ABSTRACT: Chitotriosidase, a macrophage marker, which is extremely increased in plasma of Gaucher patients, was measured in patients with beta-thalassemia, an haematological disorder characterized by the genetic defect of beta-globin chains synthesis resulting in unproductive erythropoiesis and enormous expansion of the reticuloendothelial system. Plasma chitotriosidase was increased to a variable extent in 13 of 70 patients with beta-thalassemia major treated with the intense transfusion regimen and iron chelation therapy. It was normal in 22 and slightly elevated in 3 subjects with beta-thalassemia intermedia which were not transfused.

The highest levels of plasma chitotriosidase, as high as in Gaucher patients, were found in 7 (10%) of the beta-thalassemia major patients which also had the highest degree of iron overload as judged by their serum ferritin level (> 3000 ng/ml), high SGPT level and elevated urinary iron excretion.

To our knowledge, beta-thalassemia is hitherto the only disorder in which an increase of plasma chitotriosidase, comparable to that seen in Gaucher disease, may occur. The increase of plasma chitotriosidase activity in beta-thalassemia patients with high iron overload, could be related to an iron mediated damage to the lysosomal apparatus. In addition, similarly to Gaucher disease, the increased chitotriosidase production in beta-thalassemia might reflect macrophage activation probably related to the intracellular iron overload, storage of erythrocytes membrane break-down products and oxidation of excess alpha-hemoglobin subunits. Further studies are required to define the role of chitotriosidase evaluation to assess the efficacy of chelation therapy in reducing the macrophage activation due to intracellular iron overload in beta- thalassemia.

Keywords: Beta-thalassemia, chitotriosidase, Gaucher disease.

Reprint requests to: Barone Rita, M.D., Division of Pediatric Neurology, Institute of Pediatrics, V. le A. Doria, 6, 95125 Catania-Italy, phone: 39 095256407, fax: 39 095222532, e-mail: r.barone@tau.it.

ABSTRACT: The mechanisms of recognition, trapping and destruction of senescent human erythrocytes are not completely understood. Here we discuss some evidences supporting the idea that red cell ageing is closely related to a progressive increase in intracellular ionic Ca. This in turn, is the determining factor of a series of events such as Ca pump proteolysis and opening of the Ca-dependent K channel, that finally lead to the removal of old cells by macrophages at spleen level.

Keywords: Erythrocytes, ageing, intracellular Ca, K(Ca)channel, Ca pump proteolysis.

Reprint requests to: Dr. Pedro J. Romero, Laboratory of Membrane Physiology. Institute of Experimental Biology. Faculty of Sciences, Central University of Venezuela. Apartado 47114, Caracas 1041-A, Venezuela, phone: (582) 751 0766 x222, fax: (582) 753 7087, e-mail: romepe@mixmail.com.

ABSTRACT: Withdrawal of trophic support from growth factor- dependent MO7e human myeloid progenitor cells induces apoptosis characterized by DNA fragmentation and degradation of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Inhibitors of caspase (ICE) protease family members did not inhibit apoptosis or DNA fragmentation induced by factor withdrawal, but blocked degradation of DNA-PKcs. Thus, caspase activity accounts for only a component of the apoptotic program in MO7e hematopoietic cells. The protease inhibitor TPCK, but not other protease inhibitors, blocked DNA fragmentation, but not degradation of DNA-PKcs during apoptosis of MO7e cells. Thus, caspase-independent and caspase-dependent protease cascades mediate distinct features of MO7e cell apoptosis. The proteasome inhibitors calpain inhibitor I and lactacystin promoted DNA fragmentation, degradation of DNA-PKcs and apoptosis of MO7e cells. The ability of lactacystin to promote DNA fragmentation was abrogated by TPCK, but not by caspase inhibitors, whereas the ability of lactacystin to promote degradation of DNA-PKcs was blocked by caspase inhibitors, but not by TPCK. Thus, caspase- dependent and caspase-independent protease cascades are downstream of and regulated by the proteasome, which plays a central role in regulating the multiple protease cascades that induce apoptosis.

Keywords: DNA fragmentation, factor withdrawal, cell death.

Reprint requests to: David B. Donner, Ph.D., The Walther Oncology Center, 1044 West Walnut St., Indiana University School of Medicine, Indianapolis, IN 46202, phone: (317) 278-2155, fax: (317) 274-7564, e-mail: ddonner@iupui.edu.