Obesity is associated with increased levels of circulating hepatocyte growth factor

OBJECTIVES: This study evaluated whether obesity in humans was associated with an increase in circulating hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) levels. BACKGROUND: Obesity acts as a cardiovascular risk factor by mechanisms that are not fully understood. Adipose tissue is able to secrete multiple cytokines and growth factors ex vivo. We hypothesized that the increased presence of adipose tissue in obese subjects results in systemic elevations of the mitogenic factors HGF and VEGF. METHODS: Blood samples were obtained from lean (n = 21) and obese (n = 44) volunteers. Serum HGF and VEGF levels were assessed by enzyme-linked immunoadsorbent assay. Insulin and fasting glucose levels were measured to evaluate insulin sensitivity. Conditioned medium of adipose cells was assayed for HGF secretion. RESULTS: Serum HGF levels in obese subjects were more than three-fold higher than those of lean subjects (2,462 +/- 184 pg/ml vs. 765 +/- 48 pg/ml, p < 0.0001). The VEGF levels were not significantly elevated in obese subjects (135 +/- 31 pg/ml vs. 128 +/- 37 pg/ml). The HGF concentrations, but not VEGF concentrations, were significantly correlated with body mass index (BMI) (p < 0.0001, r = 0.74). The observed increases in HGF concentrations of obese subjects were not secondary to insulin resistance or hypertension. Freshly isolated human adipose cells secreted HGF. CONCLUSIONS: Our results indicate that obesity is associated with a marked increase in circulating HGF levels, which correlate linearly with BMI. Because vascular growth factors have been associated with the pathogenesis of atherosclerosis, the possible role of such humoral factors as a link between obesity and cardiovascular disease is very intriguing.     

Plasma hepatocyte growth factor is a novel marker of AL cardiac amyloidosis

Abstract

Background: Cardiac amyloidosis is an infiltrative cardiomyopathy that is challenging to diagnose. We hypothesized that the novel biomarkers hepatocyte growth factor (HGF), galectin-3 (GAL-3), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) would be elevated in cardiac amyloidosis and may be able to discriminate from non-cardiac systemic amyloidosis or other cardiomyopathies with similar clinical or morphologic characteristics.

Methods: Patients were selected from the Vanderbilt Main Heart Registry according to the following groups: (1) amyloid light-chain (AL) cardiac amyloidosis (n?=?26); (2) transthyretin (ATTR) cardiac amyloidosis (n?=?7); (3) left ventricular hypertrophy (LVH) (n?=?45); (4) systolic heart failure (n?=?42); and (5) non-cardiac systemic amyloidosis (n?=?7). Biomarkers were measured in stored plasma samples. Biomarkers' discrimination performance in predicting AL cardiac amyloidosis (i.e., Concordance index) was reported. A survival analysis was used to explore the relationship between HGF levels and mortality among AL cardiac amyloidosis patients.

Results: HGF levels were markedly elevated in patients with AL cardiac amyloidosis (median?=?622, interquartile range (IQR): 299–1228?pg/mL) compared with the other groups, including those with non-cardiac systemic amyloidosis (median?=?134, IQR: 94–163?pg/mL, p?<?0.001). HGF was not a specific marker for ATTR amyloidosis. Gal-3 was elevated in all groups with amyloidosis but could not differentiate between those with and without cardiac involvement. There was no difference in IL-6 or VEGF between those with AL cardiac amyloidosis compared to other groups (p?=?0.13 and 0.057, respectively).

Conclusions: HGF may be a specific marker that distinguishes AL cardiac amyloidosis from other cardiomyopathies with similar clinical or morphologic characteristics. Further studies are necessary to determine whether HGF levels predict the likelihood of survival.     

