الفهرس 
REVIEW OF LITERATUREOnly 14 pages are availabe for public view
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Abstract
Radiotherapy (RT) has proven to be a successful therapy for unresectable liver disease and intermediate-stage hepatocellular carcinoma (HCC). However, the use of RT is restricted due to radiotoxicity in surrounding tissue that is not tumorous and, unfortunately, can have certain negative side effects, such as radiation-induced liver disease (RILD). RILD can manifest as an acute reaction during or shortly after RT or as a late reaction month to years afterwards. A significant drawback of RT in the treatment of liver cancer is RILD, which is also linked to a high death rate in liver cancer patients. Furthermore, because to its close proximity to the digestive system and its size, the liver is one of the organs that is frequently exposed to radiation during RT treatment of gastrointestinal malignancies.
It is well known that radiosensitivity exists in hepatic nonparenchymal cells such as Kupffer cells (KCs), sinusoidal endothelial cells (SECs), and hepatic stellate cells (HSCs). When exposed to radiation, the liver’s structure and function are changed because of the substances released by these cells, which induce liver fibrosis. Patients with RILD are increasingly struggling with this radiation-induced hepatic fibrosis. Therefore, understanding the pathophysiological underpinnings of RILD is crucial to halting the disease’s development, boosting the effectiveness of RT treatment, and ultimately raising overall quality of life.
Hepatomegaly, abdominal ascites, and an increase in aspartate transaminase (AST), alanine transaminase (ALT), and other liver enzymes are characteristics of the clinical pathophysiology of RILD. However, administering prophylactic treatments before radiation is the most efficient defense against RILD. So far, the major clinical therapies for acute RILD consist of steroids and certain antioxidants. These medications’ drawbacks include side effects and a lack of specificity. In other words, there is no accepted standard treatment for RILD, and treatment is only symptomatic and supportive. Consequently, RILD cannot yet be treated effectively. Thus, there is an urgent need for innovative treatments that are efficient, specific, low-toxic and efficacious.
Mesenchymal stem cells (MSCs) are self-renewing, pluripotent cells that may develop into a variety of lineages. Both in preclinical and clinical trials, there are significant advancements in the use of MSCs to treat liver disease. In the 1970s, mesenchymal stem cells—multipotent stromal cells derived from the mesoderm—were discovered in adult bone marrow. Adipose tissue, muscle, dermis, tooth pulp, synovium, umbilical cord, placenta, chorionic villi, menstrual blood, breast milk, and amniotic fluid are all considered as sources to isolate MSCs. Under appropriate in vitro culture circumstances, the MSCs can be stimulated to terminally differentiate into a number of lineages. They have the potential to be used in regenerative medicine since they can repair bone, adipocytes, endothelium cells, muscle cells, and neurons.
Transplantation of bone marrow mesenchymal stem cells BMMSCs has demonstrated preclinical effectiveness in ameliorating liver fibrosis similar to their effects in animal models of lung, heart, and kidney fibrosis. One clinical trial of BMMSCs in decompensated liver failure has also shown the safety and therapeutic capacity for BMMSCs transplantation in patients with advanced liver fibrosis.
In light of this and based on what was shown by previous studies about the ability of BMMSCs to improve chemically induced liver fibrosis, this research aimed to study the ability of BMMSCs to reduce hazardous effects caused by RILD in rats in order to reduce its occurrence in liver cancer patients who receive RT and are at risk of developing this disease.
This study was carried out using 69 white Wistar rats, and the practical experiments were carried out at the Medical Research Center - Faculty of Medicine - Ain Shams University.
The study began by using 15 rats to isolate MSCs from the bone marrow and cultivate them in vitro to obtain a sufficient number to be used in the experiment. It was confirmed that the produced cells are MSCs by measuring percentage of CD105, CD 44, CD 90 and CD34 using a flowcytometer instrument.
54 Wester rats were divided into three groups:
• Control group (Gr I): 18 rats
• Radiation group (GR II): 18 rats
• Radiation and Stem Cell group (GR III): 18 rats
Each group was divided into three subgroups according to the time lapse after exposure to radiation, and each subgroup included 6 rats as follows:
• Sub group A: After Two weeks,
• Sub group B: After four weeks,
• Sub group C: After six weeks
The position of livers of group II and III rats were determined using a CT scan device in the Oncology Unit at Ain Shams University Hospitals, then the rats of the third group were injected with 1 x 10 6 BMMSCs immediately prior to radiation exposure.
Rats in the second and third groups were anesthetized and the liver area was exposed to a single localized dose of 20 Gray of ionizing gamma rays using a radiotherapy device in the Oncology Unit at Ain Shams University Hospitals. This step aimed to cause RILD and induce liver fibrosis.
Two weeks after exposure to radiation, the rats of subgroup A were sacrificed and serum samples were collected for measurements. Animals in subgroups B and C were scarified after four weeks and six weeks respectively. Each time serum samples were collected for measurements.
In addition, serum glutathione (GSH) concentration was measured during the three periods of the experiment to assess the radiation induced oxidative stress and to evaluate the ability of BMMSCs to reduce this oxidative damage.
Statistical studies were conducted using the twentieth version of the SPSS program
By comparing the values of direct and indirect markers of liver fibrosis in the different groups during the study, it was found that fibrosis occurred in the groups that were exposed to radiation compared to the control group after two weeks of exposure to radiation. However, and after four weeks and six weeks, there was a positive improvement in the fibrosis markers in group III that was injected with BMMSCs. This positive effect of BMMSCs could be attributed to the activation of apoptosis of hepatic stellate cells (HSCs), which secrete many inflammatory factors that stimulate liver fibrosis. Moreover, BMMSCs have a homing mechanism through which they can migrate to the affected liver, proliferate and then differentiate into healthy hepatocytes, break down collagen fibers and improve liver function.
Through this study, the ability of BMMSCs to resist RILD can be inferred when injected concurrently with radiation exposure. The study also highlights the need to conduct several studies in this field to understand the full mechanism of action of BMMSCs in reducing the incidence of RILD and the benefit of using other therapies concurrently with BMMSCs in combating the harmful effects of this disease.