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Hepatocyte growth factor: Studies on local and systemic release and effects during infectious disease; in vivo and in vitro
Linköping University, Department of Molecular and Clinical Medicine. Linköping University, Faculty of Health Sciences.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The interaction of mesenchymal and epithelial cells that occurs after organ injuries results in enhanced production of cytokines, such as hepatocyte growth factor (HGF). HGF is a glycoprotein with unique properties that contribute to wound healing after injuries. In the present thesis, the release and role of HGF during infectious diseases have been investigated with particular emphasis on pneumonia and meningitis. First, a standard method for serum handling of HGF was determined. It was shown that HGF was stable in the serum after separation and several freeze-thaw cycles, keeping at room temperature for several hours or storage at -70 °C for several months, shaking or adding heparin and albumin did not affect HGF levels in serum. However, for reliable results whole blood had to be separated within one hour after venipuncture at room temperature or kept at 4-8 °C in the case of longer storage before separation. Following this standard method, the concentration of HGF during infectious diseases was studied. In another study we had previously shown that levels of HGF in serum increased during the acute phase of several infectious diseases. In this thesis a simultaneous enhanced production of HGF locally at the site of injury was studied. It was shown that concentration of HGF increased locally in cerebrospinal fluid during meningitis. Levels of HGF were significantly higher during bacterial meningitis than viral meningitis and concentration of HGF in cerebrospinal fluid might be used as a tool in diagnosis of bacterial meningitis. It was shown an enhanced local production of HGF in exhaled breath condensate in pneumonia that did not decrease significantly after 4 weeks in spite of the fact that the patient had recovered clinically and in the X-ray controls. This might show a long repair and healing process after pneumonia. Serum levels of HGF were significantly higher in pneumonia caused by Streptococcus pneumoniae than in other causes of pneumonia. In pneumonia, serum levels ofHGF decreased within 48 hours after efficient antibiotic therapy was started and normalized at convalescence. However, the levels of HGF in serum increased when treatment was ineffective and no clinical improvement was observed. When the appropriate therapy was initiated, the levels of HGF decreased followed by clinical recovery. Serum levels of HGF were able to predict therapy results at least as reliably as CRP within 48 hours after treatment. Thus HGF was shown to be a diagnostic moment for acute bacterial infections, and following levels of HGF in serum may perhaps be used as a prognostic marker in the course of treatment of infectious diseases such as pneumonia. The physiological effects of HGF on chronic leg ulcers(> 1 år) in 11 elderly patients were studied and an enhanced microcirculation that was significantly correlated to the healing percentage was observed after local HGF treatment. The infected ulcers that received a combined treatment of HGF and appropriate antibiotic responded with a high percentage of healing in three patients with chronic leg ulcers that had not responded to other treatments (including antibiotics) previously. The effect of HGF on injured mouse melanoma cell monolayer was investigated in vitro and showed that HGF caused migration of neighbouring cells towards the nude injured area in a dose-dependent manner. Concomitant morphogenic effects were observed. The actin structure in the cytoskeleton was changed by HGF treatment as studied by confocal microscopy. According to these results it could be cocluded that injuries caused by infectious organisms enhance the local and systemic production of HGF. This might be beneficial in healing of damage after such injuries. Determination of natural HGF in serum might be used as a diagnostic and prognostic marker during infectious diseases. Exogenous administration of recombinant HGF could be a beneficial treatment for injuries such as chronic leg ulcers particularly combined with the appropriate antibiotic in the case of obvious infection.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2002. , 81 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 739
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26664Local ID: 11230ISBN: 91-7373-185-4 (print)OAI: oai:DiVA.org:liu-26664DiVA: diva2:247213
Public defence
2002-09-20, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-10Bibliographically approved
List of papers
1. Sample handling and stability of hepatocyte growth factor in blood samples
Open this publication in new window or tab >>Sample handling and stability of hepatocyte growth factor in blood samples
2002 (English)In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 19, no 4, 201-205 p.Article in journal (Refereed) Published
Abstract [en]

