Table 1.
Therapeutic strategies with described effects improving the sinusoidal cell phenotype. We classified the reported effects of each study according to whether they directly targeted the main cells of the sinusoid (direct cellular effects), the hemodynamics of the liver (the dynamic component of hepatic vascular resistance), or structural effects (static component of hepatic vascular resistance, e.g., fibrosis or necrosis). ACLF, acute on chronic liver failure; ACLD, advanced chronic liver disease; ASK1, apoptosis signal-regulating kinase 1; BDL, common bile duct ligation; CH, cirrhosis; CTP, Child-Turcotte-Pugh; eNOS, endothelial nitric oxide synthase; ET, endothelin receptor; HFD, high-fat diet; HFGFD, high-fat glucose-fructose diet; HSC, hepatic stellate cell; HVPG, hepatic venous pressure gradient; HVR, hepatic vascular resistance; LSEC, liver sinusoidal endothelial cell; MAP, mean arterial pressure; MELD, model for end-stage liver disease; PH, portal hypertension; PP, portal pressure; PPP, portal perfusion pressure; sGC, soluble guanylate cyclase; SOD, superoxide dismutase; TAA, thioacetamide; TXA2, thromboxane A2; TXB2, thromboxane B2; TP, prostaglandin-endoperoxide.
| Mechanism | Drug | Administration Method | Experimental Model | Structural Effects | Hemodynamic Effects | Direct Cellular Effects | Reference |
|---|---|---|---|---|---|---|---|
| Inhibition of vasoconstriction | SC-560 (COX-1 selective inhibitor) and SQ 29,548 (TXA2 receptor antagonist) | 5 µM during 15 min before the hemodynamic study. Preincubation of the liver. | Male Wistar CCl4-cirrhotic rats | - | ↑ Vasodilatory response to acetylcholine, ↓TXB2 | - | [152] |
| Terutroban (TP-receptor antagonist) | 30 mg/kg once a day for 2 weeks after development of ascites | Male Wistar CCl4-cirrhotic rats | ↓Fibrosis, ↓collagen I and TGF-β mRNA, ↓α-SMA protein | ↓ PP, ↓ HVR | - | [153] | |
| COX-1 siRNA | Intravenous injections with 0.6 mg/kg every other day at 8 weeks after starting CCl4-cirrhosis induction | Male C57BL/6 CCl4-cirrhotic mice | - | ↓ PP | Inhibition of the COX-1/TXA2 pathway | [154] | |
| Ifetroban sodium (TX receptor antagonist) or CGS 12970 (TX synthase inhibitor) | 3 mg/kg or 10 mg/kg, respectively, every day, starting the last 2 weeks of alcohol treatment | Male Wistar alcohol and fat-induced cirrhotic rats | ↓ Necrosis, ↓ inflammation and ↓ fibrosis ↓NF-kB activation, ↓TNFα, COX-2 and TGF-β1 expression. | - | - | [155] | |
| Nitroflurbiprofen or flurbiprofen | In vivo: 45 mg/kg or 30 mg/kg, respectively, intraperitoneally injected 24 h and 1 h prior to the hemodynamic and perfusion experiments. In vitro: From 25 to 250 umol/L | Male Wistar TAA-cirrhotic rats | - | ↓ PP, ↓ splanchnic hyperemia, ↓HVR, ↑ vasodilation, ↓TXB2 | In vitro: ↓ HSC contraction | [156] | |
| ET-A (ABT-627), ET-B (A-192621) or a mixed ET receptor antagonist (A-182086) | 50 mg/kg, 40 mg/kg, or 30 mg/kg, respectively, once a day for 8 weeks during cirrhosis induction | Male BALB/c CCl4-cirrhotic mice | ↓Fibrosis, ↓α-SMA protein and collagen I mRNA | ↓ PP | - | [157] | |
