Properties of Metals May Govern Toxicities in the Lungs

描述（由申请人提供）：需要将无机化学和医学联系起来的研究，以便建立合理设计/筛选金属药物的原则，特别是可吸入形式。对金属在原位作用的更好理解将使研究人员能够提高这种新化合物的特异性，并控制其毒性。为确定暴露于空气中的金属污染物对健康的不良影响的潜在机制而进行的研究提供了信息，可据此发展所需的研究类型。研究表明，吸入某些金属会导致肺部细菌耐药性和局部免疫细胞功能的改变，很明显，免疫调节程度的变化不仅取决于肺中沉积的金属量，还取决于所使用的药物。由此可见，如果药物特异性决定了免疫调节的诱导程度，那么每种金属固有的物理化学性质可能在引发这种效应方面起着重要作用。基于这个前提，这个项目的目标是双重的——提高对生命系统中金属反应的理解，并帮助建立可能促进新型金属药物设计的基本原理。利用诱导肺免疫调节作为反映吸入异种生物潜在毒性的参数，我们假设对于任何金属，就地免疫调节电位的主要决定因素是它的(a)氧化还原行为和价，部分原因是它们控制着金属可能影响谷胱甘肽（GSH）和NAD(P)H还原剂的可用性/利用程度，这些还原剂对优化肺泡巨噬细胞（PAM）和中性粒细胞（PMN）功能至关重要；(B)溶解度。因为它控制着这些细胞的整体金属生物利用度。提出了一种综合分层方法来检查肺免疫毒性内部和之间的潜在差异。各种钒、铬、铅和锌试剂将作为具有不同物理化学性质的环境金属污染物的模型。每种药物首先将被测试临床效果（即，暴露5天（5小时/天）对随后单核细胞增生李斯特菌感染的肺部先天免疫反应的影响），因为这产生的数据反映了对肺部免疫能力的总体影响，重要的是，让没有效果的药物从分析中删除。为了确定在明显的免疫调节剂之间是否可能存在共同的作用机制，并利用实施的变化作为检查每种特性影响的手段，研究将检查暴露对PAM和PMN的影响：谷胱甘肽和NAD(P)H状态；在先天反应中，还原剂影响对细胞募集/激活和激活状态至关重要的因子的产生/表达。通过确定金属的某些性质是否比其他性质与毒性更相关，这可能为研究人员提供必要的基础，以预先在金属药物中使用某些金属离子/配合物。

DESCRIPTION (provided by applicant): Research bridging inorganic chemistry and medicine is needed so principles can be established to permit rational design/screening of metallopharmaceuticals, particularly inhalable forms. An improved understanding of how metals act in situ would enable Investigators to improve the specificity, and control the toxicity, of such novel compounds. Studies to define mechanisms underlying adverse health effects from airborne metal pollutant exposure have provided information from which the types of studies needed can evolve. In studies showing that inhalation of some metals led to altered lung bacterial resistance and local immune cell function, it was clear that variations in degree of immunomodulation induced did not simply depend on amount of metal deposited in the lung, but also on the agent used. It follows that if agent specificity governs extent of immunomodulation induced, then physicochemical properties inherent to each metal may have contributing roles in eliciting the effects. Based on this premise, the goal of this project is two-fold - to improve understanding of reactions of metals in living systems and to help establish basic principles that may facilitate design of novel metallopharmaceuticals. Using induction of pulmonary immunomodulation as a parameter to reflect potential toxicity of an inhaled xenobiotic, we hypothesize that for any metal, major determinants of immunomodulatory potential in situ are its (A) redox behavior and valency, due, in part, to their governing the extent to which the metal might affect availability/utilizability of glutathione (GSH) and NAD(P)H reductants critical to optimal alveolar macrophage (PAM) and neutrophil (PMN) function and (B) solubility, in that it governs overall metal bioavailability to these cells. An integrated hierarchical approach is proposed to examine potential differences in pulmonary immunotoxicity within and between properties. Various vanadium, chromium, lead, and zinc agents will serve as models for ambient metal pollutants with diverse physicochemical properties. Each agent will first be tested for a clinical effect (i.e., impact of 5 d (5 hr/d) exposure on the lung innate immune response to a subsequent Listeria monocytogenes infection) as this yields data reflecting overall impact on lung immunocompetence and, importantly, lets agents with no effect to be dropped from analyses. To determine if there may be a common mechanism of effect among the demonstrably immunomodulatory agents, and to use variations in implementation as a means to examine influence of each property, studies will then examine exposure effects on PAM and PMN: GSH and NAD(P)H status; reductant-influenced production/expression of factors critical to cell recruitment/activation and, activation status, during innate responses. By establishing if certain properties of metals are more relevant to toxicity than others, this may provide Investigators a needed basis to preempt use of some metal ions/complexes in metallopharmaceuticals.