The Effect of Retinol Acetate on Liver Fibrosis Depends on the Temporal Features of the Development of Pathology.

Background: The effect of vitamin A on the manifestations of liver fibrosis is controversial and establishing the causes of its multidirectional influence is an urgent problem. In the work, the functional characteristics of the liver with Cu-induced fibrosis were determined after the restoration of vitamin A to the control level at the F0/F1 stage. Methods: In animals with liver fibrosis, classical indicators of physiology, functional activity of the liver, histological, and hematological characteristics were determined; the content of calcium and ROS was determined in bone marrow cells. Results: It was shown that in the liver with Cu-induced fibrosis, the restoration of vitamin A content to control values after per os injections of a retinol acetate solution at a dose of 0.10 mg (300 IU)/100 g of body weight in the early stages of this pathology development (Fо/F1) was accompanied by: a decrease in the number of immunocompetent cells in the bloodstream to control values; normalization of the amount of calcium ions and ROS in bone marrow cells; restoration to the control level of activity of alkaline phosphatase; an increase in the number of binuclear hepatocytes; and restoration of the dynamics of body weight growth in experimental animals, even against the background of the ongoing action of the hepatotoxic factor. Conclusion: We came to the conclusion that the multidirectional action of vitamin A, which occurs in liver fibrosis, depends not only on the concentration of vitamin A in the liver but also on temporal characteristics of cellular and metabolic links involved in the adaptive response formation. It was suggested that knowledge of the initial temporal metabolic characteristics and the amount of vitamin A in the liver, taking into account the stages of fibrosis development, can be an effective way to restore the altered homeostatic parameters of the body.

Vitamin A Reduces the Mortality of Animals with Induced Liver Fibrosis by Providing a Multi-level Body Defense System.

Background: Liver diseases remain the most important medical and biological problem. Works devoted to the study of the vitamin A role have shown conflicting results of its effect on the fibrosis development. We tested the hypothesis that an increase of the copper content in the liver, an example of which is Wilson's disease, shifts the balance in the redox system towards pro-oxidants, which leads to the antioxidant systems inhibition, including a decrease in the vitamin A content; this affects the levels of liver function regulation and the development of fibrosis. Methods: In animals with Cu-induced liver fibrosis, neutrophil activity, the immunocompetent cells content, the activity of alanine aminotransferase and γ-glutamylaminotransferase, the content of urea and creatinine in blood serum, as well as the vitamin A content in the liver, copper ions and its regenerative potential were determined. Results: It was found that three consecutive injections of copper sulfate to animals with an interval of 48 h between injections led to the death of 40% of the animals, and 60% showed resistance. The content of vitamin A in "resistant" animals at the beginning of the development of the fibrosis was reduced by 4 times compared to the control, the functional activity of the liver was somewhat reduced, and a connective tissue capsule was formed around the liver lobes in 75% of the animals. If animals with the initial stage of liver fibrosis received daily vitamin A at a dose of 300 IU/100 g of body weight, which was accompanied by its multiple increase in the liver (15 times on day 14), the mortality of animals decreased by almost 7 times, the functional activity of the liver did not differ from control. In the blood of these animals, the number of leukocytes, granulocytes, and monocytes was increased and phagocytic activity was increased. At the same time, the connective tissue capsule was developed more intensively than in animals receiving only copper sulfate, and was detected in 91% of the animals. Fragments of the liver, even more than in the case of fibrosis, lost the ability to regenerate in culture. Conclusion: We came to the conclusion that vitamin A leads to the connective tissue "specialization" formation of the liver and triggers vicious circles of metabolism and includes several levels of regulation systems. Further studies of the vitamin A effect mechanisms on the liver with fibrosis will allow the use of this antioxidant in the treatment.