| BQ-123 (ET-A antagonist) | 10 nmol/min infused via a catheter in the mesenteric vein for 10 min | Healthy male Wistar rats | - | ↓ PP | ↑ Number and diameter of fenestrae | [158] | |
| BQ-123 (ET-A antagonist) | 1000 and 3000 nmol/min infused for 20 min | 16 CH patients with PH | - | ↓ MAP and pulmonary vascular resistance index. No effects on HVPG. | - | [159] | |
| BQ-123 or Ambrisentan (ET-A antagonists) | 300, 500, 1000 and 2000 nmol/L of BQ-123 infused through the hepatic artery. 5 or 10 mg single oral administration of ambrisentan | 26 CH patients | - | BQ123: Vasodilation of the hepatic artery, ↓ HVPG. Ambrisentan: ↓ HVPG | - | [160] | |
| Ambrisentan (ET-A antagonist) | 2 or 30 mg/kg/day for 2 weeks alone or in combination with 10 mg/kg/day of atorvastatin. | Male Sprague-Dawley rats with NASH induced by a HFGFD. | ↓ NAS score | ↓ PP, ↓ HVR | Improved markers of microvascular dysfunction, ↓ HSC contraction. | [161] | |
| Induction of vasodilation | BAY 60-2770 (sGC activator) | 0.3 mg/kg daily for 1 week | LSEC and HSC isolated from healthy and TAA-cirrhotic male Sprague-Dawley rats | ↓ Fibrosis, ↓ Cirrhosis | - | Restoration of LSEC phenotype and quiescence of HSC | [127] |
| Riociguat (sGC stimulator) | 1 mg/kg daily, for 1 to 3 weeks | Male Sprague Dawley cBDL or CCl4-cirrhotic rats | ↓ Fibrosis, ↓ Inflammation | ↓ PP, ↑ vasodilation pathways | ↓ HSC α-SMA expression | [162] | |
| Praliciguat (sGC stimulator) | STAM/HC: 3 or 10 mg/kg/day for 6 weeks during cirrhosis induction. TAA: 1, 3 or 10 mg/kg/day for 4 weeks during cirrhosis induction. CCl4: 1, 3 or 10 mg/kg/day for 6 weeks during cirrhosis induction. | Male C57/B6 mouse model with steatosis and metabolism with high cholesterol (STAM/HC), and TAA or CCl4-induced cirrhotic Sprague-Dawley rats | ↓ Fibrosis, ↓ Inflammation | ↓ MAP | ↓ TGF-β-induced HSC activation, ↓TGF-β and PDGF-b, ↓ Macrophage infiltration | [163] | |
| Sildenafil (PDE5 inhibitor) | 0.25 mg/kg twice a day for 1 week, starting 3 weeks after the surgery | Male Sprague-Dawley rats with cBDL-induced cirrhosis | ↑ BH4, total hepatic biopterin and GTPCH-I activity | ↑ sinusoid area, volumetric flow and perfused sinusoids ↓ PP, ↓ PPP | ↑ NO bioavailability, ↑ phosphorilation of eNOS and Akt, ↑ NOx production | [164] | |
| Udenafil (PDE5 inhibitor) | Series A: 1, 5 or 25 mg/kg/day, starting 1 week after the cBDL surgery and continued for 3 weeks. Series B: Single dose of 5 or 25 mg/kg 4 weeks after surgery | Male Sprague-Dawley cBDL-cirrhotic rats | - | ↓ PP | ↓ HSC mRNA expression of procollagen type I and α-SMA | [165] | |
| Udenafil | 1 mg/kg and 5 mg/kg for 60 min | Male Sprague Dawley cBDL or CCl4-cirrhotic rats | - | ↓ PP, ↓ HVR, ↑ intrahepatic vasodilation | ↑ eNOS protein, ↑ cGMP | [166] | |
| Vardenafil (PDE5 inhibitor) | A single dose of 10 mg | 18 CH patients | - | ↑ Portal blood flow, ↓ PP | - | [167] | |
