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Abstract

Occupational stress can affect physiological and psychological homeostasis. In addition, the occupational challenges associated with firefighting and law enforcement have been linked to increased mortality ratios for ischemic heart disease when compared with other population cohorts. Laboratory studies have shown that the exacerbation of stress hormones (eg, catecholamines) following dual challenge (physical and psychological stress) may affect immune system responses, which may partially explain the link between cardiovascular disease and inflammation. Physical fitness has been shown to attenuate both cardiovascular and inflammatory cytokine responses following physical and/or psychological stress; however, criteria for safe and effective occupation-specific fitness levels have not been established. In addition, firefighters and police officers have high overweight and obesity rates, which also contribute significantly to the development of cardiovascular disease. Future investigation on the possible interaction (additive or synergistic) of obesity and psychological stress on the development of cardiovascular diseases in these professions is warranted, and a criterion for fitness level should be established for safe and effective participation in occupation-related activities.

Keywords

firefighters police military exercise psychological stress immunity cytokines inflammation obesity

A critical area of current interest is the link between the CVD [cardiovascular disease] and the immune system that may explain, at least in part, the relationship between stress and CVD.

Overview of Occupational Stress and the Immune System

Numerous occupations, especially emergency responders (ie, firefighters, ambulance personnel, and police officers), are often subject to a unique combination of physical and psychological stress. This combined challenge may be associated with elevated mortality risks.¹ For example, law enforcement officers and firefighters have high mortality rates for ischemic heart disease.^1-4 Furthermore, Kales and colleagues⁵ have demonstrated that fire suppression activities result in an increased risk of death to firefighters (12-136 times higher) when compared with nonemergency duties. These professionals are exposed to a broad range of stressful stimuli that may affect the development of cardiovascular disease (CVD). A critical area of current interest is the link between the CVD and the immune system that may explain, at least in part, the relationship between stress and CVD.

Stress hormones (ie, cortisol and catecholamines) are thought to have detrimental effects on the immune system, leading to an imbalance between innate (immediate antigen-nonspecific defense) and adaptive immunity (specific response to a particular foreign antigen creating immunological memory) via cytokine release from immune cells.⁶ In response to acute stress, the innate immune promptly prepares to provide immune protection followed by adaptive immunity when exposed to repeated or prolonged stress, whereas chronic stress can suppress these immune defenses. This stress–immune interaction is an important antiviral defense and fosters the elimination of invading microorganisms.^7,8 This review will focus on the stress-induced changes in immune cell distribution,^9-12 which ensures that the bodies’ immune response is efficient or elicits an effective immunoprotection. More directly related to the cardiovascular system, this review will also focus on the stress-induced pro-inflammatory response. Finally, recent studies have reported approximately 77% overweight and obesity rates in professionals such as young emergency responders (firefighters and ambulance recruits), police officers, and military personnel.^13-16 Thus, this review will also discuss the synergistic effects of physical activity, obesity, and psychological stress on inflammation, which may enhance our understanding of the link between obesity, stress, and CVD.

Catecholamine-Induced Immune Cell Redistribution to Concurrent Stress

Many studies in psychoneuroimmunology have investigated the effects of physical and psychological stress on immune system responses. An appropriate distribution of peripheral immune cells provides for the performance of surveillance and effector functions of the immune system.¹⁷ The release of both catecholamines and cortisol in response to either psychological stress or physical stress can mediate changes in the immune cell distribution.^18,19 However, Isowa and colleagues¹¹ have concluded that, under acute psychological stress, the influence of cortisol on immune function is minimal and that the acute immune response is primarily regulated by catecholamines.

