Metabolic Injury 2023 PDF

BASIC SURGERY – HINDI RAW SAMPLEX, PERO HINDI RAW TITIGIL MAG-GREEN TABLE SI KUMUNOY 😊 METABOBO LECTURER: “HINDI NAG-S’SAMPLEX ANG BASIC SURGERY” – DOC INGUSAN, 2023. “DOC, LEAVE IT TO US.” – KUMUNOY, ETERNITY...

BASIC SURGERY – HINDI RAW SAMPLEX, PERO HINDI RAW TITIGIL MAG-GREEN TABLE SI KUMUNOY 😊 METABOBO LECTURER: “HINDI NAG-S’SAMPLEX ANG BASIC SURGERY” – DOC INGUSAN, 2023. “DOC, LEAVE IT TO US.” – KUMUNOY, ETERNITY TRAUMA DAMPS DAMP – Damage-Associated Molecular Patterns (Alarmins) CELLULAR INJURY Promote activation of innate immune cells Recruitment and activation of antigen-presenting cells. Traumatic injury activates the innate immune system to Body detects cellular injury through DAMPs produce a systemic inflammatory response (SIR) in an Endogenous molecules which are immunologically active attempt to limit damage and to restore homeostasis. Released from necrotic/damaged cells either passively or Two mechanisms: by up regulation or over expression of physiologically stressed cells. ACUTE PRO-INFLAMMATORY ANTI-INFLAMMATORY HMGB1 (High-Mobility Group Protein B1) – best RESPONSE RESPONSE characterized DAMP (HMGBest okay?) Resulting from innate May serve to modulate the immune system recognition pro-inflammatory phase and of ligands. direct a return to homeostasis PRO = ANTI dapat. Si Pro ‘yung aaway, si anti ‘yung pipigil Mememorize mo ‘yan para ‘di na ma-damage ‘yung katawan, para homeostasis. Kumunoy? Hindi. Trauma nanaman, Innate ulo ni SIR Paano kapag tinanong sa shiftings or exams? Edi mali. The degree of systemic inflammatory response following trauma is proportional to injury severity and is an independent predictor of HMGB1 (HMGBEST-characterized DAMP) subsequent organ dysfunction and resultant mortality. – MALALAMAN The diverse proinflammatory biologic responses that result MO GAANO KALAKAS SI SIR BASED SA KUNG GAANO ‘YUNG NA- from HMGB1 signaling include: INJURE/NA-CAUSE NA DAMAGE o Release of cytokines from macrophages/ monocytes/ dendritic cells o Neutrophil activation and chemotaxis o Alterations in epithelial barrier function (increased permeability) o Increased procoagulant activity on platelet The image shows a directly proportional relationship, surfaces explaining that SIRS (infection is the etiology most of the time) HMGB1 binding to TLR4 (Toll-like receptor 4) triggers pro- has the same immune response with a sterile environment in inflammatory cytokine release that mediates SICKNESS cases of trauma. BEHAVIOR. CLINICAL FEATURES (SIRS) ‘Yung HMGB1 best characterized DAMP ulet-ulet. It causes Clinical features of the injury mediated systemic inflammation dahil in-aactivate niya release ng cytokines sa mga inflammatory response is characterized by: macrophages/monocytes/dendritic cells, nag-aactivate rin siya neutrophil, tapos para makapasok ‘yung mga substances, binabago Increase body temperature niya epithelial barrier function by increasing permeability sa injured site. Increase Heart rate Increase Respiration CLINICAL APPLICATIONS FOR HMGB1 WBC count is similar to those who are observed with Traumatic brain injury: Doubling in serum HMGB1 infection. Hemorrhagic shock: Increased plasma level HOWEVER, it is widely accepted that systemic inflammation Proteins from the mitochondria produces following trauma is sterile, and these changes are inflammasome that will stimulate STING (Stimulator of stimulated by endogenous molecules that are produce as interferon genes). a consequence of tissue damage or cellular stress KUMUNOY’S IMPROPERTY 1  BASIC SURGERY – HINDI RAW SAMPLEX, PERO HINDI RAW TITIGIL MAG-GREEN TABLE SI KUMUNOY 😊 METABOBO LECTURER: “HINDI NAG-S’SAMPLEX ANG BASIC SURGERY” – DOC INGUSAN, 2023. “DOC, LEAVE IT TO US.” – KUMUNOY, ETERNITY TLR2 and TLR6 will form a dimer that can interact with the GPI anchor of a parasite. TLR5 (works solo) can interact will the flagellin