Nasal solitary chemosensory cells linking irritation to inflammation

鼻孤立化学感应细胞将刺激与炎症联系起来

• 批准号: 8426159
• 负责人: Marco Tizzano
• 金额: $ 14.35万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426159
• 关键词: Acetylcholine; Acute; Address; Affect; Animals; Antibodies; Apnea; Asthma; Bacterial Infections; Breathing; CX3CL1 gene; Cations; Cell Maturation; Cell physiology; Cell surface; Cells; Chemicals; Choline; Coughing; Dendritic Cells; Disease; Elements; Enzyme-Linked Immunosorbent Assay; Enzymes; Epithelial; Epithelial Cells; Epithelium; Exhibits; Exposure to; Extravasation; Financial compensation; Free Nerve Ending; GTP-Binding Proteins; Genes; Goals; Hour; Hypersensitivity; Immune; Immune response; Immune system; Immunoassay; Inflammation; Inflammatory; Inflammatory Response; Ion Channel; Irritants; Larynx; Lead; Leukocytes; Link; Lung; Lung diseases; Measures; Mediating; Molecular; Molecular Analysis; Mucous Membrane; Mus; Nasal Epithelium; Nasal cavity; Neurogenic Inflammation; Neutrophil Infiltration; Nose; Olfactory Epithelium; Parasitic infection; Pathway interactions; Peroxidases; Plasma; Play; Population; Preparation; Process; Receptor Cell; Recruitment Activity; Reflex action; Respiratory System; Respiratory tract structure; Role; Side; Signal Transduction; Signaling Molecule; Sneezing; Staining method; Stains; Stimulus; Structure of mucous membrane of nose; Structure of respiratory epithelium; Surface; Taste Perception; Testing; Time; Tissue Stains; Tissues; Transferase; Transgenic Mice; Trigeminal nerve structure; Up-Regulation; Upper respiratory tract; chemokine; choline transporter; combat; cytokine; denatonium benzoate; eosinophil; homoserine lactone; immunocytochemistry; inflammatory marker; irritation; macrophage; mast cell; monocyte; neutrophil; pathogenic bacteria; promoter; quorum sensing; rat Gnat3 protein; receptor; research study; respiratory; respiratory reflex; response; vomeronasal organ

DESCRIPTION (provided by applicant): Chemical irritation of airway mucosa elicits a variety of reflex responses such as sneezing, apnea, coughing and laryngeal closure aimed to protect the lungs from damage. Nasal mucosa irritation also activates inflammatory and local immune responses aimed to protect the nasal epithelium and avoid disorders affecting the olfactory epithelium. Inhaled irritants can activate either chemo-responsive free nerve endings or solitary chemosensory cells (SCCs) which are specialized chemo-sensitive epithelial cells innervated by the trigeminal nerve. SCCs express elements of the bitter taste transduction cascade, i.e. Tas2R bitter taste receptors, G- protein -gustducin, PLC2 and the TrpM5 transient receptor potential ion-channel (Tizzano et al. 2010). In this proposal, I focus on the downstream action of SCCs as modulators of function of the surrounding epithelial cells including dendritic or macrophage cells of the immune system. I will test the hypothesis that irritant- induced activation of nasal SCCs leads to an immune and/or inflammatory response in the local epithelium. A consequence of that is whether the airway immune cells can be activated and attracted to the chemo-responsive SCCs, and whether SCC excitation activates the immune cells to mature and express new molecular and functional markers. In the proposed studies we will test whether activation of SCCs by an inhaled irritant causes an inflammatory response of the nasal epithelium and determine if SCC activation leads to a local response by macrophages and/or dendritic cells. In order to test whether SCCs are necessary for these responses, we will utilize mice that lack TrpM5 (TrpM5-KO), a transient receptor potential cation channel necessary for SCC function. We previously established that these mice have impaired responsiveness to particular irritants (Tizzano et al. 2010). However, the interactions of SCCs with the surrounding respiratory epithelial or immune cells and the link between SCCs and inflammation after irritant exposure are not understood. To address this issue, the current proposal will determine whether immune cells are recruited by the SCCs in response to an irritant stimulus and whether in response to irritants, the SCCs will lead to a local inflammatory response of the nasal epithelium. These studies will provide the first evidence for an epithelial cell, the SCCs, as a ke receptor cell involved in the local inflammatory and immune responses to irritant compounds.

描述（由申请方提供）：气道粘膜的化学刺激引起各种反射反应，如打喷嚏、呼吸暂停、咳嗽和喉闭合，旨在保护肺部免受损伤。鼻粘膜刺激还激活炎症和局部免疫反应，旨在保护鼻上皮并避免影响嗅觉上皮的疾病。吸入的刺激物可以激活化学反应性游离神经末梢或单独的化学感受细胞（SCC），其是由三叉神经支配的特化化学敏感上皮细胞。SCC表达苦味转导级联的元件，即Tas 2 R苦味受体、G蛋白-味觉蛋白、PLC 2和TrpM 5瞬时受体电位离子通道（Tizzano等人，2010）。在这个提议中，我专注于SCC作为周围上皮细胞（包括免疫系统的树突状细胞或巨噬细胞）功能调节剂的下游作用。我将检验刺激物诱导的鼻腔SCC激活导致局部上皮免疫和/或炎症反应的假设。其结果是气道免疫细胞是否可以被激活并被吸引到化学反应性SCC，以及SCC激发是否激活免疫细胞以成熟并表达新的分子和功能标志物。在拟议的研究中，我们将测试吸入刺激物是否激活SCC导致鼻上皮的炎症反应，并确定SCC激活是否导致巨噬细胞和/或树突状细胞的局部反应。为了测试SCC是否是这些反应所必需的，我们将利用缺乏TrpM 5（TrpM 5-KO）的小鼠，TrpM 5是SCC功能所必需的瞬时受体电位阳离子通道。我们先前确定这些小鼠对特定刺激物的反应性受损（Tizzano等人，2010）。然而，SCC与周围呼吸道上皮细胞或免疫细胞的相互作用以及SCC与刺激物暴露后炎症之间的联系尚不清楚。为了解决这个问题，目前的建议将确定免疫细胞是否被SCC招募以响应刺激物刺激，以及SCC是否响应刺激物将导致鼻上皮的局部炎症反应。这些研究将提供第一个证据，上皮细胞，SCC，作为一个ke受体细胞参与局部炎症和免疫反应的刺激性化合物。