Hepatocyte Growth Factor Content Research Articles

THE EFFECT OF AUTOMESOCONCENTRATE OF PLATELETS ON THE STAGES OF REGENERATION OF THE LIVER REMNANT OF RATS UNDER THE CONDITIONS OF PERFORMING VOLUMETRIC EXPERIMENTAL LIVER RESECTIONS

Introduction. Liver regeneration occurs in three stages, each of which is regulated by different factors: the initiation phase is regulated by interleukin 6 (IL-6) and tumor necrosis factor (TNFα); expansion phase – by hepatocyte growth factor (HGF) and transforming growth factor alpha (TGFα); the terminal phase – transforming growth factor beta (TGFβ) and activins. The work determined the level of markers of the main stages of liver regeneration after resection of 65-70% of the parenchyma of this organ in rats under the conditions of using different doses and schemes of administration of automesoconcentrate of platelets (AMС). The purpose of the study is to establish the characteristics of changes in the level of cytokines and growth factors in the homogenate of the liver of rats after resection of 65-70% of the parenchyma of this organ under the conditions of the use of different doses and schemes of AMС administration.
 Materials and methods. The study was conducted on white Wistar rats aged 1.5-2 months, weighing 150-180 g. AMС was injected: into the parenchyma of the liver remnant during resection at a dose of 0.5 ml/kg (group I); into the tail vein in the postoperative period at a dose of 0.5 ml/kg 3 hours and 48 hours after liver resection (group II); into the tail vein in the postoperative period at a dose of 1.0 ml/kg 3 hours and 48 hours after resection.
 Research results and discussion. It was shown that on the 7th day after liver resection, the level of TNF-α and IL-6 increased in all experimental groups, followed by a decrease on the 10th day to control values in the group of animals that received AMA intravenously at a dose of 1 ml/kg masses of animals. It was established that the values of HGF and TGFα in the liver homogenate of animals that underwent liver resection were significantly higher than in the control group on the 7th day of the experiment. At the later stages of the experiment, a decrease in the levels of HGF and TGFα in the liver homogenate was observed in the animals of groups I and III, but the studied indicators did not reach control values. In animals of group II, indicators of HGF and TGFα content remained at the highest level. The increase in the content of TGFβ and activins in the homogenate of the liver of rats in all experimental groups indicates the intensification of the terminal phase of liver regeneration on the 10th day after liver resection.
 Conclusions. Therefore, under the action of a dose of АМС equal to 1 ml/kg, the regeneration processes occur most intensively, the peak of which occurs 7-10 days after the resection. Administration of AMA into the liver parenchyma at a lower dose of 0.5 ml/kg or intravenous administration of the same dose does not contribute to the complete restoration of regenerative processes in the liver, as indicated by increased levels of TGFα and HGF on the 10th day after liver resection and administration of AMA.

Circulating Hepatocyte Growth Factor Reflects Activation of Vascular Repair in Response to Stress

Hepatocyte growth factor (HGF) is released by stressed human vascular cells and promotes vascular cell repair responses in both autocrine and paracrine ways. Subjects with a low capacity to express HGF in response to systemic stress have an increased cardiovascular risk. Human atherosclerotic plaques with a low content of HGF have a more unstable phenotype. The present study shows that subjects with a low abilityto express HGF in response to metabolic stress have an increased risk to suffer myocardial infarction and stroke.

Lipopolysaccharide-preconditioned allogeneic adipose-derived stem cells improve erectile function in a rat model of bilateral cavernous nerve injury

