Systemic Response to Injury


Hormonal Response to Injury

  1. Stimuli
    • Hormone-mediated response to injury results from multiple inputs:
      • Neural and nociceptive inputs originating from the site of injury
      • Baroreceptor stimulation from intravascular volume depletion
      • Mediators released by injured tissue (cytokines)
      • Emotion (fear, anxiety)
    • Pituitary gland and the autonomic nervous are primarily responsible for the hormonal response to injury

  2. Hypothalamic-Pituitary Axis (HPA)
    • Pituitary is divided anatomically and functionally into two parts: adenohypophysis (anterior) and neurohypophysis (posterior)

    1. Anterior Pituitary
      • No direct arterial supply
      • Blood inflow is supplied by venous blood from long portal veins connecting the median eminence of the hypothalamus and the anterior pituitary
      • Short portal veins from the posterior pituitary also contribute to the anterior lobe’s blood supply
      • Hypothalamic nuclei produce factors which are secreted into the hypothalamic-hypophyseal portal system, where they stimulate or inhibit anterior pituitary hormone release

    2. Posterior Pituitary
      • Anatomic extension of the CNS
      • Factors are synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and are transported by axoplasmic flow to the posterior pituitary for secretion

  3. Hormones Under Anterior Pituitary Regulation
    1. CRH, ACTH, Cortisol
      1. CRH
        • Synthesized in the hypothalamus in response to pain, fear, anxiety, or emotional arousal
        • Interleukin-1 also induces CRH synthesis and release
        • Serves as the major stimulus for ACTH in the anterior pituitary
        • Circulating glucocorticoids exert a potent negative feedback signal

      2. ACTH
        • Synthesized, stored, and released by the anterior pituitary in response to CRH stimulation
        • In nonstressed individuals, ACTH release is circadian in nature, with the greatest elevation occurring late at night and ending before sunrise
        • In injured patients, this circadian release is abolished and elevations of CRH and ACTH are proportional to the severity of the injury
        • ACTH stimulates the synthesis of cortisol within the zona fasciculata of the adrenal cortex

      3. Cortisol
        • Essential for survival after significant physiologic stress
        • Major effect is on host metabolism
        • Stimulates hepatic gluconeogenesis
        • Potentiates the actions of glucagon and epinephrine → hyperglycemia
        • Decreases insulin-binding to insulin receptors in muscles and adipose tissue
        • In skeletal muscle, induces proteolysis and augments release of lactate (provides substrates for hepatic gluconeogenesis)
        • Stimulates lipolysis and inhibits glucose uptake by adipose tissue
        • Downregulates the inflammatory response by decreasing secretion of pro-inflammatory cytokines and increasing secretion of anti-inflammatory cytokines

    2. TRH, TSH, T4, T3
      • TRH is the primary stimulant for the synthesis, storage, and release of TSH from the anterior pituitary
      • TSH stimulates the thyroid gland to produce thyroxine (T4)
      • T4 is converted by peripheral tissues to T3
      • After major injury, T3 and TSH levels are reduced and peripheral conversion of T4 to T3 is impaired
      • Total T4 may be reduced after major injury, but free T4 remains relatively constant

    3. Growth Hormone
      • GHRH from the hypothalamus stimulates release of GH
      • Other stimuli include stress, hypovolemia, hypoglycemia
      • Role of GH during stress is to promote protein synthesis while enhancing the mobilization of fat stores
      • GH also inhibits insulin release and decreases glucose oxidation, leading to hyperglycemia
      • Protein synthesis properties are partially mediated by the secondary release of insulin-like growth factor-1 (IGF-1)
      • Overall decreased protein synthesis and negative nitrogen balance observed after injury are attributed to decreased IGF-1 levels

  4. Hormones Under Posterior Pituitary Regulation
    1. Vasopressin (ADH)
      • ↑ plasma osmolality is the primary stimulus for ADH release
      • Na-sensitive osmoreceptors are located in the hypothalamus
      • Hypovolemia, sensed by baroreceptors and left atrial stretch receptors, is also an important stimulus for ADH release
      • In the kidney, ADH promotes absorption of water from the distal collecting ducts
      • Peripherally, ADH mediates vasoconstriction
      • Stimulates hepatic glycogenolysis and gluconeogenesis, and the resulting hyperglycemia, via increased osmolality, contributes to the restoration of effective circulating volume

  5. Hormones of the Autonomic System
    1. Catecholamines
      • Norepinephrine and epinephrine are the major catecholamines
      • Epinephrine is secreted by the adrenal medulla
      • Norepinephrine in plasma results from synaptic leakage during sympathetic nervous system activity
      • Peak elevations occur 24 - 48 hrs after injury

      1. Metabolic Effects
        1. Liver
          • ↑ Glycogenolysis
          • ↑ Gluconeogenesis
          • ↑ Lipolysis
          • ↑ Ketogenesis

