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Adhesion Molecules and Inflammation: The Next Targets for Perioperative Organ Protection?

Hickey, Paul R. MD; McGowan, Francis X. MD


Departments of Anesthesia, Children's Hospital and Harvard Medical School, Boston, Massachusetts.

Accepted for publication October 11, 1995.

Address correspondence and reprint requests to Paul R. Hickey, MD, Department of Anesthesiology, The Children's Hospital, 300 Longwood Ave., Boston, MA 02115.

In this issue of Anesthesia & Analgesia, Boldt et al. [1] publish their observations on blood concentrations of adhesion molecules during pediatric cardiac surgery. What are these substances and what is their potential importance to anesthesiologists?

Immune cells must be able to circulate as nonadherent blood- and lymph-borne elements that then migrate and adhere in response to injury and foreign antigens. The adhesion molecules measured by Boldt et al. are soluble, circulating forms of membrane-bound receptors that mediate a complex series of interactions between white blood cells, platelets, and vascular endothelium. These interactions result in leukocyte adhesion and entry across the endothelium into tissue. Substantial evidence, accumulated over the past 5 years, indicates that adhesion molecule expression is crucial to the development and modulation of inflammatory and immune processes [2]. It is now established that the appearance of these compounds on the cell membrane of polymorphonuclear leukocytes and monocytes, together with the appearance of complimentary receptors on the endothelial cell, results in leukostasis and white cell-endothelial cell adhesion and facilitates tissue invasion and subsequent injury. Three different structural families of such adhesion molecules have been described to date. The immunoglobulin superfamily, which includes intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, is found predominantly on endothelium. The integrins, including Mac-1 and LFA-1, are found on polymorphonuclear leukocytes. The selectin family includes E-selectin, located on endothelium; L-selectin located on polymorphonuclear leukocytes, monocytes, and some lymphocyte subsets; and P-selectin, found on endothelial cells and platelets.

Since their initial discovery by Springer and others in the past decade [3], adhesion molecules have been shown to play pivotal roles in normal immune surveillance and function and in the pathogenesis of tissue injury from ischemia-reperfusion, atherogenesis, chronic inflammatory and autoimmune diseases, and organ transplant rejection [4-7]. Adhesion receptors can also be expressed on the surface of other (i.e., nonendothelial) cells within an organ, perhaps increasing the ability of activated white cells to target parenchymal cells for destruction. Monoclonal antibodies and other experimental agents that block adhesion have been shown to limit organ injury and/or increase survival in experimental models of thermal injury, sepsis and endotoxic shock, acid aspiration, stroke, arthritis, transplant rejection, and myocardial ischemia-reperfusion [2,8]. While these therapies are sometimes effective when given in the hours after injury has occurred, their most logical application is prior to, or at least coincident with, the injury, as is feasible during surgical procedures under anesthesia.

Mediators that stimulate adhesion molecule synthesis and/or expression are produced by routine events during surgery, such as tissue trauma, ischemia-reperfusion, exposure to foreign tissue or substances, blood coagulation, and fibrinolysis. These mediators include histamine, oxygen-derived free radicals, thrombin, platelet activating factor, activated complement fragments, endothelin, endotoxin, and several cytokines such as tumor necrosis factor-alpha and interleukin-1 beta. It is therefore clear that perioperative manipulation of adhesion events is likely to be of benefit for improving organ function and outcome.

Activation of the coagulation, complement, and fibrinolytic pathways, ischemia-reperfusion, and the release of endotoxin, cytokines, and endothelin can occur as a consequence of extracorporeal circulation. Thus, it is clear that adhesion molecules are likely to be involved in the whole body inflammatory response to cardiopulmonary bypass, which tends to be particularly severe in children [9]. It has been shown in our laboratories here that cardiopulmonary bypass in pediatric patients increased messenger RNA coding for expression of E-selectin and intracellular adhesion molecule-1 [10] and that antibody to the leukocyte adhesion molecule CD18 (a common moiety of Mac-1 and LFA-1 integrins) improved recovery of isolated, blood-perfused neonatal lamb hearts from ischemia-reperfusion [11] and attenuated other deleterious effects of hypothermic cardiopulmonary bypass and circulatory arrest in neonatal piglets [12].

The paper by Boldt et al. is an observational study examining circulating (soluble) forms of membrane-bound adhesion molecules during clinical bypass in children and adults. Its significance is limited by its descriptive nature, a diverse patient population, the failure to measure other indices of immune activation or endothelial injury, and the fact that circulating adhesion molecule concentrations were not changed during bypass (in spite of the preceding discussion of the many factors present during bypass that should up-regulate adhesion molecule expression). Furthermore, the role and significance of these circulating forms, their pharmacokinetics, and their effect on adhesion molecule expression and function are unknown at present. Among the possibilities are that circulating adhesion receptors are simply part of normal synthesis and catabolism which may or may not reflect underlying endothelial activation or damage. If the circulating fraction does reflect the state of white cell-endothelial activation, the fact that preoperative concentrations were higher in children, many of whom were cyanotic, raises intriguing and potentially important questions about underlying inflammatory "tone" in young and/or cyanotic patients. It is also possible that circulating molecules may block complimentary receptors and thereby be important regulators of leukocyte-endothelial adhesion.

Regardless of what role is eventually ascribed to soluble forms of adhesion molecules, the Boldt paper stimulates interest and investigation in an area that is at the interface of cell biology, molecular biology, and the clinical applications of such work. It remains to be seen whether therapies based on this new knowledge will fulfill their theoretical promise or go the way of many similar "advances." The hope is that investigations in this area will eventually make it possible to target precisely antiadhesion and other antiinflammatory modalities. Targeting these processes will reduce or eliminate cellular damage from immune and inflammatory activation occurring during therapeutic interventions such as surgery, organ reperfusion, and cardiopulmonary bypass, while minimizing effects on protective functions, such as tissue repair and immune surveillance. Such therapies may be a new weapon in the anesthesiologist's fight to preserve organ function and improve outcome in the perioperative period.

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© 1995 International Anesthesia Research Society