Stress and Inflammation
- Psychosocial stress has been associated with poor oral hygiene and smoking, and they seem to have a synergistic effect.
- Stressors have a detrimental effect on chronic immune-mediated inflammatory diseases, including periodontitis and also on the immune system.
- Stress seems to have a hyperinflammatory effect rather than a hypoinflammatory effect.
- Taken together, recent research indicates that stress can be considered a risk factor for periodontal disease.
- Clinical implications are obvious as it is important for members in the dental team to be aware of how stress can influence patient compliance and response to treatment.
Stress has been proposed to be a “risk factor” for periodontal diseases and to play a central role in disease development and progression (Stabholz, Soskolne, & Shapira, 2010). Cross-sectional and case-controls studies have highlighted a possible relationship between different psychological stresses and periodontitis (Monteiro da Silva et al., 1996; Croucher et al., 1997; Genco et al., 1999; Hugoson, Ljungquist, & Breivik, 2002; Dolic et al., 2005). This review will examine different mechanisms, such as biochemical mediators, immune functions, neurological and endocrine alterations, as well as behavioral changes, including oral hygiene and smoking habits, which can influence periodontal status. The periodontal disease–stress relationship is complex, but it is possible to relate important pathways together to explain the link between stress and inflammation. How stress influences inflammation and at what level has not been fully determined and needs to be interpreted with caution.
Stress is a response state of the organism to forces acting simultaneously on the body which, if excessive, lead to diseases of adaptation and eventually to diseases of exhaustion and death (Selye, 1956).
Stress as a “state of threatened homeostasis, which is constantly challenged or outright threatened by intrinsic or extrinsic, real or perceived disturbing forces or stressors.” Stress may have adverse consequences on physiologic functions such as growth, metabolism, circulation, reproduction, and the inflammatory/immune response (Chrousos & Gold, 1992; Chrousos, 1995)
The term “stress” should be restricted to conditions where an environmental demand exceeds the natural regulatory capacity of an organism, in particular, situations that include unpredictability and uncontrollability (Koolhaas et al., 2011).
Stress and Periodontal Disease: Epidemiological and Clinical Findings
In the 1960s, animal studies conducted and demonstrated a possible detrimental role for stress in periodontal tissues (Shklar & Glickman, 1959; Stahl, 1961). However, more recently, Gaspersic, Stiblar-Martincic, and Skaleric (2002) reported significant differences in attachment loss and bone resorptions between stress restraint group compared to control group. Similar results were shown in a very recent study in Wistar rats (Semenoff-Segundo et al., 2012). The study showed physical stress increased attachment and bone loss after ligature-induced periodontitis. The nonperiodontitis side, that is, the side without ligature, was not affected by the stress.
Several earlier studies found a relationship between psychosocial stress, for example, unemployment, work-related mental demand, marital status, and periodontal disease (Marcenes & Sheiham, 1992; Croucher et al., 1997; Hugoson et al., 2002). Severe periodontitis has been associated with depression and loneliness compared to patients with chronic periodontitis (Monteiro da Silva et al., 1996). High levels of anxiety appear to be closely associated with periodontal disease (Vettore et al., 2003). Similarly, Ng and Leung (2006) showed, in a cross-sectional study comprising 1000 subjects aged 25–64 years in Hong Kong, that anxiety and depression significantly increased clinical attachment loss (CAL) (OR = 1.51; 95% CI = 1.09–2.72 and OR = 1.41; 95% CI = 1.17–2.78, respectively). Financial strain have been shown to be significantly related to increased CAL and alveolar bone loss (ABL) (OR = 1.70; 95% CI = 1.09–2.65 and OR = 1.68; 95% CI = 1.20–2.37, respectively), after adjustments for age, gender, and cigarette smoking (Genco et al., 1999). Furthermore, persons with greater financial strain and inadequate coping experienced a higher risk of more severe CAL (OR = 2.24; 95% CI = 1.15–3.17), and ABL (OR = 1.91; 95% CI = 1.15–3.17). In addition, marital status and loss of spouse were significantly related to an increased risk of severe periodontal disease (OR = 2.69; 95% CI = 1.28–5.64) (Hugoson et al., 2002). Number of teeth with CAL > 5 mm, and stress reported a positive correlation, when adjusted for age (r = 0.56, 0.001) (Rai et al., 2011). However, there are studies that did not show an association between stress and periodontal disease. A study from Brazil, comprising 160 randomly selected subjects, could not show an association between psychiatric symptoms, depression symptoms or hopelessness, and a greater risk for developing periodontitis (Solis et al., 2004). In a similar study, Castro et al. (2006) failed to demonstrate that psychosocial factors increased the risk of periodontal disease.
Conflicting evidence concerning the influence of stress on periodontal disease might be due to the diversity of self-reported questionnaires that have been used as the psychometric instrument. It should be considered that stress is not the same experience for everyone. Similar stressors could have different effects on different individuals, for example, depending on how much social support is available from family and friends (see Sheiham & Nicolau, 2005, for a review), and how a person handles or copes with stress (Folkman, 1984). Therefore, the measurement of biological markers could provide a more objective method to monitor psychosocial status. Furthermore, it is important to take into account different kinds of stress, acute or chronic, controllable or not controllable. Acute stress can be defined as a sudden and short-lasting stress event, such as academic stress, which can induce inflammatory signals at sites of ongoing inflammation (Weik et al., 2008). The selection of patients with different levels of periodontal disease may influence the outcome of stress measurements, as well as the definition of periodontitis. Although taking into consideration the above-mentioned limitations, it can be concluded that a majority of the studies investigating stress and periodontal status show a detrimental effect.
