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Biomaterials & Bioengineering |
N-acetyl Cysteine Protects Pulp Cells from Resin Toxins in vivo
A. Paranjpe ,
E.C. Sung,
N.A. Cacalano,
W.R. Hume and
A. Jewett*
The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center (JCCC), Dental Research Institute, Division of Oral Biology and Medicine, UCLA Schools of Dentistry and Medicine, University of California, 10833 Le Conte Ave., Los Angeles, CA 90095, USA
Correspondence: * corresponding author, ajewett{at}ucla.edu
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ABSTRACT
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Potential risks of the use of resin-based restorative materials include direct damage to the pulp cells and the induction of hypersensitivity reactions in patients. In this study, we tested the hypothesis that N-acetyl cysteine (NAC) inhibits resin toxicity and restores the function of pulp cells. Analysis of our data demonstrates toxicity of composite resins on pulp cells in both an in vivo rat and an ex vivo human model system. Moreover, cells that survive after the placement of composites are weaker, and they are induced to undergo cell death when exposed to 2-hydroxyethyl methacrylate (HEMA). The toxic effect of composites on pulp cells is neutralized by NAC. Therefore, NAC protects the cells from damage induced by clinically relevant levels of restorative materials, in both rat and human model systems. The addition of N-acetyl cysteine prior to or concomitant with the application of restorative materials may be beneficial for the health and safety of dental patients.
Key Words: composite resins • dental pulp stromal cells • apoptosis • NAC
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INTRODUCTION
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Resin-based materials are now used widely in dental restorations. Most dentin bonding technologies use a primer containing the hydrophilic resin hydroxyethyl methacrylate (HEMA) and a bonding resin, triethylene glycol dimethacrylate (TEGDMA). In dentistry, resin materials require intra-oral polymerization, and they may contain 30% unpolymerized monomers, which may leach out (Gerzina and Hume, 1996) and cause significant local and systemic adverse effects (Qvist et al., 1989; Kanerva et al., 2002). Therefore, in this study, we tested the hypothesis that composite resins and HEMA have significant growth-inhibitory effects on dental pulp stromal cells, and that the use of N-acetyl cysteine (NAC) can protect the pulp from damage induced by clinically relevant levels of these restorative materials, in both rat and human model systems. Specifically, we wanted to address the effects of the restorative materials during initial or acute phases of pulp exposure under low blood flow, since reduced blood flow rate has previously been reported after the administration of local anesthetics. In addition, secretion of Vascular Endothelial Growth Factor (VEGF) was also used as a measure of functional competency, since healthy and viable dental pulp cells secrete large amounts of VEGF constitutively (Mantellini et al., 2006).
Clinical studies in humans and monkeys have shown that acute pulpal inflammation occurs with the application of resins to dentin (Qvist et al., 1989; Hebling et al., 1999). Dental pulp contains a diverse population of cells consisting of odontoblasts, fibroblasts, immune cells, nerve cells, and vascular cells (Jontell et al., 1987, 1995; Bjorndal and Mjör, 2001). Differentiation of pulp stromal cells into odontoblasts is beneficial, since these cells are capable of laying tertiary/reparative dentin, which, in turn, can protect the pulp from further damage. We have previously shown that HEMA induces apoptosis in cells in a dose-dependent manner (Paranjpe et al., 2005, 2007). HEMA-induced apoptosis has been linked to a decrease in intracellular glutathione (GSH) and the production of reactive oxygen species (ROS) in the cells (Stanislawski et al., 2000, 2003; Hunag et al., 2001; Walther et al., 2002).
NAC is a membrane-permeable aminothiol compound with diverse functions (De Vries and De Flora, 1993; Zafarullah et al., 2003). Although previously published reports on the function of NAC have concentrated largely on its anti-oxidant effect, recent reports have highlighted the significance of this compound in the induction of differentiation (Gustafsson et al., 2005; Parasassi et al., 2005; Paranjpe et al., 2007). NAC has also been regarded as an anti-inflammatory compound (Gillissen and Nowak, 1998; Radomska-Lésniewska et al., 2006). Previous work has attributed the protective effect of NAC to its anti-oxidant effect (Lee et al., 2006; Schweikl et al., 2006a; Spagnuolo et al., 2006). In contrast to these reports, analysis of our data suggests mechanisms for NAC function, which are distinct from those mediated by other well-established anti-oxidants, such as Vitamin E (Trolox) and Vitamin C (Ascorbates) (Paranjpe et al., 2007).
In this study, we tested the hypothesis that, in an in vivo rat model and an ex vivo human model system, the application of NAC prior to tooth restoration with clinically relevant restorative materials protects the pulp cells from damage induced by dental restorative materials. In addition, we also investigated whether NAC is protective even after the application of a high concentration of HEMA (8.2 mM) following composite restoration.
