IntroductionTwo murine monoclonal antibodies (CL-3 and CL-37, both F(ab')2) to human endothelial-leukocyte adhesion molecule-i (ELAM-1) were found to react immunohistochemically with rat pulmonary artery endothelial cells that had been pretreated with tumor necrosis factor (TNFa). CL-3, but not CL-37, blocked in vitro adherence ofneutrophils to TNFa-treated endothelial cells and the killing of TNFa-treated rat endothelial cells by phorbol ester activated neutrophils. In rats treated systemically with CL-3, there was a 70% reduction in accumulation of neutrophils in glycogen-induced peritoneal exudates.

The influence of chronic antidepressant administration on expression of the three major phosphodiesterase (PDE) 4 subtypes found in brain (PDE4A, PDE4B, and PDE4D) was examined. The treatments tested included representatives of four major classes of antidepressants: selective reuptake inhibitors of serotonin (sertraline and fluoxetine) or norepinephrine (desipramine), a monoamine oxidase inhibitor (tranylcypromine), and electroconvulsive seizure. Expression of PDE4A and PDE4B, but not PDE4D, mRNA and immunoreactivity were significantly increased in rat frontal cortex by chronic administration of each of the four classes of antidepressants. We also found that antidepressant administration significantly increased the expression of PDE4B mRNA in the nucleus accumbens, a brain region thought to mediate pleasure and reward that could also contribute to the anhedonia often observed in depressed patients. In contrast, expression of PDE4A and PDE4B were not influenced by short-term treatment (1 or 7 d) and were not influenced by chronic administration of nonantidepressant psychotropic drugs (cocaine or haloperidol), demonstrating the time dependence and pharmacological specificity of these effects. Upregulation of PDE4A and PDE4B may represent a compensatory response to antidepressant treatment and activation of the cAMP system. The possibility that targeted inhibition of these PDE4 subtypes may produce an antidepressant effect is discussed.

Previous studies in vitro have shown an important role for intercellular adhesion molecule-i (ICAM-1) in adherence interactions of canine neutrophils with canine jugular vein endothelial cells and in cytotoxicity of canine neutrophils for adult cardiac myocytes. To evaluate the regulation of ICAM-1 in myocardial inflammation and its role in the pathogenesis of myocardial ischemia and reperfusion, a series of in vivo and ex vivo studies were performed in canine animals. Systemic administration of LPS elicited ICAM-1 mRNA in several tissues, including myocardium, which demonstrated increasing ICAM-1 staining on intercalated discs of cardiac myocytes. In ischemia and reperfusion protocols: (a) ICAM-1 mRNA was found in ischemic segments within 1 h of reperfusion and in both ischemic and normally perfused segments by 24 h of reperfusion; (b) expression of ICAM-1 was detected in cardiac myocytes in the ischemic region by 6 h of reperfusion; increased expression was seen thereafter as a function of time; (c) postischemic (but not preischemic) cardiac lymph collected at intervals from 1 to 24 h after reperfusion elicited ICAM-1 mRNA, ICAM-1 expression, and ICAM-1-dependent neutrophil adhesion in canine jugular vein endothelial cells and in cardiac myocytes with peak cytokine activity seen by 1 h; (d) extravascular localization of neutrophils was detected in ischemic areas only, and was associated with endothelium bearing high levels of ICAM-1 within 1 h of reperfusion; infiltration increased thereafter in association with increasing levels of ICAM-1 mRNA in myocardial segments and increasing levels of ICAM-1 expression on cardiac myocytes. These findings provide the first direct evidence for inflammatory regulation of ICAM-1 in ischemic and reperfused canine myocardium. They support the hypothesis that ICAM-1 participates in neutrophil-mediated myocardial damage. (J. Clin. Invest. 1993.

The adhesiveness of isolated canine cardiac myocytes for neutrophils is greatly increased by stimulation with cytokines such as tumor necrosis factor a (TNFa). Since this adhesion is significantly inhibited by an anti-CD18 MAb, experiments were performed to test the hypothesis that the newly expressed adhesion molecule on the cardiac myocytes was intercellular adhesion molecule-l (ICAM-1). A newly developed MAb, CL18/6, was found to exhibit the functional and binding characteristics with canine neutrophils and canine jugular vein endothelial cells expected of an antibody recognizing ICAM-1. MAb CL18/6 also bound to isolated cardiac myocytes after stimulation of the myocytes with cytokines, and it blocked by > 90% the adhesion of neutrophils to stimulated myocytes. A partial cDNA clone for canine ICAM-1 was isolated, and ICAM-1 mRNA was found to be increased in both endothelial cells and cardiac myocytes after cytokine stimulation. Cytokines that both increased the CL18/6-inhibitable adhesion of neutrophils to myocytes and induced expression of ICAM-1 were IL-10, TNFa, and LPS. These results are consistent with the conclusion that canine endothelial cells and cardiac myocytes express ICAM-1 in response to cytokine stimulation, and that ICAM-1 functions as an adhesive molecule for neutrophils on both cell types. (J. Clin. Invest. 1991. 88:1216-1223

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