of a bacteria These receptors will interact with the genetic material of the bacteria or virus. Through the stimulation of certain parts of bacteria, it will now send messages to the nucleus, to form the cytokines and Which of the following pro interferons. inflammatory biological response will Activation of best characterize DAMP with significant preclinical evidence for cytokines and post-trauma release in High-mobility chemokines group protein B1? INCREASING a. Activation of cytokines and PROCOAGULANT; # chemokines ALTERATIONS IN Increase / b. Decreasing procoagulant activity EPITHELIAL BARRIER of platelet FUNCTION, /Increaseepithelial barrier c. Decreasing ACTIAVTION OF function Activation NEUTROPHILS AND ***Toll like receptors 3, 7, 8, 9 are found within the endosomes d. Inactivation ↑ of neutrophils and CHEMOTAXIS chemotaxis TLR STIMULATORS TLR 1 + TLR 2 Triacyl lipopeptides (1+2 = Tri lol) HEAT SHOCK PROTEINS TLR 4 Lipopolysaccharides (Lipofourlysac) Intracellular proteins that are expressed in times of TLR 5 Flagellin (5gellin) oxidative stress or following tissue injury. GPI Anchor (Parasite); Zymosan (Yeast); MOLECULAR CHAPERONES TO MONITOR AND MAINTAIN TLR 6 + TLR 2 Diacyl Lipopetides and LTA (Bacteria) APPROPRIATE PROTEIN FOLDING TLR 3 dsRNA (Virus) – 3D Targeting of misfolded proteins for degradation TLR 7 + TLR 8 SsRNA (Virus) Sequestering of partially folded proteins for movement to TLR 9 CpG DNA (Bacteria) appropriate membrane compartments. Binding with bacterial DNA and endotoxin ACTIVATION OF TRANSCRIPTION FACTORS Tandaan niyo lang daw sa HSP, “oxidative stress” tapos AP1: RNA translation → proteins for cell signaling correcting different abnormal proteins!!! IRF: RNA translation → activation of interferons NFKB: RNA translation → activation of cytokines **The activation of each toll like receptors with a specific property of bacteria or virus will initiate cascade of events that will activate certain transcription factors, and all this factors will enter the nucleus and stimulate to produce interferons, cytokines and other cells for signaling. What characterized DAMP the best in the context of injury associated inflammatory response? a. Heat shock proteins c. Toll Like Receptors HMGB1 b. HMGB1 d. Mitochondrial DNA HMGBEST NGA Which of the following protein complexes is IRF TOLL-LIKE RECEPTORS responsible in activating interferons during AP1 – Cell signaling systemic inflammation? NFKB – Cytokines Plasma bound receptors approximately 10 in humans. a. IRF b. AP1 c. HMGB1 d. NFKB HMGB1 – BEST These receptors initiate immune response. Which toll-like receptor is sensitive to flagellin? TL5 TLR1 and TLR2 will form a dimer that can interact with Which toll like receptor forms a dimer with TLR2? TLR1 triacyl lipopeptides. KUMUNOY’S IMPROPERTY 2  BASIC SURGERY – HINDI RAW SAMPLEX, PERO HINDI RAW TITIGIL MAG-GREEN TABLE SI KUMUNOY 😊 METABOBO LECTURER: “HINDI NAG-S’SAMPLEX ANG BASIC SURGERY” – DOC INGUSAN, 2023. “DOC, LEAVE IT TO US.” – KUMUNOY, ETERNITY Which of the following routes can Leaky blood CNS REGULATION OF INFLAMMATION IN inflammatory signals reach the central nervous system in response to injury? brain barrier A – Wala naman a. Activation of complement system C – FENESTRATED DAPAT HOW DOES THE CNS DETECT INFLAMMATION? Ib. Leaky blood brain barrier Fenestrated D – Generation of blood c. Intact endothelium flow lang The central nervous system communicates with the body d. Increased activity of chemokines through ordered systems of sensory and motor neurons which Which of the following routes of Fenestrated receive and integrate information to generate a coordinated inflammatory signals can reach the central endothelium response. nervous system in response to injury? Pinalitan lang ‘di ba, CNS receives information with regards to injury induced a. Intact blood brain barrier mali si INTACT ha, inflammation via