Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats.

Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats.

Roles and mechanisms of circulating CEACAM1 in the cirrhosis-related intestinal hyperpermeability: in vitro approach.

BACKGROUND: Cirrhosis-related intestinal hyperpermeability and endotoxemia are characterized by intestinal epithelial cell apoptosis, impaired restitution (proliferation and migration), decreased tight junction protein levels, and subsequent barrier dysfunction. In addition to endotoxin and tumor necrosis factor-α (TNFα), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) plays crucial roles in the regulation of apoptosis, restitution, tight junction protein-maintained barrier function of intestinal epithelial cells. METHODS: This study aims to explore the roles and underlying mechanisms of CEACAM1 in cirrhosis-related intestinal hyperpermeability through in vitro approach. RESULTS: In cirrhotic patients, high serum levels of intestinal hyperpermeability (zonulin and endotoxin) markers were accompanied by elevated serum levels of TNFα and soluble CEACAM1. In in vitro experiments, we evaluated the individual and interacted roles of TNFα and human recombinant CEACAM1 (hrCEACAM1) in LC-sera (sera of cirrhotic patients)-induced intestinal hyperpermeability-related pathogenic signals. In the cell Line human from human colon (Caucasian colon adenocarcinoma) (Caco-2) cell culture, LC-sera, TNFα, and hrCEACAM1 increased apoptosis (measured by Terminal deoxynucleotidyl transferase [TdT] dUTP nick end labeling+/annexin-5+propidium iodide+ cells and caspase-3 activity), decreased restitution capacity (proliferation and migration), and disrupted tight junction protein-maintained barrier function in Caco-2 cells. The pathogenic changes mentioned above were accompanied by an increase in intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase release, and endoplasmic reticulum stress-related signals in the LC-sera or TNFα-pretreated Caco-2 cells. Concomitant incubation of Caco-2 cells with anti-CEACAM1 suppressed these LC-sera or TNFα-induced negative effects on restitution, barrier function, and cell viability. CONCLUSION: This study demonstrated that sera from cirrhotic patients contain soluble CEACAM1, which is involved in the pathogenesis of intestinal hyperpermeability. Accordingly, it is noteworthy to explore the potential use of anti-CEACAM1 treatment for cirrhosis-related intestinal hyperpermeability and endotoxemia.

Intestinal SIRT1 Deficiency-Related Intestinal Inflammation and Dysbiosis Aggravate TNFα-Mediated Renal Dysfunction in Cirrhotic Ascitic Mice.

In advanced cirrhosis, the TNFα-mediated intestinal inflammation and bacteria dysbiosis are involved in the development of inflammation and vasoconstriction-related renal dysfunction. In colitis and acute kidney injury models, activation of SIRT1 attenuates the TNFα-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFα-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Systemic and renal hemodynamics, intestinal dysbiosis [cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstrictive response (renal vascular resistance (RVR) and glomerular filtration rate (GFR)) to cumulative doses of TNFα were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. In SIRT1IEC-KO-BDL-ascitic mice, the worsening of intestinal dysbiosis exacerbates intestinal inflammation/barrier dysfunction, the upregulation of the expressions of intestinal/renal TNFα-related pathogenic signals, higher TNFα-induced increase in RVR, and decrease in GFR in perfused kidney. In intestinal SIRT1 knockout groups, the positive correlations were identified between intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between CDR and RVR, with the positive correlation between CDR and GFR. In mice with advanced cirrhosis, the expression of intestinal SIRT1 is involved in the linkage between intestinal dysbiosis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNFα-related pathogenic inflammatory signals.

The Potential Role of Genetics, Environmental Factors, and Gut Dysbiosis in the Aberrant Non-Coding RNA Expression to Mediate Inflammation and Osteoclastogenic/Osteogenic Differentiation in Ankylosing Spondylitis.

Ankylosing spondylitis (AS) or radiographic axial spondyloarthritis is a chronic immune-mediated rheumatic disorder characterized by the inflammation in the axial skeleton, peripheral joints, and soft tissues (enthesis, fascia, and ligament). In addition, the extra-skeletal complications including anterior uveitis, interstitial lung diseases and aortitis are found. The pathogenesis of AS implicates an intricate interaction among HLA (HLA-B27) and non-HLA loci [endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin-23 receptor (IL23R), gut dysbiosis, immune plasticity, and numerous environmental factors (infections, heavy metals, stress, cigarette smoking, etc.) The latter multiple non-genetic factors may exert a powerful stress on epigenetic regulations. These epigenetic regulations of gene expression contain DNA methylation/demethylation, histone modifications and aberrant non-coding RNAs (ncRNAs) expression, leading to inflammation and immune dysfunctions. In the present review, we shall discuss these contributory factors that are involved in AS pathogenesis, especially the aberrant ncRNA expression and its effects on the proinflammatory cytokine productions (TNF-α, IL-17 and IL-23), T cell skewing to Th1/Th17, and osteoclastogenic/osteogenic differentiation. Finally, some potential investigatory approaches are raised for solving the puzzles in AS pathogenesis.