A number of experimental protocols using laboratory-induced acute psychological stressors have observed transient immune cell redistribution via β-adrenergic activation.^10,18,20,21 Specifically, following acute psychological stress, elevation in monocytes, natural killer (NK) cells, and cytotoxic T cells have been observed,^9,10,22 whereas helper T cells and B cells have been shown to decrease.^9-12 Furthermore, in response to acute physical stress (physical activity), the magnitude of these immune cell responses is dependent on exercise intensity and duration.²³ High-intensity exercise has been shown to induce the release of catecholamines with corresponding alterations in various immune cells.²⁴ Typically, following exercise monocytes and NK cells exhibit the greatest fluctuation followed by T cells and B cells.^25,26 Previous research has demonstrated that the percentage of CD3+ T cells and CD19+ B cells (adaptive immunity) decrease with an elevation in the percentage of NK cells (innate immunity) following incremental exercise.²⁷ These findings indicate that acute stress enhances innate immunity and possibly suppresses adaptive immunity and that these alterations can be likely enhanced at higher intensities of psychological and physical stress. The appropriate redistribution of immune cells in response to psychological and/or physical stress is imperative to an effective and efficient immune response in preparation for potential invaders and injury.^17,28 This direction of enhancement and suppression on immune function is dependent on the duration and magnitude of stress response. However, when exposed to chronic stress, immunoprotection can be suppressed by decreasing immune cell number and function, thereby promoting susceptibility to diseases.

Previous studies have demonstrated greater epinephrine (EPI) and norepinephrine (NE) responses to combined mental and physical stress (dual stress condition) relative to physical challenge/stress alone in apparently healthy individuals²⁹ and professional firefighters.³⁰ This finding suggests that the greater catecholamine response to dual stress may further alter the components of innate immunity, specifically the pro-inflammatory components. Furthermore, this response may be associated with the combined mental and physical stress of conducting fire suppression activities and help explain the high mortality rates in firefighters.^5,31 Recently, Huang et al³² examined the associations among catecholamines and immune cell distribution in professional firefighters exposed to a computerized firefighting strategies and tactics drill (FSTD; mental challenge) while participating in moderate intensity exercise. Firefighters participated in 2 counterbalanced exercise conditions on a cycle ergometer: 37 minutes of cycle ergometry at 60% Vo_2max (exercise alone condition; EAC) and 37 minutes of cycle ergometry at 60% Vo_2max along with 20 minutes of FSTD (firefighting strategies condition; FSC). As expected, FSC elicited significantly greater HR, NE, and EPI when compared with EAC. Furthermore, both EAC and FSC elicited increases in NK cells. The percentages of CD3+ T cells, CD3+CD4+ helper T cells, CD4/CD8 ratio, CD19+ B cells, and total lymphocytes were lower immediately following both conditions. Although no group differences were found in this study, these results provide the basis for further examination of the lymphocyte subset redistribution following prolonged or repeated bouts of physical and/or psychological stress.

In addition, Huang et al³² found that following the dual challenge, NE area under the curve was negatively correlated with percentage of CD19+ B cells immediately after challenge, and HR was negatively associated with the percentage change in the CD4/CD8 ratio from before to after challenge. These elevations in NE and heart rate simultaneously in response to the dual challenge suggest greater sympathetic activation that, in turn, could possibly explain the alteration in the distribution of lymphocyte subsets, resulting in ineffective cell-mediated immune responses.^33,34 It is important to note that firefighters are engaged in fire suppression activities with standard work-to-rest ratios; approximately 15 to 20 minutes of work and then resting for approximately 10 minutes.³⁵ The repeated work–rest regimen of firefighting may potentially exacerbate catecholamine and heart rate responses,^36,37 further contributing to the perturbation of lymphocyte subsets. Early studies have reported reduced NK and cytotoxic cell number/cytotoxicity and suppression of lymphocyte proliferation in humans after exposure to chronic stress.^38,39 The examination of the lymphocyte subset redistribution following prolonged or repeated bouts of physical and/or psychological stress is warranted.

Synopsis

Elevated stress hormones alter immune cell responses, and this important immune system response coordinates a number of the body’s adaptations to the stressor. However, a combined physical and psychological stress often experienced chronically by emergency responders exacerbates these stress hormone responses, which may be a contributing factor to the elevated risk of CVD and increased proportionate mortality risks. A greater understanding of stress–immune system interaction can assist in finding strategies (eg, exercise training) to overcome the inherent psychobiological challenges associated with mentally and physically demanding professions.