BackgroundErectile dysfunction (ED) often occurs due to cavernous nerve injury (CNI) after colorectal surgery. Cell-based therapies have great potential for the treatment of CNI-related ED; however, it needs to be optimised. In this study, we explored the therapeutic effects of lipopolysaccharide-preconditioned allogeneic adipose-derived stem cells (L-ADSCs) on CNI-induced ED in rats.ResultsThe results of this in vitro study revealed that low-dose lipopolysaccharide could increase the viability of ADSCs, inhibit caspase 3 activation induced by hydrogen peroxide and promote cell migration. Compared with the ADSC supernatant, the L-ADSC supernatant could better reduce fibrosis in the corpus cavernosum smooth muscle cells induced by transforming growth factor-beta 1 protein. In the in vivo study, it was compared to ADSCs therapy, where the L-ADSCs therapy indicated that could better improve erectile function by increasing smooth muscle content and alleviating penile fibrosis in rats 2 weeks after CNI. The outcome may be related to the increase in the hepatocyte growth factor content in the corpus cavernosum and myelin basic protein in the major pelvic ganglion.ConclusionsL-ADSC treatment may be a promising approach for restoring erectile function after CNI.

Circulating Hepatocyte Growth Factor Reflects Activation of Vascular Repair in Response to Stress

Background: Acute cardiovascular events arise when the arterial wall fails to repair the damage caused by cardiovascular risk factors. Hepatocyte growth factor (HGF) stimulates growth of vascular cells but has been associated with increased risk of cardiovascular disease (CVD) in epidemiological studies. Here we tested the hypothesis that this association reflects activation of a protective vascular repair response. Methods: Small interfering RNA (siRNA) and recombinant human HGF were used to assess the role of HGF in regulation of human umbilical cord endothelial and coronary artery smooth muscle cell proliferation, migration and viability. Proximity extension assay was used to determine HGF and other biomarkers in 4742 subjects participating in the Malmo Diet and Cancer study and in extracts of 200 human carotid plaques. Findings: HGF promoted migration, proliferation and survival of human endothelial and smooth muscle cells. Human atherosclerotic plaques with a high content of HGF had a more stable phenotype. Cultured vascular cells expressed HGF in response to stress. Plasma HGF correlated with circulating levels of cellular stress biomarkers such as soluble TRAIL receptor-2 and caspase-8. Decreased ability to respond with elevated HGF levels to cellular stress, as assessed by the ratios of HGF to soluble TRAIL receptor-2 and caspase-8, associated with increased risk of cardiovascular events during a follow-up period of 19.4±5.0 years. Interpretations: These findings provide support for a protective role of HGF in CVD and show that subjects with a low ability to express HGF in response to stress have an increased risk of cardiovascular events. Funding Information: The work was supported by the Swedish Society for Medical Research, Emil and Wera Cornell foundation, Hjelt foundation, the Swedish Research Council, the Swedish Foundation for International Cooperation in Research and Higher Education, Crafoord foundation, the Swedish Medical Society, Diabetes foundation, Swedish Heart and Lung Foundation, Diabetes Research and Wellness foundation, Albert Pahlssons foundation, SUS foundations and funds, Lund University Infrastructure grant ”Malmo population-based cohorts” (STYR 2019/2046) and Lund University Diabetes Center (Swedish Research Council - Strategic Research Area Exodiab Dnr 2009-1039 and the Swedish Foundation for Strategic Research Dnr IRC15-006). Declaration of Interests: None. Ethics Approval Statement: All studies were approved by the respective Regional Ethical Review Boards and conducted in accordance with the Helsinki Declaration. All subjects gave written consent.

Changes in direct markers of liver fibrosis in patients with steatohepatitis non-alcoholic and alcoholic origin on the background of obesity and pathology of the biliary tract

