Epidemiological studies of the past decades have provided a strong body of evidence that elevated levels of ambient particulate air pollution (PM) are associated with increased cardiovascular and respiratory morbidity and mortality. Exacerbations of ischemic and/or arrhythmic cardiac diseases have been linked to PM exposure. At a workshop held at the GSF- National Center for Environment and Health in November 2003, relevant epidemiological and toxicological data of the past 5 years were compiled and potential biological pathways discussed. Available clinical and experimental evidence lends support to the following mechanisms mediating cardiovascular effects of inhaled ambient particles: (i) pulmonary and/or systemic inflammatory responses inducing endothelial dysfunction, a pro-coagulatory state and promotion of atherosclerotic lesions, (ii) dysfunction of the autonomic nervous system in response to direct reflexes from receptors in the lungs and/or to local or systemic inflammatory stimuli, and (iii) cardiac malfunction due to ischemic responses in the myocardium and/or altered ion-channel functions in myocardial cells. While an increasing number of studies addressing these questions support the notion that PM exposure is associated with cardiovascular effects, these studies at present provide only a fragmentary and at times inconclusive picture of the complex biological pathways involved. The available data are consistent with the occurrence of a systemic inflammatory response and an alteration of autonomic cardiac control, but evidence on endothelial dysfunction, pro-coagulatory states, and PM-related myocardial malfunction is as yet scarce. Further studies are therefore needed to substantiate our current understanding of the pathophysiological links between PM exposure and adverse cardiovascular outcomes.
Junctional adhesion molecule-A (JAM-A IntroductionLeukocyte migration across vessel walls and into the surrounding tissue is a characteristic feature of an inflammatory response in physiologic host defense and also under pathologic scenarios in inflammatory disease states such as myocardial infarction. This process is known to occur via a number of sequential leukocyte responses beginning with the tethering to and rolling of leukocytes on the vascular endothelium. 1 After stimulation by surface-bound activating molecules such as chemokines, rolling leukocytes can then establish a firm adhesive interaction with endothelial cells and finally begin to migrate through the endothelial-cell component of the vessel wall. This latter stage is believed to occur largely through junctions between adjacent endothelial cells; indeed, numerous endothelial-cell junctional molecules have now been implicated in this process. 2 Such molecules include PECAM-1 (CD31), ICAM-2 (CD102), CD99, and members of the junctional adhesion molecule (JAM) family, 3 although there remain many unanswered questions regarding their mode of action and potential additive/cooperative interactions.JAMs are a family of transmembrane IgG glycoproteins expressed on a number of cell types throughout the vascular system. There are currently 5 known members of the family: JAM-A, JAM-B, JAM-C, JAM4, and JAML. [4][5][6] JAM-A is the most widely expressed member of the family, and has been shown to be expressed on endothelial and epithelial cells, on platelets, and on a number of leukocyte subsets. 2 In endothelial and epithelial cells, JAM-A locates to the tight junctions, where it appears to engage in homophilic binding to JAM-A on adjacent cells, an interaction that in endothelial cells is considered to play a critical role in angiogenesis. 2,7 The integrin LFA-1 (CD11a/CD18) has also been reported to act as a ligand for JAM-A, an interaction that has been implicated in leukocyte transendothelial cell migration, 8 though the role of JAM-A in leukocyte transmigration in vivo requires further clarification.The involvement of JAM-A in leukocyte transmigration was first reported by Dejana and colleagues using the neutralizing antibody BV-11. 5 Specifically, BV-11 was found to inhibit spontaneous and chemokine-induced monocyte transmigration through cultured endothelial cells, and chemokine-induced monocyte migration into murine subcutaneous air pouches. 5 BV-11 was also found to suppress leukocyte recruitment to cerebrospinal fluid following cytokine-induced meningitis. 9 Despite these positive effects of JAM-A blockade, other studies reported on the inability of anti-JAM-A antibodies to inhibit leukocyte transmigration. Hence, Shaw et al 10 found that leukocyte transmigration through cultured endothelial cells under flow was not inhibited by another anti-JAM-A antibody, whereas under the same conditions, blockade of PECAM-1 did reduce transmigration. In addition, in vivo, BV-11 failed to inhibit leukocyte influx into the meninges following bacterial or viral mu...
