抄録
That respiratory defense mechanisms are stimulated by oxidants/electrophiles has long been appreciated. Our work has focused on characterizing two such defense pathways from an inhalation toxicological perspective: 1) neuronal reflex responses, initiated by the transient receptor potential ankyrin 1 (TRPA1) receptor, and 2) cellular antioxidant defenses initiated via the nuclear factor erythroid 2-related factor (NRF2). TRPA1 and NRF2 are oxidant sensitive receptors expressed throughout the respiratory tract. They are activated by reactive inhaled agents (acrolein) or by local metabolic activation of inhaled or systemically delivered agents (naphthalene, acetaminophen). Exposure to inhaled and systemic oxidants in combination results in synergistic TRPA1 and NRF2 responses. Oxidant responses have also been characterized among respiratory tract regions and between electrophiles with differing reactivity. When normalized to delivered dose, inhaled oxidant/electrophile induction of pro-inflammatory genes is similar throughout the airways, however, differences exist in the NRF2-dependent antioxidant gene induction patterns between regions. Activation of both TRPA1 and NRF2 depends on toxicant interaction with sulfhydryl moieties. The oxidant exposure levels necessary for activation of TRPA1 and NRF2 responses are similar suggesting both oxidant sensors are of comparable sensitivity. While soft electrophiles, such as acrolein, react with sulfhydryls, hard electrophiles, such as diacetyl, do not. Unlike acrolein, inhaled diacetyl is only a weak activator of either neuronal reflexes or NRF2 pathways, suggesting the chemical electrophilic reactivity profiles of TRPA1 and NRF2 are comparable. Overall, the oxidant sensitive receptors TRPA1 and NRF2 demonstrate many toxicologically relevant similarities
