Therapeutic Potential of Valproic Acid for Postviral Olfactory Dysfunction: A Single-Arm Pilot Study.

OBJECTIVES: Although some patients with postviral olfactory dysfunction (PVOD) recover spontaneously, many others are left with the degree of smell loss and there are no established drugs for the treatment of patients with PVOD. Valproic acid (VPA) has been widely used for the treatment of epilepsy. Its potential neuroregenerative effects have been shown via animal studies. This is the first study to treat PVOD patients with VPA. This open-label, single-arm, phase II study was conducted to investigate the effects of VPA in patients with PVOD. METHODS: The patients received oral tablets of VPA 200 mg twice a day for 24 weeks. In total, 11 patients with PVOD were recruited. Oder scores of recognition and detection threshold (measured with a T&T olfactometer), and visual analog scale were examined during the treatment. RESULTS: All odor scores significantly improved over time. Although the mean duration of olfactory dysfunction in this study was 11.5 months, both odor recognition threshold and odor detection threshold scores significantly improved 4 weeks after treatment initiation compared to the pre-treatment threshold scores. The olfactory recovery rates in patients treated with VPA were clearly better than those we previously reported in PVOD patients who received Toki-shakuyaku-san, the traditional treatment in Japan. The olfactory recovery rates of patients with PVOD at 12 weeks and 24 weeks of VPA treatment were both 77.8%, and the olfactory cure rates at 12 weeks and 24 weeks of VPA treatment were 33.3% and 44.4%, respectively. No serious adverse events were observed. CONCLUSIONS: VPA seems to be a safe treatment option in patients with PVOD. The effects of VPA treatment for PVOD patients should be studied with a controlled study design in the future.

Immunological effects of sublingual immunotherapy with Japanese cedar pollen extract in patients with combined Japanese cedar and Japanese cypress pollinosis.

Sublingual immunotherapy (SLIT) with Japanese cedar (JCe) pollinosis was expected to be effective for Japanese cypress (JCy) pollinosis. However, only a half of JCy pollinosis patients clinically improved. Therefore, we examined the immunological effect of SLIT for JCy pollinosis. Peripheral blood mononuclear cells (PBMCs) from patients with JCe and JCy pollinosis who did and did not receive SLIT were incubated with Cry j 1, Cha o 1 and Cha o 3 antigens. Basophil activation test (BAT) were performed. Production of IL-5 and IL-17 induced by antigens was inhibited in the SLIT group. Cry j 1-specific production of IL-10 was increased, and serum Cry j 1-specific IgE and -IgG4 were elevated. However, Cha o 1- or Cha o 3-specific production of IL-10 and specific IgG4 was not increased. Antigens-specific BAT did not decrease after SLIT. New SLIT with JCe and JCy is needed for patients with combined JCe and JCy pollinosis.

Evidence for the induction of Th2 inflammation by group 2 innate lymphoid cells in response to prostaglandin D2 and cysteinyl leukotrienes in allergic rhinitis.

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) play important roles in allergic inflammation. However, their roles in the pathophysiology of allergic rhinitis (AR) are poorly understood. OBJECTIVE: Prevalence of ILC2s in the inferior nasal turbinate (INT) tissues and the activating mechanisms of ILC2s were examined in patients with house dust mite (HDM)-induced AR. METHODS: Eighteen patients with HDM-induced AR and 13 control subjects were recruited. Fresh INT tissues and peripheral blood mononuclear cells (PBMCs) were analysed using flow cytometry. Nasal lavage fluids (NLF) were collected at 10 minutes after the nasal provocation test (NPT) with HDM disc, and released mediators were measured by ELISA. Sorted ILC2s were cultured and stimulated with mediators associated with AR. RESULTS: The prevalence of ILC2s was significantly increased in nasal mucosa of patients with HDM-induced AR, and it was positively correlated with the number of infiltrating eosinophils. ILC2s in the INT tissues expressed a prostaglandin D2 (PGD2 ) receptor, chemoattractant receptor-homologous molecule-expressed TH2 cells (CRTH2) and a cysteinyl leukotriene (cysLTs) receptor, CysLT1. After NPT, the number of eosinophils and concentrations of PGD2 and cysLTs were significantly increased in the NLF from AR patients. PGD2 and cysLTs significantly induced IL-5 production from cultured PBMC-derived ILC2s dose-dependently. PGD2 -induced and cysLTs-induced productions of IL-5 and IL-13 from ILC2s were completely inhibited by ramatroban, a dual CRTH2 and thromboxane receptor antagonist, and montelukast, a CysLT1 antagonist, respectively. CONCLUSIONS: PGD2 -CRTH2 and cysLTs-CysLT1 axes may activate tissue-resident ILC2s to produce Th2 cytokines, IL-5 and IL-13, leading to the development of allergic inflammation in AR.

Soluble ST2 suppresses IL-5 production by human basophilic KU812 cells, induced by epithelial cell-derived IL-33.

