10.2 From Notes - Stress and Disease: A Psychoneuroimmunological View

Stress and Disease: A Psychoneuroimmunological Perspective

• Walter B. Cannon first used the term "stress" in 1914, applying the engineering concept of stress and strain to physiologic and psychologic ideas.
• Hans Selye popularized the concept of stress in 1946, viewing it as a biologic phenomenon.
• Selye discovered the general adaptation syndrome (GAS) while experimenting with ovarian extracts in rats.
• The triad of structural changes Selye observed included:
  • Enlargement of the adrenal cortex
  • Atrophy of the thymus gland and other lymphoid structures
  • Bleeding ulcers in the stomach and duodenal lining
• Selye defined stressors as noxious stimuli like cold, surgical injury, and restraint.
• The GAS has three stages:
  • Alarm stage: CNS arousal and mobilization of body defenses ("fight or flight" response)
  • Resistance stage: continued mobilization to support "fight or flight"
  • Exhaustion stage: breakdown of compensatory mechanisms and homeostasis, leading to diseases of adaptation
• During the alarm stage, the hypothalamus and sympathetic nervous system (SNS) are activated.
• The resistance phase involves hormones like cortisol, norepinephrine, and epinephrine.
• Exhaustion, or allostatic overload, occurs if stress persists and adaptation fails, potentially leading to immune impairment, heart failure, kidney failure, and death.
• Modern understanding views the stress response as a complex model involving the CNS, autonomic nervous system (ANS), hypothalamic-pituitary-adrenal (HPA) axis, and the immune system.
• The idea of stress as a purely physiologic response is oversimplified; psychologic factors significantly influence the stress response.
• Stress is defined transactionally as the state arising when a person appraises and reacts to situations.
• Stress occurs when a perceived demand exceeds an individual's coping abilities, leading to disturbances in cognition, emotion, and behavior
• Psychologic stressors can elicit reactive or anticipatory stress responses.
• Anticipatory responses can be innate or learned and involve brain regions like the hippocampus, amygdala, and prefrontal cortex, stimulating the paraventricular nucleus (PVN) of the hypothalamus.
• Chronic stress is immunosuppressive, while acute stress may be immunoenhancing.
• Adverse life circumstances can alter circulating leukocytes, increase pro-inflammatory gene expression, and decrease antiviral response gene expression.
• Chronic inflammation is a major contributor to morbidity and mortality.
• Allostatic overload results from long-term functional changes in the stress-related HPA axis and SNS, potentially compromising the immune system and health.

Concepts of Stress, Homeostasis, and Allostasis

• Homeostasis involves a set point and physiologic equilibrium.
• Allostasis proposes that physiologic systems are dynamic and can change their set points after exposure to stress.
• Chronic stress can induce changes in physiologic set points, which may underlie pathophysiologic conditions.
• Allostatic load represents the individualized cumulative effects of stressors on an individual's physiologic responses.
• Factors contributing to allostatic load include:
  • Vulnerable physiology/genetics
  • Lifestyle
  • Daily stress
  • Extraordinary events
• Over time, allostatic load can cause wear and tear on the body.
• The brain is crucial in perceiving what is stressful and determining when toxic allostatic overload is felt.
• Under allostatic overload, the parasympathetic system's restraint on the sympathetic system may decrease, leading to increased or prolonged inflammatory responses.
• In response to acute and chronic stress, brain regions like the hippocampus, amygdala, and prefrontal cortex can undergo structural remodeling.
• Structural remodeling can alter behavioral and physiologic responses, such as cognitive impairment or depression.
• The adult and developing brain exhibit structural and functional plasticity in response to stress.
• Brain-derived neurotrophic factor (BDNF), tissue plasminogen activator (tPA), corticotropin releasing hormone (CRH), Lipocalin-2, and endocannabinoids (eCBs) are involved in brain remodeling during stress and recovery.
• Stress can cause an imbalance in neural circuitry, affecting cognition, decision-making, anxiety, and mood.
• Imbalances affect systemic physiology via neuroendocrine, autonomic, immune, and metabolic mediators.
• Key mediators and biomarkers of allostatic overload include cortisol, catecholamines, and pro-inflammatory cytokines.
• Sleep deprivation can lead to elevated evening cortisol, insulin, and blood glucose levels, increased blood pressure, reduced parasympathetic activity, increased pro-inflammatory cytokines, and increased ghrelin.
• Sleep deprivation may cause increased caloric intake, depressed mood, and cognitive problems.
• Research focuses on interactions among social, psychologic, biologic, and behavioral risk factors in disease processes.
• There is a more holistic model of health and disease involving the CNS, ANS, endocrine, and immune systems, as well as stress-elicited coping behaviors.

