methimazole and Fibrosis

It has been demonstrated that trimethylamine N-oxide (TMAO) serves as a driver of atherosclerosis, suggesting that reduction of TMAO level might be a potent method to prevent the progression of atherosclerosis. Herein, we explored the role of TMAO in the stability of carotid atherosclerotic plaques and disclosed the underlying mechanisms. The unstable carotid artery plaque models were established in C57/BL6 mice. L-carnitine (LCA) and methimazole (MMI) administration were applied to increase and reduce TMAO levels. Hematoxylin and eosin (H&E) staining, Sirius red, Perl's staining, Masson trichrome staining and immunohistochemical staining with CD68 staining were used for histopathology analysis of the carotid artery plaque. M1 and M2 macrophagocyte markers were assessed by RT-PCR to determine the polarization of RAW264.7 cells. MMI administration for 2 weeks significantly decreased the plaque area, increased the thickness of the fibrous cap and reduced the size of the necrotic lipid cores, whereas 5-week of administration of MMI induced intraplate hemorrhage. LCA treatment further deteriorated the carotid atherosclerotic plaque but with no significant difference. In mechanism, we found that TMAO treatment impaired the M2 polarization and efferocytosis of RAW264.7 cells with no obvious effect on the M1 polarization. In conclusion, the present study demonstrated that TMAO reduction enhanced the stability of carotid atherosclerotic plaque through promoting macrophage M2 polarization and efferocytosis.

Topics: Animals; Carotid Arteries; Carotid Artery Diseases; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Fibrosis; Humans; Jurkat Cells; Macrophages; Male; Methimazole; Methylamines; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Necrosis; Oxygenases; Phagocytosis; Phenotype; Plaque, Atherosclerotic; RAW 264.7 Cells

A 45-year-old man was hospitalized because of weight loss, finger tremor, thirst, polydipsia and increased urinary frequency. He was diagnosed with Graves' disease (GD) and central diabetes insipidus (CDI). Magnetic resonance imaging revealed the enlarged posterior pituitary with thickened stalk. Histological examination obtained from biopsy of the pituitary revealed lymphocytic infundibulo-neurohypophysitis. He received treatment with thiamazole (MMI) for GD and desmopressin acetate (DDAVP) for CDI. However, DDAVP administration could be discontinued as GD was gradually improved. This course indicates that not only the recovered renal response to arginine-vasopressin but also the immunomodulative effects of MMI might attribute to the improvement of polyuria.

Topics: Arginine Vasopressin; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Fibrosis; Graves Disease; Humans; Inflammation; Lymphocytes; Male; Methimazole; Middle Aged; Osmolar Concentration; Pituitary Gland, Posterior; Polyuria; Remission Induction; Saline Solution, Hypertonic; Thyroxine; Urine

Thyroid destruction leading to endemic myxoedematous cretinism is highly prevalent in central Africa, where iodine (I) and selenium (SE) deficiencies as well as thiocyanate (SCN) overload are combined. All three factors have been studied experimentally in the etiology of the disease, but they have never been studied in combination. In a model using rats, we have previously shown that combining I and SE deficiencies increases the sensitivity of the thyroid to necrosis after iodide overload, an event unlikely to occur in the African situation. To develop a model that would more closely fit with the epidemiological findings, we have determined whether an SCN overload would also result in thyroid necrosis as does the I overload. The combination of the three factors increased by 3.5 times the amount of necrotic cells, from 5.5 +/- 0.3% in the I-SE+ thyroids to 18.9 +/- 1.6% in the I-SE-SCN-overloaded ones. Methimazole administration prevented the SCN-induced necrosis. SE- thyroids evolved to fibrosis, whereas SE+ thyroids did not. TGFbeta was prominent in macrophages present in SE- glands. Thyroid destruction in central Africa might therefore originate from the interaction of three factors: I and SE deficiencies by increasing H(2)O(2) accumulation, SE deficiency by decreasing cell defense and promoting fibrosis, and SCN overload by triggering follicular cell necrosis.

Topics: Africa, Central; Animals; Antithyroid Agents; Congenital Hypothyroidism; Disease Models, Animal; Endemic Diseases; Female; Fibrosis; Hydrogen Peroxide; Inflammation; Iodine; Macrophages; Methimazole; Myxedema; Necrosis; Perchlorates; Rats; Rats, Wistar; Selenium; Sodium Compounds; Thiocyanates; Thyroid Gland; Transforming Growth Factor beta