Expression and Function of Hemoglobin in Alveolar Epithelial Cells

描述(申请人提供)：我们已经证明了人和啮齿动物的肺上皮细胞表达血红蛋白，包括肺泡II型(ATII)细胞和细支气管型Clara样细胞系。这一新发现可能对肺的生理学和病理学具有巨大的影响，因为血红蛋白具有许多明确的作用，包括气体交换、一氧化氮(NO)代谢、血压调节以及对氧化和亚硝化应激的保护。此外，由于大多数脊椎动物的珠蛋白基因通常只由红系组织表达这一信条，这些结果在血液学、遗传学和发育生物学中提出了许多重要的问题。除了在肺泡上皮细胞的发育和再生中发挥核心作用外，ATII细胞还在肺表面活性物质的产生和肺的先天免疫中发挥作用，这是已知的受NO影响的过程，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性周转产生几个生物活性多肽，统称为血型，可能会影响血管紧张素转换酶(ACE)的活性，血管紧张素转换酶(ACE)在血压调节中发挥重要作用，并由ATII细胞表达。我们假设血红蛋白在ATII细胞中表达，这种表达可能涉及与红系细胞相同的一些调节机制，血红蛋白在肺中的一些功能与NO和肺表面活性物质的产生有关，以及来自血红蛋白的多肽可能影响ATII细胞中的ACE活性。检验这一假说的具体目的是：1)进一步确定ATII细胞珠蛋白基因表达的特征，2)确定ATII细胞珠蛋白基因表达、一氧化氮生理和表面活性物质产生之间的关系，以及3)确定ATII细胞珠蛋白周转和血沉的影响。项目简介：拟议中的实验将定义血红蛋白呼吸道细胞的功能。这项研究的结果可能导致确定治疗药物治疗呼吸道疾病的靶点，如早产儿持续性肺动脉高压(血压升高)、肺纤维化(细胞因氧化应激而受损)和急性呼吸窘迫。

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.