the soluble mediators and direct neural b. Increased activity of chemokines FENESTRATED DAPAT. projections that transmit information to regulatory areas in the I Fenestrated endothelium c. BASTA MEMORIZE NIYO ‘YANG LIMA brain. d. Inactivation of cytokines system Thru DAMPs and inflammatory molecules. Which of the following neurotransmitter is involved in regulation of central nervous Acetylcholine - - INFLAMMATORY SIGNALS REACH CNS THRU: system inflammation in response to injury? Nag-pr’produce siya Fenestrated endothelium a. Thyroxine b. Enkephalins T cells, aceTTTTTTTTTyl Leaky BBB (property of the brain) c. Aldosterone d. I Acetylcholine sphlanchnic nerve Generation of blood flow in pro-inflammatory mediators In critically ill patients, CIRCI is characterized as blunting of adreno- HYPERKALEMIA (cytokines, chemokines, adhesion molecules, complement cortical response. Which of the following HYPOglycemia, system) laboratory findings is expected? HYPOnatremia at Inflammatory reflex through the Vagus Nerve Hypo Hypo HYPERkalemia A. Hyperglycemia C. Hypernatremia Acetylcholine producing T cells from the splanchnic nerves ↓ B. Hyperkalemia D. HypercalcemiaX The HPA axis is one of the main HPA AXIS MECHANISM mechanisms by which brain responds to ACTH ACTS ON ZONA Following injury, the CRH (Corticotrophin releasing hormone) is injury associated stress. Which among the FASCICULATA TO secreted from the hypothalamus (paraventricular nucleus) following statements is true? SECRETE and this will go to the anterior pituitary to produce ACTH a. CRH is secreted from PVN on anterior GLUCOCORTICOIDS ACTH will now go to the adrenals, specifically, the zona -Hypothalamus pituitary gland e A – ANG PVN NASA fasciculata producing Glucocorticoid: cortisol b. CRH will act on posterior pituitary to HYPOTHALAMUS Cortisol will now be responsible for the inflammation. stimulate release of ACTH B – SA ANTERIOR PO c. ACTH acts on zona fasciculata to ANG ACTH CLINICAL APPLICATION Y. secrete glucocorticoids cortical inc d. The resulting decrease in cortisol levels D – INCREASE IN CORTISOL DAPAT Critical Illness related corticosteroid insufficiency following trauma have several I MISS ENDO PHYSIO (CIRCI) describes a phenomenon in which an important inflammatory functions exaggerated pro inflammatory response is associated with a Blunted adreno-cortical response. This has been described to be a dysregulation of the HPA Axis, altered adrenal synthesis of cortisol, altered REACTIVE OXYGEN SPECIES AND OXIDATIVE STRESS cortisol metabolism and tissue resistance to corticosteroid with adequate glucocorticoid receptor Highly reactive because of unpaired outer orbit electrons activity. Causes cellular injury through oxidation As a consequence, cortisol levels proved insufficient for Signaling messengers in the immune system the severity of stress. Oxygen radicals (superoxide anion, hydroxyl radical, hydrogen peroxide) are produced as a by-product of oxygen Ok, mga bobo wag kayo mabobobo dito, during injury daw or metabolism acute stress, diba tataas cortisol levels natin? Pag tumaas cortisol, Inflammasome mediates the activation of inflammatory ano mangyayari? Hyperglycemia, hypernatremia at hypokalemia. caspases leading to the production and secretion of mature Pero dito sa CIRCI, secondary to sa SEVERE stress, kaya nga ayan oh critical illness-related pangalan, dito mababa cortisol mo kasi cytokines in macrophages. pwedeng nadrain na cortisol mo kasi nga mataas na yung severity Protection of host cells: ANTIOXIDANTS ng stress, so kabaliktaran ngayon which are HYPOglycemia, Superoxide dismutase; Catalase; Glutaredoxins; Pyruvate HYPOnatremia at HYPERkalemia ang nangyayari. kinase KUMUNOY’S IMPROPERTY 3  BASIC SURGERY – HINDI RAW SAMPLEX, PERO HINDI RAW TITIGIL MAG-GREEN TABLE SI KUMUNOY 😊 METABOBO LECTURER: “HINDI NAG-S’SAMPLEX ANG BASIC SURGERY” – DOC INGUSAN, 