Satoshi Seno

Airway Uric Acid Is a Sensor of Inhaled Protease Allergens and Initiates Type 2 Immune Responses in Respiratory Mucosa

Although type 2 immune responses to environmental Ags are thought to play pivotal roles in asthma and allergic airway diseases, the immunological mechanisms that initiate the responses are largely unknown. Many allergens have biologic activities, including enzymatic activities and abilities to engage innate pattern-recognition receptors such as TLR4. In this article, we report that IL-33 and thymic stromal lymphopoietin were produced quickly in the lungs of naive mice exposed to cysteine proteases, such as bromelain and papain, as a model for allergens. IL-33 and thymic stromal lymphopoietin sensitized naive animals to an innocuous airway Ag OVA, which resulted in production of type 2 cytokines and IgE Ab, and eosinophilic airway inflammation when mice were challenged with the same Ag. Importantly, upon exposure to proteases, uric acid (UA) was rapidly released into the airway lumen, and removal of this endogenous UA by uricase prevented type 2 immune responses. UA promoted secretion of IL-33 by airway epithelial cells in vitro, and administration of UA into the airways of naive animals induced extracellular release of IL-33, followed by both innate and adaptive type 2 immune responses in vivo. Finally, a potent UA synthesis inhibitor, febuxostat, mitigated asthma phenotypes that were caused by repeated exposure to natural airborne allergens. These findings provide mechanistic insights into the development of type 2 immunity to airborne allergens and recognize airway UA as a key player that regulates the process in respiratory mucosa.

Role of platelet-derived growth factor in airway remodeling in rhinosinusitis.

Background The purpose of this study was to elucidate the role of platelet-derived growth factor (PDGF) in the pathogenesis of rhinosinusitis. Methods Nasal mucosa and polyps were obtained during surgery in patients with allergic rhinitis, chronic rhinosinusitis (CRS) without asthma, and CRS with asthma. PDGF concentrations in nasal discharge were measured, and the histological distribution and expression levels of mRNA for PDGF and PDGF receptors were examined. PDGF-producing cells were determined by double-staining for PDGF and CD68 or major basic protein. Results The concentration of PDGF was significantly higher in CRS with asthma. An immunohistochemical study showed that PDGF was localized in epithelial cells, gland cells, vascular endothelial cells, and inflammatory cells. Expression of PDGF increased in epithelial cells in all three diseases, in macrophages in CRS without asthma, and eosinophils in CRS with asthma, and PDGF receptors were detected in epithelial cells and submucosal fibroblasts. Increased expression of PDGF mRNA was found in CRS with asthma. Conclusion The results indicate that PDGF is produced by macrophages, eosinophils, and epithelial cells in rhinosinusitis and that it acts on receptors in epithelial cells and fibroblasts. PGDF may be an important cytokine in the pathogenesis of rhinosinusitis by promoting tissue fibrosis and formation of nasal polyps.

Endoscopic ligation of the sphenopalatine artery and the maxillary artery for the treatment of intractable posterior epistaxis.

Background Intractable posterior epistaxis sometimes requires intensive treatment, such as surgery or embolization. Maxillary artery ligation has been widely used for the treatment of intractable posterior epistaxis. It is highly effective, but significant complications may occur, including an oroantral fistula and damage to the infraorbital nerve. Embolization is less invasive and can be performed in poor surgical candidates. However, it has more serious complications, such as facial nerve paralysis and hemiplegia. This investigation evaluates the effectiveness and complications of endoscopic ligation of the sphenopalatine or maxillary artery for the treatment of intractable posterior epistaxis. Methods Between April 2003 and March 2007, 46 patients were hospitalized for the treatment of severe posterior epistaxis in our University Hospital. Thirty patients were successfully treated by anterior and/or posterior nasal packing, and five patients were treated by electrocoagulation. Endoscopic ligation was performed under general anesthesia in 11 patients (6 men and 5 women; age range, 50-80 years). Results Eight patients underwent endoscopic ligation of the sphenopalatine artery, and three patients underwent endoscopic ligation of the maxillary artery through the middle meatus and posterior antral wall opening. There were no complications, and the patients’ postoperative courses were uneventful. Recurrent epistaxis occurred in one patient on oral anticoagulants 15 months after ligation of the sphenopalatine artery, and it was successfully treated by anterior nasal packing. Conclusion Endoscopic ligation of the sphenopalatine or maxillary artery is safer than arterial embolization and is less invasive than transantral ligation of the maxillary artery. This technique appears to be a simple and highly effective surgical treatment for patients with intractable posterior epistaxis.

Expression and localization of aquaporin 1, 2, 3, 4, and 5 in human nasal mucosa.

Background Aquaporins (AQPs) are water-specific membrane channel proteins that regulate water homeostasis for cells and organisms. The purpose of this study was to elucidate the role of AQPs 1, 2, 3, 4, and 5 in normal and diseased human nasal mucosa. Methods Nasal polyps were obtained from eight patients with chronic rhinosinusitis (CRS). Inferior turbinate tissue was obtained from five patients with allergic rhinitis (AR) and from six patients with septal deviation (controls). Expression of AQP1–5 mRNA was examined using reverse transcriptase–polymerase chain reaction (RT-PCR) and immunoblotting, and tissue localization of AQP1–5 was studied by immunohistochemistry. Semiquantitative RT-PCR was used to investigate disease-specific changes in the expression in AQP1, -3, and -5 mRNA. Results Expression of AQP1, -3, -4, and -5 mRNA and AQP1–5 protein were confirmed in normal human nasal mucosa. Immunohistochemical studies revealed that AQP1 was localized in fibroblasts (especially in the subepithelial area) and endothelial cells of blood vessels, AQP2 was localized in the cytoplasm of epithelial cells and acinar cells, AQP3 was localized in the basolateral sites of epithelial cells and acinar cells, AQP4 was localized in the basolateral sites of acinar cells, and AQP5 was localized in the apical sites of epithelial cells and acinar cells. Semiquantitative RT-PCR revealed that there were no significant differences in the mRNA expression of AQP1, AQP3, and AQP5 among control, AR, and CRS patients. Conclusion AQP1, -2, -3, -4, and -5 were present in normal human nasal mucosa. mRNA expression of AQP1, -3, and -5 did not change among control, AR, and CRS patients.

