Islamic founding principles on organ transplantation and the evolution of Islamic scholarly opinions on the subject.

BACKGROUND: Muslims constitute about one-fourth of the human population, and a significant fraction of the organ recipients identify themselves as Muslims. A large fraction of the Muslim population is devout but unclear regarding the religious principles on organ donation and transplantation and is dependent on scholars' and imams' opinions. METHODS: The Qur'an, the authentic Prophetic Traditions, and expert opinions on the subject were investigated. RESULTS: The sources of the Islamic founding principles on organ donation and transplantation are the Qur'an, the Prophetic Traditions, Usulul Fiqh or expert opinions based on the Qur'an and Traditions, and Maslaha or the principles of public interest deduced by the scholars. Some Muslim scholars, mostly from the Indian subcontinent, opine that live organ donation, extraction of organs from dead persons, and transplantation are prohibited. Many Arab scholars and Muslim scholars settled in the western hemisphere opine that live organ donation, organ extraction from dead persons, and transplantation are permitted, but organ donation must be a voluntary act of charity. Of late, the Iranian imams/scholars have recognized that the national government may acquire live donor organs for a uniform compensation and equitably distribute the acquired organs to patients with failing organs. CONCLUSIONS: The current Islamic working principles on transplantation medicine are nonuniform, transitory, and somewhat detached from the bulk of the population. How such heterogeneity is affecting transplantation medicine, and organ donation in particular, among Muslim populations warrants further investigation.

Motivation for organ donation among college students in the United States.

BACKGROUND: The majority of the patients presently waiting for an organ are waiting for a kidney. Living kidney donation by about 0.1% of the adult population of a nation may completely eliminate kidney shortage. We investigated the concerns of college students toward charitable and compensated organ donation. METHODS: A 40-question survey was conducted. The respondents were students of the Biology Department of Utah Valley University, Orem, Utah, United States. The data were tabulated and analyzed. Tests of association among potentially linked attributes and the difference between two independent proportions were performed at the 0.05 level of significance and P-values were also calculated using XLSTAT software. RESULTS: The participants (n = 321) were 47% male, 53% female, 89% Caucasian, and 93% healthy, and 7% of the respondents had some health conditions. Of the respondents, 55% were ages 18 to 25 and 40% were ages 26 to 50 years; 43% were unmarried or single, 57% were married, and 85% had health insurance. About 65% of the respondents lived in small cities and the rest lived in large cities (23%) or the countryside (9%). There was no significant association between gender, level of education, location of living, and household income in relation to belief in organ donation with or without compensation, except that males favored compensated organ donation over females (P = .004). Rumors on organ theft and extraction of organ from questionable brain-dead patients had not negatively affected the decision of participants on being listed as organ donors in their driver's license (P = .0001). Those who considered organ donation ethically acceptable also believed that a person has the right to sale a kidney (P = .015) and the donor party should be somehow compensated (P = .001). CONCLUSIONS: A large percentage of college students supports compensated organ donation and considers that compensation will increase organ donation.

Endotoxin treatment causes an upregulation of the endothelin system in the liver: amelioration of increased portal resistance by endothelin receptor antagonism.