Enhanced acyl-CoA dehydrogenase activity is associated with improved mitochondrial and contractile function in heart failure

AIMS: Heart failure is associated with decreased myocardial fatty acid oxidation capacity and has been likened to energy starvation. Increased fatty acid availability results in an induction of genes promoting fatty acid oxidation. The aim of the present study was to investigate possible mechanisms by which high fat feeding improved mitochondrial and contractile function in heart failure. METHODS AND RESULTS: Male Wistar rats underwent coronary artery ligation (HF) or sham surgery and were immediately fed either a normal (14% kcal fat) (SHAM, HF) or high-fat diet (60% kcal saturated fat) (SHAM+FAT, HF+FAT) for 8 weeks. Mitochondrial respiration and gene expression and enzyme activities of fatty acid-regulated mitochondrial genes and proteins were assessed. Subsarcolemmal (SSM) and interfibrillar mitochondria were isolated from the left ventricle. State 3 respiration using lipid substrates octanoylcarnitine and palmitoylcarnitine increased in the SSM of HF+FAT compared with SHAM+FAT and HF, respectively (242 +/- 21, 246 +/- 21 vs. 183 +/- 8, 181 +/- 6 and 193 +/- 17, 185 +/- 16 nAO min(-1) mg(-1)). Despite decreased medium-chain acyl-CoA dehydrogenase (MCAD) mRNA in HF and HF+FAT, MCAD protein was not altered, and MCAD activity increased in HF+FAT (HF, 65.1 +/- 2.7 vs. HF+FAT, 81.5 +/- 5.4 nmoles min(-1) mg(-1)). Activities of short- and long-chain acyl-CoA dehydrogenase also were elevated and correlated to increased state 3 respiration. This was associated with an improvement in myocardial contractility as assessed by left ventricular +dP/dt max. CONCLUSION: Administration of a high-fat diet increased state 3 respiration and acyl-CoA dehydrogenase activities, but did not normalize mRNA or protein levels of acyl-CoA dehydrogenases in coronary artery ligation-induced heart failure rats.     

自发性高血压大鼠左室重构过程中肝细胞生长因子与心肌纤维化的相关研究

目的:探讨在自发性高血压大鼠左室重构过程中肝细胞生长因子（HGF）的变化与心肌纤维化的关系。方法:①自发性高血压大鼠（SHR）18只,分别为6周龄,14周龄和24周龄,以18只WKY鼠为正常对照组,年龄和体质量配比,每组各6只,雌雄配对。②采用大鼠血压心率测定仪测量大鼠安静、清醒状态尾动脉收缩压。测量左心室质量。采用ELISA法测量血浆及心肌组织HGF浓度。心肌胶原容积（CVF）和血管周围胶原容积（PVCA）采用病理图像分析检测法。结果:各年龄组SHR血压水平、左室质量指数、血浆HGF浓度均高于对照组,心肌组织HGF浓度在14,24周龄时低于对照组。同对照组相比,CVF在14、24周龄之间有统计学差异（P<0.05）。在6周龄之间无统计学差异（P>0.05）。各年龄段PVCA均高于对照组。CVF,PVCA与血浆HGF浓度有显著正相关性(r=0.7284,P<0.01;r=0.7191,P<0.01〉,与组织HGF浓度呈负相关(r=-0.4245,P<0.05;r=-0.4749,P<0.05〉。结论:在自发性高血压大鼠左室重构过程中,组织HGF水平降低与心肌纤维化的形成密切相关,这可能与其抗纤维化作用减弱有关。     

High glucose and hyperosmolality stimulate hepatocyte growth factor secretion from cultured human mesangial cells

Summary Hepatocyte growth factor is a recently cloned potent mitogen to hepatocytes, but its extrahepatic roles are not completely defined. It causes proliferation of endothelial and epithelial cells implicating potential action in the glomerulus. We aimed to determine whether cultured human mesangial cells secrete hepatocyte growth factor and the effect of high glucose conditions. Mesangial cells were isolated from the normal cortex of a child's kidney. After differential glomerular sieving and trypsin digestion of glomeruli, mesangial cells were cultured in 20 % fetal calf serum/RPMI. Glucose concentration in the medium was adjusted to 5 mmol/l, 11 mmol/l, 25 mmol/l or 5 mmol/l/20 mmol/l mannitol to correct for osmolality. After 0, 24, 48, 72 h incubation, hepatocyte growth factor was measured in the supernatant by enzyme immuno assay using recombinant hepatocyte growth factor and monoclonal antibodies to human hepatocyte growth factor. Hepatocyte growth factor was secreted by cultured mesangial cells. High glucose and hyperosmolar conditions caused a 100–200 % increase in hepatocyte growth factor secretion at 48–72 h (p =0.001). Hepatocyte growth factor secretion at 48 h in 5 mmol/l glucose was 16.46±1.09 ng/ml (mean ± SEM), 11 mmol/l glucose: 32.98±4.54, 25 mmol/l glucose: 33.32±7.89, 5 mmol/l glucose/20 mmol/l mannitol: 34.05±3.64; at 72 h in 5 mmol/l glucose: 23.92±2.85 ng/ml, 11 mmol/l glucose: 28.26±2.03, 25 mmo/l glucose: 62.04±12.2, 5 mmol/l glucose/20 mmol/l mannitol: 45.76±6.25. Trypan blue exclusion demonstrated membrane integrity. These findings demonstrate for the first time that cultured human mesangial cells secrete hepatocyte growth factor and there is stimulation by high glucose and hyperosmolar conditions. Hepatocyte growth factor may have a renotropic role in the pathogenesis of diabetic nephropathy. [Diabetologia (1994) 37: 533–535] Received: 11 November 1993 and in revised form: 13 December 1993     

冠心病患者动脉僵硬度与左心室重构及心功能的相关性

目的探讨冠心病患者动脉僵硬度与左心室重构及心功能的相关性。方法选择心内科住院患者480例,根据冠状动脉造影结果分为冠心病组373例及非冠心病组107例,冠心病组根据超声心动图结果分为左心室正常构型组139例及左心室异常构型组234例。各组行肱踝脉搏波传导速度(BaPWV)测定及超声心动图检查,同时在入选的冠心病组患者中选取42例行多普勒组织成像。结果冠心病组BaPWV明显高于非冠心病组(P<0.01)。左心室异常构型组BaPWV明显高于左心室正常构型组[(1689±305)cm/s vs(1508±280)cm/s,P<0.05]。冠心病组BaPWV与室间隔厚度(IVST)、左心室后壁厚度(PWT)、相对室壁厚度(RWT)、左心室质量指数(LVMI)和二尖瓣舒张早期血流速度/二尖瓣环侧壁舒张早期最大运动速度(Ea)呈正相关,与LVEF、Ea、Ea/二尖瓣环侧壁舒张晚期最大运动速度(Aa)呈负相关(P<0.05,P<0.01)。在除外高血压等的影响后,偏相关分析结果显示,BaPWV与IVST、PWT、RWT、LVMI、LVEF、Ea、Ea/Aa、E/Ea仍显著相关(P<0.01)。多元逐步回归分析显示,BaPWV是LVMI及LVEF的独立影响因素。结论 BaPWV是冠心病患者左心室重构及心功能的影响因素。     

MSCs transfected with hepatocyte growth factor or vascular endothelial growth factor improve cardiac function in the infarcted porcine heart by increasing angiogenesis and reducing fibrosis

Background

Cell transplantation and gene therapy have been demonstrated to have beneficial effects after a myocardial infarction (MI). Here, we used a large animal model of MI to investigate the beneficial effects of mesenchymal stem cells (MSCs) transfected with hepatocyte growth factor (HGF) or vascular endothelial growth factor (VEGF) genes.