| Udenafil | 12.5, 25, 50, 75 and 100 mg daily for one week | 35 patients with compensated liver cirrhosis and HVPG ≥12 mmHg | - | ↓ HVPG, MAP | - | [168] | |
| Tempol (SOD mimetic) | In vivo: 180 µmol for 30 min during the hemodynamic study. In vitro: 50 µM for 6 h. | In vivo: Male Wistar CCl4 cirrhotic rats. In vitro: LSEC isolated from treated Wistar rats incubated for 6 h with a superoxide dismutase inhibitor. | In vivo: ↓ oxidative stress, ↑ cGMP. | ↓ PP, ↑ portal blood flow, ↓ vascular resistance, ↓ MAP | In vitro: ↓ oxidative stress, ↑ NO. | [169] | |
| rMnSOD (recombinant manganese SOD) | Healthy rats: 15 µg/kg 2 h before the experiment. Cirrhotic rats: 15 µg/kg daily for 7 days. In vitro: 1 µM overnight | Male Wistar healty, CCl4 and cBDL-cirrhotic rats. In vitro: LX2 cells | ↓ oxidative stress, ↓ deposition of fibrillar collagen | ↓ PP, ↓ HVR, ↑ vasorelaxation | In vitro: ↓ oxidative stress, ↓ α-SMA and collagen I gene expression | [170] | |
| Simvastatin | One time dose of 40 mg, 30 and/or 60 min before the study | 30 CH patients with HVPG ≥ 12 mm | - | ↑ Hepatic blood flow, ↓ HVR | ↑ NO levels | [171] | |
| Simvastatin | 20 mg/day for 15 days, and 40 mg/day the following 15 days | 59 patients with CH and PH | - | ↓ HVPG, ↑ liver perfusion and function | - | [172] | |
| Atorvastatin, mevastatin, simvastatin or lovastatin | 0.1, 1 or 10 µM for 24 h | LSEC isolated from male Wistar CCl4-cirrhotic rats | - | - | ↑ KLF2, eNOS and thrombomodulin mRNA expression | [76] | |
| Simvastatin | LX-2 cells: 0.1, 1 and 10 µM for 24 and 72 h. HSC: 10 uM | LX-2 cells and primary HSC | - | - | ↑ KLF2 mRNA expression, ↓ α-SMA mRNA and protein expression | [136] | |
| Atorvastatin | 15 mg/kg once per day for 1 week | Male Sprague-Dawley BDL-cirrhotic rats | - | ↓ PP, ↓ HVR, ↓ shunting | ↑ eNOS mRNA, protein expression, ↑ PKG activity, ↓ HSC contraction | [173] | |
| Atorvastatin | 15 mg/kg daily. Prophylaxis group: 1, 2, 3 or 5 weeks of treatment after BDL. Therapy group: 1 week of treatment at different time points after BDL. | Male Sprague-Dawley BDL-cirrhotic rats | Prophylaxis: ↓ fibrosis, Therapy: ↓ fibrosis, apoptosis. | - | Prophylaxis: ↓ ECM and HSC activation. Therapy: ↓ ECM, ↓ HSC activation, proliferation and apoptosis. | [174] | |
| Simvastatin | 25 mg/kg/day for 3 days | Male Wistar CCl4-cirrhotic rats | ↑ eNOS activity | - | ↑ LSEC function | [175] | |
| Simvastatin | Chronic treatment: 20 mg/kg/day by gavage. Acute treatment: incubation of the portal-systemic collateral vascular bed for 25 min with 10 µM | Male Sprague-Dawley with portal hypertension induced by partial portal vein ligation | - | ↓ PP, ↓ collateral vascular resistance | ↑ SRS eNOS, COX-2 and TXA2 mRNA expression | [176] | |
| Simvastatin | 20 mg/kg by gavage from 2 days prior to ligation until 7 days after the operation | Male Sprague-Dawley with portal hypertension induced by partial portal vein ligation | - | ↓ PP, ↓ collateral vascular resistance | - | [177] | |
