Hypoxia induces an inflammatory cascade that results in injury to the microvasculature. Specifically, leukocyte adhesion to the endothelium begins, and leukocyte emigration and vascular leak follow. The mechanism of hypoxia related injury is incompletely understood, but involves oxidant stress. Infusion of antioxidants has been shown to prevent hypoxia induced microvascular injury. Activated protein C is reported to have anticoagulant and anti-inflammatory properties. Its protective role is best described during sepsis. However, it has been utilized, with some success, in experimental models of ischemic injury. Our experiments are designed to characterize the effects of activated protein C on the microvasculature during systemic hypoxia and compare them to those of a potent antioxidant, alpha-lipoic acid.
Experiments utilize intravital microscopy of the intact rat venular bed. Five groups were utilized: saline control, activated protein C infusion alone (100mcg/kg bolus), hypoxia alone (10% O2), simultaneous hypoxia + activated protein C infusion, and hypoxia + alpha lipoic acid. Measurements of leukocyte adherence (# per 100um venule), leukocyte emigration (# per 4000 um2), and venular leak by fluorescein isothiacyanate-labeled albumin (Fi/Fo) are reported below.
Activated protein C infusion and antioxidant infusion prevent hypoxia-related microvascular injury as evidenced by measurements of leukocyte adherence, leukocyte emigration and vascular leak.
This similarity may reflect a common mechanism of action. This work is important because the understanding of the hypoxia-induced inflammatory cascade is essential to a plethora of disease states, such as myocardial infarction, sepsis, ARDS and trauma. Further characterization of the effects of activated protein C in hypoxic injury could lead to new therapeutic use.
Leukocyte AdherenceLeukocyte EmigrationVascular LeakNormoxia1.6 ± .52.6 ± .19.14 ± .04Hypoxia14.5 ± 1.212.3 ± 2.2.82 ± .14Activated protein C2.0 ± .83.1 ± .4.19 ± .05Activated protein C + hypoxia4.4 ± 1.53.5 ± .3.25 ± .14Alpha-lipoic acid + hypoxia0.6 ±0.42.3 ± .3.10 ± .04
Sonja Bartolome, None.