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The role of peridontitis and hepatocyte growth factor in systemic inflammation
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

An essential goal in addressing inflammation is the return of tissue to homeostasis. Persistent infections often cause prolonged response and accumulation of immune cells, inducing imbalance in pro- and anti-inflammatory mediators, tissue destruction, and chronic inflammation. In periodontal disease, bacteria of the dental plaque are the primary aetiologic agents. Coronary artery disease (CAD) and chronic renal failure (CRF) are associated with periodontitis and involve systemic inflammation with atherosclerotic and fibrotic processes. The aims of this thesis were to study the effect of the bacterium Porphyromonas gingivalis and the anti-inflammatory mediator lipoxin A4 (LXA4) on blood cells in vitro, as well as to measure the expression of hepatocyte growth factor (HGF) in patients with periodontitis, CAD, and CRF. We found that LXA4 inhibits P. gingivalis–induced leukocyte platelet aggregation and reactive oxygen species (ROS) production in whole blood, by antagonizing the upregulation of CD11b/CD18 on leukocytes. The serum concentration of HGF was elevated in patients with periodontitis, CAD and CRF, indicating a systemic inflammation. However, the biological activity of HGF was reduced in serum from CRF patients and in saliva and gingival crevicular fluid of patients with periodontitis. This finding correlated with reduced growth of gingival epithelial cells incubated with saliva from patients with periodontitis. Neutrophil proteases reduced the biological activity of HGF in patients with CRF, and HGF expression in patients with periodontitis was associated with higher concentration and numbers of species of periodontal bacteria. In conclusion, these studies suggest that systemic spreading of periodontal bacteria, leukocyte-platelet activation and disturbed HGF-expression are crucial components involved in tissue degradation and progression of chronic inflammation.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2013. , p. 86
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 83
Keywords [en]
Hepatocyte growth factor, Porphyromonas gingivalis, periodontitis, systemic inflammation, coronary artery disease, chronic renal failure, lipoxin
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-28541ISBN: 978-91-7668-922-6 (print)OAI: oai:DiVA.org:oru-28541DiVA, id: diva2:614188
Public defence
2013-05-08, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-04-03 Created: 2013-04-03 Last updated: 2017-10-17Bibliographically approved
List of papers
1. Lipoxin A(4) inhibits porphyromonas gingivalis-induced aggregation and reactive oxygen species production by modulating neutrophil-platelet interaction and CD11b expression
Open this publication in new window or tab >>Lipoxin A(4) inhibits porphyromonas gingivalis-induced aggregation and reactive oxygen species production by modulating neutrophil-platelet interaction and CD11b expression
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2011 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 4, p. 1489-1497Article in journal (Refereed) Published
Abstract [en]

Porphyromonas gingivalis is an etiological agent that is strongly associated with periodontal disease, and it correlates with numerous inflammatory disorders, such as cardiovascular disease. Circulating bacteria may contribute to atherogenesis by promoting CD11b/CD18-mediated interactions between neutrophils and platelets, causing reactive oxygen species (ROS) production and aggregation. Lipoxin A(4) (LXA(4)) is an endogenous anti-inflammatory and proresolving mediator that is protective of inflammatory disorders. The aim of this study was to investigate the effect of LXA(4) on the P. gingivalis-induced activation of neutrophils and platelets and the possible involvement of Rho GTPases and CD11b/CD18 integrins. Platelet/leukocyte aggregation and ROS production was examined by lumiaggregometry and fluorescence microscopy. Integrin activity was studied by flow cytometry, detecting the surface expression of CD11b/CD18 as well as the exposure of the high-affinity integrin epitope, whereas the activation of Rac2/Cdc42 was examined using a glutathione S-transferase pulldown assay. The study shows that P. gingivalis activates Rac2 and Cdc42 and upregulates CD11b/CD18 and its high-affinity epitope on neutrophils, and that these effects are diminished by LXA(4). Furthermore, we found that LXA(4) significantly inhibits P. gingivalis-induced aggregation and ROS generation in whole blood. However, in platelet-depleted blood and in isolated neutrophils and platelets, LXA(4) was unable to inhibit either aggregation or ROS production, respectively. In conclusion, this study suggests that LXA(4) antagonizes P. gingivalis-induced cell activation in a manner that is dependent on leukocyte-platelet interaction, likely via the inhibition of Rho GTPase signaling and the downregulation of CD11b/CD18. These findings may contribute to new strategies in the prevention and treatment of periodontitis-induced inflammatory disorders, such as atherosclerosis.

