2026 Surgery 1 Systemic Response To Injury & Metabolic Support PDF

PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT SURGERY LECTURE LECTURER: Dr. Abraham Cinio DATE: January 20, 2024 TOPIC OUTLINE Overview - Inflammatory response to injury - Trauma - Immune system - DAMPs - PAMPs - Unhealthy cells Inflammation: Acute/ Chronic Mult...

PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT SURGERY LECTURE LECTURER: Dr. Abraham Cinio DATE: January 20, 2024 TOPIC OUTLINE Overview - Inflammatory response to injury - Trauma - Immune system - DAMPs - PAMPs - