ABSTRACT
Tissue-type plasminogen activators (tPA) and urokinase-type plasminogen activators (uPA) are involved in liver repair. We examined the potential immunomodulatory actions of uPA, tPA and uPA-receptor (uPAR) in carbon-tetrachloride-induced hepatic fibrosis in wild-type (WT), tPA-/-, uPA-/- and uPAR-/- mice. Carbon-tetrachloride treatment increased fibrosis in four groups but significantly less in three knock-out models. Serum cytokines and intrahepatic T cells elevated significantly following fibrosis process in WT animals but not in the knock-out groups. In culture, uPA increased lymphocyte proliferation significantly in WT and uPA-/- but not uPAR-/- animals. Following uPA exposure in vivo, there was CD8 predominance. To isolate uPA's effect on lymphocytes, WT mice were irradiated sublethally and then reconstituted with WT or uPA-/- lymphocytes. In these animals fibrosis was decreased and T cells were reduced in the uPA-/- recipients. Based on these data we postulate that plasminogen activators affect fibrosis in part by liver-specific activation of CD8 subsets that govern the fibrogenic activity of hepatic stellate cells.
Subject(s)
Liver Cirrhosis, Experimental/immunology , Plasminogen Activators/immunology , Animals , Carbon Tetrachloride , Cell Communication/immunology , Cell Proliferation , Cells, Cultured , Cytokines/blood , Hepatocytes/immunology , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/pathology , Lymphocyte Activation/immunology , Lymphocyte Transfusion , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Plasminogen Activators/genetics , Receptors, Cell Surface/genetics , Receptors, Cell Surface/immunology , Receptors, Urokinase Plasminogen Activator , T-Lymphocyte Subsets/immunology , Whole-Body IrradiationABSTRACT
OBJECTIVE: In Lebanon there is very limited restriction on drug use. Accordingly, self-medication is highly prevalent. This study examined the influence of these factors on the development of drug-related illnesses that lead to hospitalization. METHODS: Patients admitted to the medical and pediatric wards of a tertiary teaching center in Beirut, Lebanon, over a period of 6 months were interviewed and their charts were reviewed. Admissions attributable to adverse drug reactions or therapeutic failures were identified and characterized with respect to demographic factors, medical history, drug intake, and self-medicating behavior. The influence of these variables on the development of drug-related illnesses was examined by logistic regression. RESULTS: Of 1745 adults and 457 children, there were 177 (10.2%) and 36 (7.9%) drug-related illnesses, respectively. Adverse drug reactions accounted for 7.0% and 5.7% and therapeutic failures for 3.2% and 2.2% of adult and pediatric admissions, respectively. Self-medication was commonly practiced (52.6% of adults and 41.6% of children). Logistic regression analysis revealed that female sex increased the risk of adverse drug reaction in adults, whereas self-medication decreased the risk. In children, the risk of adverse drug reaction was increased in lower socioeconomic groups, whereas the risk of therapeutic failure was increased by a positive history of atopy or drug reaction. CONCLUSIONS: These results provide the first detailed analysis of the problem of drug-related illnesses in a developing country and identify a number of related or risk factors. Despite the lack of regulation of drug dispensing and the unchecked access to drugs in Lebanon, the incidence of drug-related illnesses is not different from that in Western nations. This finding may have relevance to policies of drug regulation in other countries.