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MATERIALS & METHODS
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Cells and Reagents
DMEM (Cellgro, Manassas, VA, USA) supplemented with 10% FBS, 1% non-essential amino acids, 1% sodium pyruvate, 1% streptomycin, and 1% L-glutamine (Invitrogen, Carlsbad, CA, USA) was used for cultures of dental pulp stromal cells. β-glycerophosphate, ascorbic acid, NAC, HEMA, sodium hydroxide, HEPES, and the ALP staining kit were all purchased from Sigma (St. Louis, MO, USA). A fluorescein isothiocyanate-conjugated Annexin V/Propidium Iodide kit was purchased from Coulter Immunotech (Miami, FL, USA).
Restoration of Rat Teeth with Composite and NAC
Nine 8-week-old male Sprague-Dawley rats were used. The teeth were restored with composite in the presence and absence of NAC within an hr after the rats were killed by CO2. Animals were treated according to the guidelines established by the Animal Research Committee at UCLA. Upper and lower incisors from rats were prepared with class V preparations near the level of the gingiva. The teeth were prepared with a #1 round bur in a high-speed dental handpiece. The preparation was approximately 0.5 mm (± 0.1 mm) deep (half the depth of the bur) and did not expose the pulp. The prepared cavity was then acid-etched, and a dentin bonding agent (ProBOND, DENTSPLY, York, PA, USA) was applied as per the manufacturer’s instructions. NAC at 20-mM solution was applied for 5 sec with a micro-brush before dental bonding agent was applied. The prepared cavity was then restored with a composite resin restorative material (Herculite XR, Kerr, Orange, CA, USA), cured with a LED light-curing unit for 40 sec (Ultralume 5, Ultradent, South Jordan, UT), and polished. The restorative materials were placed for 5 hrs, after which the teeth were extracted, pulps removed, single-cell suspensions made and plated in media for growth.
Restoration of Human Teeth with Composite and NAC in an ex vivo System
Freshly extracted human 3rd molars were restored within 1 hr of extraction. Human tissues were used according to the guidelines set by the Institutional Review Board (IRB). Teeth were prepared with class V preparations at the level of the cemento-enamel junction (CEJ). Cavities were prepared with a #8 round bur (2.3 mm in diameter) in a high-speed dental handpiece (Brasseler, Savannah, GA, USA). The preparation was approximately 1 mm deep (half the depth of the bur), and did not violate the pulp space, ~ 2.3 mm in depth (width of the bur), and ~ 4.6 mm in diameter (2x the width of the bur). Cavity preparation was etched with 37% phosphoric acid for 10 sec, after which the dental bonding agent was applied, and the tooth was restored with composite (Matrixx shade A2, Discus Dental, Culver City, CA, USA) per the manufacturer’s directions (Clearfil SE Bond, Kuraray America, Inc., New York, NY, USA). After 5 hrs, the tooth was split open, and the pulp was extracted for evaluation. Restoration of the teeth in the presence of NAC was carried out in exactly the same way, except that NAC solution (20 mM) was applied with a micro-brush for 5 sec before the dental bonding agent was applied, per the manufacturer’s directions.
Treatment of Restored Teeth with HEMA
Human pulp cells from extracted 3rd molar teeth that were restored in the presence and absence of NAC were grown, and the numbers of viable cells were determined in each group by trypan blue exclusion assay and adjusted to 1 x 105 cells in all 3 groups before they were treated with and without HEMA (0.0082 M), and the levels of cell death were determined by Annexin V and PI staining.
Dental Pulp Stromal Cell Cultures, FITC-Annexin V/PI and Alkaline Phosphatase (ALP) Staining, and ELISA
These procedures were all performed as described previously (Paranjpe et al., 2007).
Statistical Analysis
Analysis of Variance (ANOVA) with a Bonferroni multiple-comparison test was used for statistical analysis.
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RESULTS
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NAC Protects the Pulp Cells from Toxic Effects of Composite Restorations
NAC inhibited the toxic effects of composites on pulp cells (Fig. 1A ). Prevention of cell death and increased growth and function of pulp cells in the presence of NAC were evident when either the numbers of cells were determined (Fig. 1B) or ALP staining was performed (Fig. 1C).
