Abstract 10249: Differential Regulation of Neutrophil Mobilization and Integrin Expression in Females Protects Against Ischemia/Reperfusion-Induced Local and Remote Tissue Injury
Ischaemia/reperfusion (I/R) injury is implicated in several important clinical scenarios including stroke and myocardial infarction; conditions where the incidence and severity is substantially lower in women compared to age-matched men. Similarly, in experimental models, females are protected from the consequences of I/R in the heart, liver, kidney and brain. However, many fundamental aspects of the nature of this sex-difference are unknown. Herein we tested the hypothesis that sex-differences in the phenotype of leukocytes that are mobilized and recruited during I/R underlies protection from vascular injury in females. To visualise leukocyte dynamics and assess leukocyte phenotype during I/R, we performed mesenteric I/R (by occlusion of superior mesenteric artery for 30 min followed by 2h reperfusion) in age-matched male and female Wistar rats. Reperfusion-induced gut necrosis and lung neutrophil-infiltration were significantly less (P<0.001, n=6) in females than males (necrosis: 13±1.3% & 37±1.2% at 2h, respectively) and directly correlated (r2=0.78, P<0.001) with the number of circulating PMNs. In-line with these observations; I/R-induced bone marrow (BM) granulopoiesis and PMN mobilization were significantly less in females. Moreover leukocyte flux, adhesion and emigration through mesenteric venules were profoundly suppressed in females throughout the reperfusion period. FACS analysis revealed lower expression of integrins β1, β2, αL, αM & α4 on BM and circulating PMNs in females and lower expression of integrin ligands VCAM-1 and ICAM-1 in mesenteric tissue. Thus in females, dampened elevation in total circulating PMNs in conjunction with reduced expression of PMN integrins and tissue expression of specific pathways that mediate PMN trafficking results in substantially less tissue PMN infiltration and tissue injury at sites local and remote to the ischemic insult. Our study demonstrates for the first time that differential regulation of granulopoiesis and mobilization of BM-derived PMNs and integrin expression underlies the dramatic protection from tissue injury in females.
- © 2011 by American Heart Association, Inc.