The Synergistic Effects of Concurrent Stress on Inflammation

Singhai⁴⁰ has stated that one of the earliest subclinical stages in the atherosclerotic process is an impairment of endothelium-dependent vasodilation, also known as endothelial dysfunction, and acute psychological stress induces transient endothelial dysfunction.⁴¹ One potential mechanism that links acute psychological stress to endothelial dysfunction is the level of circulating pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which have been shown to play important roles in the initiation and propagation of vascular inflammation and may provide insight into the mechanisms that explain the inflammatory processes in health and stress-related diseases.^7,8,42-44

Many studies have used laboratory-induced acute psychological stressors to examine the inflammatory response. Previous research has suggested that individuals who have a greater laboratory-induced stress response are more likely to experience higher stress in daily life,⁴⁵ and this response is associated with increased risk for atherosclerosis.⁴⁶ An increase in circulating TNF-α and IL-6 was observed following acute psychological stress⁴⁷ via activation of nuclear factor-kappa B.^48,49 In addition, previous research has shown that acute psychological stress exposure is also associated with increased pro-inflammatory cytokine, IL-2 levels.⁵⁰ Using a more prolonged stress model, Uchakin et al⁵¹ have examined several inflammatory cytokines following 24 hours of an examination in medical students and found that IL-2 levels were lower than the control group, but no changes were observed in interferon-γ (IFN-γ) and IL-10. Furthermore, Kang and Fox⁵² also examined chronic academic stress during examinations and found that decreased IL-2 (in both peripheral blood mononuclear cell [PBMC] and whole blood measures) and IFN-γ (only PBMC) levels were observed whereas an elevation was seen in IL-6 (in both PBMC and whole blood measures).

The magnitude and direction of inflammatory cytokine response (eg, IL-2 and IL-6) to exercise vary and are dependent on the acute or chronic nature of the stimuli (intensity and duration). For example, Akimoto et al⁵³ examined the effects of brief anaerobic maximal exercise and found that plasma IL-12 increased significantly after exercise. IL-12 has been demonstrated to generate the IL-2 response, further enhancing the activity of cytotoxic T cells and NK cells.^54-56 In addition, Steensberg et al⁵⁷ found that IL-6 increased following 2.5-h of treadmill exercise at 75% of maximal oxygen uptake. It is important to note that although IL-6 acts as a pro-inflammatory cytokine, it has also been identified as an anti-inflammatory agent. More specifically, Steensberg et al⁵⁸ infused IL-6 to attain intense exercise-induced concentrations in human subjects and observed elevated anti-inflammatory cytokines (eg, IL-10) 1 hour after IL-6 infusion. These findings indicate that an elevation in circulating IL-6 following exercise may initiate a reciprocal anti-inflammatory response that can promote recovery.

In a recent study, Ramey et al² examined the inflammatory cytokine response in law enforcement officers and found that the job demand (physical and psychological) assessed by the Job Content Questionnaire was positively associated with resting IL-β and IL-6. Furthermore, Huang and colleagues³⁰ examined stress hormone and immunological responses to a dual challenge in professional firefighters. This study used an FSTD as the mental challenge and cycling at 60% of Vo _2max (physical stress) as described above. This combination of physical and psychological challenge activated the sympathetic–adrenal–medullary axis, eliciting the release of catecholamines (NE and EPI) and elevating HR. Furthermore, firefighters demonstrated greater IL-2 levels following the dual challenge with a significant increase in CD56+ lymphocytes (mostly NK cells) in both conditions, but no change was observed in cytotoxic T cells and IL-6. These findings suggest that the addition of a mental challenge to physical stress can alter the hormonal and immunological responses during firefighting activities and, if exacerbated or prolonged, may play a role in the development of stress-related diseases.

Other investigators have found changes in IL-6 following exercise using a different protocol.⁵⁹ More specifically, Brenner et al⁵⁹ used a protocol of 2 hours of cycle ergometry at 60% Vo_2max, whereas the duration in the Huanget al study was 37 minutes. Furthermore, although the study by Huang et al³⁰ did not demonstrate elevations in IL-6, it is possible that changes occurred following the last measure that was taken at 1 hour of recovery. Previously, an increase in IL-6 has been reported to occur between 45 and 120 minutes after acute psychological stress (eg, Stroop Color Word and Mirror Tracing Tasks).^60-63 Interestingly, Groer et al⁶⁴ examined blood and salivary IL-6 levels in police officers following simulated incident scenarios: motorcycle scenario (2 minutes of a chase and traffic stop of a person on a motorcycle) and workplace scenario (6 minutes of tracking a gunman through a building). This study did not find elevated blood IL-6 levels in either scenario, but a significant increase in salivary IL-6 was observed in the workplace scenario group after 10 and 30 minutes of stimulation. To foster a better understanding of the cytokine responses to occupational stress, further studies with extended recovery periods are needed.

