Il6 and Il10 IN Hepatic Arterial infusion then DIC

However, highly regulated expression of several enzymes present in the urea cycle occurs also in many other tissues, where these enzymes are involved in synthesis of nitric oxide, polyamines, proline and glutamate. Glucagon, insulin, and glucocorticoids are major regulators of the expression of urea cycle enzymes in liver. In contrast, the "urea cycle" enzymes in nonhepatic cells are regulated by a wide range of pro- and antiinflammatory cytokines and other agents.

 

Molecular Genetics and Metabolism

September–October, 2003 Volume 80, Issues 1-2, Pages 148–158

Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer

Steven E Raper
Raper ,              

Adam Bagg

 

Guang-ping Gao

James M Wilson

Mark L Batshaw

Narendra Chirmule

Narendra Chirmul

Frank S Lee

 

Frank S Lee

Nelson A Wivel

Nelson A Wive

 

Corresponding author. Fax: 1-202-884-5988

 

Received: May 30, 2003; Received in revised form: August 8, 2003; Accepted: August 11, 2003;

DOI: http://dx.doi.org/10.1016/j.ymgme.2003.08.016

 

Fig. 1

Relevant clinical pathology parameters during hospital course. Note the improvement in laboratory parameters at a time when pulmonary function began to deteriorate. CVVHD, continuous veno-venous hemodialysis; ECMO, extracorporeal membrane oxygenation. The arrows indicate the start and end of vector infusion, and institution of intubation, CVVHD, and ECMO. Normal ranges are represented in shaded bars. Units for clinical and laboratory parameters are as follows: NH₄—μmol/L; bilirubin—mg/dl; alanine aminotransferase (ALT)—U/L; prothrombin time (PT)–s; platelets–×10³/μl; fibrin split products (FSP)—μg/ml; fraction of oxygen in inspired air (FiO₂)—%.

(A) Microscopic appearance of normal lung parenchyma (left) compared to microscopic appearance of lung parenchyma from OTC.019 (right). For detailed description, see text. (B) Microscopic appearance of normal liver (L) compared to the microscopic appearance of liver, with necrosis, from OTC.019 (R). Arrow indicates central vein of hepatic lobule: note centrilobular necrosis. For detailed description, see text. (C) Microscopic appearance of normal spleen (L) compared to the microscopic appearance of spleen, with necrosis, from OTC.019 (R). Arrow indicates scattered lymphocytes in area of widespread necrosis. For detailed description, see text. (D) Immunohistochemical evaluation of normal bone marrow (L) demonstrating presence of erythroid precursors compared to bone marrow from OTC.019 (R), demonstrating absence of hemoglobin A⁺ erythroid precursors. Arrows indicate normal erythroid precursors.

Serum levels of two cytokines in all 18 subjects dosed with recombinant adenoviral vector. (A) Time course of IL-6 elevation in cohorts 5 and 6. (B) Average peak IL-6 level by cohort. (C) Time course of IL-10 elevation in cohorts 5 and 6. (D) Average peak IL-10 level by cohort

Biodistribution of OTC vector in OTC.019. Real-time PCR shows the number of copies of vector DNA detected in each organ at the time of post-mortem examination.

Abstract

We report the death of an 18-year-old male with partial ornithine transcarbmaylase (OTC) deficiency who participated in a pilot (safety) study of gene therapy. The vector used for this trial was based on human adenovirus type 5, deleted in E1 and E4, and contained human OTC cDNA. It was infused into the right hepatic artery at a dose of 6×10¹¹particles/kg. Approximately 18h. following gene transfer the subject was noted to have altered mental status and jaundice—clinical signs not seen in any of the first 17 subjects in this study. Subsequently, his clinical course was marked by systemic inflammatory response syndrome, biochemically detectable disseminated intravascular coagulation, and multiple organ system failure, leading to death 98h following gene transfer. Post-mortem examination was consistent with the clinical course, and vector DNA sequences were readily detectable in most tissues. The subject had high serum levels of IL-6 and IL-10 but normal TNFα immediately after infusion of the vector. This experience points to the limitations of animal studies in predicting human responses, the steep toxicity curve for replication defective adenovirus vectors, substantial subject-to-subject variation in host responses to systemically administered vectors, and the need for further study of the immune response to these vectors.

