In animals or humans suffering the consequences of hemorrhagic shock (HS), polymorphonuclear neutrophilic granulocytes (PMN) are the major cellular element that mediates the inflammatory process. We propose that PMN activation is an early event in HS initiated by the consequences of ischemia and resuscitation which includes the production and action of granulocyte colony-stimulating factor (G-CSF). We have demonstrated elevated G-CSF mRNA levels in critical organs including the lung, liver, and bowel in our rat model of HS. Levels of G-CSF mRNA increased with increasing severity of HS. We have identified bronchial epithelial cells as the major cellular source of G-CSF production in the lung in HS. In addition to our findings in rats, we have observed a 55-fold increase in G-CSF mRNA production in the livers of patients with HS. To establish that G-CSF production in the organs of animals and patients with HS is deleterious to the host, we demonstrated that instillation of G-CSF alone into the lungs of rats results in PMN recruitment and lung damage. In related work, we have shown that G-CSF specifically activates a distinct member of the signal transduction and activator of transcription (STAT) family, Stat3(, in PMN. PMN of rats subjected to HS revealed greater Stat3( activity than sham animals. In addition, PMN from patients suffering from HS showed clear evidence of G-CSF-induced Stat3( activation. Taken together, our findings to date strongly support the hypothesis that G-CSF is produced in critical organs in HS where it binds to PMN resulting in organ inflammation. The overall goal of this proposal is determine how G-CSF production occurs in HS and how its production leads to PMN recruitment and activation in HS and its morbid sequellae. Towards this end, the two Specific Aims of this project are:
AIM I : To determine the consequences of G-CSF production on PMN recruitment, Stat3( activation, and organ injury in HS and to examine the effect of blocking the G-CSF signaling pathway in PMN on morbidity and mortality of HS.
AIM II : To determine the factors contributing to G-CSF production at critical sites of PMN recruitment and organ injury.
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