A limited number of studies have used a combination of acute laboratory stressors as a paradigm to examine the neuroendocrine and immune-inflammatory adaptations to physical and mental challenge. To alleviate the potential for the negative health outcomes in these occupations (ie, firefighting and law enforcement), investigators should examine possible mechanisms that may help explain the inflammatory processes in health and stress-related diseases. In turn, a greater understanding of inflammatory responses will facilitate efforts to address the potential negative impact of the immune system responses associated with professions exposed to the dual challenge.

Psychoneuroimmunological Responses and Physical Activity/Fitness

The benefits of physical activity and fitness on physiological and psychological health have been widely investigated. One of the purported benefits associated with aerobic fitness is the attenuation of the cardiovascular response during psychological stress and recovery.^65-67 Dienstbier⁶⁵ has proposed that this physiologically toughened response is demonstrated by an attenuation of central nervous system activation, including the sympathoadrenal axis, in response to a perceived threat. More specifically, aerobically trained individuals exhibit lower reactivity of the sympathetic nervous system (eg, heart rate) following acute psychological stress.^67-69 Furthermore, physically active individuals have exhibited lower state anxiety responses.^69,70 Although criteria for safe and effective fitness level has not been established in many occupations, the International Association of Fire Fighters⁷¹ and the National Fire Protection Association⁷² have recommended that firefighters achieve a maximal oxygen uptake of at least 42 ml/kg/min. Previous studies have documented firefighter fitness levels (Vo_2max) and found an average Vo_2max of 35 ml/kg/min.^32,73 However, Roberts et al⁷³ has also demonstrated an improvement in fitness level (Vo_2max) of 28% (35-45 ml/kg/min) following 16 weeks of exercise training.

Most important, Yoo et al⁷⁴ showed that approximately 23% of law enforcement officers who reported metabolic syndrome were physically inactive. In a cross-sectional study of 527 firefighters, Durand et al⁷⁵ demonstrated the CVD risk factors such as triglyceride and low-density lipoprotein cholesterol levels are negatively associated with time and frequency of physical activity per week. Furthermore, epidemiological evidence consistently shows that regular physical activity and exercise are effective prevention and treatment for CVD, type II diabetes, and stress-related diseases.^76-80 More specifically, previous research has examined the effects of physical fitness on the inflammatory response. For example, a reduction in pro-inflammatory levels (TNF-α and IL-6) was found in patients with coronary heart disease following aerobic exercise training,⁸¹ and lower IL-6 concentrations have been observed in individuals who had self-reported higher physical activity levels.⁸² In a cross-sectional study of 1004 participants, those who participated in moderate to high physical activity exhibited lower resting IL-6 levels compared with sedentary individuals.⁸³ Additionally, participation in exercise training may result in beneficial adaptations of physiological systems (eg, low inflammatory response) that are activated during acute psychological stress. Interestingly, in response to acute psychological stress, physical fitness is associated with a diminished pro-inflammatory cytokine response.⁸⁴ Poole et al⁸⁵ have also shown that mood change is associated with IL-6 levels following exercise withdrawal and training. These findings indicate that increased physical activity and higher levels of physical fitness may result in a more resilient immune defense and greater stress protection. Thus, exercise training program is likely a beneficial intervention to reduce the risks of CVD and stress-related diseases in occupations such as firefighting and law enforcement, and consideration should be given to annual physical performance evaluations.