As regards clinical studies performed on hepatocyte growth factor (HGF) during recent years, we have aimed in the present study to investigate the eventual differences in sample handling of this cytokine that might influence the results of serum concentrations. Venous blood from patients with current infectious diseases and controls was used in different sub-studies. Compared with samples separated within one hour, no significant changes in serum HGF levels were observed when whole blood stayed 4, or 24 h at 6°C before or 6 h in room temperature after separation but HGF levels were significantly higher (P<0.01) when whole blood was kept at room temperature 4 and 24 h before separation. Serum HGF was stable up to 20 freeze-thaw cycles. The serum concentrations of HGF were significantly higher than levels in the plasma (19%; P<0.05). A significant increase in serum HGF levels (12%, P<0.05) was observed after shaking the whole blood sample to a visible haemolysis, although the HGF concentration in blood cells was around half of that in serum. HGF tolerated storage at −70°C for at least 4 months. We conclude that standardized methods in sample handling are important in the study of HGF concentrations in blood samples.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26446 (URN)10.1006/cyto.2002.1050 (DOI)10989 (Local ID)10989 (Archive number)10989 (OAI)
Note

On the day of the defence day the status of this article was in press.

Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13
2. Hepatocyte Growth Factor Levels in Cerebrospinal Fluid: A Comparison between Acute Bacterial and Nonbacterial Meningitis
Open this publication in new window or tab >>Hepatocyte Growth Factor Levels in Cerebrospinal Fluid: A Comparison between Acute Bacterial and Nonbacterial Meningitis
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2000 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 181, no 6, 2092-2094 p.Article in journal (Refereed) Published
Abstract [en]

The organotrophic functions of the hepatocyte growth factor (HGF) have been the subject of several studies. In the more recent studies, this function has been reported in the brain. In the present study, we have measured the levels of HGF in cerebrospinal fluid (CSF) and sera from 78 patients divided into 6 different groups according to central nervous system (CNS) infection and control. Quantitative measurements of HGF in the CSF and serum were performed by an enzyme-linked immunosorbent assay. Elevated values of CSF HGF were found in the patients with acute bacterial/probable bacterial meningitis (P < .001), compared with nonbacterial CNS infections and facial palsy, as well as with a control group without signs of CNS involvement. The values of CSF HGF were not correlated to blood-brain-barrier disruption in the groups. These observations might indicate an intrathecal production of HGF in acute bacterial/probable bacterial meningitis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25911 (URN)10.1086/315506 (DOI)10353 (Local ID)10353 (Archive number)10353 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
3. Hepatocyte growth factor may act as an early therapeutic predictor in pneumonia
Open this publication in new window or tab >>Hepatocyte growth factor may act as an early therapeutic predictor in pneumonia
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2002 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 34, no 7, 500-504 p.Article in journal (Refereed) Published
Abstract [en]

High serum levels of hepatocyte growth factor (HGF) may reflect the regenerative effect and enhanced local and systemic production of this cytokine after organ injuries. The possibility of using serial serum HGF values in order to predict the results of therapy for pneumonia was investigated in this study. In a prospective multicenter study we investigated the serum levels of HGF and CRP before and within 48 h after treatment in 70 patients with pneumonia. Serum levels of HGF before treatment were significantly higher than the HGF levels of a normal population (p < 0.0001). Within 48 h serum HGF levels had decreased significantly in those patients who ultimately responded to the initial antibiotic therapy (p < 0.0001). Serum HGF levels at 48 h were unchanged or increased in cases in whom the initial therapy was ineffective and had to be changed. CRP and HGF levels were significantly correlated. Using multivariate logistic regression analysis it was found that individual changes in acute serum HGF levels and serum HGF levels obtained within 48 h could predict the results of therapy at least as significantly (p < 0.003) as CRP (p = 0.05), although CRP levels were known and used by the physician to decide whether or not to change the initial therapy. We conclude that serial control of serum HGF levels can be used as an early indicator to predict the results of therapy during treatment of pneumonia.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26409 (URN)10.1080/00365540110080890 (DOI)10950 (Local ID)10950 (Archive number)10950 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. Exhaled breath condensate and serum levels of hepatocyte growth factor in pneumonia
Open this publication in new window or tab >>Exhaled breath condensate and serum levels of hepatocyte growth factor in pneumonia
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2002 (English)In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 96, no 2, 115-119 p.Article in journal (Refereed) Published
Abstract [en]