Pro-Resolution Mediator Lipoxin A4 and its Receptor in Upper Airway Inflammation

Objectives: The resolution of inflammation is an active process controlled by several anti-inflammatory and pro-resolution mediators. Lipoxin A4, an endogenous lipid mediator, is a potential pro-resolution mediator that could attenuate inflammation. This study was conducted to elucidate the role of lipoxin A4 in upper airway inflammation. Methods: Nasal secretions were collected from patients with chronic rhinosinusitis with nasal polyposis, patients with allergic rhinitis, and control subjects. The concentration of lipoxin A4 was measured by enzyme-linked immunosorbent assay. Nasal tissues were obtained from nasal polyps and inferior turbinates during endonasal surgery. The mRNA expressions of lipoxygenases (LOXs), lipoxin receptor (formyl peptide receptor-like 1; FPRL-1), and cysteinyl leukotriene type 1 receptor (CysLT1R) in nasal tissues were examined by reverse-transcription polymerase chain reaction. Tissue localization of FPRL-1 was determined by immunohistochemical staining. The in vitro effect of lipoxin A4 on airway epithelial cells was also examined. Results: A significant concentration of lipoxin A4 was found in nasal secretions, and the concentration was increased in patients with allergic rhinitis. The mRNA expressions of 5-LOX, 15-LOX-1, FPRL-1, and CysLT1R were significantly greater in nasal polyps than in inferior turbinates. FPRL-1 was localized in nasal epithelial cells. Lipoxin A4 inhibited tumor necrosis factor α-induced interleukin 8 release from airway epithelial cells via its receptor FPRL-1. Conclusions: These results indicate that lipoxin A4 may play a role in the resolution of upper airway inflammation. A low concentration of lipoxin A4 may be involved in chronic inflammation of the upper airways.

A Case of Earpick Injury with Delayed Facial Paralysis

We reported a rare case of ear trauma with delayed facial paralysis, ossicular chain dislocation and perilymph fistula caused by an earpick. A 36-year-old male consulted our clinic with a complaint of left otalgia, hearing loss, tinnitus and dizziness after left ear trauma with an earpick. Otoscopic examination showed perforation of the left ear-drum and pure tone audiometory demonstrated a mixed hearing loss with an average air conduction threshold of 53dB on the initial examination. He was diagnosed as having a traumatic ear-drum perforation. Left facial paralysis occurred 6 days after the trauma, then recovered after the intravenous steroid treatment. Hearing impairment did not improve after spontaneous closure of the ear-drum perforation, and exploratory tympanoplasty was performed. At surgery, the incus was dislocated and the anterior and posterior crura of stapes were fractured. Perilymphatic leakage from the fractured footplate was noted. The footplate was covered with temporal fascia and ossicular chain reconstruction was performed using the incus on the foot plate as a columella. Post operationally, the hearing threshold improved with an average air conduction threshold of 31.7dB.

A Case of Inflammatory Pseudotumor of the Orbit

An inflammatory pseudotumor is one of the major neoplasm arising in the orbit. We reported a case of inflammatory pseudotumor of the orbit that was successfully treated. A 73-old-male was referred to our department with a complaint of swelling of the left eye lid. CT findings showed a tumor of the left orbit extending into the ethmoid sinus. Incisional biopsy was performed through the left maxillary sinus. Histologic examination demonstrated a non-specific inflammatory lesion with fibrous tissues and inflammatory cells. The pathologic diagnosis was benign pseudotumor. The patient was given steroid therapy (for 5 weeks) and radiotherapy (2 Gy•~10 days) which resulted in complete response at discharge. Steroid therapy was continued for 6 months after discharge. There has not been any recurrence of the tumor during more than 2 years follow up. Clinical manifestations, histopathologic findings and treatment of this lesion are discussed.

Sudden Deafness with Diabetes Mellitus.

212 patients diagnosed with sudden deafness between October, 1978 and April, 1998 were reported in our department. In order to clarify the relationship between sudden deafness and diabetes mellitus, the treatment course of 18 patients with sudden deafness, who were affected by diabetes, was analyzed retrospectively. The patients with sudden deafness were divided into two groups (diabetic and non-diabetic) and were analyzed. The following results were obtained:1) The mean age of patients in the diabetic group was 51.8 years, approximately 8 years older than the non-diabetic group. The number of patients with diabetes mellitus increased markedly in the last 10 years.2) There was no significant difference in hearing improvement after treatment as well as in hearing levels between the two groups.3) The rate of patients with dizziness or vertigo in the diabetic group was significantly higher than in the non-diabetic group. The patients with dizziness or vertigo showed a poorer prognosis in their hearing loss.4) There was no relationship between the duration of diabetes and the prognosis of hearing loss. The patients with retinopathy due to diabetes tended to show less hearing improvement.5) Steroid therapy for sudden deafness patients with diabetes was executed without worsening the diabetic condition if insulin was administered adequately.