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ses Correlate all of the above to better understand how our body adapts itself to bring about homeostasis in stress Role of inflammation as a response in stress To activate cellular processes To restore function To remove invading organism Clinical spectrum of Infection & Systemic inflammatory response syndrome (SIRS) Infection: Identifiable source of microbial insult SIRS: 2 or more of the following: T > 38C or < 36C HR > 90/min RR > 20/min PCO2 < 32 mmHg Mechanical ventilation WBC > 12,000 or < 4,000, > 10 band forms Sepsis: Identifiable source of infection Severe sepsis: Sepsis & organ dysfunction Septic shock: Sepsis + cardiovascular collapse (requiring vasomotor support) Two Hit theory in Multiple Organ Dysfunction (MODS)
First Hit Second Hit
Mediators Cytokines Eicosanoids Nitric oxide Complement fragments Endotoxin Heat shock proteins Reactive O2 metabolites Kallikrein-kinin system Fatty acid metabolites CHRABI Cytokines Glycoprotein secreted for the purpose of altering function of target cells in an endocrine like fashion Not from specialized cells but from activated cells Interferon Gamma Together with IL-12 & IL-18, activate TH0 helper cells to TH1 cells capable of secreting several pro-inflammatory cytokines (Independently or synergistically act together Inhibits differentiation of lymphocytes to TH2 (Producer of anti-inflammatory cytokines) Pro-inflammatory interleukins (IL-1, IL-6, IL-8) Vasodilation Increased vascular permeability Chemoattractant to neutrophils & mononuclear phagocytes Anti-inflammatory interleukins (IL-4, IL-10, IL-13) Tumor necrosis factor Obtained from LPS challenged animals Capable of killing cells in vitro Cause necrosis of transplantable tumor in mice Also known as cachectin
Nitric oxide Formerly known as endothelium derived relaxing factor Activates guanylate cyclase in smooth muscle to form cyclic guanosine monophosphate dependent vasodilation Eicosanoids
Membrane Phospholipids Phospholipase
Death
Death
S I R S
Cyclooxygenas e PGG2
Arachidonic Acid
Lipoxygenas e Leukotriene s
C A R S
HOURS
MOF
PGH2 Thromboxane A2
DAYS
Prostacycli n
Decreased effective circulatory volume Vasomotor center Catecholamines Vasoconstriction, Increase heart rate, increase blood pressure Increased plasma osmolality, Decreased effective circulatory volume Posterior pituitary Vasopressin Reabsorption of water in the renal distal tubules & collecting ducts, Splanchnic vasoconstriction, Enhances glycogenolysis & gluconeogenesis Decreased blood flow Juxtaglomerular apparatus Renin Angiotensinogen Angiotensin I Angiotensin II Aldosterone Restoration of blood volume
MICROPHAGE Th0
IL-12 IL-18
I N F L A M M A TI O N
Induces proteolysis & lactate release in skeletal muscle Induces lipolysis Inhibit glucose uptake by adipose tissue Hyperglycemia Injury Hypothalamus Increased growth hormone releasing hormone Anterior pituitary Increased growth hormone Promotes protein synthesis, enhances mobilization of fat stores Catecholamines Glycogenolysis Gluconeogenesis Lipolysis Ketogenesis Anti-insulin Promote glucagons secretion Increase intracellular cAMP leading to decrease immune response Summary Inflammation is needed to initiate cellular activities to restore function & remove invading organisms Inflammation will not answer for the immediate responses to life-threatening situation Hormonal vasoactive responses do Energy to effect changes for homeostasis is provided CHRABI
Th1 Cell
Th2 cell
CNS M V Acetylcholin e s v
Injury site TNF, IL1
s ACTH y Glucocorticoi m ds p a t h e t i c
Injury
Angiotensin II Vasoconstrictor Stimulates aldosterone & vasopressin synthesis Stimulates heart rate & contractility Stimulates epinephrine & CRH release Activates sympathetic nervous system Induces glycogenolysis & gluconeogenesis Aldosterone Maintain intravascular volume by conserving sodium Eliminate potassium & hydrogen ions What we learn up to this point Inflammatory response Vasomotor response (hormonal) The responses are active efforts to attain homeostasis & are energy driven The greater the stimulus, the greater the disturbance in equilibrium The greater the disturbance, the bigger effort needed to bring back to normal The bigger the effort needed to equilibrate, the higher is energy requirement Injury Hypothalamus Proinflammatory cytokines, arginine, angiotensin II Corticotropin releasing hormone Anterior pituitary Increased ACTH Increased cortisol Cortisol Liver: Promotes gluconeogenesis Peripheral enzymatic activities leading to