Functional protection by acute phase proteins alpha(1)-acid glycoprotein and alpha(1)-antitrypsin against ischemia/reperfusion injury by preventing apoptosis and inflammation

Background-Ischemia followed by reperfusion (I/R) causes apoptosis, inflamm ation, and tissue damage leading to organ malfunction. Ischemic preconditio ning can protect against such injury. This study investigates the contribut ion of the acute phase proteins alpha(1)-acid glycoprotein (AGP) and alpha( 1)-antitrypsin (AAT) to the protective effect of ischemic preconditioning i n the kidney. Methods and Results-Exogenous AGP and AAT inhibited apoptosis and inflammat ion after 45 minutes of renal VR in a murine model. AGP and AAT administere d at reperfusion prevented apoptosis at 2 hours and 24 hours, as evaluated by the presence of internucleosomal DNA cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, and the determination of rena l caspase-1- and caspase-3-like activity. AGP and AAT exerted anti-inflamma tory effects, as reflected by reduced renal tumor necrosis factor-alpha exp ression and neutrophil influx after 24 hours. In general, these agents impr oved renal function. Similar effects were observed when AGP and AAT were ad ministered 2 hours after reperfusion but to a lesser extent and without fun ctional improvement. Moreover, I/R elicited an acute phase response, as ref lected by elevated serum AGP and serum amyloid P (SAP) levels after 24 hour s, and increased hepatic acute phase protein mRNA levels after 18 hours of renal reperfusion. Conclusions-We propose that the antiapoptotic and anti-inflammatory effects of AGP and AAT contribute to the delayed type of protection associated wit h ischemic preconditioning and other insults. This mechanism is potentially involved in the course of many clinical conditions associated with I/R inj ury. Moreover, exogenous administration of these proteins may provide new t herapeutic means of treatment.