Future Research Directions: Obesity and Psychological Stress

Obesity-attributable illnesses are associated with chronic inflammatory responses such as elevated pro-inflammatory cytokine production and activation of inflammatory signaling pathways.⁸⁶ A recent study reported 77% of young emergency responders (firefighters and ambulance recruits) were overweight and obese.¹³ Further studies also reported similar overweight and obese rates in other professions such as law enforcement¹⁴ and the military profession.^14-16 Along with physical illnesses, obesity is associated with psychosocial disorders such as depression and chronic anxiety.^87,88 Interestingly, Yoo and Franke⁸⁹ have reported that obesity is the most significant contributor of CVD in female law enforcement officers, who elicit a higher job-related stress level than male law enforcement officers. Furthermore, chronic stress has been shown to be associated with disturbances of the hypothalamic–pituitary–adrenal and sympathetic–adrenal–medullary axes and is linked to abdominal adiposity.⁹⁰ For example, elevated cortisol responses to mental stress are associated with high central adiposity,^91-93 and with corresponding elevations in pulse pressure and heart rate.^94,95 Interestingly, Wirtz et al⁴⁵ have demonstrated that individuals with higher body mass index demonstrated lower glucocorticoid sensitivity, resulting in a diminished ability to inhibit production of TNF-α following acute psychological stress. This finding suggests that in response to acute psychological stress individuals with higher body mass index exhibit elevations in pro-inflammatory cytokine production (eg, TNF-α) due to diminished glucocorticoid suppression.

Recent studies have shown that obese subjects exhibit higher circulating and in vitro IL-6 levels compared with normal-weight subjects in response to acute psychological stress.^92,96 Because β-adrenergic receptors have been shown to have an inhibitory effect on the release of pro-inflammatory cytokines (ie, TNF-α and IL-6),^97,98 these results suggest the possibility that obesity could diminish the inhibitory effect of β-adrenergic receptors on the release of pro-inflammatory cytokines in response to psychological stress. In addition, leptin, an adipocyte-derived hormone, is positively associated with elevated percentage body fat and plays an important role in metabolism, adiposity, and vascular inflammation, and it has recently been implicated in the development of coronary heart disease.⁹⁹ Furthermore, recent research has shown that people who undergo acute psychological stress demonstrate increases in leptin levels, and these increases are positively correlated with waist circumference.^100,101 Brydon and colleagues¹⁰¹ also showed that a positive correlation between basal circulating leptin and IL-6 responses in response to mental stress.

It is important to note that a recent investigation has demonstrated that peripheral blood mononuclear cells were involved in the elevated concentrations of pro-inflammatory cytokines (eg, TNF-α and IL-6) in obese individuals,¹⁰² but no differences in the number of immune cell subsets including peripheral blood mononuclear cells (eg, monocytes and lymphocytes) have been observed between normal-weight and obese subjects following acute psychological stress.⁹² This suggests that the association of obesity with pro-inflammatory cytokines in response to acute psychological stress is not likely due to differences in immune cell subsets, and thus, the possible mechanisms contributing to the relationship of the stress response, obesity, and pro-inflammatory cytokines still remains unknown. Future investigation on the possible interaction (additive or synergistic) of obesity and psychological stress on the development of cardiovascular diseases in these professions is warranted and may help in finding practical and innovative strategies (eg, weight loss, exercise training, and pharmacological interventions) for the prevention and treatment of stress-related diseases.

Conclusion

Occupational stress, in particular combined physical and psychological stress, often experienced by firefighter, military personnel, and law enforcement officers may be a contributing factor to the elevated risk of CVD and stress-related diseases and relative increased mortality. Many studies have supported the benefits of physical activity on physiological and psychological health including greater immune defense and stress protection. Furthermore, high rates of obesity have been reported in many occupations, and studies have demonstrated that obesity exacerbates the inflammatory responses (eg, elevated pro-inflammatory cytokine production) following psychological stress. Thus, it seems apparent that a criterion for fitness level should be established for safe and effective participation in occupation-related activities. Fitness training programs should also be implemented to improve physical fitness levels for workers in these occupations, and annual physical fitness and performance evaluations should be conducted. Finally, while the mechanisms contributing to the relationship of the stress response, obesity, and pro-inflammatory cytokines still remains unknown, programs to encourage and support emergency responders in achieving and/or maintaining healthy body weight may produce health benefits.

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