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1.
Cell Mol Gastroenterol Hepatol ; 15(4): 841-867, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36521660

RESUMO

BACKGROUND & AIMS: Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis in vivo and in vitro. METHODS: FAP expression was analyzed in mice and patients with fibrotic liver diseases of various etiologies. Fibrotic mice received a specific FAP inhibitor (FAPi) at 2 doses orally for 2 weeks during parenchymal fibrosis progression (6 weeks of carbon tetrachloride) and regression (2 weeks off carbon tetrachloride), and with biliary fibrosis (Mdr2-/-). Recombinant FAP was added to (co-)cultures of hepatic stellate cells (HSC), fibroblasts, and macrophages. Fibrosis- and inflammation-related parameters were determined biochemically, by quantitative immunohistochemistry, polymerase chain reaction, and transcriptomics. RESULTS: FAP+ fibroblasts/HSCs were α-smooth muscle actin (α-SMA)-negative and located at interfaces of fibrotic septa next to macrophages in murine and human livers. In parenchymal fibrosis, FAPi reduced collagen area, liver collagen content, α-SMA+ myofibroblasts, M2-type macrophages, serum alanine transaminase and aspartate aminotransferase, key fibrogenesis-related transcripts, and increased hepatocyte proliferation 10-fold. During regression, FAP was suppressed, and FAPi was ineffective. FAPi less potently inhibited biliary fibrosis. In vitro, FAP small interfering RNA reduced HSC α-SMA expression and collagen production, and FAPi suppressed their activation and proliferation. Compared with untreated macrophages, FAPi regulated macrophage profibrogenic activation and transcriptome, and their conditioned medium attenuated HSC activation, which was increased with addition of recombinant FAP. CONCLUSIONS: Pharmacological FAP inhibition attenuates inflammation-predominant liver fibrosis. FAP is expressed on subsets of activated fibroblasts/HSC and promotes both macrophage and HSC profibrogenic activity in liver fibrosis.


Assuntos
Hepatite , Hepatopatias , Humanos , Camundongos , Animais , Tetracloreto de Carbono/toxicidade , Cirrose Hepática/metabolismo , Inflamação , Fibrose , Colágeno/metabolismo , Fibroblastos/metabolismo , Macrófagos/metabolismo
2.
Ann. hepatol ; Ann. hepatol;16(1): 123-132, Jan.-Feb. 2017. graf
Artigo em Inglês | LILACS | ID: biblio-838094

RESUMO

Abstract: Introduction and aim. Hyponatremia is common in patients with decompensated cirrhosis and is associated with increased mortality. Tolvaptan, a vasopressor V2 receptor antagonist, can increase free wáter excretion, but its efficacy and safety in cirrhotic patients remain unclear. Material and methods. We studied the usage and safety of tolvaptan in cirrhotic patients in a real-life, non-randomized, multicenter prospective cohort study. Forty-nine cirrhotic patients with hyponatremia were treated with tolvaptan 15 mg daily, and 48 patients not treated with tolvaptan in the same period served as controls. Improvement in serum sodium level was defined as an increase in serum sodium from < 125 to ≥ 125 mmol/L or from 125-134 to ≥ 135 mmol/L on day 7. Results. Twenty-three (47%) patients in the tolvaptan group and 17 (35%) in the control group had normal serum sodium on day 7 (p = 0.25). Serum sodium improved in 30 (61%) patients in the tolvaptan group and 17 (35%) patients in the control group (p = 0.011). Adverse events occurred in 46-47% of patients in both groups, and tolvaptan was not associated with worsened liver function. No patient with normal serum sodium on day 7 died within 30 days of treatment, whereas 16% of those with persistent hyponatremia died (p = 0.0019). Conclusion. In conclusion, short-term tolvaptan treatment is safe and can improve serum sodium level in cirrhotic patients with hyponatremia. Normalization of serum sodium level is associated with better survival.


Assuntos
Humanos , Pessoa de Meia-Idade , Idoso , Sódio/sangue , Benzazepinas/uso terapêutico , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Hiponatremia/tratamento farmacológico , Cirrose Hepática/complicações , Fatores de Tempo , Benzazepinas/efeitos adversos , Biomarcadores/sangue , Estudos de Casos e Controles , China , Estudos Prospectivos , Fatores de Risco , Resultado do Tratamento , Estimativa de Kaplan-Meier , Antagonistas dos Receptores de Hormônios Antidiuréticos/efeitos adversos , Tolvaptan , Hiponatremia/etiologia , Hiponatremia/mortalidade , Hiponatremia/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/mortalidade
3.
Ann Hepatol ; 16(1): 123-132, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28051801

RESUMO

Introduction and aim. Hyponatremia is common in patients with decompensated cirrhosis and is associated with increased mortality. Tolvaptan, a vasopressor V2 receptor antagonist, can increase free water excretion, but its efficacy and safety in cirrhotic patients remain unclear. MATERIAL AND METHODS: We studied the usage and safety of tolvaptan in cirrhotic patients in a real-life, non-randomized, multicenter prospective cohort study. Forty-nine cirrhotic patients with hyponatremia were treated with tolvaptan 15 mg daily, and 48 patients not treated with tolvaptan in the same period served as controls. Improvement in serum sodium level was defined as an increase in serum sodium from < 125 to ≥ 125 mmol/L or from 125-134 to ≥ 135 mmol/L on day 7. RESULTS: Twenty-three (47%) patients in the tolvaptan group and 17 (35%) in the control group had normal serum sodium on day 7 (p = 0.25). Serum sodium improved in 30 (61%) patients in the tolvaptan group and 17 (35%) patients in the control group (p = 0.011). Adverse events occurred in 46-47% of patients in both groups, and tolvaptan was not associated with worsened liver function. No patient with normal serum sodium on day 7 died within 30 days of treatment, whereas 16% of those with persistent hyponatremia died (p = 0.0019). CONCLUSION: In conclusion, short-term tolvaptan treatment is safe and can improve serum sodium level in cirrhotic patients with hyponatremia. Normalization of serum sodium level is associated with better survival.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Benzazepinas/uso terapêutico , Hiponatremia/tratamento farmacológico , Cirrose Hepática/complicações , Sódio/sangue , Idoso , Antagonistas dos Receptores de Hormônios Antidiuréticos/efeitos adversos , Benzazepinas/efeitos adversos , Biomarcadores/sangue , Estudos de Casos e Controles , China , Feminino , Humanos , Hiponatremia/sangue , Hiponatremia/etiologia , Hiponatremia/mortalidade , Estimativa de Kaplan-Meier , Cirrose Hepática/diagnóstico , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Tolvaptan , Resultado do Tratamento
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