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.

环境污染物可导致炎症未消退或消退受损， 是导致慢性疾病的关键机制之一。镉（Cd）是一种环境污染物， 对人类健康产生负面影响并增加负担的十大危险化学污染物之一 疾病。一个与环境镉污染相关的负面健康影响的现实例子是北方 伯明翰超级基金网站。已确定位于N.伯明翰环境镉含量高 由于靠近该地区的焦炭和钢铁厂，我们的实验室与 UAB的超级基金研究中心，并与伯明翰超级基金网站的社区密切合作。 在我们对超级基金所在地社区的生物样本的研究中，我们发现， 来自超级基金现场（受影响地区）的慢性呼吸道疾病发病率是其他地区的两倍。环境 暴露于镉可以诱导与持续性炎症相关的失调的解决途径， 这也是呼吸道疾病发病率上升的原因之一。这些人的肺组织和AM 居民表现出较高的镉水平比正常水平。巨噬细胞也表现出减少 红细胞增多能力，存在增加的PAD4和瓜氨酸化CaMKII。我们将研究镉的毒性 PAD4相关下游通路对受损的红细胞增多和气道重塑的介导作用。 我们有3个具体的目的来验证我们的假设，即镉通过PAD 4抑制AM的细胞增殖， 持续的炎症和气道重塑本研究的具体目标是：（1）确定镉的作用机制 诱导PAD 4活性对体外AM细胞增殖的影响，并确定功能障碍的AM 先前描述的3D离体肺球模型。(2)确定镉暴露是否介导 PAD 4依赖性功能障碍性红细胞增多症与体内气道疾病相关。(3)确定是否 镉环境暴露与居民红细胞减少和肺功能的关系 北伯明翰超级基金网站