of action for these regenerative therapies. Further experimental and clinical studies are warranted, and these would dictate the impact of vocal fold regenerative therapies. Regenerative medicine may soon be at the forefront for treating vocal fold disorders. Clinicians should be open to advancements in treatment and consider the potential of novel therapies to treat specific pathologies.

To describe the pathogenesis of human papillomavirus (HPV) and recurrent respiratory papillomatosis (RRP) caused by HPV6/11, immunologic and oncogenic properties, and currently available treatment strategies and to identify and discuss potential treatment targets that can become new foundations for development of future treatments. A comprehensive literature search was conducted using PubMed and Google Scholar utilizing search terms which includes "recurrent respiratory papillomatosis" "human papillomavirus" "HPV" "laryngeal papillomatosis" in combination with keywords "physiology" "treatment" "surgery" "adjunct therapy" "antiviral therapy" "gene therapy". No particular inclusion/exclusion criteria and no chronologic limitation were set during the search for studies to be used as references. HPV infection begins with breaches in the epithelial barrier where it gains entry and access to the undifferentiated basal layer keratinocytes where the HPV genome interact with the host cell through the production of viral proteins encoded by the early and late gene regions facilitating viral entry, replication and proliferation. Oncoproteins interfere with host immune surveillance mechanism, promote growth factor signaling, and create a tumor microenvironment resulting in uncontrolled cell proliferation and progression of HPV infection. While high-risk HPV types integrate into the host genome and aggressively promote oncogenesis, low-risk HPV remain superficial with limited oncogenic activity and immune activation which allows avoidance of inflammation induction and cytolysis thereby preventing significant antigen production and facilitates immunosurveillance evasion. The current standard of treatment of RRP is surgical debulking using lasers or cold instruments with or without and adjuvant therapies like antivirals, interferons, VEGF/EGFR inhibitors, and immunomodulators. Novel immunotherapies such as gene therapies and immune checkpoint inhibitors show promising results in boosting immune responses and reducing the frequency of surgical interventions. The treatment for recurrent respiratory papillomatosis still remains as a challenge due to its high recurrence rates needing repeated surgical and medical intervention attributed to its capability to evade the host immune responses. With the current standard of treatment, advances in the understanding of HPV pathogenesis paved a way for development of new treatment strategies. Understanding the complexities of the cellular and immune mechanisms involved between HPV and the host immune system will provide us with better foundation in identifying potential treatment targets in the future.

Vocal fold motion impairment (VFMI) is the inappropriate movement of the vocal folds during respiration, leading to vocal fold adduction and/or abduction problems and causing respiratory and vocal impairments. Neurodegenerative diseases (NDDs) are a wide range of disorders characterized by progressive loss of neurons and deposition of altered proteins in the brain and peripheral organs. VFMI may be unrecognized in patients with NDDs. VFMI in NDDs is caused by the following: laryngeal muscle weakness due to muscular atrophy, caused by brainstem and motor neuron degeneration in amyotrophic lateral sclerosis; hyperactivity of laryngeal adductors in Parkinson’s disease; and varying degrees of laryngeal adductor hypertonia and abductor paralysis in multiple system atrophy. Management of VFMI depends on whether there is a presence of glottic insufficiency or insufficient glottic opening with/without severe dysphagia. VFMI treatment options for glottic insufficiency range from surgical interventions, including injection laryngoplasty and medialization thyroplasty, to behavioral therapies; for insufficient glottic opening, various options are available based on the severity and underlying cause of the condition, including continuous positive airway pressure therapy, botulinum toxin injection, tracheostomy, vocal fold surgery, or a combination of interventions. In this review, we outline the mechanisms, clinical features, and management of VFMI in NDDs and provide a guide for physicians who may encounter these clinical features in their patients. NDDs are always progressive; hence, timely evaluation, proper diagnosis, and appropriate management of the patient will greatly affect their vocal, respiratory, and swallowing functions as well as their quality of life.

Objectives: Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 and 11. However, the cellular and molecular mechanisms underlying its pathogenesis remain to be elucidated. Recently, the conditional reprogramming (CR) method, which reprograms epithelial cells to an undifferentiated stem cell state, has been shown to be effective for studying RRP. Here, we investigated the relationship between viral and host gene expression in CR cells and explored the molecular pathogenesis of RRP.Methods: We evaluated the passage capacity and growth rate of CR cells from fresh RRP tissues and adjacent normal tissues from patients with RRP. Furthermore, we performed RNA‐seq analysis of CR cells across multiple passages to characterize the gene expression profiles associated with RRP.Results: RRP‐derived CR cells exhibited greater passage capacity and proliferation rates than adjacent normal tissue‐derived CR cells. HPV6 gene was expressed in all RRP‐derived CR cells and its expression decreased with each passage. We identified three categories of genes correlated with HPV6: inflammatory genes (e.g., CTSS, CFB), oncogenic genes (e.g., CEACAM5, CEACAM6), and glycosylation‐related genes (e.g., ST6GALNAC1, FUT2).Conclusion: HPV6‐induced gene expression signature in infected epithelial cells may play a role in RRP pathogenesis. Further molecular investigations are necessary to determine whether controlling these genes and related factors can control the progression of RRP.Level of Evidence: N/A.