propylthiouracil and Inflammation

Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality. Current evidence suggests that the pathogenesis is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity. Several clinical scoring systems have been derived to predict the clinical outcomes of patients with AH; such as Child-Turcotte-Pugh score, the Maddrey discriminant function, the Lille Model, the model for end stage liver disease scores, and the Glasgow alcoholic hepatitis score. At present, Corticosteroids or pentoxifylline are the current pharmacologic treatment options; though the outcomes from the therapies are poor. Liver transplantation as the treatment of alcoholic hepatitis remains controversial, and in an era of organ shortage current guidelines do not recommend transplantation as the treatment option. Because of the limitations in the therapeutic options, it is no doubt that there is a critical need for the newer and more effective pharmacological agents to treat AH.

Topics: Acetylcysteine; Adrenal Cortex Hormones; Alcoholism; End Stage Liver Disease; Enteral Nutrition; Hepatitis, Alcoholic; Humans; Immunity, Innate; Inflammation; Liver Transplantation; Pentoxifylline; Propylthiouracil; S-Adenosylmethionine; Treatment Outcome

Drug-induced liver injury is a major concern in clinical studies as well as in post-marketing surveillance. Previous evidence suggested that drug exposure during periods of inflammation could increase an individual's susceptibility to drug hepatoxicity. The antithyroid drugs, methimazole (MMI) and propylthiouracil (PTU) can cause adverse reactions in patients, with liver as a usual target. We tested the hypothesis that MMI and PTU could be rendered hepatotoxic in animals undergoing a modest inflammation. Mice were treated with a nonhepatotoxic dose of LPS (100 µg/kg, i.p) or its vehicle. Nonhepatotoxic doses of MMI (10, 25 and 50 mg/kg, oral) and PTU (10, 25 and 50 mg/kg, oral) were administered two hours after LPS treatment. It was found that liver injury was evident only in animals received both drug and LPS, as estimated by increases in serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and TNF-α. An increase in liver myeloperoxidase (MPO) enzyme activity and tissue lipid peroxidation (LPO) in addition of liver glutathione (GSH) depletion were also detected in LPS and antithyroid drugs cotreated animals. Furthermore, histopathological changes including, endotheliitis, fatty changes, severe inflammatory cells infiltration (hepatitis) and sinusoidal congestion were detected in liver tissue. Methyl palmitate (2 g/kg, i.v, 44 hours before LPS), as a macrophage suppressor, significantly alleviated antithyroids hepatotoxicity in LPS-treated animals. The results indicate a synergistic liver injury from antithyroid drugs and bacterial lipopolysaccharide coexposure.

Topics: Animals; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Inflammation; Lipopolysaccharides; Male; Methimazole; Mice; Mice, Inbred BALB C; Propylthiouracil

This protocol describes microsphere-based protease assays for use in flow cytometry and high-throughput screening. This platform measures a loss of fluorescence from the surface of a microsphere due to the cleavage of an attached fluorescent protease substrate by a suitable protease enzyme. The assay format can be adapted to any site or protein-specific protease of interest and results can be measured in both real time and as endpoint fluorescence assays on a flow cytometer. Endpoint assays are easily adapted to microplate format for flow cytometry high-throughput analysis and inhibitor screening.

Topics: Animals; Biotinylation; Flow Cytometry; Fluorescence Resonance Energy Transfer; Green Fluorescent Proteins; High-Throughput Screening Assays; Humans; Inflammation; Kinetics; Microspheres; Peptide Hydrolases; Peptides; Reproducibility of Results; Temperature

We report on a case of pulmonary capillaritis with diffuse alveolar hemorrhage in a child due to propylthiouracil (PTU). PTU treatment is a rare cause of pulmonary capillaritis in adults; we report on the first case in a pediatric patient. The treatment of pulmonary capillaritis often requires corticosteroid therapy, other immunosuppressive medications, or withdrawal of the causative agent. Our patient recovered completely after treatment with a limited course of corticosteroids and removal of PTU.

