👤 Koichi Tsuneyama

Lysophosphatidic acid (LPA) and its receptor LPA1 have been implicated in tissue inflammation and fibrosis; however, their role in mucus overproduction remains unclear. Pulmonary neuroendocrine cells (PNECs), which are rare airway epithelial cells, contribute to mucus overproduction and immune modulation. In this study, we investigated the role of the LPA/LPA1 receptor axis in goblet cell hyperplasia and mucus overproduction, as well as the contribution of PNECs, using a chronic mouse model of bronchial asthma. A chronic mouse model of asthma was established by sensitization and challenge with the house dust mite antigen Dermatophagoides pteronyssinus (Dp), with or without treatment using the LPA1 antagonist AM095. Airway hyperresponsiveness, histopathology, mediator concentrations, and molecular expression in lung homogenate supernatants were evaluated. Lysophospholipid levels and low-molecular-weight metabolites were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Lung LPA 22:5 levels were elevated in Dp-challenged mice. LPA1 receptors were co-localized with PNECs in the lung. Treatment with AM095 reduced goblet cell hyperplasia by inhibiting the production of gamma-aminobutyric acid (GABA) and calcitonin gene-related peptide (CGRP) by PNECs. It also suppressed arginase 1 and polyamine production in CGRP-stimulated M2 macrophages. AM095 did not affect eosinophil extracellular trap (EET) formation in bronchoalveolar lavage fluid, which activates PNECs. The LPA/LPA1 axis promotes goblet cell hyperplasia through PNEC activation and downstream GABA and CGRP signaling in a chronic asthma model. LPA1 antagonism may represent a potential therapeutic strategy for controlling mucus overproduction in asthma. Show less

The relationship between cancer and autoimmunity is complex. However, the incidence of solid tumors such as melanoma has increased significantly among patients with previous or newly diagnosed systemic autoimmune disease (AID). At the same time, immune checkpoint blockade (ICB) therapy of cancer induces Show less

Association between gastric inhibitory polypeptide receptor polymorphism, rs10423928, and body mass index in olanzapine-treated schizophrenia was examined. Body mass index change for the A/T+A/A genotypes was significantly higher than that for the T/T genotype. rs10423928 may predict weight gain in schizophrenia. Show less

Several studies have shown increased rates of hyperglycemia and diabetes in schizophrenic patients treated with olanzapine. However, the underlying mechanism is poorly understood. Glucose-dependent insulinotropic polypeptide (GIP) is known to affect insulin secretion by pancreatic β cells. Recently, a meta-analysis study reported an association between a GIP receptor (GIPR) gene polymorphism (rs10423928) and insulin secretion measured by an oral glucose tolerance test (OGTT). We assessed the influence of this GIPR gene polymorphism on glucose metabolism in 60 schizophrenic patients treated with olanzapine and 103 healthy controls. The GIPR gene polymorphism was determined using TaqMan methods. We performed repeated-measures analysis of variance (ANOVA) and one-way ANOVA for the glucose and insulin levels during OGTTs in four groups divided by the GIPR gene polymorphism and cohort (schizophrenia or control). We found significant effects of the GIPR gene and cohort on the insulin levels at 30 min. Our findings suggest that schizophrenic patients with the A allele of GIPR rs10423928 are at risk of developing hyperinsulinemia when treated with antipsychotics. Show less