Methods

A porcine MI model was created by balloon occlusion of the distal left anterior descending artery for 90 min followed by reperfusion. At 1 week after MI, the pigs were infused via the coronary vein with saline (n = 8), MSCs + AdNull(n = 8), MSC + VEGF(n = 10), or MSC + HGF(n = 10). Cardiac function and myocardial perfusion were evaluated by using echocardiography and gated cardiac perfusion imaging before and 4 weeks after transplantation. Morphometric and histological analyses were performed.

Results

All cell-implanted groups had better cardiac function than the saline control group. There were further functional improvements in the MSC + HGF group, accompanied by smaller infarct sizes, increased cell survival, and less collagen deposition. Blood vessel densities in the damaged area and cardiac perfusion were significantly greater in the MSC + AdNull group than in the saline control group, and further increased in the MSC + VEGF/HGF groups. Tissue fibrosis was significantly less extensive in the MSC and MSC + VEGF groups than in the saline control group and was most reduced in the MSC + HGF group.

Conclusion

MSCs (alone or transfected with VEGF/HGF) delivered into the infarcted porcine heart via the coronary vein improved cardiac function and perfusion, probably by increasing angiogenesis and reducing fibrosis. MSC + HGF was superior to MSC + VEGF, possibly owing to its enhanced antifibrotic effect.     

Correlations between plasma concentrations of atrial natriuretic factor and right ventricular function in patients with severe cardiac failure]

The atrial natriuretic factor (ANF) is secreted by the atria in mild and moderate cardiac failure but, during the evolution of the cardiac failure, the ventricles are also recruited and secrete ANF. In order to investigate the relation between plasma ANF and Doppler echocardiographic parameters of severe cardiac failure, the concentrations were measured simultaneously in 20 patients with NYHA Class III and IV cardiac failure (10 due to ischaemic and 10 due to primary dilated cardiomyopathy) despite optimal medical treatment including an angiotensin converting enzyme inhibitor. Overall, there was a weak negative correlation between the plasma ANF concentrations and the decrease in right ventricular surface area (r = -0.58, p less than 0.005, n = 20 patients). This relation was highly significant in ischaemic cardiomyopathy (r = -0.81, p less than 0.002, n = 10 patients) and not significant in primary dilated cardiomyopathy (r = -0.29, NS, n = 10 patients). No relationship was observed between plasma ANF and other echocardiographic parameters (atrial surface area, right and left ventricular dimensions, left ventricular ejection fraction and mass) or with Doppler aortic indices (acceleration, maximum and mean velocities, aortic velocity-time integrals). However, plasma ANF was related to the velocity of mitral regurgitant jets (r = -0.70, p less than 0.01) which is dependent on left ventricular pump function. These results show that plasma ANF concentrations are only related to right ventricular systolic function and the velocity of mitral regurgitation in patients with severe cardiac failure.     

Intramyocardial sustained delivery of basic fibroblast growth factor improves angiogenesis and ventricular function in a rat infarct model

 Recently we have demonstrated that the release of basic fibroblast growth factor (bFGF) from a biodegradable gelatin hydrogel carrier depends on the degradation of hydrogel in vivo. The purpose of our study was to assess whether bFGF-incorporating gelatin hydrogels induce myocardial angiogenesis and improve left ventricular function in the infarcted myocardium of rats. Studies were conducted in 22 Lewis rats after a 4-week ligation of the proximal left anterior descending coronary artery. The rats were randomized into the following two groups: the control group (n = 11) had an intramyocardial injection of saline alone, and the FGF group (n = 11) had gelatin hydrogel microspheres containing 100 μg of bFGF injected into the border zone of the infarct area after the repeat left thoracotomy. For visualization of the regional myocardial blood flow in the rat heart, ²⁰¹Tl images were taken just before and 4 weeks after the treatment using a 4-head single photon emission computed tomography scanner with pinhole collimators. Left ventricular function was also assessed with echocardiography and a micromanometer-tipped catheter. Finally, the extent of myocardial angiogenesis was evaluated quantitatively in the postmortem analysis. The ²⁰¹Tl defect score in the control group remained unchanged before and after the treatment, whereas it decreased significantly in the FGF group. Both regional and global left ventricular function was significantly better in the FGF group compared with the control group. The vascular density in the border zone of the infarct in the FGF group was significantly higher than that in the control group. In conclusion, intramyocardial injection of bFGF-impregnated gelatin hydrogels induces functionally significant angiogenesis and improves left ventricular systolic and diastolic function in the infarcted myocardium of rats. Received: July 31, 2002 / Accepted: November 22, 2002 Acknowledgment This study was supported by the “Research for the Future” Program (JSPS-RFTF 99 I 00201) from the Japan Society for the Promotion of Science, Japan.     

