Lower Body Ischemia-Reperfusion during: DISCUSSION

Ischemia Reperfusion during DISCUSSION

CDllb and CD 18 are members of the integrin family of adhesion molecules, which consist of transmembrane glycoproteins expressed primarily on neutrophils and monocytes. They form heterodimer complexes from the noncovalent union of the alpha and beta subunits before being transported to the cell sur face. In this regard, the CD 18 (beta2) integrin combines with three distinct alpha chains, namely CDl la, CDl lb or CDl lc. The association of CDl lb and CD 18 forms the complement receptor, CR3 (or MAC-1) heterodimer, which participates in complement binding, phagocytosis and intercellular adhesion. The sequence of this neutrophil-endothelial binding has recently been studied carefully. After an inflammatory stimulus, neutrophils roll along the postcapillary venules at velocities distinctly below that of flowing blood. After some rolling, the cells stop, change shape and extravasate into extravascular tissue. The initial capture of the traveling neutrophils is mediated through the expression of another family of adhesion molecules known as selectins. Firm adhesion and transmigration of the leukocytes, however, does not occur unless the integrin molecules are engaged and bind to their endothelial ligands. Thus, a primary function of the CDl lb/CD18 adhesion complex (CR3) is the facilitation of neutrophil-endothelial binding through its interaction with endothelial ligands, such as CD54 (ICAM-1, intercellular adhesion molecule 1). This interaction is a critical step in the neutrophil response to inflammatory stimuli that can ultimately result in tissue damage.

CDl lb and CD 18 have been widely implicated in the pathogenesis of local and distant (especially pul monary) neutrophil-mediated tissue injury arising from ischemia and reperfusion. Pretreatment of animals with monoclonal antibodies against CDl lb/ CD 18 has been shown to decrease the infiltration of neutrophils into reperfused ischemic tissues and to limit tissue injury. In addition, in animal models, pretreatment with CD 18 antibody lowers pulmonary sequestration of neutrophils and mitigates the associated rise in lung permeability following lower-torso ischemia and reperfusion. Also, in an animal model, blockade of CD 18 during reperfusion has been shown to decrease edema and subsequent necrosis of the previously ischemic tissue. Though experiments have demonstrated a role for leukocyte CDl lb and CD 18 in ischemia/reperfusion injury via the use of monoclonal antibodies against those receptors,there is a paucity of data regarding the actual cell surface expression of CD1 lb and CD 18 during ischemia/ reperfusion, especially in humans. Recently, individuals with unstable angina were found to have increased surface expression of CD1 lb/CD 18 on the circulating monocytes following coronary angioplasty. Similarly, patients undergoing an acute ischemic stroke were noted to have increased expression of CD 18 on circulating neutrophils. cialis professional

We found that surface expressions of CD1 lb and CD 18 on neutrophils and monocytes increase during reperfusion following aortic clamping, confirming our original hypothesis. The magnitude of rise and the time to peak receptor expressions did not correlate with the duration of aortic clamping, which ranged between 47-130 minutes in the present study. In addition, there were no differences in the receptor expression between neutrophils and monocytes in the venous blood draining the ischemic lower extremity and those found in the systemic arterial blood.

In a previous study, Hill et al. reported signifi cant upregulation of neutrophil CD1 lb expression in patients undergoing supraceliac, aorta clamping for aorta aneurysm repair in single samples obtained 90 minutes after reperfusion. Upregulation of neutrophil CD1 lb expression following supraceliac aorta clamping reported by those investigators is consistent with results found in our patients undergoing infrarenal aorta clamping. In addition, the present study extended the findings of Hill et al. by measuring both CDllb and CD18 expression on neutrophils and monocytes at multiple time points.
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The mechanism responsible for upregulations of neutrophil and monocyte CD1 lb and CD 18 expressions during reperfusion is not entirely clear, and several factors may be involved. For instance, some investigators have suggested that neutrophil activation may be due to the release from the ischemic tissues of inflammatory mediators, such as activated complement products, reactive oxygen species, cytokines, (IL-1, IL-6, IL-8 andTNF-cc) thromboxane-B2 and leukotriene-B4. In fact, increased plasma levelsof IL-6, IL-8 and thromboxane-B2 (but not TNF-oc or C3a) have been observed following lower-body reperfusion in humans undergoing aortic aneurysm surgery. These events could potentially stimulate surface expression of CDl lb and CD 18 observed in the present study. This supposition is supported by an earlier study published by Swartbol et al., who demonstrated that plasma obtained after aortic declamping from patients undergoing aorta aneurysm repair can activate CDl lb and CD 18 expressions on leukocytes obtained from normal volunteers. Together, these observations suggest that activation of the circulating populations of these cells may occur via the systemic action of an inflammatory mediators) as opposed to or in addition to local activation and/or release of the sequestered leukocytes from the ischemic tissues.

The observed activation of circulating monocytes is noteworthy. Even though monocytes have a central role in most inflammatory responses, their activation and regulation during ischemia and reperfusion, especially in humans, have not been clearly elucidated. As noted above, Qi et al. have observed evidence of increased surface expression of CDl lb/CD 18 on circulating monocytes following coronary angioplasty. In vitro studies have shown that monocytes subjected to hypoxia produce IL-1 upon reoxygenation. Moreover, monocytes preconditioned to anoxia exhibit augmented IL-8 production following exposure to hyperoxia. In our study, upregulation of monocyte surface CDl lb and CD 18 was quantitatively and temporally similar to that of neutrophils. Thus, it appears that production of inflammatory mediators from cells within the affected tissues can lead to activation of circulating monocytes. This can, in turn, amplify the systemic inflammatory response to ischemia and reperfusion.
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Earlier studies have reported leukopenia during reperfusion of the ischemic lower body in animal models and in humans undergoing abdominal aneurysm repair. This phenomenon has been attributed to sequestration of leukocytes in the reperfused tissues and in the pulmonary microvasculature. However, our patients as a group exhibited increased total leukocyte and neutrophil counts during reperfusion. In addition, there was no difference in the leukocyte counts between venous and arterial blood. In two patients, an initial leukocytosis shortly after aortic unclamping was followed by a decrease in the leukocyte and neutrophil counts later during reperfusion. Even in these patients, leukocyte counts did not fall below that observed prior to aortic clamping. Our findings are consistent with those of Gadaleta and associates, who demonstrated an increase in the neutrophil count five- and 30 minutes after removal of the aortic clamp during abdominal aortic aneurysm repair. Therefore, it appears that any local or pulmonary sequestration of leukocytes was offset by a concurrent leukocytosis caused by aortic unclamping.

It is of interest that no significant correlation was observed between the duration of ischemia (aortic clamping) and the magnitude and rapidity of the rise in the integrin expression during reperfusion. The precise reason for this lack of correlation is not clear. However, it is possible that the shortest duration of ischemia (47 minutes) used in the present series was sufficient to elicit a maximal response.
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In summary, lower-body reperfusion occasioned by unclamping of the aorta following repair of abdominal aortic aneurysms results in marked leukocytosis in both local venous effluent and systemic arterial blood. This is associated with upregulation of neutrophil and monocyte integrins that peak approximately 30 minutes after reperfusion. The biological impact of this phenomenon, if any, is currently unknown and requires further investigation.