The aim of this work is to investigate the direct markers of liver fibrosis (LF) in patients with steatohepatitis non-alcoholic and alcoholic origin in combination with obesity (OB) and pathology of the biliary tract (BT).Materials and Methods. We examined 30 patients with steatohepatitis of different etiology, in 15 patients of them was non-alcoholic steatohepatitis (NASH) and 15 had alcoholic steatohepatitis (ASH). The control group consisted of 15 practically healthy persons (PHP). Direct markers of fibrosis – matrix metalloproteinase-1 (MMP-1), laminin (LN), hepatocyte growth factor (HGF) were determined by ELISA.Results. In all groups of patients we found a significant decrease in MMP-1 1.7 times in NASH (p < 0.001) and 1.6 times at ASH in comparison with the reference values of PHP (p < 0.05). It has been defined the increase in the content of LN 1.8 times in the NASH group in relation to PHP (p < 0.001). A high level of LN was observed in the group of ASH and increased in 2.2 times compared with PHP (p < 0.001) and 1.2 times compared with NASH patients (p < 0.001). The content of HGF was reduced compared with control 1.5-fold and 1.6-fold respectively, in NASH and ASH (p < 0.001 for all comparisons).Conclusions. It has been established that reduced levels of MMP-1 and increased levels of LN indicated the progression of LF in patients with steatohepatitis with more pronounced progression during the ASH. It has been proved that the elevated level of LN and reduced level of HGF, coupled with the presence of non-alcoholic or alcoholic factor, had made a significant contribution to the development of LF in patients with NASH and ASH in combination with theOB and pathology of BT.

Circulating Betatrophin and Hepatocyte Growth Factor in Type 2 Diabetic Patients: Their Relationship With Disease Prognosis

Background: In Saudi Arabia, diabetes established itself as an epidemic that necessitates dissection of its predisposing factors and pathogenesis to set appropriate preventive measures. In a cross-sectional study, relationships between plasma betatrophin (BetaT) and hepatocyte growth factor (HGF) on one side, and, glycemic control, lipogram, anthropometric indices, treatment and prognosis on the other side were assessed in Saudi patients with type 2 diabetes mellitus (T2DM) vs. healthy controls. Methods: The study voluntarily enrolled 202 T2DM patients (44 males and 158 females) and socioeconomically, age- and body mass index (BMI)-matched 106 healthy participants (71 males and 35 females). All participants were subgrouped according to gender and BMI ( = 25) and patients were also subgrouped according to disease duration ( 5 years) and treatment (insulin/non-insulin). Demographic and anthropometric data were anonymously collected. EDTA whole blood for HbA1c and its plasma for bioassays were frozen at -80 °C. Standard procedures and specific immunoassays were employed for biomarkers. Results: Plasma insulin paralleled BMI and disease duration and was highly significantly different comparing patients and healthy controls. As expected glycemic control and lipogram indices were also highly significantly different comparing patients and healthy controls. Because of the massive individual variation in the plasma levels of each of betatrophin (except for a higher level in patients with lower BMI) and HGF (except for a higher level in females and those with higher BMI among controls), there were non-significant differences comparing patients and healthy controls. Males were more inclined to have more insulin treatment. Surprisingly, the later doubled the disease severity complication score and correlated negatively with plasma HDL-cholesterol. Betatrophin did not show much correlation among controls but correlated negatively with age and cholesterol and positively with BMI and HbA1c in patients. HGF showed very clear negative correlation with age and plasma insulin in patients. Conclusion: The massive individual variation in plasma content of betatrophin and HGF did allow specific diagnostic/pathogenetic classification for these two hepato-/adipokines. This may reflect gene polymorphism at their gene regulatory sequences and/or resistance correlating insulin resistance. The former is being pursued in our laboratory for patients with distinctly higher and lower levels. J Endocrinol Metab. 2017;7(1):31-43 doi: https://doi.org/10.14740/jem405w

Circulating Betatrophin and Hepatocyte Growth Factor in Type 2 Diabetic Patients: Their Relationship With Disease Prognosis