Obeticholic acid ameliorates hepatorenal syndrome in ascitic cirrhotic rats by down-regulating the renal 8-iso-PGF2α-activated COX-TXA2 pathway.

BACKGROUNDS/AIMS: The present study explores the potential of chronic treatment with the Foresaid X receptor (FXR) agonist obeticholic acid (OCA), which inhibits oxidative stress-related pathogenesis, in ascitic cirrhotic rats with hepatorenal syndrome (HRS) developed 6 weeks after bile duct ligation (BDL). METHODS: Systemic, splanchnic, and renal hemodynamics and pathogenic cascades were measured in ascitic BDL and sham rats receiving 2-weeks of either vehicle or OCA treatments (sham-OCA and BDL-OCA groups), and NRK-52E cells, rat kidney tubular epithelial cells. RESULTS: Chronic OCA treatment significantly normalized portal hypertension, glomerular filtration rate, urine output, renal blood flow; decreased ascites, renal vascular resistance, serum creatinine, and the release of renal tubular damage markers, including urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury moleculae-1 (uKim-1) in BDL-OCA rats. In the BDL group, inhibition of the renal oxidative stress (8-iso-PGF2α)-activated cyclooxygenase-thromboxane A2 [COX-TXA2] pathway, apoptosis, and tubular injury accompanied by a decrease in hyper-responsiveness to the vasoconstrictor 8-iso-PGF2α in perfused kidneys. In vitro experiments revealed that 8-iso-PGF2α induced oxidative stress, release of reactive oxygen species, and cell apoptosis, which were reversed by concomitant incubation with the FXR agonist. CONCLUSIONS: Through the inhibition of renal 8-iso-PGF2α production and the down-regulation of the COX-TXA2 pathway, our study suggests that chronic OCA treatment can ameliorate the HRS in ascitic cirrhotic rats. Thus, OCA is an agent with antioxidative stress, antivasoconstrictive, antiapoptotic properties which benefit ascitic, cirrhotic rats with systemic, hepatic, and renal abnormalities.

Propranolol Is Associated with Lower Risk of Incidence of Hepatocellular Carcinoma in Patients with Alcoholic Cirrhosis: A Tertiary-Center Study and Indirect Comparison with Meta-Analysis.

Alcoholic cirrhosis (AC) leads to enormous disease burden and occupies a substantial proportion in the etiology of hepatocellular carcinoma (HCC), but scarce attention has been paid to this topic. Besides, propranolol has been reported to decrease the rate of HCC in viral hepatitis. We conducted a retrospective tertiary-center cohort study to identify the HCC incidence in AC patients with or without propranolol. A total of 1,046 AC patients with hospitalization had been screened, and those with regular follow-up for three years or otherwise until the date of malignancy diagnosis without meeting exclusion criteria were enrolled; finally, 23 AC patients with propranolol and 46 AC patients without propranolol were analyzed after twofold propensity-score matching. The cumulative incidence of HCC was lower in the propranolol group (log-rank test, P = 0.046). Furthermore, we undertook the meta-analysis of annual incidence of HCC in AC patients, and 1,949 publications were screened, within which eight studies were analyzed; the pooled annual incidence was 2.41%, which was higher than the calculated annual incidence of HCC in our AC cohort with propranolol (1.45%). In conclusion, propranolol is associated with decreased risk of HCC incidence in patients with AC.

Propranolol Suppresses the T-Helper Cell Depletion-Related Immune Dysfunction in Cirrhotic Mice.

