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.

环境污染物可促进炎症的未解决或受损的分解， 是发展慢性病的关键机制之一。镉是一种环境污染物，是一种 十大有害化学污染物之一，会对人类健康造成负面影响，并增加负担 疾病的威胁。与环境镉污染相关的负面健康影响的一个真实例子是北方 伯明翰超级基金网站。位于伯明翰北部的超级基金网站已被确定具有高环境CD 由于靠近该地区的焦炭和钢铁厂，造成了污染。我们的实验室与 UAB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。 在我们对超级基金网站社区的生物样本进行的研究中，我们发现居民 来自超级基金站点(受影响地区)的慢性呼吸道疾病的发病率是其他地区的两倍。环境 接触Cd可诱导与持续性炎症相关的调节失调的分解途径，这可能是 这是呼吸道疾病发病率增加的原因之一。它们的肺组织和肺泡巨噬细胞 居民的镉水平高于正常水平。巨噬细胞也表现出减少。 泡腾能力，PAD4和瓜氨酸CaMKII的增加。我们将调查镉的毒性 PAD4相关下游通路在泡腾功能受损和气道重塑中的中介作用。 我们有三个特定的目的来验证我们的假设，即CD通过PAD4抑制AM的泡腾作用，PAD4导致 持续的炎症和呼吸道重塑。我们的具体目标是：(1)确定CD的机制 体外诱导肺泡巨噬细胞PAD4活性及功能障碍对肺泡巨噬细胞功能的影响 泡腾吞噬作用先前描述的是3D体外肺气肿模型。(2)确定CD暴露是否通过 体内依赖PAD4的功能障碍的胞吐与呼吸道疾病有关。(3)确定是否 环境镉暴露与居民气泡吞噬功能和肺功能的关系 来自北伯明翰超级基金网站。