        2. Adipose Tissue
          • ↑ Lipolysis

        3. Skeletal Muscle
          • ↑ Glycogenolysis
          • ↓ Insulin-stimulated glucose uptake

      2. Hemodynamic Effects
        • Venous + arterial vasoconstriction (α1)
        • ↑ Myocardial rate, ↑ contractility, and ↑ conductivity (β1)
        • ↑ Smooth muscle relaxation (β2)

      3. Hormonal Modulations
        • ↑ Renin
        • ↑ Glucagon
        • ↓ Insulin

    2. Renin-Angiotensin
      • Synthesized and stored within the renal juxtaglomerular apparatus near the afferent arteriole
      • Renin release is under the control of three different mechanisms:

      1. Macula Densa
        • Receptor senses chloride concentration in the fluid of the distal nephron
        • ↓ Chloride → ↑ renin

      2. Juxtaglomerular Apparatus
        • Baroreceptor
        • ↓ Stretch → ↑ renin

      3. Adrenergic
        • β-adrenergic stimulation → ↑ renin

      • Renin catalyzes the conversion of angiotensinogen to angiotensin I in the kidney
      • Angiotensin I is converted into angiotensin II (AII) in the lungs by angiotensin-converting enzyme
      • Angiotensin II:
        • Potent vasoconstrictor
        • Increases heart rate and contractility
        • Stimulates aldosterone synthesis and secretion
        • Regulates thirst
        • Stimulates ADH synthesis

    3. Aldosterone
      • Secreted by the zona glomerulosa of the adrenal
      • Stimulated by angiotensin, hyperkalemia, and ACTH
      • ACTH is the most potent stimulus in the injured patient
      • Major function is to maintain intravascular volume by absorbing sodium (and water) in the distal convoluted tubule

    4. Insulin
      • Produced by pancreatic β cells
      • In normal metabolism, glucose is the major stimulus for insulin secretion
      • Major anabolic hormone, promoting storage of carbohydrate, lipid, and protein
      • Promotes entry of glucose into cells, increases glycogenesis, and inhibits gluconeogenesis
      • In the first hours after injury, epinephrine and sympathetic stimulation inhibit insulin release
      • Later, insulin production is normal or increased but hyperglycemia persists, reflecting a peripheral insulin resistance

    5. Glucagon
      • Produced by pancreatic α cells
      • Stimulates hepatic glycogenolysis and gluconeogenesis
      • In normal metabolism, hypoglycemia is the major stimulus for secretion
      • In injury, the sympathetic nervous system is the major stimulus

Immune-Mediated Response to Injury

  1. Overview
    • Inflammatory response to injury occurs as a response to the local or systemic release of “damage-associated” molecules (DAMPs or alarmins)
    • DAMPS activate the innate immune system and initiate a ‘sterile’ systemic inflammatory response following major trauma
    • Cells of the innate immune system (NK cells, monocytes, macrophages, neutrophils) interact with DAMPs via pattern-recognition receptors (PRRs)
    • PRRs initiate an intracellular signaling cascade that results in the production of a huge range of cytokines
    • Cytokines are indispensable in tissue healing and in the immune response generated against microbial invasions

  2. Detection of Cellular Injury
    1. DAMPS
      • Endogenous molecules that are immunologically active
      • Released from damaged/necrotic cells
      • once outside cells, DAMPS activate innate immune cells and antigen-presenting cells via PRR receptors

      1. High Mobility Group Protein B1 (HMGB1)
        • Nonhistone chromosomal protein rapidly released into the circulation within 30 minutes of trauma
        • Levels correlate with Injury Severity Score
        • Exogenous administration produces fever, weight loss, epithelial barrier dysfunction, and death in normal animals

      2. Mitochondrial DNA
        • Plasma concentrations are thousands of times higher in injured patients compared to normal volunteers
        • Results in activation of the macrophage inflammasome, a cytosolic signaling complex that responds to cellular stress
        • Injection of mitochondrial lysates in animals causes remote organ damage

      3. Additional DAMPs
        • Extracellular matrix molecules (proteoglycans, etc)
        • Heat shock proteins
        • S100

    2. Pattern Recognition Receptors (PRRs)
      • Same receptors that mediate the innate immune response to pathogens

      1. Toll-Like Receptors (TLRs)
        • Best characterized PRRs in mammalian cells
        • TLR expression is significantly increased following blunt traumatic injury
        • Receptor binding results in activation of gene transcription and production of multiple cytokines

  3. Regulation of Inflammation in Response to Injury
    1. CNS Regulation
      • CNS receives inputs from DAMPs and cytokines as well as neural inputs
      • Neural inputs from the periphery are mediated by the vagus nerve
      • Vagal fibers interconnect in the hypothalamus to modulate the HPA axis