苦参素注射液联合促肝细胞生长素治疗慢性乙型重型肝炎的疗效

目的探讨苦参素注射液(Oxymarine,OM)联合促肝细胞生长素(pHGF)治疗慢性乙型重型肝炎(CSHB)的临床价值。方法慢性乙型重型肝炎37例,随机分为治疗组22例,对照组15例,两组均给予综合基础治疗,治疗组22例再加用抗病毒药物OM 600mg,肌注,1次/d,联合pHGF200～300mg+10％GS250～500ml中,静滴,1次/d,存活者坚持3个月一疗程。结果治疗组和对照组的病死率分别为36.4％(8/22)和73.3％(11/15),P<0.01;在CSHB早、中期二组病死率分别为10％与57.1％和42.9％与80％,P<0.01,而晚期二组病死率为75％与100％,P>0.05;二组治疗后HBsAg均无改变,而HBeAg和HBV DNA在治疗组的阴转率为71.4％(10/14)和64.3％(9/14),而对照组分别为 25％(1/4)和0(0/4),P<0.01。结论OM联合pHGF治疗CSHB,通过抑制乙型肝炎病毒复制、促进肝细胞生长、阻断肝细胞凋亡等作用,可降低病死率,安全无副反应。     

A genomic region associated with protection against severe COVID-19 is inherited from Neandertals

It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is inherited from Neandertals. New, larger genetic association studies now allow additional genetic risk factors to be discovered. Using data from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region on chromosome 12 associated with requiring intensive care when infected with the virus is inherited from Neandertals. This region encodes proteins that activate enzymes that are important during infections with RNA viruses. In contrast to the previously described Neandertal haplotype that increases the risk for severe COVID-19, this Neandertal haplotype is protective against severe disease. It also differs from the risk haplotype in that it has a more moderate effect and occurs at substantial frequencies in all regions of the world outside Africa. Among ancient human genomes in western Eurasia, the frequency of the protective Neandertal haplotype may have increased between 20,000 and 10,000 y ago and again during the past 1,000 y.

Neandertals evolved in western Eurasia about half a million years ago and subsequently lived largely separated from the ancestors of modern humans in Africa (1), although limited gene flow from Africa is likely to have occurred (2–5). Neandertals as well as Denisovans, their Asian sister group, then became extinct about 40,000 y ago (6). However, they continue to have a biological impact on human physiology today through genetic contributions to modern human populations that occurred during the last tens of thousands of years of their existence (e.g., refs. 7–10).Some of these contributions may reflect adaptations to environments outside Africa where Neandertals lived over several hundred thousands of years (11). During this time, they are likely to have adapted to infectious diseases, which are known to be strong selective factors that may, at least partly, have differed between sub-Saharan Africa and Eurasia (12). Indeed, several genetic variants contributed by archaic hominins to modern humans have been shown to affect genes involved in immunity (e.g., refs. 7, 8, 13, 14). In particular, variants at several loci containing genes involved in innate immunity come from Neandertals and Denisovans (15), for example, toll-like receptor gene variants which decrease the susceptibility to Helicobacter pylori infections and the risk for allergies (16). Furthermore, proteins interacting with RNA viruses have been shown to be encoded by DNA regions introgressed from Neandertals more often than expected (17), and RNA viruses might have driven many adaptive events in humans (18).Recently, it was shown that a haplotype in a region on chromosome 3 is associated with becoming critically ill upon infection with the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) (19) and was contributed to modern humans by Neandertals (20). Each copy of this haplotype approximately doubles the risk of its carriers requiring intensive care when infected by SARS-CoV-2. It reaches carrier frequencies of up to ∼65% in South Asia and ∼16% in Europe, whereas it is almost absent in East Asia. Thus, although this haplotype is detrimental for its carriers during the current pandemic, it may have been beneficial in earlier times in South Asia (21), perhaps by conferring protection against other pathogens, whereas it may have been eliminated in East Asia by negative selection.A new study from the Genetic of Mortality in Critical Care (GenOMICC) consortium, which includes 2,244 critically ill COVID-19 patients and controls (22), recently became available. In addition to the risk locus on chromosome 3, it identifies seven loci with genome-wide significant effects located on chromosomes 6, 12, 19, and 21. Here, we show that, at one of these loci, a haplotype associated with reduced risk of becoming severely ill upon SARS-CoV-2 infection is derived from Neandertals.     

