Expression of Cell Adhesion Molecules in Eosinophilic Disorders of the Skin and Nose
Bruce S. Bochner in Adhesion Molecules in Allergic Disease, 2020
The expression of endothelial E-selectin has been shown to correlate with neutrophil or skin-homing memory T cells that bear the phenotypic marker cutaneous lymphocyte antigen (CLA) (2,44,45) (see Chap. 15). The chronic expression of E-selectin found commonly in inflammatory skin disorders such as AD has been confusing because in vitro stimulation of HUVEC or HDMEC results in maximal E-selectin expression by 4 to 6 hours with rapid decline despite continued cytokine stimulation (33). Recent work suggests that this rapid decline may be due to the fact that E-selectin mRNA is unstable. This instability is thought to be a consequence of multiple AUUUA destabilizing elements in the 3’-untrans- lated region (46). Because there are three functional polyadenylation sites, it is feasible to generate three distinct E-selectin transcripts. The shortest of these transcripts lacks six of the destabilizing elements and is therefore more stable than the others. Interestingly, this transcript was not found in HUVEC or HDMEC but was found in inflammatory skin biopsies, suggesting that the presence of this short transcript may be responsible for the chronic E-selectin expression seen in cutaneous diseases (46). Collectively this work suggests that there is heterogeneity among vascular endothelial cells that is dependent not only on their location (arterial vs. venous circulation) and size, but also on their microenvironment.
Pulmonary Endothelium in Health and Viral Infections
Sunit K. Singh in Human Respiratory Viral Infections, 2014
ECs provide an adequate substrate for leukocyte adhesion and facilitate their transportation through the barrier. The cell-to-cell interactions developed between ECs and leukocytes play a key role for the latters’ migration from capillaries to lung parenchyma in order for the immune response to unfold. The main cell type that participates in lung injury and the ARDS pathogenesis are neutrophils, while macrophages and eosinophils are also involved.21,22 The adhesion of leukocytes is a multistep procedure. The initial phase is referred to as cell capture and rolling. The main protein family implicated in this procedure is the selectin family. Selectins constitute a family of cell adhesion receptors that mediate the initial tethering and rolling of leukocytes on inflamed endothelium as a prelude to their firm attachment and extravasation into tissues.23 There are three members of the selectin family; E-selectin is expressed only in the ECs, P-selectin is found in platelets, as well as the EC, and L-selectin is constitutively expressed in neutrophils. The latter is expressed within minutes on the EC surface following its activation by stimuli, such as histamine, thrombin, bradykinin, leukotriene C4, or free radicals. P-selectin interacts with neutrophil counter-receptors, such as the P-selectin glycoprotein-1. E-selectin is rapidly synthesized by the ECs after its activation by cytokines, such as TNF-α and IL-1, or endotoxin.24
Wound Healing and Surgical Planning
Alexander Berlin in Mohs and Cutaneous Surgery, 2014
Platelets synthesize or store a variety of vasoactive, chemotactic, and proliferative mediators. Histamine is released by platelets and other cells and causes vasodilation and vascular permeability, allowing for cellular infiltration into the wound. PDGF has been shown to be chemotactic for neutrophils, macrophages, fibroblasts, and smooth muscle cells.11,12 TGF-β1 is also chemotactic for fibroblasts, macrophages, and other cell types but, in addition, stimulates new collagen production.13,14,15 Furthermore, together with endothelial cell selectin (E-selectin), platelet selectin (P-selectin) facilitates neutrophil margination, rolling, and capture, stimulating neutrophil influx.16 Thus, platelet activation and aggregation directly contribute to the ensuing cellular response.