Place, publisher, year, edition, pages
American Society for Microbiology, 2011
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-17096 (URN)10.1128/IAI.00777-10 (DOI)000288532300010 ()21263017 (PubMedID)2-s2.0-79953296864 (Scopus ID)
Available from: 2011-09-05 Created: 2011-09-02 Last updated: 2018-04-05Bibliographically approved
2. Hepatocyte growth factor in patients with coronary artery disease and its relation to periodontal condition
Open this publication in new window or tab >>Hepatocyte growth factor in patients with coronary artery disease and its relation to periodontal condition
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2012 (English)In: Results in Immunology, ISSN 0105-1121, E-ISSN 2211-2839, Vol. 2, p. 7-12Article in journal (Refereed) Published
Abstract [en]

Hepatocyte growth factor (HGF) is an angiogenic, cardioprotective factor important for tissue and vascular repair. High levels of HGF are associated with chronic inflammatory diseases, such as coronary artery disease (CAD) and periodontitis, and are suggested as a marker of the ongoing atherosclerotic event in patients with CAD. Periodontal disease is more prevalent among patients with CAD than among healthy people. Recent studies indicate a reduced biological activity of HGF in different chronic inflammatory conditions. Biologically active HGF has high affinity to heparan sulfate proteoglycan (HSPG) on cell-membrane and extracellular matrix. The aim of the study was to investigate the serum concentration and the biological activity of HGF with ELISA and surface plasmon resonance (SPR), respectively, before and at various time points after percutaneous coronary intervention (PCI) in patients with CAD, and to examine the relationship with periodontal condition. The periodontal status of the CAD patients was examined, and the presence of P. gingivalis in periodontal pockets was analyzed with PCR. The HGF concentration was significantly higher, at all time-points, in patients with CAD compared to the age-matched controls (P< 0.001), but was independent of periodontal status. The HGF concentration and the affinity to HSPG adversely fluctuated over time, and the biological activity increased one month after intervention in patients without periodontitis. We conclude that elevated concentration of HGF but with reduced biological activity might indicate a chronic inflammatory profile in patients with CAD and periodontitis.

Keywords
Hepatocyte growth factor, coronary artery disease, angiography, periodontal disease, porphyromonas gingivalis
National Category
Medical and Health Sciences Cardiac and Cardiovascular Systems
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-26775 (URN)10.1016/j.rinim.2011.12.002 (DOI)2-s2.0-84855719213 (Scopus ID)
Available from: 2013-01-07 Created: 2013-01-07 Last updated: 2017-12-06Bibliographically approved
3. High Concentration but Low Activity of Hepatocyte Growth Factor in Periodontitis
Open this publication in new window or tab >>High Concentration but Low Activity of Hepatocyte Growth Factor in Periodontitis
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2014 (English)In: Journal of Periodontology, ISSN 0022-3492, E-ISSN 1943-3670, Vol. 85, no 1, p. 113-122Article in journal (Refereed) Published
Abstract [en]

Background: High levels of hepatocyte growth factor (HGF), a healing factor with regenerative and cytoprotective effects, are associated with inflammatory diseases, including periodontitis. HGF biological activity requires binding to its receptors, the proto-oncogene c-Met (c-Met) and heparan sulphate proteoglycan (HSPG). Here we investigated HGF expression and its relationship to subgingival microbiota in medically healthy individuals with and without periodontitis.