Background: In Saudi Arabia, diabetes established itself as an epidemic that necessitates dissection of its predisposing factors and pathogenesis to set appropriate preventive measures. In a cross-sectional study, relationships between plasma betatrophin (BetaT) and hepatocyte growth factor (HGF) on one side, and, glycemic control, lipogram, anthropometric indices, treatment and prognosis on the other side were assessed in Saudi patients with type 2 diabetes mellitus (T2DM) vs. healthy controls. Methods: The study voluntarily enrolled 202 T2DM patients (44 males and 158 females) and socioeconomically, age- and body mass index (BMI)-matched 106 healthy participants (71 males and 35 females). All participants were subgrouped according to gender and BMI (< 25 and >= 25) and patients were also subgrouped according to disease duration (<= 5 and > 5 years) and treatment (insulin/non-insulin). Demographic and anthropometric data were anonymously collected. EDTA whole blood for HbA1c and its plasma for bioassays were frozen at -80 °C. Standard procedures and specific immunoassays were employed for biomarkers. Results: Plasma insulin paralleled BMI and disease duration and was highly significantly different comparing patients and healthy controls. As expected glycemic control and lipogram indices were also highly significantly different comparing patients and healthy controls. Because of the massive individual variation in the plasma levels of each of betatrophin (except for a higher level in patients with lower BMI) and HGF (except for a higher level in females and those with higher BMI among controls), there were non-significant differences comparing patients and healthy controls. Males were more inclined to have more insulin treatment. Surprisingly, the later doubled the disease severity complication score and correlated negatively with plasma HDL-cholesterol. Betatrophin did not show much correlation among controls but correlated negatively with age and cholesterol and positively with BMI and HbA1c in patients. HGF showed very clear negative correlation with age and plasma insulin in patients. Conclusion: The massive individual variation in plasma content of betatrophin and HGF did allow specific diagnostic/pathogenetic classification for these two hepato-/adipokines. This may reflect gene polymorphism at their gene regulatory sequences and/or resistance correlating insulin resistance. The former is being pursued in our laboratory for patients with distinctly higher and lower levels. J Endocrinol Metab. 2017;7(1):31-43 doi: https://doi.org/10.14740/jem405w

Autologous adipose tissue‑derived mesenchymal stem cells are involved in rat liver regeneration following repeat partial hepatectomy.

Adipose tissue-derived mesenchymal stem cells (ADSCs) have been considered to be attractive and readily available adult mesenchymal stem cells, and they are becoming increasingly popular for use in regenerative cell therapy, as they are readily accessible through minimally invasive techniques. The present study investigated whether autologous ADSC transplantation promoted liver regeneration following a repeat partial hepatectomy in rats. The rats were divided into three groups as follows: 70% partial hepatectomy (PH) group; repeat PH (R-PH) group and R-PH/ADSC group, subjected to R-PH and treated with autologous ADSCs via portal vein injection. In each group, the rats were sacrificed at different time points postoperatively in order to evaluate the changes in liver function and to estimate the liver regenerative response. The expression of proliferating cell nuclear antigen (PCNA) labeling index in the liver was measured using immunohistochemistry. The expression levels of hepatocyte growth factor (HGF) mRNA were measured using reverse transcription polymerase chain reaction. The results showed that regeneration of the remaining liver following R-PH was significantly promoted by ADSC transplantation, as shown by a significant increase in liver to body weight ratio and the PCNA labeling index at 24 h post-hepatectomy. Additionally, ADSC transplantation markedly inhibited the elevation of serum levels of alanine aminotransferase, aspartate aminotransferase and total bilirubin, increased HGF content and also attenuated hepatic vacuolar degeneration 24 h postoperatively. Furthermore, the liver was found to almost fully recover from hepatocellular damage due to hepatectomy among the three groups at 168 h postoperatively. These results indicated that autologous ADSC transplantation enhanced the regenerative capacity of the remnant liver tissues in the early phase following R-PH.

Clinical significance of joint detection of serum VEGF, SIL-2R and HGF in patients with primary hepatocellular carcinoma before and after percutaneous microwave coagulation therapy.

