Erythropoietin hypersensitivity in primary familial and congenital polycythemia: Role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain

AbstractErythropoietin receptor (EPOR) gene mutations leading to truncations of the cytoplasmic, carboxy-terminal region of EPOR have been described in some patients with primary familial and congenital polycythemia (PFCP), a disorder characterized by isolated erythrocytosis and increased sensitivity of erythroid progenitors to Epo. We studied the role of EPOR in the pathogenesis of PFCP and the requirement for intracytoplasmic tyrosine residues Y285 and Y344 in generation of Epo hypersensitivity phenotype. Interleukin-3-dependent hematopoietic cells were engineered to express variant human EPORs using retrovirus-mediated gene transfer. We introduced tyrosine to phenylalanine substitutions in EPOR-ME, a naturally occurring, mutant human EPOR (G5881T), truncated by 110 carboxy-terminal amino acids and associated with autosomal dominantly inherited PFCP. Cells expressing EPOR-ME exhibited increased Epo sensitivity compared to cells expressing wild type EPOR. Mutation of Y285 alone had a relatively minor effect on Epo hypersensitivity whereas mutation of Y344 resulted in loss of increased Epo sensitivity. Expression of a tyrosine-null truncated EPOR conferred further decrease of Epo-mediated proliferation suggesting that both Y285 and Y344 may contribute to proliferation signals. In the context of EPOR-ME, Y344 was required for Epo-induced Stat5 tyrosine phosphorylation. The positive effect of either Y285 or Y344 on cellular proliferation was associated with Epo-induced tyrosine phosphorylation of Stat1. These findings suggest that both tyrosine residues Y285 and Y344 in the cytoplasmic domain of EPOR-ME may contribute to increased Epo sensitivity that is characteristic of PFCP phenotype

Plasma Cytokines and Chemokines in Primary Graft Dysfunction Post-Lung Transplantation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72208/1/j.1600-6143.2008.02497.x.pd

Intravenous Immunoglobulin for Hypogammaglobulinemia after Lung Transplantation: A Randomized Crossover Trial

Background We aimed to determine the effects of treatment with intravenous immunoglobulin on bacterial infections in patients with hypogammaglobulinemia (HGG) after lung transplantation. Methods We performed a randomized, double-blind, placebo-controlled two-period crossover trial of immune globulin intravenous (IVIG), 10% Purified (Gamunex, Bayer, Elkhart, IN) monthly in eleven adults who had undergone lung transplantation more than three months previously. We randomized study participants to three doses of IVIG (or 0.1% albumin solution (placebo)) given four weeks apart followed by a twelve week washout and then three doses of placebo (or IVIG). The primary outcome was the number of bacterial infections within each treatment period. Results IVIG had no effect on the number of bacterial infections during the treatment period (3 during IVIG and 1 during placebo; odds ratio 3.5, 95% confidence interval 0.4 to 27.6, p = 0.24). There were no effects on other infections, use of antibiotics, or lung function. IVIG significantly increased trough IgG levels at all time points (least square means, 765.3 mg/dl during IVIG and 486.3 mg/dl during placebo, p<0.001). Four serious adverse events (resulting in hospitalization) occurred during the treatment periods (3 during active treatment and 1 during the placebo period, p = 0.37). Chills, flushing, and nausea occurred during one infusion of IVIG. Conclusions Treatment with IVIG did not reduce the short-term risk of bacterial infection in patients with HGG after lung transplantation. The clinical efficacy of immunoglobulin supplementation in HGG related to lung transplantation over the long term or with recurrent infections is unknown

Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinoma

Ribatti D, Marzullo A, Gentile A, Longo V, Nico B, Vacca A & Dammacco F (2007) Histopathology 50, 591–596 Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinom

Donor Surfactant Protein A2 Polymorphism and Lung Transplant Survival.