Bacterial translocation (BT) and splenomegaly contribute to cirrhosis-associated immune dysfunction (CAID) including T cell depletion, infection, and chronic inflammation. ß-blockers have been reported to decrease BT and improve splenomegaly. This study explores the modulation of ß1 and ß2 adrenergic receptors (ADRB1/ADRB2) by propranolol treatment on the peripheral and splenic immune dysfunction of cirrhotic mice. In vivo experiments were performed in bile duct ligation (BDL)- and thioacetamide (TAA)-cirrhotic mice receiving two weeks of propranolol treatment. Acute effects of propranolol were evaluated in T-helper (Th) cells isolated from spleen of cirrhotic mice. Over-expression of ß1 and ß2 adrenergic receptors (ADRB1/ADRB2) in spleen and T lymphocytes was associated with high peripheral/splenic lipopolysaccharide binding protein levels. Moreover, a decrease in Th cells percentage, increase in Treg subset, and cytokines were accompanied by increased apoptosis, proliferation, and reduced white pulp hyperplasia in cirrhotic mice, which were counteracted by propranolol treatment. The Th-cell depletion, systemic inflammation, BT, and infection were improved by chronic propranolol treatment. Acute propranolol treatment inhibited apoptosis, Treg-conditioned differentiation, and promoted Th2-conditioned differentiation through ADRB-cyclic adenosine monophosphate (cAMP) signals in cirrhotic mice. In conclusion, suppression of ADRB1 and ADRB2 expressions in spleen and splenic T lymphocytes by acute and chronic propranolol treatment ameliorate systemic and splenic immune dysfunction in cirrhosis.

Beneficial Effects of the Peroxisome Proliferator-Activated Receptor α/γ Agonist Aleglitazar on Progressive Hepatic and Splanchnic Abnormalities in Cirrhotic Rats with Portal Hypertension.

Recent studies have reported that peroxisome proliferator-activated receptor α (PPARα) agonist decreases intrahepatic resistance, whereas PPARγ agonist reduces portosystemic shunts (PSSs) and splanchnic angiogenesis in cirrhotic rats. The present study investigated the effects of a 21-day treatment with the dual PPARα/γ agonist aleglitazar (Ale) on progressive abnormalities in bile-duct-ligated and thioacetamide-induced cirrhotic rats with portal hypertension (PH). In vivo and in vitro effects were evaluated. Chronic Ale treatment significantly up-regulated PPARα/PPARγ receptors and down-regulated tumor necrosis factor-α (TNF-α) and NF-κB expression in the liver, splanchnic tissues, collateral vessels, and intestines of cirrhotic rats with PH. Notably, Ale improved PH by the suppression of systemic/tissue inflammation, hepatic fibrosis, hepatic Rho-kinase-mediated endothelin-1 hyperresponsiveness, intrahepatic/mesenteric angiogenesis, vascular endothelial growth factor expression, PSS, intestinal mucosal injury, and hyperpermeability in cirrhotic rats. Acute Ale treatment inhibited TNF-α-enhanced endothelin-1-induced contraction of primary hepatic stellate cells, vascular endothelial growth factor-induced migration/angiogenesis of liver sinusoidal endothelial cells, and TNF-α-induced disruption of Caco-2 cell monolayer-epithelial barrier. The present study suggested that Ale can potentially treat relevant abnormalities through the inhibition of inflammatory, vasoconstrictive, angiogenic, and mucosal-disrupted pathogenic markers in cirrhosis. Overall, chronic Ale treatment ameliorated PH syndrome by the suppression of hepatic fibrogenesis, neoangiogenesis, vasoconstrictor hyperresponsiveness, splanchnic vasodilatation, and PSS; and decreased intestinal mucosal injury and hyperpermeability in cirrhotic rats.

Effects and mechanisms of caffeine to improve immunological and metabolic abnormalities in diet-induced obese rats.

In obesity, there are no effective therapies for parallel immune and metabolic abnormalities, including systemic/tissue insulin-resistance/inflammation, adiposity and hepatic steatosis. Caffeine has anti-inflammation, antihepatic steatosis, and anti-insulin resistance effects. In this study, we evaluated the effects and molecular mechanisms of 6 wk of caffeine treatment (HFD-caf) on immunological and metabolic abnormalities of high-fat diet (HFD)-induced obese rats. Compared with HFD vehicle (HFD-V) rats, in HFD-caf rats the suppressed circulating immune cell inflammatory [TNFα, MCP-1, IL-6, intercellular adhesion molecule 1 (ICAM-1), and nitrite] profiles were accompanied by decreased liver, white adipose tissue (WAT), and muscle macrophages and their intracellular cytokine levels. Metabolically, the increase in metabolic rates reduced lipid accumulation in various tissues, resulting in reduced adiposity, lower fat mass, decreased body weight, amelioration of hepatic steatosis, and improved systemic/muscle insulin resistance. Further mechanistic approaches revealed an upregulation of tissue lipogenic [(SREBP1c, fatty acid synthase, acetyl-CoA carboxylase)/insulin-sensitizing (GLUT4 and p-IRS1)] markers in HFD-caf rats. Significantly, ex vivo experiments revealed that the cytokine release by the cocultured peripheral blood mononuclear cell (monocyte) and WAT (adipocyte), which are known to stimulate macrophage migration and hepatocyte lipogenesis, were lower in HFD-V groups than HFD-caf groups. Caffeine treatment simultaneously ameliorates immune and metabolic pathogenic signals present in tissue to normalize immunolgical and metabolic abnormalities found in HFD-induced obese rats.