To investigate the changes of serum vascular endothelial growth factor (VEGF), soluble interleukin-2 receptor (SIL-2R) and hepatocyte growth factor (HGF) contents in patients with primary hepatocellular carcinoma (HCC) before and after percutaneous microwave coagulation therapy (PMCT) and determine their clinical significance. Fasting venous blood (3 mL) from 81 patients with primary HCC diagnosed by pathology was collected in the mornings 1 day before PMCT, and 1 day, 7 days and 1 month after PMCT, and then the serum was separated and stored in -70°. The contents of VEGF, SIL-2R and HGF were detected by enzyme linked immunosorbent assay (ELISA). The serum VEGF, SIL-2R and HGF contents in 81 patients with primary HCC had obviously dynamic changes before and after PMCT. By comparison to 1 day after PMCT with pre-operation, there was no statistical significance regarding VEGF and SIL-2R contents (P>0.05), but HGF content showed significant difference (P<0.01). Compared with pre-operation, VEGF, SIL-2R and HGF contents 7 days and 1 month after PMCT all manifested significant differences (P<0.01). By comparison to 7 days with 1 month after PMCT, there was no statistical significance regarding the VEGF content (P>0.05), whereas SIL-2R and HGF contents showed significant change (P<0.01). The contents of serum VEGF, SIL-2R and HGF have obviously dynamic changes in primary HCC before and after PMCT, and their joint detection is expected to be an effective hematologic evaluation index of PMCT for primary HCC.

Evaluation of two decellularization methods in the development of a whole‐organ decellularized rat liver scaffold

Hepatic tissue engineering is considered as a possible alternative to liver transplantation for end-stage liver disease. Several methods of decellularization of xenogeneic liver are available to produce three-dimensional organ scaffolds for engineering liver tissues. However, rare studies have examined and compared the effectiveness of different methods on the structure and composition of intact decellularized liver extracellular matrix. Two decellularization methods were adopted herein. Their effects on collagen, elastin, glycosaminoglycans (GAGs), hepatocyte growth factor (HGF) content and influence to the function of hepatocytes cultured in scaffolds were examined and compared. The complete tissue decellularization was successfully achieved after treatment with sodium dodecyl sulphate (SDS) and Triton X-100. The total absence of nuclear structures and removal of viable cells were confirmed by haematoxylin-eosin staining and scanning electron microscopy. Collagen was preserved after both treatments. However, the elastin content decreased to about 20% and 60%, the GAGs content decreased to about 10% and 50% and the HGF content decreased to about 20% and 60% of the native liver level after SDS and Triton X-100 treatment respectively. The Triton X-100-treated scaffolds were much superior than SDS-treated scaffolds in supporting liver-specific function, including albumin secretion (P = 0.001), urea synthesis (P = 0.002), ammonia elimination (P = 0.007) and mRNA expression levels of drug metabolism enzymes. This study suggested that liver extracellular matrix scaffolds constructed using perfusion of Triton X-100 as described herein might provide a more effective and ideal material for the usage in tissue engineering and regenerative medicine approaches.

An Antithrombin III product containing biologically active hepatocyte growth factor may be beneficial in deep ulcer infections

BackgroundWidely studied for the past 20years, hepatocyte growth factor (HGF) has been identified as a regenerative marker and an important factor in the development and healing of injuries. Antithrombin III (AT III) is a protein in the blood stream with anti-thrombotic and anti-inflammatory properties and has been used as an adjuvant treatment along with antibiotics in severe sepsis. ObjectiveTo study the content and properties of HGF in plasma-derived AT III products, and the regenerative effect in severe deep ulcer infections. MethodsCommercial AT III products were analyzed for the presence and biological activity of HGF. One AT III product containing biologically active HGF was used to treat 18 cases of critical, deep ulcer infections scheduled for major invasive intervention. The patients were followed up for 6–60months. ResultsThe AT III products contained HGF with different biological activity. No adverse reactions were observed after local administration of AT III during the study or follow-up period. In 16 of 18 cases no surgical intervention was needed within the first 6month of inclusion. ConclusionAT III products containing biologically active HGF may contribute to regeneration and healing in severe deep ulcer infections which do not respond adequately to different combinations of antibiotics alone.

Serum hepatocyte growth factor and interleukin-6 as prognostic markers for stage III non-small cell lung cancer.