缬沙坦对家兔慢性冬眠心肌细胞中肝细胞生长因子水平和心功能的影响

目的观察缬沙坦对慢性冬眠心肌细胞中肝细胞生长因子(HGF)和心功能的影响。方法 36只新西兰大白兔用简单随机抽样法分为3组:假手术组、慢性冬眠心肌组、缬沙坦组各12只。结扎冠状动脉左室支制备慢性冬眠心肌模型,在此基础上给予血管紧张素Ⅱ受体(AT1)的拮抗剂缬沙坦干预8周后,用多功能生理记录仪检测左心室功能,酶联免疫吸附法(ELISA)测定心肌组织中HGF含量,末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法(TUNEL)检测凋亡细胞。结果与假手术组比较,慢性冬眠心肌组左心室功能减退,心肌组织中HGF含量降低[(2.99±0.57)ng/g组织比(5.16±0.64)ng/g组织,P<0.01];与慢性冬眠心肌组比较,缬沙坦组心肌组织中HGF含量升高[(4.65±0.72)ng/g组织比(2.99±0.57)ng/g组织,P<0.01],细胞凋亡指数降低(99.45±17.32比120.129±15.97,P<0.01),且与心肌组织中HGF含量呈负相关(r=-0.666,P<0.01),缬沙坦可抑制慢性冬眠心肌组织间质纤维化,改善心功能(P<0.01)。结论慢性冬眠心肌中HGF含量降低,缬沙坦可保护缺血心肌。     

Obesity is associated with left atrial enlargement, E/A reversal and left ventricular hypertrophy

BACKGROUND AND OBJECTIVE     

Statin use is associated with improved function and survival of lung allografts

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are widely used antilipidemic agents that are also immunomodulatory. We evaluated possible effects of these agents after lung transplantation by comparing outcomes of 39 allograft recipients, who were prescribed statins for hyperlipidemia, with those of 161 contemporaneous control recipients who did not receive these drugs. Acute rejection (>or= Grade II) was less frequently found in the statin group (15.1 versus 25.6% of biopsies, p < 0.01). None of 15 recipients started on statins during postoperative Year 1 developed obliterative bronchiolitis, whereas the cumulative incidence of this complication among control subjects was 37% (p < 0.01). Total cellularity, as well as proportions of inflammatory neutrophils and lymphocytes, were significantly lower in bronchoalveolar lavages of statin recipients. Among double lung recipients, those taking statins had significantly better spirometry: FVC (80 +/- 2 versus 70 +/- 1%) and FEV1 (87 +/- 2 versus 70 +/- 1%), as percentages of predicted values, and absolute FEV1/FVC (83.4 +/- 1.2 versus 78.6 +/- 0.5) (all p < 0.01). The 6-year survival of recipients taking statins (91%) was much greater than that of control subjects (54%) (p < 0.01). These data suggest statin use may have substantial clinical benefits after pulmonary transplantation.     