Endothelial cell–selective adhesion molecule (ESAM) is specifically expressed at endothelial tight junctions and on platelets. To test whether ESAM is involved in leukocyte extravasation, we have generated mice carrying a disrupted ESAM gene and analyzed them in three different inflammation models. We found that recruitment of lymphocytes into inflamed skin was unaffected by the gene disruption. However, the migration of neutrophils into chemically inflamed peritoneum was inhibited by 70% at 2 h after stimulation, recovering at later time points. Analyzing neutrophil extravasation directly by intravital microscopy in the cremaster muscle revealed that leukocyte extravasation was reduced (50%) in ESAM−/− mice without affecting leukocyte rolling and adhesion. Depletion of >98% of circulating platelets did not abolish the ESAM deficiency–related inhibitory effect on neutrophil extravasation, indicating that it is only ESAM at endothelial tight junctions that is relevant for the extravasation process. Knocking down ESAM expression in endothelial cells resulted in reduced levels of activated Rho, a GTPase implicated in the destabilization of tight junctions. Indeed, vascular permeability stimulated by vascular endothelial growth factor was reduced in ESAM−/− mice. Collectively, ESAM at endothelial tight junctions participates in the migration of neutrophils through the vessel wall, possibly by influencing endothelial cell contacts.
CD99 is a long-known leukocyte antigen that does not belong to any of the known protein families. It was recently found on endothelial cells, where it mediates transendothelial migration of human monocytes and lymphocyte recruitment into inflamed skin in the mouse. Here, we show that CD99L2, a recently cloned, widely expressed antigen of unknown function with moderate sequence homology to CD99, is expressed on mouse leukocytes and endothelial cells. Using antibodies, we found that CD99L2 and CD99 are involved in transendothelial migration of neutrophils in vitro and in the recruitment of neutrophils into inflamed peritoneum. Intravital and electron microscopy of cremaster venules revealed that blocking CD99L2 inhibited leukocyte transmigration through the vessel wall (diapedesis) at the level of the perivascular basement membrane. We were surprised to find that, in contrast to CD99, CD99L2 was not relevant for the extravasation of lymphocytes into inflamed tissue. Although each protein promoted cell aggregation of transfected cells, endothelial CD99 and CD99L2 participated in neutrophil extravasation independent of these proteins on neutrophils. Our results establish CD99L2 as a new endothelial surface protein involved in neutrophil extravasation. In addition, this is the first evidence for a role of CD99 and CD99L2 in the process of leukocyte diapedesis in vivo. IntroductionLeukocytes are recruited into inflamed tissue via endothelial adhesion molecules and chemoattractants. [1][2][3][4] Upon docking to the endothelial surface, which is mediated mainly via selectins and leukocyte integrins, leukocytes transmigrate through the vessel wall, a process called diapedesis. 5,6 Leukocytes have been reported to traverse the endothelial cell layer on either a transcellular or a paracellular junctional route. 7,8 Almost all known endothelial membrane and adhesion molecules that participate in the diapedesis process are located at endothelial cell contacts and are therefore likely to participate in the junctional migration of leukocytes.Vascular/endothelial cadherin (VE-cadherin) represents a barrier on this route, because adhesion-blocking antibodies against VE-cadherin accelerate recruitment of leukocytes into inflamed tissue. 9 In contrast to VE-cadherin, all other endothelial cell contact proteins assist in the diapedesis process. All of these proteins except one are members of the immunoglobulin supergene family (Ig-SF), such as platelet-endothelial cell adhesion molecule (PE-CAM)-1, 10,11 members of the junctional adhesion molecule (JAM) family, 12-14 endothelial cell-selective adhesion molecule (ESAM), 15 intercellular adhesion molecule (ICAM)-2 16 and polio virus receptor (PVR), 17 a member of the nectin family. It is not yet known how they function in detail and it will be a challenging goal for the future to elucidate potential cascades and the interplay of these endothelial cell contact proteins during leukocyte diapedesis.One of the most recently identified proteins participating in leukocyte diapedesis is CD...
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