Psychoneuroimmunologic Mediators of Stress

• Psychoneuroimmunology (PNI) studies the interaction of consciousness, the brain and spinal cord, and the body's defenses.
• PNI assumes all immune-mediated diseases result from interrelationships among psychosocial, emotional, genetic, and behavioral factors with the neurologic, endocrine, and immune systems.
• The immune system is integrated with other physiologic processes and is sensitive to CNS and endocrine functioning changes accompanying psychologic states.
• Various stressors can elicit the stress response through the nervous and endocrine systems.
  • Infection
  • Noise
  • Decreased oxygen
  • Pain
  • Malnutrition
  • Temperature extremes
  • Trauma
  • Exertion
  • Radiation
  • Life events
  • Obesity
  • Old age
  • Drugs
  • Disease
  • Surgery
• Stress-released hormones influence metabolic systems and physiologic events. Psychosocial stressors or interventions can modulate the immune system to impact health outcomes
• Any level of psychologic distress is associated with increased mortality and risk of death from cardiovascular disease, external causes, and cancer.
• Workplace stressors like job insecurity, high job demands, and long work hours increase the odds of reporting poor health, diagnosed illness, and mortality.
• Work-related stress can cause behavioral and psychosocial problems.

Stress Response

• The perception of stress initiates events in the central and peripheral nervous systems.
• In the brain, stress elicits an anticipatory response activating the limbic system.
• The limbic system elicits an endocrine stress response by stimulating neural pathways receiving sensory information.
• The limbic system directly stimulates the locus ceruleus (LC) to release norepinephrine.
• Norepinephrine promotes arousal, vigilance, anxiety, and other protective emotional responses.
• Real stressors elicit a reactive response beginning in the limbic system or brain in response to specific sensory information, relayed to the PVN.
• The PVN stimulates the LC and both central and endocrine stress responses.
• The sympathetic adrenal medullary system releases catecholamines (norepinephrine and epinephrine) in the periphery.
• The slower-acting HPA system culminates in cortisol secretion.
• Activation of these systems redirects adaptive energy to the CNS and peripheral sites to cope with stress.

Sympathetic Nervous System

• Stress activates the SNS to stimulate the release of catecholamines (epinephrine and norepinephrine) from the adrenal medulla into the bloodstream and nerve endings.
• The adrenal medulla is an extension of the SNS.
• Preganglionic fibers from the splanchnic nerve innervate chromaffin cells that produce catecholamines.
• Catecholamines affect gene expression and cellular function through adrenergic receptors (α1, α2, β1, β2, β3)
• Acute "fight or flight" responses:
  • Increase heart rate (β1)
  • Redistribute blood (α1, β2)
  • Increase respiratory rate (α1, β2)
  • Mobilize energy (β2, β3)
  • Mobilize immune cells (β2 on leukocytes)
• Catecholamines increase blood flow and glucose metabolism in the brain, heart rate and force, peripheral vasoconstriction, bronchodilation, glycogenolysis in skeletal muscle, glucose production in the liver, lipolysis in adipose tissue, decreased blood flow in the skin, decreased gastrointestinal and genitourinary smooth muscle contraction, and modulate immune cells. Some responses require glucocorticoids for maximal activity.
• Epinephrine causes transient hyperglycemia, decreases glucose uptake in muscles, and decreases insulin release.
• Adrenal norepinephrine's stress response effects are primarily elicited from the SNS.
• Epinephrine has a greater influence on cardiac action (inotropy, chronotropy) and metabolic regulation, increasing cardiac output, blood pressure, venous return, and dilating blood vessels in skeletal muscle.
• Epinephrine mobilizes free fatty acids and cholesterol by stimulating lipolysis and inhibiting cholesterol degradation.
• Epinephrine binds to and activates both α- and β-adrenergic receptors, while norepinephrine at physiologic concentrations primarily binds to α-adrenergic receptors.
• Epinephrine injection transiently increases lymphocytes (T and NK cells) but reduces their responsiveness.
• Catecholamines increase pro-inflammatory cytokine production.
• Chronic dysfunctional HPA axis stimulation may increase inflammation in the brain and other tissues, potentially contributing to osteoporosis, metabolic disease, and cardiovascular disease.

