For unknown reasons, intensive insulin therapy not only normalizes the elevated blood glucose levels but also, and remarkably, increases the survival of non-diabetics and diabetics with critical (ICU-type) illnesses. Our basic premise is that (1) hyperglycemia increases inflammation and acute lung injury (ALI) and (2) insulin therapy decreases inflammation and ALI. Our specific hypothesis is that hyperglycemia increases cytokines which increase mononuclear phagocyte (MNP) xanthine oxidoreductase (XOR) activity, NF-(B activation and IL-8 production which, in turn, increase neutrophil (PMN) recruitment and ALI severity;the corollary to this hypothesis is that insulin has an opposing effect on this mechanism. Our preliminary data supports this approach: 1. XOR increases in newly recruited MNP which are recovered from lungs of rats insufflated with IL-1 and IFN-( and MNP XOR can promote recruitment of PMN into lungs of control rats. 2. Hyperglycemia increases ALI, CINC (rat IL-8 equivalent) levels and PMN recruitment in lungs of rats insufflated with IL-1 and IFN-( in vivo and induces cytokines that up-regulate XOR expression in vitro. 3. Insulin therapy decreases MNP C/EBPp activity, MNP XOR activity, MNP NF-(B activity, PMN recruitment and injury in lungs of rats insufflated with IL-1 and IFN-( in vivo. 4. Cytokines, MAP kinases and C/EBP-3 increase the XOR expression of epithelial cells in vitro. Our three specific aims are the following:
Specific Aim 1 : To determine the effect of glucose infusion and/or insulin therapy on the ability of MNP to recruit PMN into the lung in vivo.
Specific Aim 2 : To determine if alterations in XOR activity in MNP contribute to the different PMN recruiting activities of MNP from rats given glucose infusions and/or insulin therapy.
Specific Aim 3 : To determine the mechanism by which glucose infusion and/or insulin therapy regulate MNP XOR expression and ROS signaling. Significance: This translational research will determine the effect of hyperglycemia and/or insulin therapy on ALI using an innovative, new technology that measures blood glucose levels continuously and non-invasively. By defining the underlying mechanisms for this life-saving clinical finding, we will improve understanding of the pathogenesis of ALI and find better strategies for controlling hyperglycemia, giving insulin and/or using other interventions to treat and prevent ALI.
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