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Figure 1. NAC protects the pulp cells from undergoing cell death and growth inhibition after composite restorations in vivo. (A) Nine 8-week-old male rats were divided into 3 groups where (A) no restoration, (B) composite restoration, or (C) composite restoration with NAC was applied. Five hrs after restoration, the teeth were split open, the pulp tissue was removed, and the pulp cells were prepared as described in MATERIALS & METHODS. Dental pulp stromal cells from each group were cultured in media with a combination of β-glycerophosphate (10 mM) and ascorbic acid (50 µg/mL) for 4 wks, after which photographs were taken by means of an inverted microscope (mag. 20X). The results are representative of 3 independent experiments. (B) Rat dental pulp stromal cells were prepared as indicated in Fig. 1A. Five wks after the culture of dental pulp stromal cells, they were trypsinized, and the cell numbers were determined for each group. The results are representative of 3 independent experiments. The cells were counted in triplicate and presented as mean ± standard deviation. p  0.001 for differences between the composite- and ‘composite with NAC’-treated groups. (C) Rat dental pulp stromal cells were prepared as indicated in Fig. 1A. After 5 wks of culture, dental pulp stromal cells were stained, and the levels of alkaline phosphatase staining were determined for each group. The results are representative of 3 independent experiments. Panel C of this Fig. appears in color in the online version.
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NAC Protects the Human Pulp Cells from Toxic Effects of Composite Restorations
NAC inhibited the toxic effects of composites on human pulp cells (Fig. 2A). Prevention of cell death and increased growth and function of pulp cells in the presence of NAC were evident when either the numbers of cells were determined (Fig. 2B), or their function, as assessed by the secreted levels of VEGF, was determined (Fig. 2C). NAC prevented the loss of VEGF secretion by dental pulp stromal cells (Fig. 2C). Pulp cells obtained from teeth restored with composite in the presence of NAC appeared similar to those obtained from unrestored teeth.
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Figure 2. NAC protects human dental pulp stromal cells from undergoing cell death and growth inhibition after ex vivo composite restorations. (A) Three freshly extracted human 3rd molars from the same individual were divided into 3 groups where (A) no restoration, (B) composite restoration, or (C) composite restoration with NAC was applied. Restorations were carried out as described in MATERIALS & METHODS. After 5 hrs of restoration, the teeth were fractured, and the pulp tissues were extracted and treated with trypsin-EDTA and collagenase to obtain single-cell suspensions, after which they were cultured in media with β-glycerophosphate (10 mM) and ascorbic acid (50 µg/mL). After 4 wks of culture, photographs were taken via an inverted microscope (mag. 20X). (B) Human dental pulp stromal cells were prepared as described in Fig. 2A. After 6 wks of culture, dental pulp stromal cells were trypsinized, and the cell numbers were determined in each group. The cells were counted in triplicate and presented as mean ± standard deviation. p 0.001 for differences between the composite- and ‘composite with NAC’-treated groups. (C) Human dental pulp stromal cells were prepared as described in Fig. 2A. After 6 wks of culture, supernatants were removed from the cultures, and the levels of VEGF secretion in dental pulp stromal cells (5 x 105/mL) were assessed by a sensitive and specific ELISA for VEGF. p 0.001 for differences between the composite- and ‘composite with NAC’-treated groups.
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NAC Protects the Human Pulp from Repeated Insults by Restorative Materials
Human pulp cells obtained from teeth which were restored with composite in the absence of NAC were significantly more sensitive to HEMA-mediated cell death, as compared with either control pulp cells or those which were restored with composite and NAC (Fig. 3). Cells which were isolated from teeth restored with composite and NAC were resistant to HEMA-mediated effects, even when compared with cells obtained from the control group that had no restoration (Fig. 3). These results indicated that NAC protects dental pulp stromal cells from injury induced by restorative materials.
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Figure 3. NAC protects the human pulp from repeated insults by restorative materials. (A) Human pulp cells extracted from control teeth and those restored with composite in the presence and absence of NAC, as described in Fig. 2A , were grown, and the viable cells from each group (1 x 105) were treated with and without HEMA (0.0082 M) for 18–24 hrs, and the levels of cell death were determined by Annexin V and Propidium Iodide (PI) staining. The numbers in each histogram are the percentages of cells positive for that quadrant. (B) We obtained levels of cell death in each histogram from Fig. 3A by adding the percentages of cells positive in quadrants 1, 2, and 4.
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DISCUSSION
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In this paper, we have demonstrated that tooth restoration with clinically relevant composite materials is toxic to pulpal cells. In addition, those cells that survived and were cultured after placement of the restorative materials were significantly more sensitive to a second exposure to HEMA. Analysis of these data indicated that dental pulp stromal cells were considerably weakened after exposure to chemicals released from dental restorative materials, and that any additional injury could be detrimental to their continued survival and function. Therefore, dental pulp stromal cells which are exposed to composites may show compromised responses to oral bacteria that have gained access to or remained in the dentin-pulp complex after restoration, allowing bacterial growth and expansion and, subsequently, additional pulp damage to occur. The application of NAC prior to tooth restoration with composite materials greatly reduced their toxic effects, even after a second exposure of the extracted pulpal cells to HEMA.
