ABSTRACT
Hepatic involvement is often encountered in gastrointestinal (GI) diseases, in part because of the close anatomic and physiologic relations between the liver and GI tract. Drainage of the mesenteric blood supply to the portal vein permits absorbed and/or translocated nutrients, toxins, bacterial elements, cytokines, and immunocytes to gain hepatic access. Liver problems in digestive disorders may range from nonspecific hepatocellular enzyme elevations to significant pathologic processes that may progress to end-stage liver disease. Hepatobiliary manifestations of primary GI diseases in childhood and adolescence are not uncommon and include several well-described associations, such as sclerosing cholangitis with inflammatory bowel disease. Liver damage may also result from the effects of drugs used to treat GI diseases, for example, the hepatotoxicity of immunomodulatory therapies. This review highlights the important features of the hepatic and biliary abnormalities associated with 3 common pediatric GI conditions: inflammatory bowel disease, celiac disease, and cystic fibrosis.
Subject(s)
Celiac Disease/complications , Chemical and Drug Induced Liver Injury/etiology , Cholagogues and Choleretics/therapeutic use , Cholangitis, Sclerosing/etiology , Cystic Fibrosis/complications , Inflammatory Bowel Diseases/complications , Liver Diseases/etiology , Adolescent , Antibodies, Monoclonal/adverse effects , Azathioprine/adverse effects , Celiac Disease/diet therapy , Child , Child, Preschool , Cholangitis, Sclerosing/diagnosis , Cholangitis, Sclerosing/epidemiology , Cholangitis, Sclerosing/therapy , Humans , Infant , Inflammatory Bowel Diseases/drug therapy , Infliximab , Liver Diseases/blood , Liver Diseases/diagnosis , Liver Diseases/epidemiology , Liver Diseases/therapy , Liver Function Tests , Mercaptopurine/adverse effects , Methotrexate/adverse effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Ursodeoxycholic Acid/therapeutic useABSTRACT
Insulin-like growth factor-1 (IGF-1) and beta-estradiol (E2) have vasodilatory effects, in part, through stimulation of vascular nitric oxide (NO) production. However, their interactive effects on endothelial nitric oxide synthase (eNOS) and NO production have not been previously studied in endothelial cells (EC). Employing rat aortic EC (RAEC), the effects of acute (20 and 30 minutes) and prolonged (4 hours) stimulation with 100 nmol/L IGF-1 and 1 nmol/L E2 (alone or in combination) were assessed with respect to protein levels and enzymatic activities for phosphatidyl inositol 3-kinase (PI3K) and serine/threonine kinase Akt (Akt), enzymes involved in eNOS activation. Exposure to IGF-1 for 30 minutes or E2 for 20 minutes increased insulin receptor substrate-1 (IRS-1) association with the regulatory (p85) subunit of PI3K, enhanced tyrosine phosphorylation of p85, and increased PI3K activity. Combined treatment had a greater effect on p85 phosphorylation and PI3K activity then either agonist alone. Moreover, IGF-1 and E2 enhanced Akt Ser(473) phosphorylation, with the effect of IGF-1 being much greater. Acute expose to both E2 (20 minutes) and IGF-1 (30 minutes) were associated with an increase in eNOS activity. Prolonged exposure (4 hours) to either IGF-1 or E2 increased expression of the p85 subunit as well as eNOS activity. Pretreatment with PI3K antagonist wortmannin (WT) prevented this increase in eNOS activity. The results suggest that IGF-1 and E2 may interact through PI3K/Akt-related pathways to increase eNOS activity.