| Simvastatin, Atorvastatin | 10 mg/kg/day of one drug for 2 weeks | Male Sprague-Dawley OFA rats with NASH induced by a HFGFD | ↓ Steatosis, ballooning and inflammation, ↓ histological NASH | ↓ PP | ↑ eNOS and AKT phosphorylation, restoration of LSEC phenotype and quiescence of HSC | [178] | |
| Simvastatin | In vivo: 4 mg/kg/day for 8 weeks. In vitro: 10 µM for 24 h | In vivo: male Wistar rats with NASH induced by HFD. In vitro: LX-2 cell line activated with TGF-β. | In vivo:↓ liver inflammatory cells infiltration, ↓ steatosis, ↑ mRNA and protein eNOS ↓ iNOS and collagen I. | - | In vivo: ↓ liver inflammatory cells infiltration. In vitro: ↓ LX-2 activation, ↓ mRNA and protein α-SMA and collagen I. | [179] | |
| Simvastatin | 25 mg/kg given 3 and 23 h after LPS challenge, or 25 mg/kg/day, from 3 days before LPS injection | Male Wistar rats administered with LPS and evaluated 6 and 24 h later | ↓ Inflammation, leukocyte infiltration | ↓ PP | ↓ Sinusoidal endothelial dysfunction, ↑ eNOS phosphorylation | [180] | |
| Simvastatin | 25 mg/kg/day in CCl4 and TAA-induced ACLD animals, 5 mg/kg/day in BDL-induced animals for 3 days and a last dose 30 min before the LPS injection | ACLD rats (CCl4, BDL or TAA) subjected to ACLF challenge with an injection of 1 mg/kg of LPS before the study | ↓ ACLF-derived complications, ↑ survival, ↓ inflammation | ↓ PP | ↑ Sinusoidal function, ↓ LPS-mediated activation of HSC | [181] | |
| Simvastatin | 5 mg/kg/day starting 3 days before the experiments | Male Sprague-Dawley cBDL-cirrhotic rats subject to hemorrhage/resuscitation | ↓ ALT, AST, ↓ RNA expression of inflammatory genes | ↓ Vasoconstriction | - | [182] | |
| Simvastatin | 5 mg/kg/day for 15 days by gavage | Male Wistar rats (16 months old) with ACLD (CCl4). | ↓ Fibrosis, | ↓ Hepatic microvascular dysfunction, | ↑ Fenestration, ↑ markers of hepatocyte function, ↓ markers of HSC activation | [183] | |
| INT-747 (FXR receptor agonist) | TAA-cirrhotic rats received two doses of 30 mg/kg 24 and 4 h before the experiments. Another grup of TAA and BDL-cirrhotic rats received 30 mg daily and 5 mg/kg every 2 days for 10 days, respectively. | Male Wistar TAA or cBDL-cirrhotic rats | - | ↓ PP, ↓ HVR, ↑ hepatic microvascular function | ↑ NO | [184] | |
| OCA (FXR agonist) | In vivo: 10 mg/kg either every 2 days during the last 4 weeks of the TAA intoxication or every 2 days for 4 weeks after cirrhosis development. In vitro: 0.1, 1 and 10 μM |
In vivo: Male Wistar TAA-cirrhotic rats In vitro: hepatocytes, LSEC, HSC and Kupffer cells isolated from mice liver |
In vivo: ↓ liver fibrosis, ↓inflammation | ↓ PP, ↓ HVR | ↓ LSEC activation, ↓ Kupffer cell activation, ↓HSC activation | [185] | |
| Targeting other vascular alterations | Enoxaparin (anticoagulant) | In vivo: 1.8 mg/kg. -Short-term: Daily for 1 week (CCl4) -Long-term: Daily for 3 weeks (CCl4 and TAA) -Preventive: Daily for the last 3 weeks of the induction of cirrhosis |
In vivo: Male Wistar CCl4 or male Sprague-Dawley TAA-cirrhotic rats In vitro: primary HSCs isolated from CCl4-cirrhotic rats |
