Role of Lselectin in disease

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Aberrant leukocyte recruitment, either in location or duration, is a major hallmark of inflammatory disease. As such, identification of the molecular pathways involved in mediating this recruitment has received a great deal of attention. An accumulating body of evidence, from both human patients and animal models, shows L-selec-tin to be a key regulator of leukocyte migration in a number of disease conditions. Therefore, selective targeting of L-selectin function may be of therapeutic benefit for these patients.

The reperfusion of ischemic tissue often results in severe cell and tissue damage that can lead to loss of organ function. Ischemia-reperfusion injury can result from a number of disease conditions including myocardial infarction, stroke, shock, trauma, and hypotension. Although the mechanisms mediating tissue damage are not fully understood, a significant component involves the rapid influx of leukocytes, primarily neutrophils. A number of reports indicate that L-selectin, in addition to P- and E-selectin, is involved in mediating neutrophil interactions with ischemic vessels. For example, blocking L-selectin function with mAb treatment reduces damage to skeletal muscle in rat models of ischemia-reperfusion injury [231, 232]. Furthermore, L-selectin was shown to be important in the generation of hepatic injury using a murine model of normothermic hepatic ischemia [233]. In these studies, L-selectin-deficient mice showed reduced neutrophil adhesion, absence of micro-circulatory failure, reduced tissue damage, and increased survival following partial hepatic ischemia compared to wild-type mice. Thus, L-selectin-mediated neutrophil recruitment is an important factor in the development of ischemic injury.

While the above findings demonstrate a role for L-selectin in recruitment of neu-trophils to the ischemic liver, whether L-selectin also contributes to T cell recruitment during hepatic inflammation was unclear. Several studies using the Concanavalin A (Con A)-induced model of human T cell hepatitis [234] reported critical roles for P- and E-selectin, VCAM-1, ICAM-1, and LFA-1 in lymphocyte recruitment [235237]. A recent study by Kawasuji et al. [238] using this model in L-selectin-deficient mice showed a prominent role for L-selectin in development of liver injury following

Con A treatment. Specifically, L-selectin-deficient mice had reductions in levels of plasma transaminase, numbers of infiltrating CD4+ T cells, TNF-a mRNA levels, and liver necrosis. Therefore, L-selectin is involved in mediating T cell recruitment and subsequent injury to the liver under inflammatory conditions.

Airway inflammation involving intense influx of leukocytes is a prominent factor in the development of chronic airway hyperresponsiveness found in asthma. Leukocyte/endothelial interactions in the lung vascular bed have been considered to be regulated differently from that of the systemic circulation due to the presence of a highly interconnected vascular bed in which the diameter of the vessels are often smaller than that of the leukocytes [239]. Because of this, it was thought that specialized adhesion molecules such as the selectins were not required for leukocyte recruitment to the lung. However, multiple studies have demonstrated a role for each of the selectins in this process. Specifically, L-selectin has been shown to support leukocyte rolling on inflamed and non-inflamed lung vessels [240-242]. Furthermore, Nishio et al. [242] found that in vivo administration of fucoidin, an L-selectin competitor, reduced the number of leukocytes rolling on pulmonary arte-rioles in a hyperoxia-induced rat lung model. Additionally, an important role for L-selectin in mediating the migration of leukocytes during pulmonary inflammation in the murine ovalbumin (OVA)-induced asthma model has been described [243]. In these studies, L-selectin-deficient mice displayed a significant reduction in the number of CD3+ cells present in the broncheoalveolar lavage following challenge compared to control mice despite demonstrating equivalent levels of sensitization. In a sheep model of allergic bronchoconstriction, treatment with an anti-L-selec-tin mAb as well as low-molecular weight selectin antagonists were shown to be therapeutic [244]. Specifically, mAb blockade of L-selectin resulted in significant reductions in severity of early and late airway responses and a lack of postchallenge airway hyperresponsiveness. Similar effects including reductions in histamine release and neutrophil numbers in bronchoalveolar lavage were found using the selectin inhibitors in challenged animals. Subsequent studies in this model showed that blockade of L-selectin ligands using the MECA-79 mAb dramatically reduced the accumulation of neutrophils, macrophages, lymphocytes, and eosinophils in the bronchoalveolar fluid of allergic sheep, and ameliorated both the late-phase airway response and airway hyperresponsiveness induced by airway allergen challenge [87]. Other studies by Hamaguchi et al. [245] using a bleomycin-induced lung injury model demonstrated that L-selectin was important for the trafficking of leukocytes during the development of pulmonary fibrosis. Specifically, L-selectin-deficient mice had reduced infiltration of neutrophils and lymphocytes and reduced collagen deposition in the lung following bleomycin treatment compared to normal mice. Therefore, L-selectin-mediated leukocyte migration has been shown to be critically involved in the generation of pulmonary inflammatory responses.

Type I diabetes is characterized by the destruction of insulin-producing p cells of the pancreas as a result of T cell recruitment into the pancreatic tissue. L-selectin ligands, specifically PNAd and MAdCAM-1, are expressed and functional in the pancreas of nonobese diabetic (NOD) mice, a murine model for type I diabetes [86, 246]. Because of the presence of L-selectin ligands, it was suggested that L-selectin-mediated interactions are involved in lymphocyte trafficking to the pancreas. In fact, administration of anti-L-selectin mAb to NOD mice can protect against the development of insulitis and diabetes [247, 248]. By contrast, L-selectin-deficient NOD mice exhibit similar islet infiltrates and similar disease progression to L-selec-tin+ NOD mice [249, 250]. These results, along with the demonstration that other adhesion molecule pairs are likely involved [247], suggest that L-selectin function is not an absolute requirement for disease in NOD mice. It is also possible that L-selectin-mediated T cell migration to pancreatic lymph nodes is necessary for disease development in this model [250]. Another interesting finding is that L-selectin+ Treg cells are involved in controlling pathogenesis in a murine transgenic model of diabetes [251]. Therefore, further studies will be needed before a definitive role for L-selectin in the development of diabetes can be established.

In addition to cell-surface adhesion molecules, the soluble forms of these molecules have been receiving an increasing amount of attention. While soluble adhesion molecules have been used successfully as markers of inflammation or disease activity, their role in physiological processes must also be considered (reviewed in [252]). Specifically, significantly increased levels of sL-selectin have been reported to be associated with a number of different disease conditions including chronic myeloid and lymphocytic leukemia [253-255], sepsis [19, 256], HIV infection [19], atopic dermatitis [257], psoriasis [258], and lupus [259]. As discussed above, since sL-selectin retains functional activity, these increased levels may have important physiological effects on leukocyte migration in these patients. In fact, higher levels of sL-selectin in acute myeloid leukemia patients at the time of diagnosis correlated with decreased probability of achieving complete remission, shorter event-free survival, and shorter overall survival [260]. Interestingly, in severe trauma patients, decreased levels of sL-selectin correlate with an increased risk of progression to acute respiratory distress syndrome [261]. In these patients, low levels of sL-selec-tin may indicate the presence of newly expressed L-selectin ligands in large vascular beds such as the lung. This loss of L-selectin buffering activity in the plasma may thereby allow increased leukocyte infiltration to occur at remote sites. Thus, membrane-bound and sL-selectin contribute significantly to leukocyte recruitment in inflammatory disease with sL-selectin levels having prognostic value.

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