BACKGROUND: Epithelial cell-derived IL-33 has an important role in the initiation and activation of innate allergic inflammation. IL-33 acts as a cytokine through the ST2 receptor (ST2L) and it stimulates the production of Th2 cytokines. Soluble ST2 (sST2) may regulate Th2 responses by neutralizing the activity of IL-33. Basophils express ST2L and produce IL-5 in response to IL-33. However, the role of the epithelial cell-basophil interaction and sST2 in IL-5 production remains unclear. METHODS: Cultured human bronchial epithelial (hBE33) cells, that contained the human IL-33 gene (i.e., hBE33 cells) and a human basophilic cell line, KU812 cells, were used to study the epithelial cell-basophil interaction in the production of IL-5 induced by HDM. RESULTS: At 15 min after incubation, HDM stimulated the rapid release of IL-33 from cultured hBE33 cells. IL-33 and the supernatant of HDM-treated hBE33 cells stimulated IL-5 production from KU812 cells. Anti-IL-33 antibody and anti-ST2 antibody treatment of KU812 cells suppressed IL-5 production, which had been induced by the supernatant of HDM-treated hBE33 cells. The hBE33 cells secreted sST2 in a time-dependent manner. The production of sST2 by KU812 cells co-cultured with hBE33 cells was significantly increased, compared with KU812 cells cultured with the supernatant of hBE33 cells. Soluble ST2 suppressed IL-5 production by KU812 cells, which was induced by the supernatant of HDM-treated hBE33 cells. CONCLUSIONS: Epithelial cell-derived IL-33 promoted IL-5 production by KU812 cells. The subsequently produced sST2 has important roles in regulating Th2 responses.

A mechanism of interleukin-25 production from airway epithelial cells induced by Japanese cedar pollen.

IL-25 likely has vital roles in initiating and activating type-2 immune responses in AR. We hypothesized that the molecules produced IL-25 by allergen-producing organisms such as JC is involved in the pathogenesis of AR. Participants included 13 patients with Japanese cedar pollinosis and 10 HCs. We measured the IL-25 protein concentration in nasal secretions and in culture supernatants of PNECs. NHBE cells were stimulated with pharmacological and immunological agents and JC. The IL-25 concentration in nasal secretions was significantly higher in patients with Japanese cedar pollinosis than in HCs. JC stimulated IL-25 production from PNECs. TNF-α, IL-4, and IL-13 significantly enhanced JC-induced IL-25 production; their activation by serine proteases was sufficient to enhance IL-25 production. Furthermore, the NADPH oxidase activity, including JC enhanced IL-25 production. A better understanding of JC-induced IL-25 production by epithelial cells may allow the development of novel therapeutic and preventive strategies for Japanese cedar pollinosis.

Severely infected pneumoceles of the frontal sinus in patients with mental retardation and brain atrophy treated by endoscopic sinus surgery.

We herein present three cases of abnormally expanded frontal sinuses (pneumoceles) with severe infection in patients with mental retardation and brain atrophy. Two patients previously underwent laryngotracheal separation surgery, and bacteriological examinations of purulent nasal discharge revealed infections caused by drug-resistant bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As conservative medical treatments were ineffective, all three patients were treated by computed tomography-guided endoscopic sinus surgery. This navigation system is useful for safer surgery in the area of anatomic deformity. The clinical findings, possible etiologies and surgical treatment of these cases are discussed.

Endogenous Protease Inhibitors in Airway Epithelial Cells Contribute to Eosinophilic Chronic Rhinosinusitis.

RATIONALE: Cystatin A and SPINK5 are endogenous protease inhibitors (EPIs) that may play key roles in epithelial barrier function. OBJECTIVES: To investigate the roles of EPIs in the pathogenesis of chronic rhinosinusitis (CRS). METHODS: We examined the expression of cystatin A and SPINK5 in the nasal epithelial cells of patients with CRS. Additionally, the in vitro effects of recombinant EPIs on the secretion of the epithelial-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin in airway epithelial cells, and the in vivo effects of recombinant EPIs in the nasal epithelium of mice exposed to multiple airborne allergens (MAA) were examined. MEASUREMENTS AND MAIN RESULTS: Compared with control subjects and patients with noneosinophilic CRS, patients with eosinophilic CRS showed significantly lower protein and mRNA expression of cystatin A and SPINK5 in the nasal epithelium. Allergen-induced production of IL-25, IL-33, and thymic stromal lymphopoietin in normal human bronchial epithelial cells was inhibited by treatment with recombinant cystatin A or SPINK5. Conversely, the production of these cytokines was increased when cystatin A or SPINK5 were knocked down with small interfering RNA. Chronic MAA exposure induced goblet cell metaplasia and epithelial disruption in mouse nasal epithelium and decreased the tissue expression and nasal lavage levels of cystatin A and SPINK5. Intranasal instillations of recombinant EPIs attenuated this MAA-induced pathology. CONCLUSIONS: Cystatin A and SPINK5 play an important role in protecting the airway epithelium from exogenous proteases. The preservation of EPIs may have a therapeutic benefit in intractable airway inflammation, such as eosinophilic CRS.