Reduction of monocrotaline‐induced hepatic injury by deleted variant of hepatocyte growth factor (dHGF) in rats

Yamashita, Yasushi; Fujise, Nobuaki; Imai, Eiichi; Masunaga, Hiroaki

doi:10.1034/j.1600-0676.2002.01643.x

Cited by 4 publications

(2 citation statements)

References 26 publications

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“…BMP9 was predictive of transplant-free survival in patients with group 1 PAH, including or excluding patients with PoPH, yet was not correlated with NYHA functional class, right atrial pressure, or BNP (see Figure E3C, and data not shown) among patients with PAH, suggesting that BMP9 predicts survival independent of RV function. Among the animal models of PH, BMP9 was diminished only in rodents with severe cirrhosis, but preserved in SU5416/hypoxia-treated mice and rats, and monocrotaline-treated rats despite the known hepatotoxicity of pyrrolizidine alkaloids (27). Taken together, these results suggest that BMP9 levels are linked to PoPH via portal hypertension rather than liver injury or synthetic dysfunction alone.…”

Section: Discussionmentioning

confidence: 84%

Bone Morphogenetic Protein 9 Is a Mechanistic Biomarker of Portopulmonary Hypertension

Nikolić

Yung

Yang

et al. 2019

Am J Respir Crit Care Med

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Rationale: BMP9 (bone morphogenetic protein 9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors, and downstream effectors have been reported in heritable PAH. Objectives: To determine how an acquired deficiency of BMP9 signaling might contribute to PAH. Methods: Plasma levels of BMP9 and antagonist soluble endoglin were measured in group 1 PAH, group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH. Measurements and Main Results: BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) versus healthy control subjects, or other etiologies of PAH or PH; distinguished PoPH from patients with liver disease without PAH; and were an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl 4-induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of ALK1-Fc, a BMP9 ligand trap consisting of the activin receptor-like kinase-1 extracellular domain, exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia versus hypoxia alone. Conclusions: BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH.

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Section: Discussionmentioning

confidence: 84%

Bone Morphogenetic Protein 9 Is a Mechanistic Biomarker of Portopulmonary Hypertension

Nikolić

Yung

Yang

et al. 2019

Am J Respir Crit Care Med

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“…The hepaplastin-test is also employed to detect abnormal coagulation factors related to hepatic injury in rats [16,21]. Among them, the thrombotest and hepaplastin-test are the least specific, since these show a prolongation of coagulation time when the activity of either factor II, VII or X has declined, regardless of whether vitamin K abnormality is involved or not.…”

Section: Abstract: a Battery Of Simple Tests For Profiling Abnormalitmentioning

confidence: 99%

Battery of Tests for Profiling Abnormalities of Vitamin K-Dependent Coagulation Factors in Drug-Toxicity Studies in Rats

et al. 2005

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A battery of simple tests for profiling abnormalities of vitamin K-dependent coagulation factors encountered in drug-toxicity studies was verified in rats treated with warfarin (3 and 10 mg/kg, p.o). The thrombotest, or hepaplastin-test, is useful as a followup test after routine screening tests for coagulation abnormalities based on PT and APTTThe rat is the species most commonly used to assess the general toxicity of compounds under development for clinical use. We sometimes observe prolongation of the routine screening parameters, prothrombin time (PT) and activated partial thromboplastin time (APTT) in general toxicity studies in rats. One of the causes of this is decreased activity of vitamin K-dependent coagulation factors due to the generation of the inactive des-carboxyl form of coagulation factors, also known as "protein induced by vitamin K absence or antagonists (PIVKA)" [7,12]. Many chemicals are known to cause such abnormalities [8,20].The abnormal vitamin K-dependent factors are detected in rats by measuring coagulation time using the Kurata, Worldwide Safety Sciences, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Inc., 5-2 Taketoyo, Aichi 470-2393, Japan thrombotest [4, 6, 14, 18], the activity of coagulation factors [9,13], and descarboxyprothrombin (PIVKA-II) [7,8]. The hepaplastin-test is also employed to detect abnormal coagulation factors related to hepatic injury in rats [16,21]. Among them, the thrombotest and hepaplastin-test are the least specific, since these show a prolongation of coagulation time when the activity of either factor II, VII or X has declined, regardless of whether vitamin K abnormality is involved or not. The activity of individual coagulation factors is insufficient to confirm the patho-mechanism of coagulation abnormalities, because it is impossible to detect the inactive form of coagulation factors (e.g., PIVKA-II). PIVKA-II, if measured alone, is also insufficient

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IsN-acetyl cysteine protective against monocrotaline-induced toxicity?

et al. 2013

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Reduction of monocrotaline‐induced hepatic injury by deleted variant of hepatocyte growth factor (dHGF) in rats

Abstract: These results suggest that dHGF prevented and repaired the monocrotaline-induced hepatic injury, and could have therapeutic potency in hepatic failure with sever centrilobular destruction.

Cited by 4 publications

References 26 publications

Bone Morphogenetic Protein 9 Is a Mechanistic Biomarker of Portopulmonary Hypertension

Bone Morphogenetic Protein 9 Is a Mechanistic Biomarker of Portopulmonary Hypertension

Battery of Tests for Profiling Abnormalities of Vitamin K-Dependent Coagulation Factors in Drug-Toxicity Studies in Rats

IsN-acetyl cysteine protective against monocrotaline-induced toxicity?

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