IntroductionThe Mer (Mertk, Nyk, c-Eyk) receptor tyrosine kinase is a transmembrane receptor consisting of an extracellular domain with 2 immunoglobulin-like and 2 membrane proximal fibronectin III motifs, a transmembrane region, and an intracellular tyrosine kinase domain. 1,2 These motifs place Mer in the same tyrosine kinase subfamily as Axl 3 and Tyro-3/Sky. 4,5 Mer, Axl, and Tyro-3 share the same ligand, 6,7 Gas6, which has significant homology to the negative coregulator of the blood coagulation pathway protein S. 8 Abnormal expression or activity of the Mer tyrosine kinase may play a role in tumorigenesis. The avian Mer ortholog, eyk, was discovered first as the oncogene in acute avian retrovirus RPL30. The constitutively active tyrosine kinase domain of v-eyk causes fibrosarcomas, endotheliomas, and visceral lymphomatosis in chickens. 9,10 Overexpression of murine Mer tyrosine kinase transforms BaF3 lymphocytes 11 and overexpression of human Mer transforms NIH3T3 cells. 12 Several human cancers overexpress Mer, including mantle cell lymphomas, 13 alveolar rhabdomyosarcomas, 14 gastric cancer, 15 and pituitary adenomas. 16 Mer is also ectopically expressed in pediatric T-cell acute lymphoblastic leukemia, 17 and a Mer transgenic mouse model with ectopic expression of Mer in thymocytes and lymphocytes develops T-cell lymphoblastic leukemia/lymphoma. 18 Axl and Tyro-3 also transform cells in vitro 3,4 and are overexpressed in a spectrum of human cancers.In addition to abnormal function of Mer in cancer, a physiologic role for Mer has recently been described in macrophages. Mer, Axl, and Tyro-3 have been shown to limit the extent of macrophage activation in response to an immune stimulus. 19,20 Mer also plays a significant role in the ability of macrophages to clear apoptotic cells, 21 and Mer deficiency has been linked to the development of autoimmune disorders in mice. Lack of Mer receptor causing defective macrophage apoptotic cell clearance in the Royal College of Surgeons (RCS) rat has also been implicated in the development of retinitis pigmentosa. 22 Interestingly, Mer gene mutations have been defined in a subset of humans with retinitis pigmentosa. 23 Furthermore, a physiologic role for the Mer tyrosine kinase has been described for the normal function of platelets. The interaction of Gas6 with Mer, Axl, and Tyro-3 is important in platelet degranulation and aggregation in response to known agonists. Mice lacking either Gas6 or Mer protein have impaired platelet aggregation in vitro and diminished clot stability in vivo. [24][25][26] A delicate balance of ligand interaction with a tyrosine kinase receptor is necessary to maintain normal tyrosine kinase function without causing overactivation, which could result in human disease. One means of regulating tyrosine kinase activation is through proteolytic cleavage of the membrane-bound protein.Through this process, the total number of membrane-bound receptors is reduced. In addition, the soluble cleavage product may function as a decoy receptor and seques...

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion death. We hypothesize that TRALI requires 2 events: (1) the clinical condition of the patient and (2) the infusion of antibodies against MHC class I antigens or the plasma from stored blood. A 2-event rat model was developed with saline (NS) or endotoxin (LPS) as the first event and the infusion of plasma from packed red blood cells (PRBCs) or antibodies (OX18 and OX27) against MHC class I antigens as the second event. ALI was determined by Evans blue dye leak from the plasma to the bronchoalveolar lavage fluid (BALF), protein and CINC-1 concentrations in the BALF, and the lung histology. NS-treated rats did not evidence ALI with any second events, and LPS did not cause ALI. LPS-treated animals demonstrated ALI in response to plasma from stored PRBCs, both prestorage leukoreduced and unmodified, and to OX18 and OX27, all in a concentration-dependent fashion. ALI was neutrophil (PMN) dependent, and OX18/OX27 localized to the PMN surface in vivo and primed the oxidase of rat PMNs. We conclude that TRALI is the result of 2 events with the second events consisting of the plasma from stored blood and antibodies that prime PMNs. IntroductionTransfusion-related acute lung injury (TRALI) is the leading cause of transfusion mortality in the United States. 1,2 TRALI is the acute onset of noncardiogenic pulmonary edema as documented by chest radiograph and profound hypoxemia, in accordance with the definition of acute lung injury (ALI), that occurs within 6 hours of transfusion. 3,4 TRALI may occur with or without conditions that predispose the patient to ALI, and may be the worsening of pulmonary function in patients with preexisting ALI. 3,4 All blood products have been implicated in TRALI, but components that contain large amounts of plasma are mainly responsible. 5,6 The current incidence of TRALI has been estimated as 1/7900 to 1/1330 in the United Kingdom and the United States with lesser incidences in Europe. [5][6][7][8] Current mortality rates vary from 5% to 35% with the lesser mortality rates predominating. [5][6][7][8] The pathophysiology of TRALI has not been elucidated despite numerous studies. [9][10][11][12][13][14] The first mechanism proposed was the infusion of donor antibodies directed against the HLA class I or granulocyte-specific antigens on the recipient's leukocytes with animal models composed of an in vivo murine model and an isolated, perfused rabbit lung that provided physiologic relevance. [9][10][11][12]14 In addition, the neutrophil (PMN) was proposed to be the effector cell, identical to other forms of ALI and the acute respiratory distress syndrome (ARDS). [9][10][11][12]14 However, look-back studies of donors with specific antibodies directed against HLA or granulocyte antigens demonstrated that the infusion of donor antibodies into a recipient that expressed the cognate antigen resulted in TRALI in a minority of these patients, implying that the clinical condition of the recipient may be important for the d...

Astrocytomas account for the majority of malignant brain tumors diagnosed in both adult and pediatric patients. The therapies available to treat these neoplasms are limited, and the prognosis associated with high-grade lesions is extremely poor. Mer (MerTK) and Axl receptor tyrosine kinases (RTK) are expressed at abnormally high levels in a variety of malignancies, and these receptors are known to activate strong antiapoptotic signaling pathways that promote oncogenesis. In this study, we found that Mer and Axl mRNA transcript and protein expression were elevated in astrocytic patient samples and cell lines. shRNA-mediated knockdown of Mer and Axl RTK expression led to an increase in apoptosis in astrocytoma cells. Apoptotic signaling pathways including Akt and extracellular signal–regulated kinase 1/2, which have been shown to be activated in resistant astrocytomas, were downregulated with Mer and Axl inhibition whereas poly(ADP-ribose) poly-merase cleavage was increased. Furthermore, Mer and Axl shRNA knockdown led to a profound decrease of astrocytoma cell proliferation in soft agar and a significant increase in chemosensitivity in response to temozolomide, carboplatin, and vincristine treatment. Our results suggest Mer and Axl RTK inhibition as a novel method to improve apoptotic response and chemosensitivity in astrocytoma and provide support for these oncogenes as attractive biological targets for astrocytoma drug development.