2023. “DOC, LEAVE IT TO US.” – KUMUNOY, ETERNITY Other role of ROS: NECROSIS Utilized by the phagocytes for pathogen killing Disorganized cell death Up regulation of inflammasome Premature uncontrolled death due to ischemia, inflammation, trauma UNFOLDED PROTEIN RESPONSE Loss of plasma membrane integrity Normally: proteins fold in the lumen of the ER Cellular collapse with extrusion of the cytoplasmic Cellular stress: this process is disrupted contents Detected by: Reestablishment of folding Nuclei remain intact o Enzymes responsible for it: Pathologic response ▪ Inositol requiring enzyme 1 (IRE1) ▪ Protein kinase RNA Kinase (PKR-like kinase) Pag necrosis ischemia agad. Or pag ischemia necrosis agad! “Cell mag nnecrose mamatay, turned puple hanggang sa maging parang ▪ Activating Transcription Factor 6 (ATF6) lantang gulay hanggang sa mamaho ok? Necrosis.” HAHAHAHAHA A mechanism by which the ER distress signals are sent to taena talaga. the nucleus to modulate transcription in an attempt to restore homeostasis PYROPTOSIS AUTOPHAGY Regulated cell death Cells need a way of disposing of damaged organelles and debris Dependent on the activity of pro inflammatory caspase aggregates that are too large to be managed by proteosomal enzyme degradation. In order to accomplish this housekeeping task, cells Very similar to apoptosis, the only difference is, its utilize a process referred to as “macroautophagy” (autophagy). activation also activates some enzymes, the caspase 1 In normal circumstances: Caspase 1 increases permeability of cell membrane o Engulfment of cytoplasm (isolation membrane): promoting cell death Phagophore Observed in macrophages, dendrite cells, PMNs Edges will fuse together: autophagosome Autophagosome + Lysosome = Auto lysosome Caspases kills pro inflammatory cells, eh nalito na kasi regulated cell o It forms a substance with the lysosome that causes Cell Death death din yung apoptosis, ang difference niya, sa pyroptosis usually yan yung mga macrophage, monocytes etc. ganito sila namamatay “So yung cell nawawala nalang parang bula, namamtay na siya ng and dahil ito sa enzyme caspases. Sa apoptosis derecho na sila kusa, kakainin niya sarili niya with the help of lysosome. Autophagy ok?” namamtay wala ng kung ano ano pa. – Doc Martinez - Ganyan lang niya diniscuss tas next slide na HAHAHAHA taena pero kay Doc Ingusan tayo so basahin niyo padin po ng/nang maayos. Di ko alam pano gamitin yung ‘ng’ na yan wag ANDAMI-DAMI PANG SINABI!!! ITONG TABLE LANG ‘YAN TAENA mo na sitahin boss. HAHAHAHAHA BAHALA KA DIYAN, PERO NANG Disposing damaged organelles that are too MAAYOS, FAKE KUMUNOY. AUTOPHAGY large to be managed by proteasomal degradation APOPTOSIS REGULATED CELL DEATH, ATP ATP ATP APOPTOSIS NECROSIS DISORGANIZED CELL DEATH Regulated cell death PYROPTOSIS CASPASE 1 Energy dependent NECROPTOSIS PREMATURE UNCONTROLLED DEATH DUE TO NO inflammatory response ISCHEMIA, INFLAMMATION, TRAUMA Physiologic mechanism Which of the following cellular stress response that is energy requiring without promoting inflammatory response prior to Apoptosis cell death? a. Autophagy b. Necroptosis I c. Apoptosis d. Pyroptosis Which of the following cellular response refers to the premature uncontrolled death of cells in a living tissue due to ischemia, Necroptosis “Regulated cell death, kahit anong gawin mo mamatay at inflammation or trauma? mamamatay din yan ok? apoptosis” – Doc Martinez next slide! a. Autophagy ↓ Necroptosis b. KULET MO NAMAN, DOC INGUSAN NGA TAYO FAKE KUMUNOY. c. Apoptosis d. Pyroptosis KUMUNOY’S IMPROPERTY 4  BASIC SURGERY – HINDI RAW SAMPLEX, PERO HINDI RAW TITIGIL MAG-GREEN TABLE SI KUMUNOY 😊 METABOBO LECTURER: “HINDI NAG-S’SAMPLEX ANG BASIC SURGERY” – DOC INGUSAN, 2023. “DOC, LEAVE IT TO US.” – KUMUNOY, ETERNITY High Mobility Groups Box chromosome HMGB1 LATE mediator of inflammation “sickness behavior” CYTOKINES DAMP molecule