Treatment strategies for ocular toxicity from chloropicrin

Michigan State University, East Lansing MI

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Abstract

Project Summary Chemical threat agents like vesicating mustard agents sulfur mustard (SM) and nitrogen mustard (NM) cause clinical and histopathological toxic changes related to inflammation and vesication in both eye and skin tissues. Vesicating agents and some other chemical agents like chloropicrin (CP) and chlorine, cause severe acute and long-term ocular injuries, and remain potential agents of warfare and terror activities. CP, used as a pesticide, is reported to be mixed with other toxic chemicals like vesicants to enhance their ocular and skin toxic effects. Both CP and mustard vesicants cause severe comparable ocular injury, especially to the cornea; however, mechanisms of their injury, especially from CP, are not well-defined and effective targeted treatments are elusive. In our ongoing studies under the current funded NIH-CCRP project, we have established an in vivo mouse ocular injury model with CP and are further defining the role of Nrf2 pathway in CP-induced ocular injury using Nrf2 knockout (KO) mice. Similar to chemical injuries from prominent chemical threats like mustard vesicants and CP, one of the leading causes of radiation induced toxicity involves inflammation and is most prominent in tissues with rapid proliferating cells. Also, acute injuries to various organs including fibrosis and bone marrow suppression as well as infections and long-term health effects are observed following both radiation and chemical exposures. This supplement proposes a collaborative effort with Dr. Saha, funded PI under the NIH RNCP U01 grant, to enhance understanding of the chemical CP and NM induced ocular injury pathways that have shown promise in radiation injury model, and validate if these could be potential therapeutic targets across radiation and chemical injury. Based on results from Dr. Saha’s lab which indicate that chemokine receptor 2 (CCR2) signaling plays an important role in radiation induced inflammation, we hypothesize that CCR2 signaling could regulate chemical induced ocular inflammation and injury as observed in radiation-induced inflammation. We propose to work together with Dr. Saha’s lab to study this hypothesis and will: 1) Obtain the CCR2 KO mice from his lab and the proposed studies will be designed based on radiation in his laboratory; 2) We will share the chemical exposed ocular tissue samples with Dr. Saha’s lab and obtain his assistance for the chemokine and T cell analysis ,and to determine the other inflammatory cells. The below aim expanding the scope of the aim 1 under the funded NIH-CCRP R21 grant is proposed. Specific Aim: Determine the role of CCR2 receptor in CP- and NM-induced acute and long- term ocular inflammation and injury in mice. This collaborative effort is anticipated to identify targets that can be manipulated to counteract broad spectrum inflammation and tissue injury from chemical or radiation exposures and aid in agnostic medical response capabilities during public health emergencies