Surgery 1 P.02.02.02 Systemic Response to Injury & Metabolic Support PDF

PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT SURGERY LECTURE LECTURER: Dr. Abraham Cinio DATE: January 20, 2024 TOPIC OUTLINE Mediators of Inflammation - Cytokines - Eicosanoids - Fatty Acid Metabolites - Plasma Contact Systems - Cell- Mediated Inflammatory Res...

PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT SURGERY LECTURE LECTURER: Dr. Abraham Cinio DATE: January 20, 2024 TOPIC OUTLINE Mediators of Inflammation - Cytokines - Eicosanoids - Fatty Acid Metabolites - Plasma Contact Systems - Cell- Mediated Inflammatory Response - Endothelium- Mediated Inflammatory Response Mediators of Inflammation - 1. Cytokines Class of protein signaling compounds essential for both innate and adaptive immune responses. Most potent mediator of the inflammatory response. Mediate a broad sequence of cellular responses including; o Cell migration o DNA replication o Cell turnover o Immunocyte proliferation The production of anti-inflammatory cytokines serves to oppose the actions of proinflammatory cytokines. To view cytokines merely as pro- or anti- inflammatory oversimplifies their functions & overlapping on bioactivity is the rule to take note of some cytokines that are purely pro- or anti-inflammatory in nature as the outcome of exaggerated responses of both pro- and antiinflammatory responses is end- organ failure or death. When functioning locally at the site of infection, cytokines: a. mediates the eradication of invading microorganisms b. promotes wound healing However, an exaggerated pro-inflammatory cytokine response to inflammatory stimuli may result in hemodynamic instability (i.e., septic shock) & other metabolic derangements (i.e., muscle wasting). NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 1 | 12 PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page | 12 PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page | 12 PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page | 12 PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT - - 2. Eicosanoids class of mediators which encompasses prostaglandins and thromboxane, leukotrienes, hydroxy eicosatetraenoic acids and lipoxins are oxidation derivatives of the membrane phospholipid arachidonic acid or eicosatetraenoic acid. Secreted by virtually all nucleated cells except lymphocytes. Not stored within cells Mostly generate a pro-inflammatory response against: - hypoxic injury - direct tissue injury - endotoxin (lipopolysaccharide) - vasopressin - norepinephrine - angiotensin II - bradykinin - serotonin - acetylcholine - cytokines - histamine COX-2 (cyclooxygenase 2) enzymes - convert arachidonic to prostaglandin E₂ (PGE₂). PGE₂ - increases fluid leakage from blood vessels. Rising PGE₂ levels over several hour peaks back to COX-2 and induces the formation of antiinflammatory lipoxin from neutrophils which inhibits chemotaxis. Non-steroidal anti-inflammatory drugs reduce the PGE₂ levels by COX-2 acetylation and increases lipoxin production. COX-2 activity can also be inhibited by glucocorticoids. The following block the end products of eicosanoid pathways: - glucocorticoids - NSAIDs - leukotriene inhibitors A. PGI₂ (prostacyclin) Associated with endothelium acts to decrease platelet aggregation promotes vasodilation, inhibits platelet aggregation, and systemic inflammation [where endothelial prostacyclin expression is impaired leading to an endothelium that favors more procoagulant profile]. B. TXA2 (thromboxane A2) - from platelets - increase platelet aggregation - promotes vasoconstriction C. Leukotrienes - potent mediators of: o capillary leakage o leukocyte adherence o neutrophil activation o bronchoconstriction o vasoconstriction - Fatty Acid Metabolites Eicosanoids are produced primarily thru 2 major pathways: Animal studies substituting omega-3 for omega-6 FA have demonstrated attenuated inflammatory response in hepatic Kupffer cells as measured by TNF & IL-1 release and PGE₂ production. 1. Arachidonic acid / Omega- 6 fatty acid - As substrate - most commonly the primary lipid source in enteral nutrition formulas - precursors of inflammatory mediators (leukotrienes, prostaglandins, and platelet-activating factor) - associated with injury and stress response NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page | 12 PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT 2. Eicosapentaenoic acid / Omega- 3 fatty acid - As substrate - anti-inflammatory (chronic autoimmune diseases e.g., RA, psoriasis, lupus) - minimizes ischemia/reperfusion injury in the myocardium, small intestine, & skeletal muscles - ameliorates endotoxin-induced acute lung injury Plasma Contact Systems - - I. The Complement System major effector mechanism of the innate immune system Thought to act initially as the required “first- line of defense” for the host against pathogens thru binding and clearing them from the circulation. Participates in the elimination of: - immune complexes - damaged and dead cells Liver - major source of complement components. the circulating Complement proteins can also be produced locally where they have been implicated in the regulation of adaptive immune processes. Complement protein synthesis has been demonstrated in immune cells including T cells. Pathway initiation occurs by the binding and activation of a specific recognition unit to a designated ligand. 