Potential mechanisms of improved left ventricular function with enoximone in severe congestive heart failure

Enoximone, a phosphodiesterase inhibitor, is a potent inotropic vasodilator agent that causes a marked improvement in systemic hemodynamics in patients with severe chronic congestive heart failure. Cardiac index, stroke volume index and stroke work index increase, and there is a significant decrease in pulmonary capillary wedge pressure. Left ventricular dP/dt increases, despite a decrease in arterial pressure and systemic vascular resistance and without any significant change in heart rate, indicating a positive inotropic effect. A marked decrease in systemic vascular resistance indicates that decreased left ventricular outflow resistance resulting from peripheral vasodilation also contributes to improvement in left ventricular function. In some patients, left ventricular end-diastolic volume increases despite a marked decrease in pulmonary capillary wedge pressure, suggesting an improvement in apparent left ventricular compliance, which may also be contributory to improved left ventricular function.     

Polymorphonuclear neutrophils are a source of hepatocyte growth factor in patients with severe alcoholic hepatitis

BACKGROUND/AIMS: Hepatocyte growth factor (HGF) is a pleiotropic cytokine involved in liver regeneration. Plasma HGF levels correlate with survival and hepatocyte proliferation in alcoholic hepatitis (AH). As AH is accompanied by inflammation, neutrophilia and polymorphonuclear neutrophil (PMN) infiltration of the liver, we postulated that PMN could be a source of HGF in such patients. METHODS: We studied 25 patients with severe AH in comparison with 20 alcoholic cirrhotic patients without AH and 20 healthy controls; the impact of a 28-day course of corticosteroids was evaluated in patients with AH. RESULTS: On day 0, HGF plasma and homogenized liver tissue levels were markedly increased in AH patients as compared to controls. The role of PMN in HGF production during AH was confirmed by a significantly higher ex-vivo HGF production capacity of lipopolysaccharide-stimulated blood PMN from AH patients relative to both control groups. Formyl-Methionyl-Leucyl-Phenylalanine-induced PMN release of HGF (degranulation conditions) was also higher in AH patients. In this setting, we found that HGF release by PMN ex vivo correlated strongly with HGF plasma levels, and that the degree of hepatic PMN correlated strongly with hepatic HGF levels. HGF plasma levels and ex-vivo HGF release by PMN were unaffected by steroid therapy. CONCLUSIONS: These findings suggest that, by releasing HGF, PMN could participate in liver regeneration during severe alcoholic hepatitis.     

Expressions of molecules associated with hepatocyte growth factor activation after hepatectomy in liver cirrhosis

BACKGROUND/AIMS: The activation pathway of hepatocyte growth factor (HGF), including HGF activator (HGFA) and HGFA inhibitor-1, 2 (HAI-1, 2), has recently been clarified. The present study examined mRNA expressions of HGF, HGFA and HAI-1 following partial hepatectomy in normal and cirrhotic rats. METHODOLOGY: Liver cirrhosis was induced by intraperitoneal injections of dimethylnitrosamine. Two weeks after, the cirrhotic and normal rats underwent 70% hepatectomy and the liver regeneration rate, DNA synthesis of hepatocytes, plasma HGF level, and mRNA expressions of HGF, HGFA, and HAI-1 in the liver, spleen, and lung were examined at different times. RESULTS: Liver regeneration in the cirrhotic rats was deteriorated with a later peak of hepatocellular DNA synthesis. Hepatic HGF mRNA and splenic HAI-1 mRNA were upregulated and liver HGFA mRNA was downregulated in the cirrhotic rats. CONCLUSIONS: Insufficient HGF activation both by a reduced expression of hepatic HGFA and an increased expression of splenic HAI-1 may be one of the reasons for the impaired liver regeneration in cirrhosis.