Parasympathetic System

• The parasympathetic system balances the SNS and influences adaptation to stress.
• It has anti-inflammatory effects and opposes sympathetic responses, such as slowing heart rate.
• Heart rate variability is used to evaluate balance between the parasympathetic and sympathetic nervous systems.

Neuroendocrine Regulation

Hypothalamic-Pituitary-Adrenal (HPA) System

• The PVN of the hypothalamus secretes corticotropin-releasing hormone (CRH).
• CRH binds to receptors on anterior pituitary cells, causing them to produce adrenocorticotropic hormone (ACTH).
• ACTH travels through the blood to the adrenal glands, stimulating the release of glucocorticoid hormones (primarily cortisol) from the adrenal cortex.
• Cortisol initiates metabolic changes and is thought to enhance immunity during acute stress but suppress it during chronic stress.
• Cortisol provides a negative feedback signal to the pituitary and hypothalamus to terminate the HPA stress response.
• Cortisol reaches all tissues, easily penetrates cell membranes, and interacts with intracellular glucocorticoid receptors.

Glucocorticoids: Cortisol

• Cortisol circulates in plasma, bound to transcortin (corticosteroid-binding globulin), with the unbound (free) fraction (around 8%) being biologically active.
• Cortisol stimulates gluconeogenesis in the liver.
• Cortisol enhances the blood glucose elevation promoted by other hormones, acting permissively.
• Cortisol inhibits glucose uptake and oxidation by many body cells, increasing blood glucose concentration.
• Cortisol has an anabolic effect in the liver, increasing protein and RNA synthesis, but a catabolic effect on protein stores in other tissues (muscle, bone, connective tissue, skin).
• Chronic excess cortisol can deplete protein stores.
• Cortisol reduces protein synthesis in nonhepatic tissues and may depress amino acid transport into muscle cells while enhancing uptake into the liver.
• Cortisol promotes gastric secretion, potentially causing gastric ulcers.
• Chronic stress-induced effects of glucocorticoids, along with catecholamines and the immune system, contribute to the development of metabolic syndrome and obesity.
• Prenatal stress or elevated glucocorticoids may increase offspring's risk of disease.
• Chronic glucocorticoid secretion inhibits the growth axis partly by elevated CRH, which increases somatostatin, inhibiting growth hormone (GH).
• Chronic stress can cause dendritic retraction or expansion, cell death, or inhibited neurogenesis in brain regions with glucocorticoid, catecholamine, and excitatory amino acid receptors.
• Stress and corticosteroids directly influence mitochondrial DNA (mtDNA) transcription and physiology.
• Moderate stress may show temporary dendritic shrinkage and spine loss in the hippocampus, but chronic stress can lead to cell death and inhibit neurogenesis.
• The amygdala shows dendritic field expansion and increased CRH neuron synthesis under chronic stress
• The prefrontal cortex exhibits dendritic shrinkage in the medial prefrontal cortex under chronic stress.
• Stress-induced brain alterations in emotional and cognitive disorders may result from an inability to readily induce synaptic changes for recovery and resilience.
• Cortisol secretion during stress can inhibit initial inflammatory effects and promote resolution and repair.
• Glucocorticoids can also induce T-cell apoptosis.
• Cortisol suppresses Th1 cell activity and stimulates Th2 cell activity.
• Epinephrine and norepinephrine have similar effects.
• Initially, immune responses are regulated by antigen-presenting cells (APCs) and Th1/Th2 lymphocytes, which secrete cytokines (interferons, interleukins, TNF).