Purpose Gene polymorphisms of surfactant proteins, key players in lung innate immunity, have been associated with various lung diseases. The aim of this study was to investigate the potential association between variations within the SP-A gene of the donor lung allograft and recipient post-transplant outcome. Methods Lung-Tx pts (n=192) were prospectively followed by PFTs, bronchoscopies with BAL and biopsies. Donor lungs were assayed for SP-A1 (6An) and SP-A2 (1An) gene polymorphism by using the pyrosequencing method. Unadjusted and adjusted stratified Cox survival models are reported. Results SP-A1 and SP-A2 genotype frequency and lung transplant recipient and donor characteristics as well as the cause of death are noted. Recipients were grouped per donor SP-A2 variants. Individuals that received lungs from donors with the SP-A2 1A0 (n=102) versus 1A1 variant (n=68) or SPA2 genotype 1A01A0 (n=54) versus 1A0A1 (n=38) had greater survival at one year (logrank p&lt;0.025). No significant association was noted for SP-A1 variants. Stratified adjusted survival models for one year survival and diagnosis showed a reduced survival for 1A1 variant and the 1A01A1 genotype. Furthermore, when survival was conditional on one year survival no significance was observed, indicating that the survival difference were due to the first year's outcome associated with the 1A1 variant. Conclusion Donor lung SP-A gene polymorphisms are associated with post-transplant clinical outcome. Lungs from donors with the SP-A2 variant 1A1 had a reduced survival at one year. The observed donor genetic differences, via innate immunity relate to the post-transplant clinical outcome.PURPOSE: Gene polymorphisms of surfactant proteins, key players in lung innate immunity, have been associated with various lung diseases. The aim of this study was to investigate the potential association between variations within the SP-A gene of the donor lung allograft and recipient post-transplant outcome. METHODS: Lung-Tx pts (n=192) were prospectively followed by PFTs, bronchoscopies with BAL and biopsies. Donor lungs were assayed for SP-A1 (6An) and SP-A2 (1An) gene polymorphism by using the pyrosequencing method. Unadjusted and adjusted stratified Cox survival models are reported. RESULTS: SP-A1 and SP-A2 genotype frequency and lung transplant recipient and donor characteristics as well as the cause of death are noted. Recipients were grouped per donor SP-A2 variants. Individuals that received lungs from donors with the SP-A2 1A0 (n=102) versus 1A1 variant (n=68) or SPA2 genotype 1A01A0 (n=54) versus 1A0A1 (n=38) had greater survival at one year (logrank p&lt;0.025). No significant association was noted for SP-A1 variants. Stratified adjusted survival models for one year survival and diagnosis showed a reduced survival for 1A1 variant and the 1A01A1 genotype. Furthermore, when survival was conditional on one year survival no significance was observed, indicating that the survival difference were due to the first year's outcome associated with the 1A1 variant. CONCLUSION: Donor lung SP-A gene polymorphisms are associated with post-transplant clinical outcome. Lungs from donors with the SP-A2 variant 1A1 had a reduced survival at one year. The observed donor genetic differences, via innate immunity relate to the post-transplant clinical outcome

Acute ST segment elevation during exercise stress echocardiography due to severe pulmonary hypertension

A 51-year-old female undergoing an outpatient stress echocardiogram to evaluate atypical chest pain developed acute ST elevation in the anterior precordial leads on electrocardiogram following exercise. Echocardiography revealed a severe rise in pulmonary artery systolic pressure (PASP) with marked right ventricular (RV) enlargement and interventricular septum flattening. Subsequently, cardiac catherization confirmed an exercise-induced elevation in PASP and diagnosed pulmonary arterial hypertension without evidence of coronary artery disease. This case suggests that an acute elevation in pulmonary artery pressure with RV dilation may be a potential cause of acute ST elevation during stress testing

Bronchial & Alveolar Lipidomic Profile as a Marker of the Immunological and Functional Status of the Lung Allograft.

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Erythropoietin/erythropoietin receptor system is involved in angiogenesis in human neuroblastoma

Ribatti D, Poliani P L, Longo V, Mangieri D, Nico B & Vacca A (2007) Histopathology50, 636–641 Erythropoietin/erythropoietin receptor system is involved in angiogenesis in human neuroblastom

Platelet activation in the postoperative period after lung transplantation

Objective During lung transplantation, cells in the pulmonary parenchyma are subjected to ischemia, hypothermic storage, and reperfusion injury. Platelets, whose granular contents include adhesion receptors, chemokines, and coactivating substances that activate inflammatory and coagulant cascades, likely play a critical role in the lung allograft response to ischemia and reperfusion. The platelet response to the pulmonary allograft, however, has never been studied. Here we report significant platelet activation immediately after lung transplantation. Methods We performed a prospective cohort study comparing markers of platelet activation in patients undergoing lung transplantation and patients undergoing nontransplant thoracotomy. Plasma levels of soluble P-selectin, soluble CD40 ligand, and platelet–leukocyte conjugates were measured before surgery, after skin closure, and at 6 postoperative hours. Results Both soluble P-selectin and soluble CD40 ligand levels increased significantly after lung transplantation but not after thoracotomy. Additionally, platelet–monocyte conjugate fluorescence was significantly higher after lung transplantation than after thoracotomy alone. Conclusion These findings suggest that platelet activation is significantly increased after lung transplantation beyond that expected from the postoperative state. The increase in circulating platelet–monocyte conjugates suggests an important interaction between platelets and inflammatory cells. Further research should examine whether platelet activation affects early graft function after lung transplantation