Role of gingival lymphatics in tissue fluid balance and periodontal disease development
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Background: The gingiva is frequently challenged to oral bacteria which are able to induce inflammatory responses with increased fluid filtration and edema formation in the tissue. Under given circumstances periodontal pathogens can also promote periodontal disease characterized by bone resorption. Lymphatic vessels drain fluid from the interstitium and transport lymphocytes and antigen-presenting toward lymph nodes to elicit immune responses. In gingiva, lymphatic vessels are found, but their function in transcapillary fluid balance and their role in periodontal disease development was hitherto unknown. Methods and Results: We demonstrated that the mouse model of lymphedema, the K14-VEGF receptor 3-Ig (K14) mice, lacked gingival lymphatic vessels and had an almost absence of lymphatics in the mucosal layer of alveolar mucosa. We therefore used this transgenic mouse model to investigate the role of gingival lymphatics intranscapillary fluid balance in steady state situation and after perturbation of the tissue. The gingiva of K14 mice had significantly higher interstitial fluid pressure (Pif) in normal situation and after inflammation-induced by lipopolysaccharide (LPS) from Porphyromonas gingivalis (P. gingivalis) compared with wild type (WT) controls. Overhydration caused more than 75% increase in interstitial fluid volume (IFV) followed by a drop in Pif after recovery in both strains. Continuous measurements during the expansion showed an increase in Pif followed by a decline, suggesting that compliance is increased during edema formation. In the alveolar mucosa, no strain differences were observed in Pif and IFV in any situation, suggesting that mucosal lymphatics are not critical for tissue fluid regulation. Using WT mice, we further demonstrated that lymphatic growth take place in gingiva after P. gingivalis oral gavage. The lymphatics area fraction was increased in infected mice at both 10 and 42 days postinfection and modest bone loss was verified in the longest observation period, whereas proliferation of vessels was observed only in the shortest observation period. Higher numbers of immune cells expressing vascular endothelial growth factor (VEGF)-C along with upregulation of IL-1 and TNF- at protein levels were found in infected mice 10 days after infection. We also demonstrated that K14 mice developed significantly more bone loss 42 days after infection with P. gingivalis. The mutant mice had also higher level of G-CSF, IL-1 and IFN- in periodontal tissues as well as increased number of macrophages and antigen presenting cells in bone resorptional areas compared to WT mice. However, significantly lower plasma level of P. gingivalis specific IgG was found in infected K14 mice compared to infected WT littermates. Our data demonstrate that P. gingivalis infection induced a strong periodontal inflammatory response accompanied by a weakened systemic humoral B-cell response in K14 mice. Conclusion: Gingival lymphatics are crucial for transcapillary fluid balance in the steady-state condition and during acute perturbation. Lymphangiogenesis takes place in gingiva during periodontal disease development and up-regulation of VEGF-C in recruited immune cells is likely important for the growth of lymphatic vessels. Moreover, gingival lymphatic vessels protect against P. gingivalis induced periodontitis, probably by enhancing clearance of bacterial products and promoting humoral immune responses.
Has partsPaper I: Mkonyi L. E., Bletsa, A., Fristad, I., Wiig, H., Berggreen, E. (2010) Importance of lymph vessels in the transcapillary fluid balance in the gingiva studied in a transgenic mouse model. AJP - Heart and Circulatory Physiology 299(2): H275 - H283, August 2010. Full text not available in BORA due to publisher restrictions. The article is available at: http://dx.doi.org/10.1152/ajpheart.01199.2009
Paper II: Mkonyi, L. E., Bakken, V., Sovik, J. B., Mauland, E. K., Fristad, I., Barczyk, M. M., Bletsa, A., Berggreen, E. (2012) Lymphangiogenesis is induced during development of periodontal disease. Journal of Dental Research 91(1): 71-77, January 2012. Full text not available in BORA due to publisher restrictions. The article is available at: http://dx.doi.org/10.1177/0022034511424747
Paper III: Mkonyi, L. E., Bletsa, A., Bolstad, A. I., Bakken, V., Wiig, H., Berggreen, E. (2012) Gingival lymphatic drainage protects against Porphyromonas gingivalis induced bone loss in mice. Full text not available in BORA due to publisher restrictions.