BACKGROUND: Mechanisms underlying hepatic microcirculatory failure during endotoxemia are incompletely understood. Because endothelin-1 (ET-1) has been implicated in endotoxin-induced liver injury, we investigated the hepatic ET-1 system in endotoxin-treated rats. METHODS: Rats were treated with endotoxin (Escherichia coli lipopolysaccharide; 3 mg/kg, i.p.), and various determinations were made 24 h later. RESULTS: Endotoxin treatment caused 11.2 +/- 1.6% weight loss, a decrease in mean arterial pressure (MAP; 96 +/- 5 mmHg vs 108 +/- 3 mmHg; P < 0.05) and an increase in portal pressure (11.6 +/- 1.3 mmHg vs 7.4 +/- 1 mmHg; P < 0.02). No significant changes in the serum levels of liver enzymes or hepatocellular necrosis were observed. Endotoxin caused increases in hepatic ET-1 (from 345 +/- 31 to 565 +/- 38 pg/g; P < 0.01), ET-1 receptor density (from 179 +/- 16 to 340 +/- 26 fmol/mg; P < 0.02), and mRNA expression of preproendothelin-1, and ET(A) and ET(B) receptors. While the serum nitric oxide (nitrite +/- nitrate) concentration was increased in endotoxin-treated rats, that of ET-1 remained unchanged. A mixed ET(A)/ET(B) receptor antagonist, TAK-044 (10 mg/kg, i.v.), reduced the weight loss from 11.2 +/- 1.6% to 5.9 +/- 2.9% (P < 0.05) and the portal pressure from 11.6 +/- 1.3 mmHg to 8.6 +/- 0.7 mmHg (P < 0.05) in endotoxin-treated rats. The mixed ET(A)/ET(B) receptor antagonist also caused an increase in serum ET-1 concentration, but did not affect serum nitric oxide and MAP in endotoxin-treated rats. CONCLUSIONS: These results suggest that the upregulated hepatic ET-1 system is an important mechanism of increased portal resistance and related complications of endotoxemia.

Enhanced synthesis and reduced metabolism of endothelin-1 (ET-1) by hepatocytes--an important mechanism of increased endogenous levels of ET-1 in liver cirrhosis.

BACKGROUND/AIMS: Hepatic concentration of endothelin-1 (ET-1) is increased in human and experimental liver cirrhosis. Because of its potent actions in the liver, ET-1 has been suggested to play an important role in the pathophysiology of cirrhosis. Since hepatocytes are the major cell type to metabolize ET-1, we investigated whether their reduced capacity to degrade ET-1 is a mechanism of its elevated levels in cirrhosis. METHODS: The expression of ET-1 receptors, ET-1 and endothelin converting enzyme (ECE), and metabolism of ET-1 and ECE activity were compared in hepatocytes isolated from control and carbon tetrachloride-induced cirrhotic rats. RESULTS: ET-1 receptor density and receptor-mediated internalization of ET-1 were significantly increased in cirrhotic hepatocytes relative to the control cells. However, compared to control hepatocytes, metabolism of ET-1 by the cirrhotic cells was reduced significantly. Interestingly, hepatocytes were found to contain preproET-1 mRNA, ECE-1 mRNA and ET-1. PreproET-1 mRNA and ET-1 levels were increased in cirrhotic hepatocytes but their ECE mRNA and ECE activity were not altered. CONCLUSIONS: These results provide the first evidence that hepatocytes have the ability to synthesize ET-1 and demonstrate that decreased metabolism and enhanced synthesis, of ET-1 in hepatocytes are an important mechanism of its elevated levels in cirrhosis.

Endothelin stimulates transforming growth factor-beta1 and collagen synthesis in stellate cells from control but not cirrhotic rat liver.

Interactions between hepatic stellate cells and endothelin-1 are implicated in liver fibrosis. We determined endothelin-1, its receptors and its effects on the synthesis of a fibrogenic agent transforming growth factor (TGF)-beta1 and collagen in stellate cells from control and CCl(4)-induced cirrhotic rats. The basal synthesis of endothelin-1, TGF-beta1 and collagen was much higher in cirrhotic stellate cells than in control cells. Endothelin-1 stimulated TGF-beta1 and collagen synthesis via endothelin ET(A) and endothelin ET(B) receptors, respectively, in control stellate cells, but did not elicit these effects in the cirrhotic cells despite increased density of the respective receptor subtypes in them. These results indicate that the actions of endothelin-1 on stellate cells may be an important physiological mechanism in maintenance of hepatic architecture. However, inability of endothelin-1 to stimulate TGF-beta1 and collagen synthesis in cirrhotic stellate cells suggests that it does not influence fibrogenic activity by direct action on them probably because the processes are already maximally activated.

