Properties of Metals May Govern Toxicities in the Lungs

点击翻译按钮获取中文摘要

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.