Ferroxidases are essential for normal iron homeostasis in most organisms. The paralogous vertebrate ferroxidases ceruloplasmin (Cp) and hephaestin (Heph) are considered to have nonidentical functions in iron transport: plasma Cp drives iron transport from tissue stores while intestinal Heph facilitates iron absorption from the intestinal lumen. To clarify the function of Cp, we acutely bled Cp-/- mice to stress iron homeostasis pathways. Red cell hemoglobin recovery was defective in stressed Cp-/- mice, consistent with low iron availability. Contrary to expectations, iron was freely released from spleen and liver stores in Cp-/- mice, but intestinal iron absorption was markedly impaired. Phlebotomy of wild-type mice caused a striking shift of Cp from the duodenal epithelium to the underlying lamina propria, suggesting a critical function of Cp in basolateral iron transport. Regulated relocalization of intestinal Cp may represent a fail-safe mechanism in which Cp shares with Heph responsibility for iron absorption under stress.

Objective To gain insights into individual variations in acute inflammation and physiology. Design Large-animal study combined with mathematical modeling. Setting Academic large-animal and computational laboratories. Subjects Outbred juvenile swine. Interventions Four swine were instrumented and subjected to endotoxemia (100 μg/kg), followed by serial plasma sampling. Measurements and Main Results Swine exhibited various degrees of inflammation and acute lung injury (ALI), including one death with severe ALI (P/F ratio <200 and static compliance <10 L/cmH2O). Plasma interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, high mobility group box-1 (HMGB1), and NO2−/NO3−,, were significantly (p <0.05) elevated over the course of the experiment. Principal Component Analysis (PCA) was used to suggest principal drivers of inflammation. Based in part on PCA, an Ordinary Differential Equation (ODE) model was constructed, consisting of the lung and the blood (as a surrogate for the rest of the body), in which endotoxin induces TNF-αin monocytes in the blood, followed by the trafficking of these cells into the lung leading to the release of HMGB1, which in turn stimulates the release of IL-1βfrom resident macrophages. The ODE model also included blood pressure, PaO2, and FiO2, and a damage variable that summarizes the health of the animal. This ODE model could be fit to both inflammatory and physiologic data in the individual swine. The predicted time course of damage could be matched to the Oxygen Index in 3 of the 4 swine. Conclusions The approach described herein may aid in predicting inflammation and physiological dysfunction in small cohorts of subjects with diverse phenotypes and outcomes.