Down-regulation of endothelin receptors by transforming growth factor beta1 in hepatic stellate cells.

BACKGROUND/AIMS: Hepatic endothelin-1 (ET-1) receptor density as well as the levels of both ET-1 and transforming growth factor beta1 (TGF-beta1) increase in liver cirrhosis. Considering their potent contractile (ET-1) and fibrogenic (TGF-beta1) actions on myofibroblastic stellate cells found in the fibrotic/cirrhotic liver, we aimed to investigate the effects of TGF-beta1 on ET-1 receptors and ET-1 synthesis in these cells. METHODS: Stellate cells isolated from rat liver by enzymatic digestion were cultured and subjected to TGF-beta1 treatment. Cellular ET-1 receptors and ET-1 released in the medium were determined. RESULTS: TGF-beta1 treatment produced time- and dose-dependent decrease in ET-1 binding sites, but did not affect the affinity of the receptors for ET-1. TGF-beta1 also stimulated the release of ET-1 from stellate cells. The extent of TGF-beta1-induced inhibition of [125I]ET-1 binding was much greater for ETB subtype (73+/-18% inhibition), which comprised a major portion (78+/-12%) of the total ET-1 receptors, than for ETA subtype (35+/-11% inhibition). The mRNA expression of the ET-1 receptors also was reduced by TGF-beta1 treatment. TGF-beta1-induced reduction in ET-1 receptor density was coupled to the inhibition of ET-1-stimulated release of [3Hlarachidonic acid from the prelabeled cells. The effects of TGF-beta1 were inhibited by a TGF-beta1 neutralizing monoclonal antibody. CONCLUSIONS: These results suggest that the TGF-beta1-induced decrease in ET-1 receptor density may be an important mechanism in limiting the pathologic actions of ET-1 on stellate cells in chronic liver disease.

Superoxide-induced changes in endothelin (ET) receptors in hepatic stellate cells.

BACKGROUND/AIMS: Reactive oxygen species are mediators of various pathophysiologic events, including postischemic reperfusion injury and inflammation. Generation of reactive oxygen species and consequent organ injury are associated with increased levels of a powerful vasoconstrictor peptide endothelin-1. Current evidence suggests that actions of endothelin-1 on the contractile and fibrogenic transdifferentiated stellate cells may play a critical role in hepatic pathophysiology. The aim of this investigation was to determine whether reactive oxygen species modulate the synthesis of endothelin-1 and its receptors in stellate cells. METHODS: Primary cultures of transdifferentiated stellate cells were exposed to reactive oxygen species-generating system, hypoxanthine/xanthine oxidase, before determination of endothelin-1 and its receptors. RESULTS: The treatment caused an initial decrease in ET-1 receptor density (about 30% at 30 min), followed by a significant increase over the basal level at 6 h. The increase in the receptors, which occurred specifically in the ET(B) subtype, progressed thereafter up to 24 h and was accompanied by an augmented functional response, as indicated by an enhanced endothelin-1-induced release of [3H]arachidonic acid from the prelabeled cells. Furthermore, treatment of cells for 24 h but not 30 min caused increased expression of ET(B) mRNA as determined by semi-quantitative polymerase chain reaction. The release of endothelin-1 in the culture medium was also enhanced by hypoxanthine/xanthine oxidase treatment. These effects of hypoxanthine/xanthine oxidase were inhibited by superoxide dismutase and dimethyl sulfoxide. ET-1-induced [3H]arachidonic acid release was also inhibited by the ET(B) receptor antagonist BQ788, but not by the ET(A) receptor antagonist BQ123. CONCLUSIONS: These findings indicate that interactions between ET-1 and stellate cells during episodes of the generation of reactive oxygen species can be an important mechanism in the pathophysiology of hepatic disorders.