In vivo: ↓ liver fibrosis, ↑liver function, ↓ liver microthrombosis | ↓ PP, ↓ HVR | In vivo: ↓ HSC activation, ↓ oxidative stress, In vitro: improved HSC phenotype | [186] |
| Rivaroxaban (Anticoagulant) | In vivo: 20 mg/kg/day for 2 weeks. In vitro: 25, 50, 100 ng/mL during 24 h |
In vivo: Wistar CCl4 or Sprague-Dawley TAA-cirrhotic rats In vitro: primary HSCs isolated from CCl4-cirrhotic rats |
No regression of fibrosis | ↓ PP | In vivo: ↑ NO (CCl4), ↑ LSEC phenotype, ↓HSC activation, ↓ liver microthrombosis. In vitro: ↑ HSC phenotype | [187] | |
| Sorafenib (multikinase inhibitor) | In vivo: 2 mg/kg/day for 2 weeks in PPVL rats. 1 mg/kg/day for 2 weeks in cBDL-cirrhotic rats. |
Male Sprague-Dawley PPVL or cBDL-cirrhotic rats (PPVL, cBDL) | ↓ splanchnic neovascularization, ↓inflammation, ↓ liver damage, ↓ liver fibrosis, ↓ angiogenesis | ↓ PP (cBDL) | - | [188] | |
| Sorafenib, Imatinib or the combination of both (multikinase inhibitors) | 30 mg/kg or 50 mg/kg, respectively, five times/week for 3 weeks | Female Balb/c Concanavalin A-acute liver fibrosis mice | ↓ liver fibrosis | - | ↓ HSC activation | [189] | |
| Cell death and inflammation | Emricasan (Caspase inhibitor) | 10 mg/kg/day for 7 days, starting 1 week after the animals developed cirrhosis | Male Wistar CCl4-cirrhotic rats | ↓ AST, ↑ Bile, ↓ fibrosis, ↓ inflammation, ↑ hepatocyte phenotype | ↓ PP, ↓ PPP, ↑ vasodilation | ↓ Cell death, ↓ HSC activation and number, ↑ LSEC fenestrae, ↓ vWF, ↑ NO, improved HSC, LSEC and KC phenotype | [190] |
| Emricasan | 5, 25 or 50 mg daily for 24 weeks | 196 patients with NASH cirrhosis | - | No significant differences in HVPG. Small ↓ HVPG in the compensated subgroup. | - | [191] | |
| Seolnsertib (ASK1 inhibitor) | 18 mg or 6 mg daily for 48 weeks | Two phase III trials: 802 and 877 patients with NASH cirrhosis | No regression of fibrosis | - | - | [192] | |
| Fenofibrate (PPARα agonist) | 25 mg/kg daily for 7 days | Male Wistar CCl4-cirrhotic rats | ↓ liver fibrosis | ↓ PP, ↑ MAP | ↓ HSC activation, ↑ NO bioavailability, ↑ hepatic microvascular function | [193] | |
| Fenofibrate, Lanifibranor pioglitazone and GW501516 (PPAR agonists) | 100, 30, 30, 10 mg/kg/day via oral gavage for up to 6 weeks | Choline-deficient, amino acid-defined high fat diet and WD-fed CCl4-cirrhotic rats | ↓ liver fibrosis, ↓steatosis, ↓liver injury | - | ↓ HSC activation | [194] | |
| Lanifibranor (pan-PPAR agonist) | In vivo: 100 mg/kg/day for two weeks In vitro: 1, 3 or 10 µM for 24 h |
In vivo: Male Sprague-Dawley TAA or cBDL-cirrhotic rats In vitro: Primary human liver cells from patients with cirrhosis |
In vivo: ↓ liver fibrosis, ↑ liver function, ↓ inflammation | ↓ PP, ↓ HVR | In vivo: ↓ HSC activation, improved LSEC phenotype, ↑ hepatic microvascular function In vitro: improved HSC phenotype, ↓ HSC contraction capacity |
[195] | |
| Liraglutide (GLP-1 analogue) | In vivo: 0.5 mg/kg/day for 15 days. In vitro: 50 µM for 72 h |