The current status and unmet needs in the management of psoriatic arthritis: Viewpoint from physicians in Taiwan.

BACKGROUND/PURPOSE: To analyze the real-world clinical practice for the treatment of psoriatic arthritis (PsA) and to assess physicians' prescription, difficulties in diagnosis, therapeutic strategy, rationales for biologic therapies and unmet needs in Taiwan. METHODS: We conducted a nationwide cross-sectional observational study by face-to-face in depth interviews with 50 rheumatologists and 30 dermatologists who took care of patients with PsA. RESULTS: The major procedures for recognizing PsA included joint, skin and nail examinations, radiographic imaging, and medical history. More dermatologists established the diagnosis when psoriatic patients with arthritis didn't present with rheumatoid factors (p < 0.05). For milder arthritis, physicians tended to prescribe etanercept in combination with conventional disease-modifying antirheumatic drugs (DMARDs). The efficacy, safety, retention rate, and non-parenteral administration are the major concerns of physicians which are also the primary unmet needs in the current management of PsA. CONCLUSION: This survey showed the status quo in Taiwan of the clinical management for PsA including diagnostic difficulties, therapeutic consideration, rationales for biologic DMARDs selection and unmet needs in treatment. It has indicated that interdisciplinary collaboration may further improve the quality for PsA care. These results may help establish new strategy to develop next generation biologics.

Decoy receptor 3 analogous supplement protects steatotic rat liver from ischemia-reperfusion injury.

BACKGROUND: For steatotic livers, pharmacological approaches to minimize the hepatic neutrophil and macrophage infiltration, and cytokine and chemokine release in ischemia-reperfusion (IR) injury are still limited. Tumor necrosis factor (TNF)-α superfamily-stimulated pathogenic cascades and M1 macrophage/Kupffer cells (KC) polarization from Th1 cytokines are important in the pathogenesis of IR liver injury with hepatic steatosis (HS). Conversely, anti-inflammatory M2 macrophages produce Th2 cytokine (interleukin-4), which reciprocally enhances M2 polarization. Toll-like receptor 4-activated KCs can release proinflammatory mediators, skew M1 polarization and escalate liver IR injury. Decoy receptor 3 (DcR3) could be potential agents simultaneously blocking the IR liver injury-related pathogenic changes and extend the survival of steatotic graft. METHODS: Rats were fed with methionine and choline-deficient high-fat diet (MCD HFD) for 6 weeks to induce HS. Preliminary experiments with HS group and IR group were conducted, and either immunoglobulin G Fc protein or DcR3 analogue was treated for 14 days in all groups to evaluate the severity. In the Zucker rat-focused experiments, various serum and hepatic substances, M1 polarization, and hepatic microcirculation were assessed. RESULTS: We found that serum/hepatic DcR3 levels were lower in nonalcoholic fatty liver disease patients with HS. DcR3a protected Zucker rats with HS from IR liver injury. The beneficial effects of DcR3a supplement were mediated by inhibiting hepatic M1 polarization of KCs, decreasing serum/hepatic TNFα, nitric oxide, nitrotyrosine, soluble TNF-like cytokine 1A, Fas ligand, and interferon-γ levels, neutrophil infiltration, and improving hepatic microcirculatory failure among rats with IR-injured steatotic livers. Additionally, downregulated hepatic TNF-like cytokine 1A/Fas-ligand and toll-like receptor 4/nuclear factor-κB signals were found to mediate the DcR3a-related protective effects of steatotic livers from IR injury. CONCLUSION: Using multimodal in vivo and in vitro approaches, we found that DcR3a analogue was a potential agent to protect steatotic liver against IR injury by simultaneous blockade of the multiple IR injury-related pathogenic changes.

Down-regulation of common NFκB-iNOS pathway by chronic Thalidomide treatment improves Hepatopulmonary Syndrome and Muscle Wasting in rats with Biliary Cirrhosis.