10542 Background: We surveyed prognostic biomarkers for resectable non-small cell lung cancer (NSCLC). Methods: We obtained preoperative serum from 109 patients admitted to our facility, and measured the levels of hepatocyte growth factor (HGF), interleukin-6 (IL-6), and nicotinamide N–methytransferase (NNMT) in the sera by the ELISA method. We also examined the clinical backgrounds of the patients. Results: The median HGF and IL-6 contents in sera from 109 patients were 860 pg/ml and 2.7 pg/ml, respectively. Analysis of survival curves indicated that HGF or IL-6 levels higher than the median were associated with poor overall survival (HGF, P = 0.019; IL-6, P = 0.002). On the other hand, carcinoembryonic antigen (CEA), a known tumor marker, and NNMT, which we found to be a candidate tumor marker, exhibited no correlation with the prognosis. The tumor status (pT factor) and stage were strong prognostic indicators (P &lt; 0.001). In addition, we analyzed stage III lung cancer alone. Higher HGF or IL-6 levels were associated with poor overall survival (HGF, P = 0.016; IL-6, P = 0.013). Disease-free survival was also affected by these cytokine contents, but not statistically significantly. The prognosis of patients with adenocarcinomas (ADC) was better than that of patients with other histological types. However, the pT factor and nodal status (pN factor) were not associated with the survival of stage III patients. Conclusions: The levels of HGF and IL-6 in serum could be useful prognostic indicator of the survival of stage III NSCLC patients undergoing surgery and chemotherapy.

Hepatocyte growth factor in cerebrospinal fluid is associated with mortality and recurrence of glioblastoma, and could be of prognostic value

Malignant gliomas--glioblastoma multiforme and anaplastic astrocytoma--are among the most fatal forms of cancer in humans. It has been suggested that hepatocyte growth factor (HGF) is a reliable predictor of glioma malignancy; amounts of HGF are directly related to cellular proliferation, angiogenesis, low apoptotic rate, and poor prognosis (WHO III and IV). We measured the HGF content of cerebrospinal fluid (CSF) from patients with malignant glioma glioblastoma multiforme (WHO IV; n = 14), anaplastic astrocytoma (WHO III; n = 4), and meningioma (WHO I; n = 9), and from control subjects (n = 25), and found a high concentration of HGF in patients with malignant glioma. However, CSF concentrations from glioblastoma multiforme and anaplastic astrocytoma patients were not statistically significantly different (893 +/- 157 vs. 728 +/- 61, respectively; P > 0.01). A negative correlation between HGF and survival was found at five years of follow-up (R = -0.922, R (2) = 0.850, P < 0.001). Also, the HGF concentration in CSF was a reliable means of explaining the highly variable survival of patients with malignant glioma. CSF concentrations of HGF higher than 500 pg/ml were associated with increased mortality whereas values higher than 850 pg/ml were associated with a brief tumor-free period after surgery (9 +/- 0.6 vs. 6 +/- 0.6 months, respectively, P < 0.001). Our findings support the idea that measurement of HGF in CSF could be a useful tool for monitoring the biological activity of malignant glioma. The findings will ultimately need to be confirmed in a much larger study.

Immunolocalization of the hepatocyte growth factor (HGF) system in the rat ovary and the anti-apoptotic effect of HGF in rat ovarian granulosa cells in vitro

Hepatocyte growth factor (HGF) regulates granulosa cell (GC) steroidogenesis and suppresses apoptosis in non-ovarian cells. The hypothesis was thus developed that intraovarian HGF supports folliculogenesis by mediating steroidogenesis and suppressing apoptosis. To investigate the latter, the anti-apoptotic actions of HGF were tested in GCs and follicles isolated from immature rats. Results showed that HGF suppressed apoptosis in GC and follicle cultures as visualized using apoptosis indicator dye, YO-PRO-1. Immunohistochemistry was used to investigate the distribution of HGF, c-met, and HGF activator (HGFA) protein during folliculogenesis in equine chorionic gonadotropin (eCG)-primed rats. Immunoreactive HGF content was the greatest in GCs within preantral follicles. Following eCG, large antral follicles showed elevated HGF staining in theca and interstitial cells when compared with GCs. Intense c-met staining was observed in GCs within non-primed small preantral follicles; following eCG, the level of c-met was diminished in GCs, but increased within theca and interstitial cells. Theca, interstitium, and GCs in non-primed and primed ovaries contained HGFA. Following eCG, HGFA was more apparent in theca cells and the interstitium when compared to that in GCs within large antral follicles. The presence of HGF, c-met, and HGFA in preantral follicles would potentially enable the anti-apoptotic effects of HGF that were observed in vitro to occur in vivo. Advanced folliculogenesis led to a change in the cellular distribution of the HGF, c-met, and HGFA, suggesting that the ovarian HGF system is hormonally regulated in vivo.

