Carbon Black Induced Activation of Lung APCs

描述（由申请人提供）： 这项基础研究提案的广泛、长期目标是确定吸入烟雾中存在的颗粒物如何通过抗原呈递细胞（APC）免疫介导的肺病理变化（如肺气肿）启动。我们已经发现，在肺APC中积累的主要烟雾衍生产物是无定形元素碳（炭黑（CB））。我们进一步发现，来自患有肺气肿的吸烟者的肺的CB负载的APC表现出独特的microRNA（miRNA）特征，并且在功能上它们诱导辅助性T细胞1型（Th 1）和Th 17细胞的活化。此外，特异性Th 1和Th 17细胞因子通过诱导基质金属蛋白酶（MMP）12的分泌促进肺气肿中的肺破坏，所述基质金属蛋白酶（MMP）12降解弹性蛋白并抑制α 1抗胰蛋白酶（嗜中性粒细胞弹性蛋白酶的抑制剂）。由此产生的弹性蛋白溶解的恶性循环削弱肺实质的完整性，随着时间的推移表现为上叶为主的肺气肿。miRNA通过控制关键的共刺激分子和促炎细胞因子的表达，潜在地促进APC的活化，并因此促进肺气肿。因为CB是由有机材料燃烧产生的所有形式的烟雾所固有的（例如，烟草）并构成一种重要的污染形式（例如，通过采煤、橡胶轮胎的磨损、柴油机尾气等）我们假设吸入CB可以诱导肺APC的成熟，并促进T细胞分化为与疾病如肺气肿和肺癌相关的Th 1和Th 17亚群。我们提出使用独特的基于CB的肺部炎症实验模型来1）确定肺的免疫表型和小鼠肺APC响应CB吸入的功能;和2）确定miRNA在CB诱导的肺APC活化中的作用。

DESCRIPTION (provided by applicant): The broad, long-term objective of this basic research proposal is to determine how inhalation of particulates present in smoke could initiate through antigen presenting cells (APC) immune-mediated lung pathological changes such as emphysema. We have found that a major smoke-derived product that accumulates in lung APCs is amorphous, elemental carbon (carbon black (CB)). We have further found that CB-laden APCs from the lung of smokers with emphysema manifest a distinct microRNA (miRNA) signature and that functionally they induce activation of T helper type 1 (Th1) and Th17 cells. Moreover, specific Th1 and Th17 cytokines promote lung destruction in emphysema by inducing the secretion of matrix metalloproteinase (MMP) 12 that degrades elastin and inhibits alpha 1 anti-trypsin, an inhibitor of neutrophil elastase. The resulting vicious cycle of elastolysis weakens lung parenchymal integrity that over time manifests as upper lobe-predominant emphysema. miRNAs potentially contribute to the activation of APC and therefore emphysema by controlling expression of key co-stimulatory molecules and pro-inflammatory cytokines. Because CB is intrinsic to all forms of smoke arising from the combustion of organic material (e.g., tobacco) and constitutes an important form of pollution (e.g., through coal mining, the wearing of rubber tires, diesel exhaust, etc.) we hypothesize that inhaled CB could induce maturation of lung APCs and promote differentiation of T cells into Th1 and Th17 subsets that are linked to diseases such as emphysema and lung cancer. We propose using a unique CB- based experimental model of lung inflammation to 1) Determine the immune phenotype of lung and the function of mouse lung APCs in response to CB inhalation; and 2) Determine the role of miRNAs in CB- induced activation of lung APC.