Physiology of Stress and Its Effects

Introduction to Stress

• Western culture's emphasis on a strong work ethic, rooted in 16th-century Protestant philosophy, can lead to stress-related disorders
• These disorders arise when the brain perceives a stimulus that triggers a stressful, adaptive, and survival-related psychological response.

The Nature of Stress

• Acute stress is generally immune-enhancing but chronic stress is often immune-suppressive.

Brain Activation and Hormonal Release

• In the brain, stress initiates an anticipatory response that activates the limbic system.
• The limbic system subsequently activates neural pathways for receiving sensory information and causes the release of norepinephrine and the slower-acting cortisol.

Adrenal Medulla and the "Fight or Flight" Response

• Stress activates the release of epinephrine and norepinephrine from the adrenal medulla
• These hormones cause various physiological effects for "fight or flight"
  • Gluconeogenesis
  • Increased cardiac output
  • Increased blood pressure

The HPA Axis

• The hypothalamic-pituitary-adrenal (HPA) axis is a crucial component of the stress response.
• The ventricular nucleus of the hypothalamus secretes corticotropic-releasing hormone (CRH).
• CRH binds to receptors on anterior pituitary cells, stimulating the production of adrenocorticotropic hormone (ACTH).
• ACTH is then transported to the adrenal glands, leading to the release of glucocorticoid hormones, primarily cortisol.

Effects of Cortisol

Immunity

• Cortisol is thought to enhance overall immunity during acute stress
• Cortisol suppresses immunity with prolonged exposure in chronic stress.

Cellular Permeability

• Cortisol can easily diffuse into all tissues and penetrate cell membranes, allowing it to exert significant adverse actions.

Negative Feedback

• Cortisol stimulates a negative feedback mechanism in the pituitary and hypothalamus to decrease further production.

Glucose Metabolism

• Cortisol causes gluconeogenesis and inhibits glucose uptake by many body cells, resulting in overall increased blood glucose levels.

Protein Metabolism

• Cortisol increases the rate of protein synthesis in the liver
• Cortisol promotes catabolism (metabolism) in other tissues.
• This process increases circulating amino acid levels but can severely deplete protein stores in muscle, connective tissue, and skin during chronic exposure.

Metabolic Syndrome and Obesity

• Chronic secretion of cortisol, combined with catecholamines and the immune system response, contributes to the development of metabolic syndrome and the pathogenesis of obesity.
• Over time, this can lead to increased visceral fat and a loss of muscle and bone mass.

Cortisol and Inflammation/Immunity (Acute Stress)

• Acutely, cortisol inhibits initial inflammatory effects.
• It suppresses the activity of TH1 cells
• TH1 cells decrease in innate immunity and a pro-inflammatory response.
• TH2 cell activity is stimulated, which increases adaptive immunity and the anti-inflammatory response.
• TH1 to TH2 shift can make individuals more susceptible to allergic responses, infections, and temporary worsening of autoimmune conditions like arthritis.

Peripheral CRH

• CRH is secreted by the hypothalamus and at sites of inflammation.
• Peripheral CRH is pro-inflammatory, stimulating mast cells, which causes vasodilation and increased vascular permeability.

Systemic vs. Local Stress Responses

• Systemic responses to stress generally cause a decrease in innate immunity and an enhancement in adaptive immunity.
• Local stress responses may induce pro-inflammatory activities that can contribute to infections, autoimmune, allergic, and neoplastic diseases.

Other Hormones Influenced by Stress

Reproductive System

• Stress generally inhibits the female reproductive system, primarily through the HPA axis.

Endorphins and Enkephalins

• Decrease pain and may play a role in excitement and exhilaration.

Prolactin

• Influences immune cells by acting as a second messenger for interleukin-2 and positively affects B-cell activation and differentiation.

Oxytocin

• Modulates fear and anxiety and attenuates the HPA stress response.

Testosterone

• Levels decrease after stressful stimulation and may contribute to a greater susceptibility to sepsis and mortality in males following injury.

Stress and Coping (Psychological Distress)

• Psychological distress involves a general state of unpleasant arousal after exposure to life events, manifesting as psychological, emotional, cognitive, and behavioral changes.
• It's important to use effective coping mechanisms and seek social support.