Hepatocyte growth factor (HGF) is a protein produced by mesenchymal cells in many organs, which can stimulate epithelial growth. An enhanced production and concentration of HGF is observed after injuries. The lung is one of the major sources of HGF. By cooling exhaled air, a condensate is formed containing molecules from bronchi and alveoli. In order to investigate HGF concentration and time course in pneumonia, paired serum and exhaled breath condensate was collected from 10 patients with pneumonia, 10 patients with non-respiratory infections and 11 healthy controls. The concentration of HGF was measured by an immunoassay kit. In the acute phase HGF-levels in breath condensate and serum were significantly higher in the patients with pneumonia compared to the control groups. Similar concentrations in breath condensate were seen in healthy controls and in patients with non-respiratory infections. In the patients with pneumonia a decrease in serum HGF was seen already after 4–7 days while HGF values in breath condensate remained elevated even after 4–6 weeks. These results might imply local production of HGF in the lungs and a long repair and healing process after pneumonia.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26447 (URN)10.1053/rmed.2001.1225 (DOI)10991 (Local ID)10991 (Archive number)10991 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
5. Hepatocyte growth factor may accelerate healing in chronic leg ulcers: a pilot study
Open this publication in new window or tab >>Hepatocyte growth factor may accelerate healing in chronic leg ulcers: a pilot study
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2002 (English)In: Journal of dermatological treatment (Print), ISSN 0954-6634, E-ISSN 1471-1753, Vol. 13, no 2, 81-86 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND : Hepatocyte growth factor (HGF) is a heparin-binding protein with mitogenic, motogenic and morphogenic activities for various cell types. The regenerative properties of HGF have been the object of several animal and in vitro studies in recent years.

OBJECTIVE : To investigate the physiological and therapeutic effects of HGF on chronic leg ulcers.

METHODS : HGF in gel form was locally applied, once daily for 7 days, to 15 of 19 chronic leg ulcers in 11 elderly patients. All patients had previously been treated by conventional methods and their leg ulcers had been in stable conditions for between 1 and 14 years. Any signs of allergy, discomfort or pain were reported daily. Microcirculation perfusion in the ulcers, compared to the intact contiguous skin, was determined by laser Doppler at the beginning of the study, after 1 week and again after 3 months (in seven patients). Ulcer size and characteristics were also documented.

RESULTS : It was observed that microcirculatory perfusion, which might reflect the angiogenic effect of HGF, was statistically significantly correlated ( r = 0.94, p < 0.002) to ulcer area reduction in the treated ulcers. Excellent (84-100% area reduction) or partial healing (58-59%) was seen in eight out of 11 patients. No control group was included in this pilot study, which must be completed by proper control studies.

CONCLUSION : This study suggests that HGF may heal chronic leg ulcers, possibly by improving the microcirculation. Proper control studies need to be performed.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-32893 (URN)10.1080/095466302317584449 (DOI)18838 (Local ID)18838 (Archive number)18838 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
6. Hepatocyte growth factor accelerates restitution of damaged mouse melanocyte monolayer in vitro
Open this publication in new window or tab >>Hepatocyte growth factor accelerates restitution of damaged mouse melanocyte monolayer in vitro
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

In a recent pilot study we observed enhanced wound repair properties in chronic leg ulcers after HGF administration. The aim of the present study was to assess the mechanism of HGF in the wound-healing process by an in vitro study of HGF on a transformed mouse skin epithelial cell line (CCL-53. 1) that expresses the HGF receptor, c-Met. HGF did not enhance cell proliferation, judged by [3H}thymidine incorporation. The restitution of injured epithelial cells was significantly increased by HGF. This effect was dose-dependant, beginning at low concentrations (1ng/ml) of HGF, and was inhibited by heparin. HGF enhanced migration of epithelial cells compared to untreated controls. The actin structure was changed by HGF, with less F-actin in the dense peripheral structures compared to untreated cells. Corresponding morphological changes in cells were found showing spread morphology with smaller intracellular spaces after HGF addition. We conclude that HGF may contribute to restitution of the damaged mouse epithelial cell monolayer by morphologic changes and enhanced motility of cells towards the injured area.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81260 (URN)
Available from: 2012-09-10 Created: 2012-09-10 Last updated: 2012-09-10

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