Time course of collagen peak in bile duct-ligated rats

<p>Abstract</p> <p>Background</p> <p>One of the most useful experimental fibrogenesis models is the "bile duct-ligated rats". Our aim was to investigate the quantitative hepatic collagen content by two different methods during the different stages of hepatic fibrosis in bile duct-ligated rats on a weekly basis. We questioned whether the 1-wk or 4-wk bile duct-ligated model is suitable in animal fibrogenesis trials.</p> <p>Methods</p> <p>Of the 53 male Wistar rats, 8 (Group 0) were used as a healthy control group. Bile duct ligation (BDL) had been performed in the rest. Bile duct-ligated rates were sacrificed 7 days later in group 1 (10 rats), 14 days later in group 2 (9 rats), 21 days later in group 3(9 rats) and 28 days later in group 4 (9 rats). Eight rats underwent sham-operation (Sham). Hepatic collagen measurements as well as serum levels of liver enzymes and function tests were all analysed.</p> <p>Results</p> <p>The peak level of collagen was observed biochemically and histomorphometricly at the end of third week (P < 0.001 and P < 0.05). Suprisingly, collagen levels had decreased with the course of time such as at the end of fourth week (P < 0.01 and P < 0.05).</p> <p>Conclusion</p> <p>We have shown that fibrosis in bile duct-ligated rats is transient, i.e. reverses spontaneously after 3 weeks. This contrasts any situation in patients where hepatic fibrosis is progressive and irreversible as countless studies performed by many investigators in the same animal model.</p

Modulation of extracellular matrix by nutritional hepatotrophic factors in thioacetamide-induced liver cirrhosis in the rat

Nutritional substances associated to some hormones enhance liver regeneration when injected intraperitoneally, being denominated hepatotrophic factors (HF). Here we verified if a solution of HF (glucose, vitamins, salts, amino acids, glucagon, insulin, and triiodothyronine) can revert liver cirrhosis and how some extracellular matrices are affected. Cirrhosis was induced for 14 weeks in 45 female Wistar rats (200 mg) by intraperitoneal injections of thioacetamide (200 mg/kg). Twenty-five rats received intraperitoneal HF twice a day for 10 days (40 mL·kg-1·day-1) and 20 rats received physiological saline. Fifteen rats were used as control. The HF applied to cirrhotic rats significantly: a) reduced the relative mRNA expression of the genes: Col-&#945;1 (-53%), TIMP-1 (-31.7%), TGF-&#946;1 (-57.7%), and MMP-2 (-41.6%), whereas Plau mRNA remained unchanged; b) reduced GGT (-43.1%), ALT (-17.6%), and AST (-12.2%) serum levels; c) increased liver weight (11.3%), and reduced liver collagen (-37.1%), regenerative nodules size (-22.1%), and fibrous septum thickness. Progranulin protein (immunohistochemistry) and mRNA (in situ hybridization) were found in fibrous septa and areas of bile duct proliferation in cirrhotic livers. Concluding, HF improved the histology and serum biochemistry of liver cirrhosis, with an important reduction of interstitial collagen and increased extracelullar matrix degradation by reducing profibrotic gene expression

NF&kappa;B activation in cutaneous lesions of leprosy is associated with development of multibacillary infection

Carlos G Wambier,1 Leandra Naira Z Ramalho,2 Marco Andrey C Frade,1 Norma T Foss1 1Division of Dermatology, Department of Internal Medicine, 2Department of Pathology, Ribeir&atilde;o Preto School of Medicine, University of S&atilde;o Paulo, Ribeir&atilde;o Preto, S&atilde;o Paulo, Brazil Background: Nuclear factor kappa B (NF&kappa;B) transcription factors play a central role in controlling the expression of genes involved in inflammatory reactions, proliferation, and survival of human cells. However, the in situ evaluation of NF&kappa;B activity in leprosy has not been completed previously. The aim of this study was to determine whether NF&kappa;B activity correlates with susceptibility or resistance to Mycobacterium leprae infection in biopsies from skin lesions of 38 patients with the clinical and laboratory diagnosis of leprosy. Methods: The NF&kappa;B activation profile was evaluated in biopsies from skin lesions of 38 patients with the clinical and laboratory diagnosis of leprosy. NF&kappa;B activation was evaluated and quantified by Southwestern histochemistry, and its activation index (range, 0&ndash;4) was calculated according to the percentage of nuclear positivity by the histochemistry. Activation index &gt;1 was considered representative of activation of NF&kappa;B. Results: Fifteen patients (39.5%) demonstrated activated NF&kappa;B. Multibacillary leprosy was associated with activated NF&kappa;B (54.5%, P=0.028). Borderline leprosy was most strongly associated with NF&kappa;B activation (80%), with an odds ratio of 32.7 (P=0.016). These clinical forms are characterized by increased susceptibility to M. leprae and by immunological instability. Activation of NF&kappa;B was absent in the granulomas in tuberculoid leprosy, which represents an effective inflammatory reaction pattern against M. leprae. Conclusion: These results indicate that NF&kappa;B activation could favor susceptibility and immunological instability to M. leprae infection, potentially by the stimulation of phagocytosis and the regulation of apoptotic mechanisms of infected cells, leading to the proliferation of this intracellular bacillus. Further studies are needed to evaluate if inhibition of NF&kappa;B activation in multibacillary leprosy could favor resistance and an effective granulomatous immune response. Keywords: transcription factors, nuclear factor kappa B, immunomodulation, Mycobacterium leprae, leprosy resistance, leprosy susceptibilit