Methods: Saliva, gingival crevicular fluid (GCF), and blood samples from 30 patients with severe periodontitis and 30 healthy controls were analyzed for HGF concentration using enzyme-linked immunosorbent assay (ELISA), and binding affinity for HSPG and c-Met using surface plasmon resonance (SPR). The regenerative effects of saliva from three patients and controls were analyzed in an in vitro model of cell injury. Subgingival plaques were analyzed for the presence of 18 bacterial species.

Results: Patients with periodontitis showed higher HGF concentrations in saliva, GCF, and serum (P < 0.001); however, the binding affinities for HSPG and c-Met were reduced in GCF and saliva (P < 0.002). In contrast to the controls, saliva from patients showed no significant regenerative effect over time on gingival epithelial cells. Compared to controls, patients had a higher prevalence of periodontal-related bacteria.

Conclusion: Higher circulatory HGF levels indicate a systemic effect of periodontitis. However, the HGF biological activity at local inflammation sites was reduced, and this effect was associated with the amount of periodontal bacteria. Loss of function of healing factors may be an important mechanism in degenerative processes in periodontally susceptible individuals.

Place, publisher, year, edition, pages
Chicago, USA: American Academy of Periodontology, 2014
Keywords
Hepatocyte growth factor, porphyromonas gingivalis, periodontitis, systemic inflammation, coronary artery disease, chronic renal failure, lipoxin
National Category
Medical and Health Sciences Dentistry
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-29141 (URN)10.1902/jop.2013.130003 (DOI)000331139400016 ()23594192 (PubMedID)2-s2.0-84890190195 (Scopus ID)
Funder
Swedish Heart Lung FoundationSwedish Research Council
Note

Funding Agencies:

Public Dental Service in Ostergotland County, Sweden

Foundation of Olle Engkvist

Available from: 2013-05-23 Created: 2013-05-23 Last updated: 2018-06-04Bibliographically approved
4. High concentration but low biological activity of hepatocyte growth factor in patients with chronic renal failure
Open this publication in new window or tab >>High concentration but low biological activity of hepatocyte growth factor in patients with chronic renal failure
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2012 (English)In: Advances in Bioscience and Biotechnology, ISSN 2156-8456, E-ISSN 2156-8502, Vol. 3, no 4, p. 516-523Article in journal (Refereed) Published
Abstract [en]

Hepatocyte growth factor (HGF) is a renotropic, antifibrotic and regenerative factor with cytoprotective effects that is produced by mesenchymal cells and shows high affinity to components of extra cellular matrix, such as heparan sulphate proteoglycan (HS-PG), in healthy. Patients with chronic renal failure (CRF) suffer from a chronic inflammatory disorder. In order to assess the underlying mechanisms for development of CRF we aimed to assess the amounts and affinity of HGF in this patient group. Elisa, western blot and surface plasmon resonance (SPR) were used to study HGF in blood samples, as well as in isolated neutrophils, in CRF patients compared to healthy controls. Patients with CRF showed higher HGF levels in serum (P < 0.0001), but decreased affinity to HSPG (P < 0.0001), compared to healthy controls. Addition of protease inhibitors decreased the difference between patients with CRF compared to healthy individuals. HGF with potent regenerative function during injury lacks affinity to HSPG in patients with CRF that may depend on production of proteases from activated immune cells. This information might be used to highlight underlying mechanisms for chronicity and leading to new strategies for treatment of chronic injuries.

Place, publisher, year, edition, pages
Irvine, USA: Scientific Research Publishing, 2012
Keywords
Chronic Renal Failure, Hepatocyte Growth Factor, Biological Activity, Neutrophils
National Category
Medical and Health Sciences Medical Bioscience
Research subject
Biomedicine; Medicine
Identifiers
urn:nbn:se:oru:diva-25337 (URN)10.4236/abb.2012.324068 (DOI)
Note

-

Available from: 2012-08-27 Created: 2012-08-27 Last updated: 2017-12-07Bibliographically approved

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Lönn, Johanna

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