HEPATIC ARTERY INJECTION WOULD YIELD IMMEDIATE PRODUCT ELEVATION AT TOXIC LEVELS POSSIBLY  An oral route with first pass through live would be better. Like a post- ischemic  correction of arterial insufficiency at cardiac level leading to arrhythmias, a pathology may require a more sensitive replacement of deficiencies

Transiently Reduced Activity of Carbamyl Phosphate Synthetase and Ornithine Transcarbamylase in Liver of Children with Reye's Syndrome

Ted Brown, B.A., George Hug, M.D., Lester Lansky, M.D., Kevin Bove, M.D., Annette Scheve, B.A., Mary Ryan, B.A., Henry Brown, M.D., William K. Schubert, M.D., John C. Partin, M.D., and John Lloyd-Still, M.D.

N Engl J Med 1976; 294:861-867April 15, 1976DOI: 10.1056/NEJM19760415294

  

Extra Urea Cycle enzyme activity / Immunity

See comment in PubMed Commons below

AMIE ENTRY .

control at  transcriptional level by inflammatory and non-inflammatory cytokines.

extra Urea cycle

 

These enzymes are involved in synthesis of nitric oxide, polyamines, proline and glutamate. Glucagon, insulin, and glucocorticoids are major regulators of the expression of urea cycle enzymes in liver

subject: Extra urea cycle arginase/arginine metabolism involved in immunity
object_opposite: not exclusively within urea cycle. Extra urea cycle Arginine metabolism and production NO2 involved in other processes relative to immunity.
misc: Regulation of enzymes of the urea cycle and arginine metabolism. Author information The urea cycle is comprised of five enzymes but also requires other enzymes and mitochondrial amino acid transporters to function fully. The complete urea cycle is expressed in liver and to a small degree also in enterocytes. However, highly regulated expression of several enzymes present in the urea cycle occurs also in many other tissues, where these enzymes are involved in synthesis of nitric oxide, polyamines, proline and glutamate. Glucagon, insulin, and glucocorticoids are major regulators of the expression of urea cycle enzymes in liver. In contrast, the "urea cycle" enzymes in nonhepatic cells are regulated by a wide range of pro- and antiinflammatory cytokines and other agents. Regulation of these enzymes is largely transcriptional in virtually all cell types. This review emphasizes recent information regarding roles and regulation of urea cycle and arginine metabolic enzymes in liver and other cell types.
author_year: Morris SM Jr/2002
journal_volume_page: Annu Rev Nutr.22:87-105

 

Annu Rev Nutr. 2002;22:87-105. Epub 2002 Jan 4.

Regulation of enzymes of the urea cycle and arginine metabolism.

Morris SM Jr¹

Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. smorris@pitt.edu

Abstract

The urea cycle is comprised of five enzymes but also requires other enzymes and mitochondrial amino acid transporters to function fully. The complete urea cycle is expressed in liver and to a small degree also in enterocytes. However, highly regulated expression of several enzymes present in the urea cycle occurs also in many other tissues, where these enzymes are involved in synthesis of nitric oxide, polyamines, proline and glutamate. Glucagon, insulin, and glucocorticoids are major regulators of the expression of urea cycle enzymes in liver. In contrast, the "urea cycle" enzymes in nonhepatic cells are regulated by a wide range of pro- and antiinflammatory cytokines and other agents. Regulation of these enzymes is largely transcriptional in virtually all cell types. This review emphasizes recent information regarding roles and regulation of urea cycle and arginine metabolic enzymes in liver and other cell types.