Molecular Pathways of Iron Detoxification in the Lung

描述（由申请人提供）： 铁是生物体中最丰富的过渡金属，在受伤期间可以从组织中释放出来。释放的催化活性铁的积累已在许多患病肺部中得到证实，例如急性呼吸窘迫综合征和囊性纤维化。相反，以催化活性较低的形式封存铁对于肺防御至关重要。尚未开发出更好、更有效且不会对健康组织造成损害的铁螯合药物。缺乏对肺部铁代谢的了解，阻碍了对其在正常和患病状态下的作用的完整了解，并阻碍了肺部特异性治疗干预的发展。我们的长期目标是了解维持肺部正常铁稳态的分子机制。我们的中心假设是，最近发现的两种跨膜铁转运蛋白 DMT1（二价金属转运蛋白 1）和 MTP1（金属转运蛋白 1）是肺部铁解毒新机制的关键组成部分。 在此过程中，铁通过 DMT1 介导的转移被肺细胞吸收，并通过 MTP1 介导的途径以危害较小的蛋白质结合形式重新输出。 这一假设是根据我们实验室的数据制定的，其中包括 1) DMT1 和 MTP1 基因在气道上皮细胞和肺泡巨噬细胞中被铁激活，2) 内毒素暴露后和在某些患病肺部中 DMT1 和 MTP1 的水平升高，3) MTP1 蛋白独特地定位于气道上皮细胞的顶膜，4) 在多孔膜、元素上培养的人支气管上皮细胞中这些细胞在顶端表面吸收的铁随后以蛋白质结合的形式在同一顶端表面重新释放。我们将使用培养的气道上皮细胞和 DMT1/MTP1 介导的铁转运缺陷的突变小鼠来检验我们的假设。 这项研究将有助于更好地了解患病肺部的铁功能障碍。

DESCRIPTION (provided by applicant): Iron the most abundant transition metal in living organisms can be released from tissues during injury. Accumulation of released catalytic reactive iron has been demonstrated in a number of diseased lungs, for examples, ARDS and cystic fibrosis. Conversely, sequestration of iron in a catalytically less reactive form is fundamentally important in lung defense. Better and more effective iron-chelating drugs, which do not inflict damage on healthy tissues, have not been developed. A lack of knowledge of iron metabolism in the lung hampers a complete understanding of its role in both normal and diseased states, and precludes the development of a lung-specific therapeutic intervention. Our long-term goal is to understand the molecular mechanisms involved in the maintenance of normal iron homeostasis in the lung. Our central hypothesis is that two recently identified transmembrane iron transporters, DMT1 (divalent metal transporter 1) and MTP1 (metal transporter protein 1), are key constituents of a novel mechanism for the detoxification of iron in the lung. In this process, iron is taken up by lung cells via DMT1-mediated transfer and re-exported by the same cells in less harmful protein-bound forms via MTP1-mediated pathway. This hypothesis is formulated based on the data from our laboratories that include 1) DMT1 and MTP1 genes are activated by iron in airway epithelial cells and alveolar macrophages, 2) the levels of DMT1 and MTP1 are elevated after endotoxin exposure and in some diseased lungs, 3) MTP1 protein is localized uniquely to the apical membrane in airway epithelial cells, and 4) in human bronchial epithelial cells cultured on a porous membrane, elemental iron taken up across the apical surface by these cells is later re-released across the same apical surface in protein-bound forms. We will test our hypothesis using cultured airway epithelial cells and mutant mice defective in DMT1/MTP1 mediated iron transport. This study will lead to a better understanding of iron dysfunction in diseased lungs.