Hepatocyte Growth Factor in Mouse Soleus Muscle Increases with Reloading after Unloading

Hepatocyte growth factor (HGF) has been suggested as a mitogen for skeletal muscle satellite cells and participates in skeletal muscle hypertrophy. The present study assessed HGF levels in mouse soleus and plantaris muscles during 14 days of tail suspension and 3 days of reloading using the enzyme-linked immunosorbent assay. Immunohistochemical analyses were used to determine the locations of HGF, its receptor (c-Met) and proliferating cell nuclear antigen. In normal mice, HGF contents were 4.4 ± 0.5 ng/g tissue in the soleus muscle and 5.9 ± 1.2 ng/g tissue in the plantaris muscle, significantly higher than in the soleus muscle. HGF level in the soleus muscle was increased 314% from normal by reloading. HGF and c-Met were expressed in small cells contiguous to muscle fibers. Cells in similar positions displayed reactivity for PCNA, suggesting that these represent activated satellite cells. Thus, production of HGF protein appears to stimulated in satellite cells during recovery from disuse atrophy.

The role of hepatocyte growth factor in the humoral regulation of inguinal hernia closure

Background Calcitonin gene–related peptide (CGRP) is proposed to indirectly cause inguinal hernia closure via hepatocyte growth factor (HGF). Studies have shown that CGRP and HGF cause processus vaginalis (PV) fusion in vitro. We localized the HGF receptor in the PV and tested whether CGRP was responsible for HGF release. Method Hernial sacs collected from 20 children (15 males, 4 females, 1 XY female) undergoing inguinal hernia repair were immunohistochemically stained for HGF receptor (c-met). Parietal peritoneum was stained for comparison. Hernial sacs from another 16 children (12 males, 4 females), with each sac divided into 4, were cultured, with and without CGRP, for 24 and 48 hours. Hepatocyte growth factor content was then assayed in the culture medium (4/16 children) and tissue extracts (12/16 children), using enzyme-linked immunosorbent assay. Children were aged 1 month to 10 years. Data were analyzed using paired Student t tests. Results C-met localized to the PV epithelial surface in 17 of 20 hernial sacs and in the parietal peritoneum. Hepatocyte growth factor levels increased over time in 4 of 4 culture medium assays, with a significant difference in 1 of 4. Seven of 12 tissue extract assays had significant differences; however, 3 of 7 had decreased HGF levels. Conclusion The presence of HGF receptors in the PV is consistent with a role for HGF in triggering epithelial-mesenchymal transformation during inguinal hernia closure. The presence of HGF receptors in the parietal peritoneum suggests that regulation of this process is complex. Enzyme-linked immunosorbent assay results indicate that, in a subset of patients, exogenous CGRP may be responsible for HGF elevation and potentially implicates deficient endogenous CGRP as one cause for inguinal hernia patency.

Cigarette Smoking Induces Overexpression of Hepatocyte Growth Factor in Type II Pneumocytes and Lung Cancer Cells

We examined gene expression of hepatocyte growth factor (HGF) and HGF receptor (HGFR), or product of proto-oncogene c-met (c-met), in smokers and nonsmokers with adenocarcinoma (ADC) by suppression subtractive hybridization and microarray techniques. Expression of HGF and c-met was confirmed by RT-PCR. HGF content in the respective tumor mass and nontumor lung tissue was measured by ELISA. HGF in pathologic samples was localized by immunohistochemistry and in situ hybridization. Our results indicate that overexpression of HGFR was frequently detected in ADC cells, whereas overexpression of HGF was detected in alveolar type II (ATII) cells. Overexpression of HGF was correlated with cigarette smoking and tumor stages. In vitro, HGF expression was evaluated in isolated murine ATII cells and in 12 ADC cell lines, and we found that nicotine activated HGF expression in ATII cells and lung cancer cells.