1. Classical Pathway / Antibodydependent pathway - Activation by: a. direct binding of C1q to its common ligands (IgM/IgG aggregates) b. alternatively, C1q can bind to soluble pattern recognition molecules such as pentraxins (e.g., C-Reactive Protein) - Leads to generation of: a. C3a & C5a: potent anaphylatoxins b. C3b: opsonin c. release of proinflammatory cytokines synergistically with TLR- signaling, which contribute to systemic inflammation and generalized capillary leak following severe injury. 2. Mannose-binding lectin (MBL) Pathway - initiated by mannose-binding lectin (MBL) or ficolins which binds specific carbohydrate structures. - speculated to be a major mechanism for complement activation post injury by interactions with matrix fragments in mitochondrial DAMPs. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page | 12 PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT - II. Kallikrein- Kinnin System “Contact” system Group of proteins that contribute to coagulation, inflammation, blood pressure control, and pain response. PREKALLIKREIN - Circulates in the plasma bound to high molecular weight kininogen (HK) activated by: - Factor XII (Hageman factor) - Factor XI - Trypsin - Plasmin - Glass surfaces - Kaolin - Collagen KALLIKREIN – activated form of pre-kallikrein - Initiates the intrinsic clotting cascade - both proinflammatory & procoagulant - cleaves HK to form BRADYKININ Hight molecular weight kininogen – produced by the liver - Metabolized by kallikrein to form bradykinin. D. Kinins Bradykinins - potent vasodilator that are produced through kininogen degradation by the serine protease, kallikrein. - mediate several physiologic processes: o increase capillary permeability o tissue edema o evoke pain o inhibit gluconeogenesis o increases bronchoconstriction o neutrophil chemotaxis o increase renal vasodilation that consequently reduce renal perfusion pressure [An increase in renin E. Serotonin / 5-hydroxytryptamine (5HT) - - - monoamine neurotransmitter derived from tryptophan Synthesized by: o neurons in the CNS o enterochromaffin cells of the GIT (major source of plasma 5-HT) o platelets Actions: o potent vasoconstriction, bronchoconstriction, and platelet aggregation o increases cardiac inotropy and chronotropy through non-adrenergic cyclic adenosine monophosphate (cAMP) Located in the CNS, GIT, & monocytes Released at sites of injury, primarily by platelets F. Histamine - synthesized by decarboxylation of the amino acid histidine either rapidly released or stored in: o neurons, skin, gastric mucosa o mast cells, basophils, platelets secondary to reduced renal perfusion promotes sodium and water retention via the RAAS]. Increased bradykinin levels are proportional to the magnitude of injury and mortality observed in following: Hypoxia, Reperfusion, Hemorrhage, Sepsis, Endotoxemia, tissue injury Clinically, bradykinin antagonist in septic shock studies have only demonstrated modest reversal in Gram-negative sepsis but no overall improvement in survival. Rise in histamine levels have been documented in hemorrhagic shock, trauma, thermal injury, endotoxemia and sepsis. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page | 12 PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT Cell- Mediated Inflammatory Response Clot formation at the site of injury releases inflammatory mediators that serves as a chemoattractant for neutrophils and monocytes. The migration of platelets and neutrophils through the vascular endothelium occurs within 3 hours of injury and is mediated by: - serotonin release - platelet activating factor - prostaglandin A2 1. Platelets - non-nucleated structures, derived from bone marrow megakaryocytes. - hemostatic response and are activated by several factors such as exposed collagen. - activated platelets: release mediatorsthe principal chemoattractant for neutrophils and monocytes. - can enhance or reduce neutrophil mediated tissue injury by modulating tissue adherence to the endothelium and subsequent respiratory burst. - important source of eicosanoids and vasoactive mediators. NSAIDs irreversibly inhibit thromboxane production and platelet function through the blockade of cyclooxygenase (COX). Thrombocytopenia - one of the hallmark conditions of septic response. 