Lethality is local, but survival is systemic: Temporal and multi-organ responses to chlorine gas exposure in a murine model

• Lung injury from chlorine gas exposure precedes systemic inflammation and predicts lethality. • Survival is associated with early, coordinated inflammatory and metabolic responses across multiple organs. • Perfusion and tissue acidosis imaging correlate with cytokine, chemokine, and metabolic hormone profiles. • Logistic regression identifies insulin, ghrelin, and eotaxin as key biomarkers of both lethality and survival. Chlorine gas (Cl 2 ) is a highly toxic chemical associated with both localized lung injury and systemic health effects. While pulmonary damage has been well characterized, the systemic inflammatory and metabolic responses remain poorly understood. We aimed to define the temporal and multi-organ responses to Cl 2 exposure in a murine model, with a focus on identifying spatiotemporal inflammation and its impact on survival and lethality. SKH1 mice were exposed for 10 min to varying concentrations of Cl 2 (94.4–810 ppm, representative of non-lethal, LD10, and LD50 doses) and monitored for respiratory function, perfusion, and acidosis using organ-specific imaging. At multiple time points (40 min, 6 h, 24 h, and 7 d), we measured phosphoproteins, cytokines, chemokines, growth factors, and metabolic hormones in the lungs, heart, cortex, and plasma. Statistical modeling and logistic regression were used to identify biomarkers associated with lethality and survival. We found that lung injury was the primary cause of potential lethality, particularly via early phosphoprotein signaling disruptions. However, survival correlated with early systemic coordination of inflammatory and metabolic signals across organs. Perfusion and acidosis imaging were strongly associated with chemokine and hormone responses. Key survival-associated plasma biomarkers included decreased insulin, increased ghrelin, and decreased eotaxin. While potential lethality from Cl 2 exposure is locally driven by pulmonary injury, survival depends on systemic, multi-organ responses that occur rapidly post-exposure. Within this model, our findings identify a potential therapeutic window to enhance survival and suggest candidate biomarkers that may be explored translationally for both triage and treatment of chlorine-related incidents.