Neutrophils (PMNs) provide the first line of host defense against bacterial periodontal infections. How and why PMNs fail to prevent this infection in adult periodontitis is currently unknown. It is clear that biological mediators which modulate the PMN response, initially interact with receptors, secondarily activate biochemical responses, and finally activate cellular responses. We therefore reasoned that toxic bacterial products may use similar mechanisms to alter PMN function. Short chain fatty acids (SCFAs) are particularly interesting in this regard because they: are metabolic by-products of periodontal pathogens; are found in gingival crevicular fluid of adult periodontitis patients in mM concentrations; trigger some secondary messengers (e.g.: cytoplasmic calcium, pH, and actin transients); but, inhibit chemotactic receptor mediated PMN functions. However, the mechanism of this action is unknown. This leads us to ask two related questions: 1) How do SCFAs trigger second messengers? and 2) How do SCFAs inhibit normal chemotactic receptor mediated function? To answer these questions we will study the in vitro and in vivo effects of SCFAs + chemotactic mediators on key steps in the signal transduction pathway and key cellular responses. Signal transduction experiments will examine receptor modulation, G-protein activation, and cytoplasmic calcium, pH, and actin transients. Cellular response experiments will examine cell polarization, actin localization, and oxygen metabolism. We will utilize four SCFAs which exhibit the highest gingival crevicular fluid concentration in periodontal disease (acetate, propionate, butyrate, and lactate). Previous work indicates that propionate and butyrate inhibit PMN function, while acetate and lactate do not. We will also examine the effect of caproate, a SCFA not associated with periodontal disease, and combinations of all the indicated SCFAS. These studies are significant for two reasons. First, they offer the potential for providing both a chemical and cellular explanation as to why PMNs fail to prevent periodontal infections. Second, they will characterize the effects of simple organic molecules on PMN signal transduction and cell function. Clearly, this information can be applied to the study of signal transduction and cell function in other cell systems (eg: epithelial barrier function and cytokine production). Finally, this information will potentially provide data which can be used to prevent periodontal pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE008415-05
Application #
3222119
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1988-06-01
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Forsyth Institute
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02142
Kashket, S; Zhang, J; Niederman, R (1998) Gingival inflammation induced by food and short-chain carboxylic acids. J Dent Res 77:412-7
Sorkin, B C; Niederman, R (1998) Short chain carboxylic acids decrease human gingival keratinocyte proliferation and increase apoptosis and necrosis. J Clin Periodontol 25:311-5
Swartwout, S; Niederman, R (1997) Bacterial metabolite mediated differential human PMN gene expression. J Periodontal Res 32:196-9
Niederman, R; Zhang, J; Kashket, S (1997) Short-chain carboxylic-acid-stimulated, PMN-mediated gingival inflammation. Crit Rev Oral Biol Med 8:269-90
Niederman, R; Buyle-Bodin, Y; Lu, B Y et al. (1997) Short-chain carboxylic acid concentration in human gingival crevicular fluid. J Dent Res 76:575-9
Kandikonda, S; Oda, D; Niederman, R et al. (1996) Cadherin-mediated adhesion is required for normal growth regulation of human gingival epithelial cells. Cell Adhes Commun 4:13-24
Kashket, S; Zhang, J; Van Houte, J (1996) Accumulation of fermentable sugars and metabolic acids in food particles that become entrapped on the dentition. J Dent Res 75:1885-91
Niederman, R; Buyle-Bodin, Y; Lu, B Y et al. (1996) The relationship of gingival crevicular fluid short chain carboxylic acid concentration to gingival inflammation. J Clin Periodontol 23:743-9
Niederman, R; Naleway, C; Lu, B Y et al. (1995) Subgingival temperature as a gingival inflammatory indicator. J Clin Periodontol 22:804-9
Papapanou, P N; Sandros, J; Lindberg, K et al. (1994) Porphyromonas gingivalis may multiply and advance within stratified human junctional epithelium in vitro. J Periodontal Res 29:374-5

Showing the most recent 10 out of 18 publications