In vivo: Male Wistar TAA-cirrhotic rats In vitro: Primary human HSC from patients with cirrhosis and Immortalized human-activated HSC LX-2 |
In vivo: ↓ liver fibrosis | ↓ PP | In vivo: ↓ HSC activation, improved LSEC phenotype, ↑ hepatic microvascular function In vitro: ↓ HSC activation, ↓ HSC contraction capacity, ↓ inflammation |
[196] | |
| Liraglutide | 1.8 mg/day for 48 weeks | 52 patients with NASH | ↓ hepatic steatosis, ↓ hepatocyte ballooning | - | - | [197] | |
| Semaglutide (GLP-1 analogue) | 0.4 mg/day for 72 weeks | 162 patients with NASH | ↑ NASH resolution. No improvement in fibrosis stage | - | - | [198] | |
| Metformin | 300 mg/kg/day for 1 week | In vivo: Male Wistar CCl4 or Sprague-Dawley cBDL-cirrhotic rats In vitro: LX-2 cell line |
In vivo: ↓ liver fibrosis, ↓ inflammation | ↓ PP, ↓ HVR | In vivo: ↓ HSC activation, ↑ NO bioavailability, ↓ oxidative stress In vitro: ↓ markers of HSC activation |
[199] | |
| ObR-Ab (Leptin receptor antagonist) | 8 µg/kg/day for 1 week | Male Wistar CCl4-cirrhotic rats | - | ↓ PP | ↑ GMPc, ↓ oxidative stress | [200] | |
| Lifestyle and dietary interventions | Docosahexaenoic acid | After cirrhosis induction, 500 mg/kg/day for two weeks | Male Sprague-Dawley TAA-cirrhotic rats | Recovery of normal fatty acid enzymatic activity and fatty acid composition, ↓ oxidative stress, ↓ inflammation, ↓ steatosis | ↓ PP | ↓ HSC activation, ↓ ECM accumulation | [201] |
| VSL#3 (probiotics) | 900 billion CFU per day for 6 weeks | 17 patients with cirrhosis | ↓ bacterial translocation, ↓ inflammation | ↓ HVPG | - | [202] | |
| VSL#3 | 900 billion CFU per day for 24 weeks | 130 patients with cirrhosis with a recent episode of hepatic encephalopathy | ↓ CTP and MELD scores, ↓plasma proinflammatory markers (TNFα, IL1β and IL6) | - | - | [203] | |
| VSL#3 | 900 billion CFU per day for 2 months | 94 patients with cirrhosis | ↓ TNFα | ↓ HVPG | - | [204] | |
| CECT7765 (Pseudocatenulatum) | 1 billion CFU daily for 1 week | Male Sprague-Dawley cBDL-cirrhotic rats | ↑ liver function: ↑ bilirubin and alkaline phosphatase. ↓ inflammation: ↓ TNFα, IL-6 and NO. ↑ FXR and eNOS gene expression. ↓ iNOS and COX-2 | ↓ portal vein area and portal flow | [205] | ||
| VSL#3 | 900 billion CFU twice daily for 2 months | 8 cirrhotic patients | - | No changes in HVPG | - | [206] | |
| VSL#3 | 900 billion CFU twice daily for 2 months | 17 patients with decompensated cirrhosis and HVPG ≥10 | - | No changes in HVPG | - | [207] | |
| Curcumin | 50 mg/kg suspended in 0.5% carboxymethyl cellulose daily for 6 weeks | Male Sprague-Dawley rats with NASH induced by HFD | ↓ inflammation, ↓ steatosis, ↓ insulin resistance | ↓ MDA, ↑ hepatic GSH content, ↑ SOD activity, ↑ HO-1 | [208] | ||
| Resveratrol | 10 and 20 mg/kg/day for 2 weeks | In vivo: Male Wistar CCl4-cirrhotic rats In vitro: LX-2 cell line |
In vivo: ↓ liver fibrosis, ↓inflammation | ↓ PP | In vivo: ↑ hepatic microvascular function, ↓ oxidative damage, ↓ HSC activation. In vitro: ↓ HSC activation markers | [209] |