2. Lymphocytes & T- Cell Immunity In Pt with major burns, a shift to TH2 cytokine response has been a predictor of infectious complications. However, studies in Pt undergoing a major surgery have demonstrated a postoperative reduction in TH1 cytokine production that is not necessarily associated with increased TH2 response. Nevertheless, depressed TH1 response and systemic immunosuppression following major insults to the host, may be a useful paradigm in predicting the subset of Pt who are prone to infectious complications and poor outcome. Injury, surgical or traumatic is associated with cell mediated immunity and macrophage function. CIRCULATING IMMUNE CELLS B cells T cells Natural killer cells 2 Groups of Helper T- Lymphocytes - T- Lymphocytes Mediators of adaptive immunity NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page | 12 PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT o phagocytosis of microbial pathogens o release of inflammatory mediators o clearance of apoptotic cells SEPSIS - reduction in monocyte surface TNFR expression with failure to recover - macrophages: ↓ surface Human Leukocyte Antigen DR (receptor antigen presentation) 3. Eosinophils - characteristically similar to neutrophils and that they migrate to the endothelium and release cytoplasmic granules that are cytotoxic. - preferentially migrate to sites of and parasitic infections and allergen challenge. - immunocytes whose primary functions are anti-helminthic. *Lungs and GIT – immune surveillance MAJOR ACTIVATORS: - IL-3, IL-5 - GM-CSF - Chemoattractant - platelet-activating factor - complement anaphylatoxin C3A, C5 SUBSEQUENT RELEASE OF TOXIC MEDIATORS - reactive oxygen species (ROS) - histamine - peroxidase 4. Monocytes - mononuclear phagocytes - differentiate into macrophages, osteoclasts, dendritic cells - main effector cells of the immune response to infection and injury - mechanisms that include: o In clinical sepsis, non-surviving Pt with severe sepsis have an immediate reduction of monocyte surface tumor necrosis factor receptor expression – with failure to recover; for surviving Pt has normal to near normal receptor levels from the onset of clinically defined sepsis, thus, TNF expression can be potentially used as a prognostic indicator of outcome in Pt with systemic inflammation. There is also a ↓ CD95 expression following experimental endotoxemia in humans which correlates with diminished CD95-mediated apoptosis, thus, the reduced receptor expression and delayed apoptosis may be a mechanism for prolonging the inflammatory response during injury or infection. 5. Neutrophils - mediate important functions in every form of acute inflammation such as: o acute lung injury o ischemia o reperfusion injury o inflammatory bowel disease - first responders - As chemotactic mediators, neutrophils adhere to the vascular endothelium cell migration - short half-lives (4-10 hours) INFLAMMATORY STIMULI includes TNF, IL-1, microbial pathogens that: - phagocytose - release lytic enzymes - generate large amounts of toxic ROS GCSF is the primary stimulus for neutrophil maturation. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page | 12 PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT Inflammatory mediators from a site of injury induce neutrophil adherence to the vascular endothelium and promote eventual cell migration into the injured tissue. Neutrophil function is mediated by a vast array of intracellular granules that are chemotactic and cytotoxic to local tissue and invading microorganisms. 6. Mast Cells - Primary response TNF release mast cells – neutrophil recruitment and pathogen clearance - Role in anaphylactic response to allergens STIMULI - Allergen - trauma ACTIVATED MAST CELLS PRODUCE: - histamine - cytokines - eicosanoids - proteases - chemokines IMMEDIATE RESULTS - vasodilation - capillary leakage - immunocyte recruitment RELEASE: - IL-3 to IL-6 - IL-10, IL-13, IL-14 Tumor necrosis factor alpha (TNF-α) - secreted rapidly by mast cells because of the abundance stores within granules. Mast cells can synthesize a variety of cytokines and macrophage migration inhibitory factor. Endothelium- Mediated Inflammatory Response 1. Vascular Endothelium Under physiologic conditions has anticoagulant properties - o o o o o mediated by the production and cell surface expression of: Heparin sulfate, dermatan sulfate tissue factor pathway inhibitor protein S Thrombomodulin Plasminogen, Tissue plasminogen activator Endothelial cells – function as barriers that regulate tissue migration of circulating cells during sepsis. Endothelial cells’ overall procoagulant shift via decreased production of anticoagulant factors which may lead to micro- thrombosis or organ injury. 