Expression and Function of Hemoglobin in Alveolar Epithelial Cells

血红蛋白在肺泡上皮细胞中的表达和功能

• 批准号: 7760163
• 负责人: JOHN E BAATZ
• 金额: $ 32.85万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760163
• 关键词: A549; Acute; Address; Affect; Alveolar; Animals; Antibodies; Binding; Blood Pressure; Cause of Death; Cell Line; Cell physiology; Cells; Coculture Techniques; Complex; Critiques; Data; Dependency; Development; Developmental Biology; Disease; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Erythroid; Erythroid Cells; Exposure to; Fiber; Gases; Gene Chips; Gene Expression; Genes; Genetic; Globin; Hematology; Hemoglobin; Human; Hypoxia; Individual; Inflammation; Injury; Ischemia; Isotope Labeling; Lead; Lung; Measures; Mesenchymal; Metabolism; Mus; NG-Nitroarginine Methyl Ester; Natural Immunity; Natural regeneration; Nickel; Nitric Oxide; Outcome; Oxidative Stress; Paper; Pathology; Peptides; Peptidyl-Dipeptidase A; Physiology; Play; Premature Infant; Process; Production; Proteins; Pulmonary Fibrosis; Pulmonary Hypertension; Pulmonary Surfactants; Reperfusion Therapy; Reporting; Research; Resources; Respiratory distress; Rodent; Role; Silicon Dioxide; Testing; Therapeutic Agents; Time; Tissues; Vertebrates; alveolar epithelium; alveolar type II cell; blood pressure regulation; cell injury; enzyme activity; in vivo; in vivo Model; liquid chromatography mass spectrometry; mortality; neutrophil; nitrosative stress; novel; preconditioning; protective effect; protein degradation; research study; surfactant

DESCRIPTION (provided by applicant): We have demonstrated that hemoglobin is expressed by human and rodent pulmonary epithelial cells, including alveolar type II (ATII) cells and a bronchiolar Clara-like cell line. This novel finding may have enormous implications in the physiology and pathology of the lung due to the many defined roles of hemoglobin, including gas exchange, nitric oxide (NO) metabolism, blood pressure regulation, and protection against oxidative and nitrosative stress. Also, because it is accepted dogma that globin genes are normally expressed solely by erythroid tissue in most vertebrates, these results raise many important questions in hematology, genetics, and developmental biology. In addition to their central role in the development and regeneration of the alveolar epithelium, ATII cell function in surfactant production and innate immunity of the lung, processes known to be affected by NO, and consequently, could also be affected by hemoglobin. Furthermore, the proteolytic turnover of hemoglobin yields several bioactive peptides, collectively termed hemorphins, that could potentially affect the activity of angiotensin-converting enzyme (ACE), which plays an important role in blood pressure regulation and is expressed by ATII cells. We hypothesize that hemoglobin is expressed in ATII cells, that this expression may involve some of the same regulatory mechanisms as those found in erythroid cells, that some of the functions of hemoglobin in the lung are related to NO and pulmonary surfactant production, and that peptides derived from hemoglobin may affect ACE activity in ATII cells. The specific aims that will test this hypothesis are 1) to further characterize the expression of globin genes by ATII cells, 2) to define the relationships between globin gene expression, nitric oxide physiology, and surfactant production in ATII cells, and 3) to determine effects of globin protein turnover and hemorphins in ATII cells. Project Narrative: The proposed experiments will define the functions of hemoglobin in airway cells. Results of this research may lead to the identification of targets for therapeutic agents to treat airway diseases such as persistant pulmonary hypertension (elevated blood pressure) in premature babies, pulmonary fibrosis where cells are damaged from oxidative stress, and acute respiratory distress.

描述（由申请人提供）：我们已经证明了血红蛋白由人和啮齿动物肺上皮细胞表达，包括II型肺泡II（ATII）细胞和支气管菌Clara样细胞系。由于血红蛋白的许多定义作用，包括气体交换，一氧化氮（NO）代谢，血压调节以及防止氧化和硝化应激的保护，这一新发现可能对肺的生理和病理具有巨大影响。同样，由于大多数脊椎动物通常仅由红细胞组织表达球蛋白基因通常被接受的教条，因此这些结果提出了血液学，遗传学和发育生物学中的许多重要问题。除了它们在肺泡上皮的发展和再生中的核心作用外，表面活性剂产生和肺部先天免疫的ATII细胞功能还受到NO的影响，因此也可能受到血红蛋白的影响。此外，血红蛋白的蛋白水解周转率产生了几种生物活性肽，这些肽统称为高电蛋白，可能会影响血管紧张素转化酶（ACE）的活性，这些酶在血压调节中起重要作用，并由ATII细胞表达。 We hypothesize that hemoglobin is expressed in ATII cells, that this expression may involve some of the same regulatory mechanisms as those found in erythroid cells, that some of the functions of hemoglobin in the lung are related to NO and pulmonary surfactant production, and that peptides derived from hemoglobin may affect ACE activity in ATII cells.将检验该假设的具体目的是1）进一步表征ATII细胞的球蛋白基因表达，2）定义球蛋白基因表达，一氧化氮生理学和ATII细胞中的表面活性剂之间的关系，以及3）以确定ATII细胞中球蛋白蛋白质跨度和高透明蛋白的作用。项目叙述：拟议的实验将定义气道细胞中血红蛋白的功能。这项研究的结果可能导致鉴定治疗气道疾病的靶标，例如早产婴儿中的持续性肺动脉高压（血压升高），肺纤维化，其中细胞因氧化应激而受损，急性呼吸困扰。