Defect of hepatocyte growth factor production by fibroblasts in human pulmonary emphysema

Pulmonary emphysema results from an excessive degradation of lung parenchyma associated with a failure of alveolar repair. Secretion by pulmonary fibroblasts of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) is crucial to an effective epithelial repair after lung injury. We hypothesized that abnormal HGF or KGF secretion by pulmonary fibroblasts could play a role in the development of emphysema. We measured in vitro production of HGF and KGF by human fibroblasts cultured from emphysematous and normal lung samples. HGF and KGF production was quantified at basal state and after stimulation. Intracellular content of HGF was lower in emphysema (1.52 pg/mug, range of 0.15-7.40 pg/mug) than in control fibroblasts (14.16 pg/mug, range of 2.50-47.62 pg/mug; P = 0.047). HGF production by emphysema fibroblasts (19.3 pg/mug protein, range of 10.4-39.2 pg/mug) was lower than that of controls at baseline (57.5 pg/mug, range of 20.4-116 pg/mug; P = 0.019) and after stimulation with interleukin-1beta or prostaglandin E(2). Neither retinoic acids (all-trans and 9-cis) nor N-acetylcysteine could reverse this abnormality. KGF production by emphysema fibroblasts (5.3 pg/mug, range of 2.2-9.3 pg/mug) was similar to that of controls at baseline (2.6 pg/mug, range of 1-6.1 pg/mug; P = 0.14) but could not be stimulated with interleukin-1beta. A decreased secretion of HGF by pulmonary fibroblasts could contribute to the insufficient alveolar repair in pulmonary emphysema.

Helicobacter pylori eradication treatment modulates epithelial cell proliferation and tissue content of hepatocyte growth factor in the gastric mucosa.

Although Helicobacter pylori infection is now acknowledged as a major promoter of gastric cancer in humans, the carcinogenetic process of this effect has not been fully elucidated. Precancerous lesions such as intestinal metaplasia, enhanced proliferation of epithelial cells and elevated level of growth factors have been postulated to play a role. To analyse a relationship between gastric mucosal proliferation, mucosal content of hepatocyte growth factor and prevalence of intestinal metaplasia before and after successful H. pylori eradication therapy. We evaluated 25 H. pylori-eradicated patients. At initial endoscopic examination, two biopsy tissue samples each were obtained from the antrum and great curvature of the corpus. Tissue content of hepatocyte growth factor and neutrophil myeloperoxidase were measured using an ELISA method, and histological assessment of intestinal metaplasia (haematoxylin and eosin) and proliferating cells (Ki-67 immunostaining) was performed. The patients were treated with a 1-week course of triple therapy. At 10 months after successful eradication, biochemical and histological assessments were repeated. Among all patients (n = 25), no intestinal metaplasia was detected in the corpus mucosa, but was observed in 10 patients (40%) in the antrum. This prevalence ratio was not changed after eradication. A slight decrease in HGF content was demonstrated in both sites, but the level of antral hepatocyte growth factor was significantly decreased in patients with intestinal metaplasia but not in those without. Proliferative index (Ki-67 positive cells/epithelium) was decreased after eradication therapy in both sites. An increase in proliferative index was observed in the antrum with intestinal metaplasia compared with that without, which significantly decreased after eradication therapy. H. pylori eradication therapy in the present study afforded an inhibitory effect on epithelial cell proliferation and on the mucosal content of HGF.

H.pylori-eradication reduces tissue content of hepatocyte growth factor (HGF) in the antral mucosa with intestinal metaplasia

H.pylori-eradication reduces tissue content of hepatocyte growth factor (HGF) in the antral mucosa with intestinal metaplasia