Inhibition of cell death by NAC may indicate the significance of oxidative stress in composite or HEMA-mediated apoptotic cell death, since NAC has been shown to have anti-oxidant effects (De Vries and De Flora, 1993; Oka et al., 2000; Zafarullah et al., 2003; Schweikl et al., 2006b; Spagnuolo et al., 2006). However, since well-known anti-oxidants such as Trolox and Ascorbates not only did not change the course of HEMA-mediated cell death, but also contributed to it (Paranjpe et al., 2007), it is possible that NAC functions via mechanisms distinct from those mediated by Trolox and Ascorbates. Indeed, we have reported previously that the addition of NAC significantly increased NF B expression in epithelial cells, and restored NFB activity in HEMA-treated cells, with concomitant rescue of cell viability and function (Paranjpe et al., 2007). HEMA is also known to induce allergic responses in susceptible hosts (Kanerva et al., 2002; Auzerie et al., 2003). Therefore, the effect of NAC on HEMA-mediated cell death may have significant consequences, not only for the survival of the cells, but also in subsequent inhibition of inflammatory reactions, since NAC is regarded as an anti-inflammatory agent (Gillissen and Nowak, 1998; Radomska-Lésniewska et al., 2006). NAC may prevent the initiation of inflammation by preventing the death of dental pulp stromal cells, since cell death is an important step in the recruitment of immune effectors (Jewett et al., 2006a). Moreover, when immune cells are recruited to the pulp, they will eventually become inactivated and cleared, since NAC will increase the survival and activation of NFB in dental pulp stromal cells. This assumption is based on our previous observation that an increase in NFB activation in keratinocytes induces immune inactivation by switching the balance toward increased Th2-type cytokines and eventual loss of the immune effectors (Jewett et al., 2003, 2006b). Cytokines such as IL-6, TNF- , or IL-1β can further increase NFB activity in dental pulp stromal cells, resulting in a faster resolution of the inflammatory process.
We have also demonstrated that the protective effect of NAC is due to its ability to increase key differentiation genes in dental pulp stromal cells (Paranjpe et al., 2007). It is important to note that we did not observe increased cell death by NAC when we added it to highly differentiated and functionally activated dental pulp stromal cells. This is in contrast to other activating agents, which induce cell death. Therefore, the function of NAC may be unique, in that it is able to trigger activation in the absence of cell death.
Tooth hypersensitivity and pain are also side-effects of composite restorations. It is possible that this hypersensitivity is caused by the death of dental pulp stromal cells, and the recruitment of inflammatory cells to clear dying dental pulp stromal cells. Therefore, by inhibiting the death of pulp cells using NAC, we may be able to prevent subsequent insults to the pulp.
The use of local anesthetics with vasoconstrictors prior to the restorative procedures has been shown to reduce 71% and 51% of blood flow rate to pulpal and gingival tissues, respectively (Musselwhite et al., 1997; Ahn and Pogrel, 1998). Reduction in pulpal blood flow by decreasing clearance into the circulation may increase the local accumulation of restorative material components, resulting in a higher risk of cell damage. Indeed, we found that exposure of pulp cells to lower concentrations of HEMA for less than 5 min, followed by its removal, resulted in significant death and loss of pulp cell function (data not shown). Interestingly, when cells that had been exposed to HEMA were washed extensively to remove all excess material and then co-cultured with cells that were never exposed to HEMA, a significant reduction in the function and viability of non-HEMA-exposed cells was observed (data not shown). At present, it is not clear whether this effect is due to the transfer of these materials from cell to cell after binding and release of HEMA from the cells, or merely to the inhibition of cell function because of interactions with apoptotic cells, which has previously been shown to be the consequence of silent or non-inflammatory interaction with apoptotic cells (data not shown) (Cvetanovic et al., 2006). Therefore, although blood flow will certainly influence the eventual clearance of both toxins and inflammatory mediators from pulp, the initial exposure of pulp cells to the restorative materials under conditions of decreased blood flow, and therefore decreased clearance induced by anesthetics and vasoconstrictors, may be sufficient to initiate significant cell death and loss of cellular function. Thus, the models presented in this paper, in which there was a cessation or absence of blood flow, could be highly relevant to initial or acute phases of pulp exposure during and immediately after tooth restoration, with local anesthetics with vasoconstrictors. However, it is important to emphasize that further studies, in particular those in live pulp models in animals and humans, will be required.
Therefore, the use of NAC prior to or together with restorative materials may be beneficial to patients. In addition, NAC may also prevent the generation of well-established hypersensitivity and immune sensitization, resulting in prevention of systemic effects induced by the composite resins.
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ACKNOWLEDGMENTS
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This work was supported by RO1-10331 from the NIH-NIDCR.
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FOOTNOTES
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 authors contributing equally to the work 
Received for publication April 16, 2007.
Revision received February 8, 2008.
Accepted for publication February 19, 2008.
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Journal of Dental Research, Vol. 87, No. 6,
537-541 (2008)
DOI: 10.1177/154405910808700603
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ABSTRACT
INTRODUCTION