Stress can influence periodontal health status in several ways. It can have a primary effect on the inflammatory response and the immune system. It can also change health behavior, including oral hygiene habits and smoking habits, and thus influence periodontal health as a secondary effect. It is probable that the detrimental effects of stress on periodontal health that have been reported in many studies are due to a combination of both pathways.
Effects on the Immune System and Inflammatory Response
The continuous interactions between physiological, immunological, and psychological responses to acute stress are important defense mechanisms and protect the individual from excessive inflammation. However, if the trauma becomes too extreme or chronic, biological changes leading to increased systemic inflammation seem to occur. The research around the mechanism for this remains still inconsistent, but some studies suggest a peripheral decrease in sensitivity for glucocorticoids (see Rohleder, 2012, for a review). An increased inflammatory response correspond to the overall hypothesis that periodontitis is a hyperinflammatory condition rather than a hypoinflammatory condition.
Breivik et al. (2000) demonstrated in a series of experiments a brain-neuroendocrine-immune regulatory mechanism. The group showed that genetically determined hypothalamus-pituitary-adrenal (HPA) reactivity seemed to play an important role in attachment and bone loss in a ligature-induced periodontitis model in rats. More recently, Peruzzo et al. (2008) also reported an animal model, whereby chronic stress induced the elevation of glucocorticoid and catecholeamine levels after 30 days. Simultaneously, chronic stress significantly increased bone loss resulting from ligature-induced periodontitis. The bone loss corresponded with an increase in RNA levels of interleukin (IL)-1β (IL-1β), IL-6, IL-10, interferon-gamma (IFN-γ), and receptor activator of nuclear factor-kappa B ligand (RANKL). In addition, a relationship between enhanced prostaglandin E2 (PGE2) and bone loss under stress in vitro was also found (Castagliuolo et al., 1996).
Corresponding results have been found in gingival crevicular fluid (GCF) from humans. Giannopoulou, Kamma, and Mombelli (2003) found a significant correlation between stress and the proinflammatory cytokines, IL-1β, IL-6, and IL-8, which could reflect ongoing periodontal destruction. In a comparable study among patients with aggressive periodontitis, a significant relationship between stress and IL-1β, IL-6, and IL-8 was found (Kamma et al., 2004). This study also demonstrated a significant interaction between stress, smoking, and increased levels of IL-8 in these patients. The authors suggest that smokers and the stressed patients may have had more disease symptoms because of both smoking and stress-influenced host-related factors, including the cytokine network.
Similar findings of elevated levels of IL-6 GCF have been found in untreated aggressive patients (Mengel, Bacher, & Flores-De-Jacoby, 2002) and in women with stress-related depression and exhaustion (Johannsen et al., 2006, 2007). Maes (1995) suggested that stress causes alterations to both cellular and humoral immune responses and, as a consequence, impairs immunological defense mechanisms and promotes the accumulation of periodontopathogens, which in turn exacerbate periodontal diseases. The extent of inflammatory periodontal disease may be predicted by reactivity of the HPA axis and its effects on T-lymphocyte numbers during emotional stress (Breivik et al., 1996). Higher concentrations of hydrocortisone (cortisol) levels increased the expression of some matrix metalloproteinases (MMPs) in human fibroblasts (Cury et al., 2007), which could constitute a potential mechanism underlying increased periodontal breakdown associated with psychosocial stress. In addition, stress can also affect the autonomic nervous system, resulting in secretion of catecholamines that affect the release of prostaglandin and proteases (Fibiger, Singer, & Miller, 1984) that in turn could cause periodontal tissue destruction.
Cortisol is a well-established stress biomarker and is regulated by the adrenocorticotopic hormone (ACTH) from the pituitary gland. Cortisol levels reflect the activation of the HPA, which is considered an indicator of psychological stress (Kirschbaum & Hellhammer, 1994). Several studies have reported that cortisol levels in saliva and GCF are correlated with probing pocket depth (PPD), CAL, ABL, and with the extent and severity of periodontitis (Genco et al., 1999; Hilgert et al., 2006; Johannsen et al., 2006; Rosania et al., 2009; Rai et al., 2011; Haririan et al., 2012). Similar findings have also been reported by Ishisaka et al. (2007) who found a significant association between higher cortisol, dehydroepiandrosterone (DHEA, another type of cortisol) levels, and the number of teeth with PPD and CAL, using multiple regression analysis. This could be explained, at least in part, by the inhibitory effects of the activation on the HPA axis on the inflammatory immune response because all components of immune response are inhibited by cortisol (Chrousos, 1995).
This is in contrast to the study by Johannsen et al. (2007) who found decreased levels of cortisol in the GCF of depressed patients. This may be explained by the fact that the patient group was composed of a homogenous group exposed to prolonged work stress. Similar findings were reported from patients with atypical depression and posttraumatic stress, where a reduced reactivity of the HPA axis response was found (Gold & Chrousos, 2002; Rohleder et al., 2004). Furthermore, chronic stress has been associated with both increased and decreased HPA activity (Ockenfels et al., 1995). However, it is mostly increased levels of cortisol in periodontitis that were suggested to affect the immune system through the alteration of immunoglobulin and neutrophil function (Genco et al., 1998; Rosania et al., 2009).
Another marker for stress is salivary chromogranin A (CgA) and α-amylase (AA), which are both supposed to link the activity of the neuroendocrine system with local and systemic immune function related to periodontitis (Wu et al., 2009; Zhang et al., 2009). A recent study from 2012 (Haririan et al.) found a significant correlation between salivary AA and CgA levels, and the number of teeth with pocket depth ≥5 mm, which was consistent with previous studies (Hironaka et al., 2008; Rai et al., 2011). These results suggest that CgA in particular plays a role in the communication between the neuroendocrine and immune system (Zhang et al., 2009), and a link to the local inflammatory reaction in severe periodontal disease. To clarify this association, further studies need to be performed.