Expression and Function of Hemoglobin in Alveolar Epithelial Cells

描述（由申请方提供）：我们已经证明血红蛋白由人类和啮齿动物肺上皮细胞表达，包括肺泡II型（ATII）细胞和细支气管Clara样细胞系。由于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、血压调节以及对抗氧化和亚硝化应激的保护，这一新发现可能对肺部的生理和病理学产生巨大影响。此外，因为它是公认的教条，珠蛋白基因通常只表达的红细胞组织在大多数脊椎动物，这些结果提出了许多重要的问题，在血液学，遗传学和发育生物学。除了它们在肺泡上皮的发育和再生中的中心作用之外，ATII细胞在肺的表面活性剂产生和先天免疫中的功能，已知这些过程受NO的影响，因此也可能受血红蛋白的影响。此外，血红蛋白的蛋白水解周转产生几种生物活性肽，统称为血红素，可能会影响血管紧张素转换酶（ACE）的活性，这在血压调节中起着重要作用，并由ATII细胞表达。我们假设，血红蛋白在ATII细胞中表达，这种表达可能涉及一些相同的调节机制，发现在红系细胞中，血红蛋白在肺中的一些功能与NO和肺表面活性物质的生产，以及来自血红蛋白的肽可能会影响ACE活性在ATII细胞。检验这一假设的具体目的是：1）进一步表征ATII细胞的珠蛋白基因表达，2）确定ATII细胞中珠蛋白基因表达、一氧化氮生理学和表面活性剂产生之间的关系，3）确定ATII细胞中珠蛋白蛋白周转和血红素的影响。项目叙述：拟议的实验将定义血红蛋白在气道细胞中的功能。这项研究的结果可能会导致治疗药物的目标，以治疗气道疾病，如早产儿持续性肺动脉高压（血压升高），肺纤维化，其中细胞因氧化应激而受损，以及急性呼吸窘迫。

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.