Yoko Horikawa

Functional Roles of Thrombopoietin-c-mpl System in Essential Thrombocythemia

Thrombopoietin (TPO) is implicated as a primary regulator of megakaryopoiesis and thrombopoiesis through binding to the cytokine receptor c-Mpl (the product of the c-mpl-proto-oncogene). In addition to its physiologic role, the TPO-c-mpl system has been suggested to participate in the pathophysiology of essential thrombocythemia (ET) which is a clonal disorder characterized by a sustained elevation of the circulating platelet count and bone-marrow hyperplasia with excessive proliferation of megakaryocytes. Recent studies have demonstrated that serum TPO levels are slightly elevated or within normal range in ET patients, whereas serum TPO levels tend to be inversely correlated with platelet mass. Flow cytometric, Western blot, and Northern blot analyses have revealed that the expression of platelet c-Mpl is strikingly reduced in all of patients with ET, possibly due to the decreased expression of c-mpl mRNA. These results suggest that normal or slightly elevated levels of serum TPO in ET patients may be attributable to the impaired uptake and catabolism of TPO owing to the low c-Mpl expression. Furthermore, immunoblotting with anti-phosphotyrosine antibody showed that no aberrant protein-tyrosine phosphorylation was observed in platelets of ET patients before treatment with TPO, and the levels of TPO-induced protein-tyrosine phosphorylation, including c-Mpl-tyrosyl phosphorylation, roughly paralleled those of c-Mpl expression, suggesting that c-Mpl-mediated signaling pathway was not constitutively activated in platelets of ET patients. Although activating mutation in the TPO gene, which leads to overexpression of TPO mRNA, has been reported in familial thrombocythemia, these results suggest that TPO-c-Mpl system may not be directly linked to pathogenesis of sporadic ET.

Preventive effect of ACE inhibitor on interstitial myofibroblast formation and matrix deposition in a nephrotic model

The nephrotic mouse (ICGN strain) is a useful model for progressive nephrotic syndrome (NS). In the present study, we demonstrated the preventive effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor, on the progression of renal dysfunction and tubulo-interstitial fibrosis in the NS mice. Administration of enalapril (5 mg/dL in drinking water) to the 4-week-old NS mice for a 4-week-period did not improve their nephrotic symptoms such as albuminuria and hypoalbuminemia, but significantly suppressed the increases in blood urea nitrogen and serum creatinine levels. Renal histopathology demonstrated that the administration of the ACE inhibitor significantly attenuated the progression of the tubular and interstitial lesions (tubular dilatation, luminal cast accumulation and interstitial expansion) rather than the glomerular sclerotic changes. The suppression of the increase in blood urea nitrogen level by enalapril depended on the attenuated tubular injury rather than on the unchanged glomerular matrix deposition. Immunohistochemical examination revealed that the administration of the ACE inhibitor suppressed the formation of myofibroblasts, identified by the alpha-smooth muscle actin-positive cells, in the interstitial spaces. Consequently, interstitial matrix deposition was significantly reduced in the NS mice treated with enalapril. From the results obtained with the spontaneous nephrotic model, we emphasize a possibility that ACE inhibitor may be effective for attenuating progression of renal dysfunction and fibrosis in human NS, even if the ACE inhibitor fails to improve nephrotic symptoms such as albuminuria and hypoalbuminemia.

Early Trilineage Recovery by Granulocyte Colony-Stimulating Factor in a Patient with Aplastic Anemia

Dr. Yuzuru Kanakura, Second Department of Internal Medicine, Osaka University Medical School, Yamadaoka 2-2, Suita Osaka 565 (Japan) Among the cytokines active in hematopoiesis, granulocyte colony-stimulating factor (G-CSF) has functions mainly on cells of neutrophilic granulocyte lineage [1]. A large number of clinical trials have suggested that G-CSF can accelerate the recovery of neutrophils when used after high-dose cytotoxic chemotherapy or bone marrow transplantation [2, 3]. In addition, G-CSF have been shown to have beneficial effects in patients with aplastic anemia (AA) who suffer from severe neutropenia [4]. With the exception of rare instances, however, G-CSF is known to have little or no effect on erythrocyte or platelet counts [2, 4-7]. We report here a unique case with acquired AA who showed trilineage recovery shortly after administration of rhG-CSF. Case Report A 57-year-old man was referred to Osaka University Hospital because of pancytopenia in April 1993. He had a 3-month history of pancytopenia and had received a total of 800 ml of red blood cell (RBC) in a previous hospital. Laboratory data were as follows: hemoglobin (Hb), 11.2 g/dl (immediately after RBC transfusion); reticulo-cytes88 × 109/1, white blood cells (WBC), 3.2 × 109/1 with differentials of 35% neutrophils and 56% lymphocytes; and platelets (PLT) 73 × 109/1. Bone marrow aspirate and biopsy revealed uniform hypocellularity (nucleated cell count, 14 × 109/l)withnomegakaryo-cytes and no morphological abnormalities. Based on these findings, he was diagnosed as having mild AA [8]. Daily anabolic steroids were thus administered orally at a dose of 30 mg/kg body weight in April 1993. This treatment did not improve the hematologic parameters and hemoglobin decreased (fig. 1). Because RBC transfusions were required every 2 or 4 weeks, the patient was admitted to our hospital on September 21, 1993. Hemoglobin was 8.6 g/dl, reticulocytes 80 × 109/1, WBC 2.71 × 109/1 (47.8% neutrophils, 3.8% eosinophils, 39.9% lymphocytes, 8.1% monocytes), and PLT