Parathyroid hormone related-protein (PTHrP), when produced in excessive amounts by tumors, is well known to cause hypercalcemia of malignancy. In contrast, the role of PTHrP in normal physiology remains an enigma. The fact that PTHrP has many features in common with cytokines led me to initiate a series of in vivo mouse studies to determine if the cascade of cytokines produced in response to endotoxin (LPS) also included the stimulation of PTHrP expression. These initial studies have shown that PTHrP mRNA levels are induced in the spleen during the host response to endotoxin, and that tumor necrosis factor is a major mediator of this increase. These studies provide the first evidence that cytokines and/or infection can regulate PTHrP expression in vivo.
The aim of this project is to determine whether PTHrP production is also stimulated in other vital organs, such as the heart, lung, kidney, and liver and in other models of infection and inflammation. Demonstrating that PTHrP is a component of the host response to infection and inflammation will open an entirely new area to explore in determining the physiologic role of PTHrP. To begin to understand the regulation of PTHrP in response to infection and inflammation, studies will be undertaken to determine which cytokines mediate PTHrP expression in each of the vital organs where PTHrP is induced. In addition, the cells producing PTHrP in these organs in response to infectious or inflammatory stimuli will be identified using both in situ hybridization and immunohistochemistry. In vivo studies will also be carried out to determine whether PTHrP, a known vasodilator, contributes to the hemodynamic changes that characterize septic shock.
