Relevance of the Platelet-activating factor system in chemical warfare agents-induced effects

The threats to chemical warfare-associated agents (CWA), including nitrogen mustard, are increasing, and no direct antidote is currently available to mitigate the deleterious cutaneous and systemic responses to prevent mortality. Though most of these agents act as alkylating agents, a significant knowledge gap exists in the molecular mechanisms of how these vesicants cause toxic effects. Studies, including ours, have shown that exposure to reactive oxygen species (ROS)-generating stimuli, including alkylating chemotherapeutic agents, and thermal burn injuries with ethanol produce the potent family of lipid mediators, Platelet-activating factor (PAF) agonists that induce local inflammation, and multi-system organ dysfunction (MOD). Notably, nano-sized microvesicle particles (MVPs), released from cells in response to stimuli, carry PAF-agonists and act as potent signaling agents to induce the local (cutaneous) and systemic responses. The current review highlights mechanistic insights and applicable approaches to mitigate CWA-induced local and systemic toxic responses with implications in cellular senescence and aging.