Topics: Adrenal Cortex Hormones; Antithyroid Agents; Capillaries; Child; Female; Hemorrhage; Humans; Hyperthyroidism; Inflammation; Lung; Lung Diseases; Propylthiouracil

We have previously reported that thyroid capsular inflammation induced by sulfadimethoxine (SDM), a goitrogen, might play a role in development of invasive follicular cell adenocarcinomas in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). The present study was designed to examine the role of cyclooxygenase (COX)-2, widely known to be up-regulated in inflammatory states, during chemically induced rat thyroid carcinogenesis. Male F344 rats received a subcutaneous DHPN (2800 mg/kg) injection, and 1 week later were allowed free access to drinking water containing antithyroidal propylthiouracil (PTU, 0.003%) or SDM (0.1%) for 4 or 10 weeks. Control groups receiving goitrogen alone and no treatment were also included. At week 4, diffuse follicular cell hyperplasia was induced in all PTU- and SDM-treated groups, along with fibrous capsular thickening and capsular thickening with inflammation, respectively. Additionally, multiple focal follicular cell hyperplasias and adenomas were observed in the DHPN + PTU and DHPN + SDM cases. At week 10, adenocarcinomas invasive to the capsule and restricted to the capsular adjacent region, were frequent in the DHPN + SDM group, but not observed in the animals given DHPN + PTU. Western blots and immunohistochemistry revealed constitutive COX-2 expression in non-neoplastic follicular cells of the control and all of the PTU- and SDM-treated rats. However, COX-2 reactivity was significantly reduced or negative in the preneoplastic/neoplastic lesions in the DHPN-treated groups. In fibrous or inflamed thickened capsules, only a few component cells with inflammatory elements were positive for COX-2, and there was no significant difference in this regard between the PTU and SDM treatments. The present results suggest that capsular inflammation could play a role in development of invasive carcinomas, but COX-2 expression does not make a major contribution.

Topics: Adenocarcinoma, Follicular; Animals; Anti-Infective Agents; Antithyroid Agents; Blotting, Western; Carcinogens; Cyclooxygenase 2; Disease Models, Animal; Enzyme Inhibitors; Immunohistochemistry; Inflammation; Iodide Peroxidase; Male; Nitrosamines; Propylthiouracil; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; Sulfadimethoxine; Thyroid Neoplasms

Concanavalin A (Con A) activates T lymphocytes and causes acute T-cell-mediated hepatic injury in mice. Decreased thyroid hormonal production is associated with a variety of immunological manifestations, including inactivation of macrophages with reduced TNF production and reduced soluble IL-2 receptors in the serum. We have recently shown that hypothyroidism prevents the development of cirrhosis and also minimizes hepatic damage in rats with fulminant hepatic failure. In the present study we examined the effects of hypothyroidism on a mouse model of Con A induced T cell-mediated acute hepatitis.. Hypothyroidism was induced both medically (MMI, PTU) and surgically. Eight groups of 10 mice each were studied: euthyroid controls (2 groups: water, Con A) and hypothyroid (6 groups: MMI, PTU, Surgical, MMI-Con A, PTU-Con A, Surgical-Con A).. Hepatic inflammation was significantly decreased in each of the Con A treated hypothyroid groups of mice. The serum transaminases, TNF-alpha and IL-6 levels were significantly elevated in the Con A treated group while near normal levels were found in the hypothyroid Con A treated groups (mean+/-SE AST: 1499+/-18 vs 78+/-10 IU/l, p<0.001; TNF: 2500+/-250 vs 135+/-15 pg/ml, p<0.001, IL-6: 12,200+/-300 vs 1260+/-140 pg/ml, p<0.001, respectively).. Hypothyroidism, independent of the mode of induction, can effectively inhibit the development of acute T cell-mediated liver damage in mice. These results suggest that some decrease in thyroid function might have a role in the prevention of immune mediated liver diseases.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Concanavalin A; Cytokines; Hypothyroidism; Immunity, Cellular; Inflammation; L-Lactate Dehydrogenase; Liver; Male; Methimazole; Mice; Mice, Inbred BALB C; Propylthiouracil; T-Lymphocytes; Thyroidectomy; Time Factors