Increased Tissue Expression of Lectin-Like Oxidized LDL Receptor-1 (LOX-1) Is Associated with Disease Severity in Chronic Rhinosinusitis with Nasal Polyps.

BACKGROUND: The oxidative stress, induced by both environmental and intrinsic stimuli, underlies the onset and persistency of chronic rhinosinusitis (CRS). Scavenger receptors (SRs) are a broad family of transmembrane receptors involved in a dysfunctional host-environment interaction through a reaction with reactive oxygen species (ROS) production. OBJECTIVE: We hypothesized possible roles of two major SRs in CRS pathology that can translate to clinical phenotypes or histological subtypes: lectin-like oxidized low-density lipoproteins (LDL) receptor-1 (LOX-1) and scavenger receptor class B type 1 (SR-B1). PATIENTS AND METHODS: We collected ethmoid sinus mucosa specimens and blood samples from patients with CRS with nasal polyps (CRSwNP; n = 31) or CRS without NP (CRSsNP; n = 13) and 19 control subjects. We performed an RT-PCR analysis, ELISA assay, and immunostaining to determine the expressions and distributions of LOX-1 and SR-B1. RESULTS: The CRSwNP group showed a significant increase in LOX-1 mRNA expression compared to the control group. There was no significant difference in SR-B1 mRNA levels among the three groups. The LOX-1 mRNA levels were positively correlated with the sinus computed tomography (CT) scores. Sinus tissue, but not serum samples, showed elevated concentrations of LOX-1 protein in the CRSwNP group versus the control group. The LOX-1 protein distribution was localized in inflammatory cells and vascular endothelial cells. CONCLUSION: LOX-1 is a major receptor for oxidized low-density lipoprotein produced by oxidative stress. This is the first study to report alterations in LOX-1 expression and production triggered by persistent inflammatory processes in CRSwNP patients. Our findings reveal complex but important roles for SRs that may contribute to the onset of different CRS phenotypes.

Management of Intractable Nasal Hyperreactivity by Selective Resection of Posterior Nasal Nerve Branches.

The posterior nasal nerves emerge from the sphenopalatine foramen and contain sensory and autonomic nerve components. Posterior nasal neurectomy is an effective method to remove pathological neural networks surrounding the inferior turbinate that cause unregulated nasal hypersensitivity with excess secretion in patients with severe allergic rhinitis (AR). We describe the sophisticated endoscopic surgical procedure that allows feasible access to the confined area and selective resection of the nerve branches with the preservation of the sphenopalatine artery (SPA). We retrospectively analyzed the cases of 23 symptomatic severe AR patients who failed to respond to standard medical treatment and underwent surgery. There have been no major complications after surgery including nasal bleeding or transient numbness of the upper teeth. The mean total nasal symptom scores (TNSS) were decreased by 70.2% at 12 months after the procedure. Our comparison of the clinical effectiveness based on the number of severed nerve branches revealed that the improvement of the TNSS was significantly higher in patients with >2 branches. We conclude that this minimally invasive technique that preserves the SPA is clinically useful and decreases the rate of postoperative complications. This trial is registered with UMIN000029025.

Neuron-specific gene transfer through retrograde transport of lentiviral vector pseudotyped with a novel type of fusion envelope glycoprotein.

The lentiviral vector system is used extensively in gene therapy trials for various neurological and neurodegenerative disorders. The vector system permits efficient and sustained gene expression in many cell types through integration of the transgene into the host cell genome. However, there is a significant issue concerning the therapeutic use of lentiviral vectors, that transgene insertion may lead to tumorigenesis by altering the expression of proto-oncogenes adjacent to the integration sites. One useful approach for improving safety is to restrict vector transduction to neuronal cells. We have reported the use of human immunodeficiency virus type 1 (HIV-1)-based vectors for efficient retrograde transport by pseudotyping with rabies virus glycoprotein (RV-G) or fusion glycoprotein B type, in which the cytoplasmic domain of RV-G was substituted with the counterpart of vesicular stomatitis virus glycoprotein (VSV-G). Here we developed a novel vector system for neuron-specific retrograde gene transfer (termed NeuRet) by pseudotyping the HIV-1 vector with fusion glycoprotein C type (FuG-C), in which a short C-terminal segment of the extracellular domain and the transmembrane/cytoplasmic domains of RV-G were replaced with the corresponding regions of VSV-G. FuG-C pseudotyping caused efficient gene transfer, mainly through retrograde transport, into neuronal cells in diverse brain regions, whereas the pseudotyping resulted in less efficiency for the transduction of glial and neural stem/progenitor cells. Our NeuRet vector system achieves efficient retrograde gene delivery for therapeutic trials and improves their safety by greatly reducing the risk of gene transduction of dividing cells in the brain.