Environmental Cadmium, persistent inflammation and airways disease

环境镉、持续性炎症和气道疾病

• 批准号: 10637234
• 负责人: Ranu Surolia
• 金额: $ 44.26万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637234
• 关键词: 3-Dimensional; Affect; Airway Disease; Area; Arginine deiminase; Biological; CD36 gene; Cadmium; Calmodulin; Chronic Disease; Coke; Communities; Data; Disease; Environmental Exposure; Environmental Pollutants; Enzymes; Exposure to; Hazardous Chemicals; Health; Homeostasis; Human; Impairment; In Vitro; Incidence; Inflammation; Inhalation; Interleukin-10; Knock-out; Laboratories; Life; Lung; Macrophage; Mediating; Mitochondria; Mitochondrial Matrix; Modeling; Molecular; Mus; NF-kappa B; Organoids; Particulate Matter; Pathway interactions; Phosphotransferases; Plants; Pollution; Population; Proteins; Pulmonary Function Test/Forced Expiratory Volume 1; Reporting; Research; Resolution; Saline; Sampling; Signal Transduction; Site; Steel; Structure of parenchyma of lung; Superfund; System; Testing; Tissues; Toxic effect; Work; airway remodeling; burden of illness; chronic respiratory disease; citrullinated protein; coal-fired power plant; gain of function; improved; in vivo; loss of function; mitochondrial dysfunction; overexpression; pollutant; pulmonary function; small airways disease; superfund site

Environmental pollutants can contribute to the unresolved or impaired resolution of inflammation which is one of the critical mechanisms for developing chronic diseases. Cadmium (Cd), an environmental pollutant, is one of the top ten hazardous chemical pollutants that negatively impacts human health and increases the burden of disease. One real-life example of environmental Cd pollution-related negative health impacts is the North Birmingham Superfund site. It is established that Superfund Site at N. Birmingham has high environmental Cd contamination due to being near coke and steel plants in the area. Our laboratory is associated with the Superfund Research Center at UAB and works closely with the community at the Birmingham Superfund Site. In our research with the biological samples from the superfund site community, we have found that residents from Superfund Site (Affected Area) have two times more incidence of chronic airway diseases. Environmental exposure to Cd can induce dysregulated resolution pathways related to persistent inflammation which can be one of the reasons for the increased incidences of airway diseases. The lung tissue and AMs from these residents demonstrate higher levels of Cd than normal levels. The macrophages also demonstrated decreased efferocytosis ability, presence of increased PAD4 and citrullinated CaMKII. We will be investigating Cd toxicity mediated effects of PAD4 related downstream pathways for the impaired efferocytosis and airway remodeling. We have 3 specific aims to test our hypothesis that Cd inhibits efferocytosis by AMs through PAD4 which leads to continued inflammation and airway remodeling. Our specific aims are: (1) determine the mechanisms of Cd induced PAD4 activity on efferocytosis by AMs in vitro and determine the impact of AMs with dysfunctional efferocytosis previously described 3D ex-vivo pulmospheres model. (2) Determine if Cd exposure mediated PAD4 dependent dysfunctional efferocytosis is associated with airway disease in vivo. (3) Determine if association of environmental exposure of Cd and decreased efferocytosis, and lung function in the residents from North Birmingham Superfund Site.

环境污染物可能导致炎症无法解决或消退受损， 是发生慢性疾病的关键机制之一。镉 (Cd) 是一种环境污染物 影响人体健康、增加负担的十大危险化学污染物之一 的疾病。环境镉污染对健康造成负面影响的现实例子之一是北方 伯明翰超级基金网站。确定位于伯明翰北部的超级基金场地具有较高的环境镉含量 由于靠近该地区的焦化厂和钢铁厂而受到污染。我们的实验室与 UAB 的超级基金研究中心与伯明翰超级基金站点的社区密切合作。 在我们对超级基金站点社区的生物样本进行研究时，我们发现居民 来自超级基金站点（受影响地区）的慢性气道疾病发病率是其两倍。环境的 暴露于镉会导致与持续性炎症相关的消解途径失调，这可能是 气道疾病发病率增加的原因之一。肺组织和来自这些的 AM 居民的镉含量高于正常水平。巨噬细胞也表现出减少 胞吞作用能力、PAD4 和瓜氨酸 CaMKII 增加的存在。我们将调查镉的毒性 PAD4 相关下游通路对胞吞作用和气道重塑受损的介导作用。 我们有 3 个具体目标来检验我们的假设，即 Cd 通过 PAD4 抑制 AM 的胞吞作用，从而导致 持续的炎症和气道重塑。我们的具体目标是：（1）确定Cd的机制 在体外诱导 PAD4 对 AMs 胞吞作用的活性，并确定 AMs 对功能失调的影响 efferocytosis 先前描述了 3D 离体肺球模型。 (2) 确定镉暴露是否介导 PAD4 依赖性功能失调的胞吞作用与体内气道疾病相关。 (3) 判断是否 镉环境暴露与居民胞吞作用减少和肺功能的关系 来自北伯明翰超级基金网站。