What is the role of apoptosis in oral disease?
Apoptosis is widely involved in disease mechanisms of the oral cavity. Oral diseases in which apoptosis plays a role include lichen planus (Dekker et al.1997, Bloor et al. 1999), odontogenic keratocysts (Muraki et al.1997), leucoplakia (Muraki et al. 1997), squamous cell carcinoma (Muraki et al.1997, Kaur & Ralhan 2000, Ravindranath et al.2000), oral lymphoma (Regezi et al.1998), aphthous ulceration (Honma et al. 1985), erythema multiforme (Chrysomali et al. 1997), Sjogrenâ€™s syndrome (Ishimaru et al. 2000) and mucocutaneous candidiasis (Heidenreich et al.1996). Can microorganisms induce or inhibit apoptosis?
Bacterial proteases have been implicated as inducers of host cell apoptosis (Wang et al. 1998). Fusobacterium nucleatum induces apoptosis in peripheral blood mononuclear cells and neutrophils (Jewett et al. 2000). This is significant because premature immune cell apoptosis may decrease host resistance and promote infection (Geatch et al.1999).
Furthermore, apoptosis of both neutrophils and monocytes decreases in the presence of LPS (Mangan et al. 1993, Preshaw et al. 1999, Tennenberg et al. 1999), resulting in a heightened immune response (Hiroi et al. 1998). Another organism, Prevotella intermedia, does not induce apoptosis in cultured human osteoblastic cells (Morimoto et al. 1999), whilst in Streptococcus mutans, lipoteichoic acid may be a factor in pulpitis as there is evidence that it causes apoptosis in human dental pulp cells of deciduous teeth( Wang et al. 2001). Generally, these interactions are complex and unpredictable as microorganisms may increase apoptosis in some host cells and decrease apoptosis in others.
Whilst bacteria and their by-products can induce pulpal inflammation, they do not always lead to pulp necrosis (Bergenholtz 2000). Bacterial proteases have been implicated as inducers of host cell apoptosis (Wang et al. 1998). Although certain characteristics of apoptotic death are favourable to necrosis, apoptosis does not lead to pulpal regeneration (Goldberg et al.1994). How is apoptosis involved in periodontal disease?
There is a considerable amount of research on the role of apoptosis in periodontal disease. Apoptosis occurs in cells of the periodontium as part of normal turnover and remodelling (Koulouri et al.1999), and may be even more prevalent than necrosis in periodontal disease (Sorkin & Niederman1998). It seems to play a role in age regulation of some immune cells and may be involved in the maintenance of local immune homeostasis in inflamed gingival tissue (Tonetti et al.1998).There is also evidence that increased inflammation is associated with increased epithelial cell apoptosis in the periodontium of patients with periodontal disease (Carro et al.1997).
Various microorganisms associated with periodontal diseases have been shown to generate different short chain carboxylic acids as metabolic by-products, which can promote inflammation by inhibiting normal apoptosis of certain inflammatory cells (Niederman et al. 1997). For example, lactic acid and propionic acid commonly produced by oral microorganisms in periodontal diseases have been shown to inhibit apoptosis of various inflammatory cells (Niederman et al. 1997, Yamamoto et al.1997, Sorkin & Niederman1998). The resultant presence of increased numbers of inflammatory cells results in an elevated inflammatory state. What is the relationship between gingival trauma, wound healing and apoptosis?
There is a strong evidence that trauma, including surgical trauma, inhibits immune cell apoptosis (Ertel et al. 1999, Fanning et al. 1999, Ogura et al. 1999, Nolan et al. 2000).Apoptosis occurs in cells at the advancing epithelial edge in wound healing (Brown et al. 1997). There is speculation that the signal for apoptosis and down regulation of inflammation in a wound may in fact be derived from the epithelium because it appears concurrently with re-epithelialisation of the wound (Brown et al. 1997, Leonardi et al. 2001).
Granulation tissue fibroblasts (myo fibroblasts) play a role in wound contraction. When granulation tissue evolves into a scar, myo fibroblasts disappear, probably as a result of apoptosis. Myo fibroblasts persist in excessive scarring conditions (Desmouliere1995), possibly because of an inappropriate inhibition of apoptosis in these cells. Certain mediators may be potential stimulators of apoptosis in myo fibroblasts after re-epithelialization in the palatal wound healing process (Funato et al.1999). What is the role of apoptosis in pharmacotherapeutics?
The principle therapeutic goal of apoptosis research is the understanding of how to induce or inhibit apoptosis in specific cells. This is probably the best approach for altering rates of apoptosis in target cells whilst avoiding systemic toxic effects that may be otherwise associated. Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), and selective cyclooxygenase 2 (COX2) inhibitors induce apoptosis in certain cells viaacaspase activation mechanism. Certain drug combinations may induce apoptosis by a mechanism involving the disruption of the cell cycle (Bamford et al. 2000).
The induction of osteoclast apoptosis for the treatment of bone resorption is another therapy that utilizes apoptotic mechanisms (Hughes&Boyce1997). Antiresorptive drugs such as the bisphosphonate family have been shown to inhibit bone resorption by inducing osteoclast (Hughes et al.1995, Rogers et al.1996, Hiroi-Furuya et al. 1999) and macrophage apoptosis (Rogers et al. 1996). Bisphosphonates inhibit osteocyte and osteoblast apoptosis contributing to their antiresorptive effects (Plotkin et al. 1999). Tetracycline can also inhibit resorption by inducing osteoclast apoptosis (Cillari et al.1998,Vernillo & Rifkin1998).This is part of the process by which doxycycline down regulates the inflammatory process (Liu et al.1999). There is some thought that tetracycline uses a unique mechanism to induce this selective apoptosis (Bettany & Wolowacz 1998); however, details of this mechanism have not been fully described. Which dental materials have apoptotic effects?
An understanding of the difference between necrotic and apoptotic forms of cell deat his important for understanding the pulp reaction to dental materials (Goldberg et al.1994). In cultured cells derived from the human PDL, evidence of apoptosis in response to different dental materials has been described (Adams et al. 1995) and may occur in damaged areas of the pulp because of certain toxic substances in those materials (Goldberg et al. 1994). In some cases, dental materials may lead to uncontrolled development of apoptosis within central pulp cells, but may leave the odontoblasts more or less intact (Goldberg et al.1994).
More specifically, and related to endodontic treatment, in vitro apoptotic changes are documented in human PDL cells exposed to calcium hydroxide (Adams et al. 1995). Calcium hydroxide has antibacterial properties and has shown predictable healing and hard tissue formation when used in cavity preparations (Bergenholtz 2000). Calciumions may also affect neutrophil apoptosis (Onishi et al.1997). Unfortunately, neither the apoptotic effects of composite resin on the dental pulp nor the potential apoptotic effects of extruded root canal sealers on the cells that make up the supporting periradicular tissues have been fully documented. Therefore, the long-term effects of these treatment variables may or may not influence the ultimate treatment outcome and should not be overlooked as potential aetiologic factors in failure.