Thalidomide can modulate the TNFα-NFκB and iNOS pathway, which involve in the pathogenesis of hepatopulmonary syndrome (HPS) and muscle wasting in cirrhosis. In bile duct ligated-cirrhotic rats, the increased circulating CD16+ (inflammatory) monocytes and its intracellular TNFα, NFκB, monocyte chemotactic protein (MCP-1) and iNOS levels were associated with increased circulating MCP-1/soluable intercellular cell adehesion molecule-1 (sICAM-1), pulmonary TNFα/NOx, up-regulated M1 polarization, exacerbated angiogenesis and hypoxemia (increased AaPO2) in bronchoalveolar lavage (BAL) fluid and pulmonary homogenates. Meanwhile, a significant correlation was noted between circulating CD16+ monocyte/M1 (%) macrophages in BAL; M1 (%) macrophages in BAL/pulmonary iNOS mRNA expression; pulmonary iNOS mRNA expression/relative pulmonary MVD; pulmonary NOx level/AaPO2; circulating CD16+ monocyte/M1 (%) macrophages in muscle homogenates; 3-nitrotyrosine (representative of peroxynitrite) concentration/M1 (%) macrophages in muscle homogenates. The in vitro data demonstrated an iNOS-dependent inhibition of thalidomide on the TNFα-stimulated angiogenesis and myogenesis in human pulmonary artery endothelial cells (HPAECs) and C2C12 myoblasts. Significantly, the co-culture of CD16+ monocyte from different rats with HPAECs, or co-culture of supernatant of above mixed cultures with HPAECs or C2C12 myoblasts stimulated angiogenesis, migration and myogenesis. Our findings demonstrate that TNFα inhibitor thalidomide markedly diminishes the severity of experimental HPS and muscle wasting by down-regulation of common peripheral and local NFκB-iNOS pathway.

Thalidomide Improves the Intestinal Mucosal Injury and Suppresses Mesenteric Angiogenesis and Vasodilatation by Down-Regulating Inflammasomes-Related Cascades in Cirrhotic Rats.

BACKGROUND AND AIMS: By blocking TNFα-related effects, thalidomide not only inhibits hepatic fibrogenesis but improves peripheral vasodilatation and portal hypertension in cirrhotic rats. Nonetheless, the investigation of thalidomide's effects on splanchnic and collateral microcirculation has been limited. Our study explored the roles of intestinal and mesenteric TNFα along with inflammasome-related pathway in relation to cirrhosis and the splanchnic/collateral microcirculation. METHODS: Using in vivo and in vitro approaches, mechanisms of the effects of thalidomide on intestinal and mesenteric inflammatory, vasodilatory and angiogenic cascades-related abnormalities were explored in cirrhotic rats that had received 1-month thalidomide (C-T) treatment. RESULTS: In cirrhotic rats, high tumor necrosis factor (TNF)α, vascular endothelial growth factor (VEGF) and nitric oxide (NO)x levels were associated with the NOD-like receptors protein 3 (NLRP3), IL-1ß and caspase-1 inflammasome over-expression in splenorenal shunt and mesenteric tissues. The thalidomide-related inhibition of mesenteric and splenorenal shunt inflammasome expression was accompanied by a significantly decreased intestinal mucosal injury and inflammasome immunohistochemical staining expression. Suppression of various angiogenic cascades, namely VEGF-NOS-NO, was paralleled by a decrease in mesenteric angiogenesis as detected by CD31 immunofluorescence staining and by reduced portosystemic shunting (PSS) in C-T rats. The down-regulation of the mesenteric and collateral vasodilatory VEGF-NOS-NO cascades resulted in a correction of vasoconstrictive hypo-responsiveness and in an attenuation of vasodilatory hyper-responsiveness when analyzed by in situ perfusion of the superior mesenteric arterial (SMA) and portosystemic collaterals. There was also a decrease in SMA blood flow and an increase in SMA resistance in the C-T rats. Additionally, acute incubation with thalidomide abolished TNFα-augmented VEGF-mediated migration of and tube formation of human umbilical vein endothelial cells, which was accompanied by corresponding changes in inflammatory and angiogenic substances release. CONCLUSIONS: The suppression of inflammasome over-expression by chronic thalidomide treatment ameliorates inflammatory, angiogenic and vasodilatory cascades-related pathogenic changes in the splanchnic and collateral microcirculation of cirrhotic rats. Thalidomide seems to be a promising agent that might bring about beneficial changes to the disarrangements of peripheral, hepatic, splanchnic and collateral systems in cirrhosis.