An overview of novel therapies in advanced clinical testing for acute myeloid leukemia
Published in Expert Review of Hematology, 2023
Sangeetha Venugopal, Zhuoer Xie, Amer M. Zeidan
E-selectin is an endothelial leukocyte adhesion molecule that plays an important role in inflammation. Leukemic blasts overexpress E-selectin ligand, and the resultant E-selectin binding sequester the leukemic blasts and LSCs in protective niches, shielding them from chemotherapy [67]. Uproleselan, an E-selectin antagonist, was developed based on this premise, and in subsequent preclinical evaluation, uproleselan also exhibited synergistic activity with doxorubicin and cytarabine in murine models [68]. The phase 1/2 study of uproleselan in combination with chemotherapy enrolled two cohorts with AML in both R/R and frontline settings [69]. Uproleselan was administered in combination with MEC (mitoxantrone, etoposide, and cytarabine) in patients with R/R AML, and with ‘7 + 3’ in patients with newly diagnosed AML and age ≥60 years. The addition of uproleselan did not evoke any dose-limiting toxicity, and low-grade mucositis was the most observed AE. Among patients with R/R AML (n = 47), the CR/CRi rate was 41%, and the median OS was 8.8 months. Among patients with newly diagnosed AML (n = 25), the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. E-selectin expression >10% on leukemic blasts was associated with improved outcomes in the R/R AML cohort. Uproleselan in combination with chemotherapy is undergoing registrational trials in both R/R (NCT03616470) and newly diagnosed AML (NCT03701308) cohorts.
Therapeutic drugs and drug delivery systems targeting stromal cells for cancer therapy: a review
Published in Journal of Drug Targeting, 2020
Zhaohuan Li, Zengjuan Zheng, Chenglei Li, Zhipeng Li, Jingliang Wu, Bo Zhang
Selectins, including L-selectin, E-selectin and P-selectin, are type I transmembrane protein [63]. L-selectin is only expressed on the surface of leukocytes. Leukocyte-mediated multiple inflammatory reactions that promote tumour growth and metastasis. E-selectin is expressed on the endothelial cells, which mediates the binding of the leukocytes with the endothelial cells. The ligand of E-selectin can enhance the adhesion between tumour cells and endothelial cells, which is beneficial to the metastasis of tumour cells [64]. P-selectin is mainly expressed on platelets and endothelial cells. P-selectin not only promotes the interaction between endothelial cells and platelet cells through microthrombus, but also promotes the combination of platelets with tumour cells, which can accelerate the progress of the tumour. Because the ligands of selectins are expressed on the surface of tumour cells, the interaction between tumour cells and endothelial cells can promote the adhesion and metastasis of tumour cells [65].
Lung cancer: active therapeutic targeting and inhalational nanoproduct design
Published in Expert Opinion on Drug Delivery, 2018
Nasser Alhajj, Chin Fei Chee, Tin Wui Wong, Noorsaadah Abd Rahman, Noor Hayaty Abu Kasim, Paolo Colombo
Peptide ligands are used to actively target the drugs to tumor vasculature in lung cancer with a specific target such as E-selectin, pericytes, and fibrin-associated plasma proteins. E-selectin is a transmembrane adhesion protein that involves in metastasis. Targeting such cellular receptor allows drug delivery to metastatic sites [183]. E-selectin binding peptide (Esbp, DITWDQLWDLMK) has been conjugated to a platform constituted of N-(2-hydroxypropyl) methacrylamide copolymeric nanoparticles for actively and selectively targeting the drug to metastatic tissues of primary Lewis lung carcinoma (3LL) tumors-bearing mice. The platform is equipped with chemotherapeutics doxorubicin or proapoptotic peptide D-(KLAKLAK) 2 (KLAK) that induces mitochondrial-dependent apoptosis. Following a single intravenous injection, the doxorubicin-loaded and peptide-conjugated nanoparticles are found to reduce the tumor growth propensity and lengthen the survival duration of mice significantly more than the group treated with unconjugated nanoparticles or with free doxorubicin. The probability of complete tumor regression increases with an increase in dose and dosing frequency [184]. Other potential peptides, such as IELLQAR enriched with their binding to antiLewis A antibody are found to bind to E-, P-, and L-selectins in a calcium-dependent manner [185].
Related Knowledge Centers
- Cell Adhesion Molecule
- Inflammation
- Selectin
- Endothelium
- Cytokine
- Gene
- N-Terminus
- C-Type Lectin
- Egf-Like Domain
- Sushi Domain