    2. HPA Axis
      • Multiple cytokines produced after injury result in CRH and ACTH secretion
      • Afferent vagal input results in CRH release as well
      • Cortisol inhibits proinflammatory gene expression

    3. Macrophage Inhibitory Factor (MIF)
      • Proinflammatory cytokine
      • Prolongs macrophage survival
      • Causes secretion of TNF-α, IFN-γ, IL-1
      • May counter the anti-inflammatory activity of cortisol

    4. Catecholamines
      • Directly influence inflammatory cytokine production
      • Have anti-inflammatory activity

  4. Mediators of Inflammation
    1. Cytokines
      • Small polypeptides or glycoproteins that exert their influence at very low concentrations
      • Produced at the site of injury by many diverse cell types and immune cells
      • Activity is primarily exerted locally via cell-to-cell (paracrine) interaction
      • Bind to specific cell receptors and activate intracellular signaling pathways leading to modulation of gene transcription
      • Biologic effects:
        • Direct the inflammatory response to infections and injury
        • Regulate wound healing
        • Influence immune cell production, differentiation, proliferation, and survival
        • Regulate the production and actions of other cytokines

      1. Tumor Necrosis Factor (TNF)
        • Earliest cytokine produced
        • Sources include monocytes/macrophages, T-cells, and dendritic cells
        • Extremely short half-life (15 - 18 minutes)
        • Activates cytokines distally in the cascade
        • Endogenous inhibitors of TNF (soluble receptors) exist to prevent propagation of unregulated TNF activity
        • Biologic effects:
          • Muscle catabolism and cachexia during stress
          • Increases coagulation activation, cell migration, and macrophage phagocytosis
          • Inhibits the major anticoagulant pathways (antithrombin III, protein C), leading to a hypercoagulable state

      2. Interleukin-1 (IL-1)
        • TNF induces synthesis and release of IL-1 from macrophages and endothelial cells
        • Responsible for the classic febrile response to injury by stimulating prostaglandin activity in the hypothalamus
        • Induces anorexia by effecting the satiety center
        • At high doses, may cause the hemodynamic instability of septic shock (so may TNF)
        • Potent stimulator of ACTH secretion

      3. Interleukin-6
        • Elevated blood levels are often observed during injury or stress and are proportional to the degree of injury
        • Used as an marker of the systemic inflammatory response syndrome
        • Important mediator of the hepatic acute-phase protein response (C-reactive protein) during injury
        • Promotes angiogenesis

      4. Interleukin-4, Interleukin-10
        • Anti-inflammatory cytokines produced by TH2 cells
        • Mitigate the effects of TNF and IL-1
        • Re-establishment of immune homeostasis requires the resolution of inflammation

      5. Interleukin-2
        • Produced by CD4 T cells after antigen activation
        • Important in T cell differentiation
        • IL-2 receptor blockade causes immunosuppression and is used in organ transplantation
        • Relatively immunosuppressed state of the surgical patient may be due to reduced IL-2 expression

      6. Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)
        • Hematopoietic growth factor and proinflammatory cytokine
        • Increases the number of circulating neutrophils
        • Being evaluated in clinical trials as an agent that can ameliorate posttraumatic immune suppression

      7. Transforming Growth Factor-β
        • Plays an important role in leukocyte development and function, wound healing, inflammation, and suppression of tumorigenesis
        • Has anti-inflammatory effects on the immune response

      8. Eicosanoids: Thromboxane, Prostaglandins, Leukotrienes
        • Cyclooxygenase (COX-1, COX-2) converts arachidonic acid into thromboxane and prostaglandins
        • Thromboxane is a potent vasoconstrictor and platelet aggregator
        • Prostaglandins promote vasodilation and microvascular permeability

      9. Complement
        • Immediately activated following traumatic injury
        • Major effector mechanism of the innate immune system via generation of the membrane attack complex
        • Participates in the removal of dead and damaged cells

      10. Nitric Oxide (NO)
        • iNOS catalyzes conversion of L-arginine to NO
        • Serves as a signaling and effector molecule
        • Biologic actions:
          • Vasodilation
          • Induction of vascular hyperpermeability
          • Inhibition of platelet aggregation
        • Excessive production of NO is thought to be a major reason for loss of vasomotor tone and loss of responsiveness to vasopressor agents in septic shock

      11. Reactive Oxygen Species (ROS)
        • Produced as a byproduct of normal metabolism
        • Highly reactive, capable of modifying lipids, proteins, and nucleic acids
        • Cells are equipped with antioxidant systems to counter the activity of ROS
        • In times of stress, ROS production can increase dramatically and overwhelm normal antioxidant defenses







References

  1. Schwartz, 10th ed., pgs 13 – 43
  2. Sabiston, 20thed., pgs 25 - 35
  3. Sabiston, 19th ed., pgs 40 – 63