2. Neutrophil Endothelium - facilitates neutrophils & other immunocyte migration for inflammatory response such as: a. ↑ vascular permeability- facilitates O2 delivery and immunocyte migration to the site injury may contribute to the cytotoxicity of vital tissues and result to organ dysfunction. Ischemia reperfusion injury (IRI), potentiates this response by unleashing O2 metabolites. b. Chemoattractant c. ↑ endothelial adhesion factors (selectins)- The recruitment of circulating neutrophils to endothelial surfaces is mediated by concerted actions of adhesions molecules referred to as selectins that are elaborated on cell surfaces. Prolonged and unremitting neutrophil activation and mediator release → lead to tissue injury through the production of toxic oxygen metabolites and lysosomal enzymes: - degrade tissue basal membranes - microvascular thrombosis - activate myeloperoxidase 3. Nitric Oxide - derived from endothelial surfaces in response to: o acetylcholine stimulation o hypoxia o endotoxin o cellular injury or mechanical shear stress from circulating blood - formed from oxidation of L-arginine [process catalyzed by nitric oxide synthase] - It is a readily diffusible substance with a half-life of a few seconds. - It spontaneously decomposes into nitrate and nitrite. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page | 12 PCC SOM 2026 SURGERY 1 P.02.02.02 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT - - - - initially known as endothelium-derived relaxing factor [can control vascular tone]. reduce micro-thrombosis by reducing platelet adhesion and aggregation mediates protein synthesis in hepatocytes. inducible NO synthase – normally not expressed, is upregulated in response to inflammatory stimuli. also occurs in neutrophils, monocytes, renal cells, Kupffer cells, and cerebellar neurons. NO synthesis is increased in response to proinflammatory mediators such as TNF-α, IL- 1β, as well as microbial products. ↑ NO: septic shock and in response to: TNF, IL-1, IL-2, hemorrhage. Mediate hypotension observed during septic shock. During acute inflammation PAF are released by neutrophils, platelets, mast cells, & monocytes, expressed at the outer leaflet of endothelial cells. - can further activate neutrophils and platelets, increase vascular permeability. Human sepsis – affected with the reduction of PAF-Acetyl hydrolase levels which is the endogenous activator of platelet activating factor. 6. Atrial Natriuretic Peptide Released primarily by atrial tissue, also synthesized by the gut, kidney, brain, adrenal glands, endothelium. - Induce vasodilation as well as fluid and electrolyte (F & E) excretion. - Potent inhibitors of aldosterone secretion and prevent reabsorption of Na. - 4. Endothelins Potent mediators of vasoconstriction a 21 amino acid peptide; of the peptides of the family endothelial cells appear to exclusively produce ET-1. release is upregulated in response to hypotension, LPS, injury, thrombin, TGF, IL-1, angiotensin II, vasopressin, catecholamines, and anoxia. half-of plasma ET is between 4 and 7 minutes. They are elaborated by vascular epithelial cells in response to injury, thrombin, transforming growth factor beta (TGF- β), IL1, angiotensin II, vasopressin, catecholamines, and anoxia. 3 members o ET-1: synthesized primarily by endothelial cells → most potent endogenous vasoconstrictor - 10x more potent than angiotensin II o most active - ET-2 - ET-3 5. Platelet- Activating Factor A natural phospholipid constituent of cell membranes, which under normal physiologic conditions is minimally expressed. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page | 12 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT Checkpoint! True / False 1. Following trauma, ACTH is superseded by pain, anxiety, and injury. 2. The inflammatory mediators derived from arachidonic acid are leukotrienes. 3. Following acute injury or acute infections, TNF-alpha induces muscle catabolism. 4. The most potent mediators of the inflammatory response are cytokines. 5. Overproduction of the proinflammatory mediators in the previous question will result to end organ failure. 6. One of the earliest and most important stimulus for triggering the endocrine response to injury after injury is the afferent nerve stimuli from the injured area. 7. Substances elevated during the acute response to injury include glucagon, glucocorticoids and catecholamines. 8. Metabolic effects of the neuroendocrine response to injury include gluconeogenesis, lipolysis & hyperglycemia. 9. The degree of the systemic inflammatory response following trauma is proportional to injury severity. 10. IL-1 induces fevers through prostaglandin activity in anterior hypothalamus. 11. IL- 1, IL- 6, TNF are pro- inflammatory cytokines. 12. Hepatic glycogenolysis occur as a result of epinephrine and norepinephrine release. 13. Tumor necrosis factor-alpha can be released as a response to bacteria or endotoxin. 14. Eicosanoids when activated leads to the formation of the anti-inflammatory compound lipoxin whose role is to inhibit chemotaxis. 15. Mast cells are responsible for the anaphylactic response to allergens in the cell-mediated immune response. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page | 12