COUNTERACT Supplement--ASPIRE: Air Pollution: Strategies for Personalized Intervention to Reduce Exposure

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ABSTRACT Chlorine is a reactive gas that is a continuing chemical threat given the large amounts produced and used for industrial application from both intentional and accidental release. The current administrative supplement to the parent application is directed towards development of next generation therapeutics that can significantly reduce mortality and morbidity in the event of release of this chemical threat. The studies published by our group in from our parent grant have collectively paved the way for the concept that PM2.5 exposure results in systemic inflammation (including neuronal inflammation) through TLR4 and oxidative stress pathways. Recently we have demonstrated that the Nrf2-Keap2 system could represent a key pathway through which barrier function may be maintained. Activation of Nrf2 may represent a therapeutic modality to abrogate barrier dysfunction and attenuate chlorine injury. In this supplemental application we will test 2 aims that besides providing mechanistic insights into cardiopulmonary injury with chlorine exposure will also test 2 strategies, TLR4 inhibition and Nrf2 activation in mitigating systemic inflammation in response to chlorine exposure. In Aim 1 we will examine the effect of different doses of chlorine exposure on generation of TLR4 activators such as oxidized phospholipids in the lung surfactant fluid and the impact of these on lung and systemic inflammation in wildtype, TLR4-/- and Keap1-/-mice. We will investigate the impact of intranasal and systemic delivery of TLR4 inhibitors in protecting against chlorine injury. In Aim 2 we will test the concept that blood brain barrier permeability with chlorine is an important component of systemic toxicity and will test the impact of several novel small molecular Nrf2 activators in reducing CNS and lung inflammation. To achieve these objectives and in order to extend the findings from the original study (based on our preliminary studies) we request a specific supplement that will enable us to test these concepts. We believe that this supplemental award is highly responsive to the special request for supplements to the NIH Countermeasures Against Chemical Threats (CounterACT) program.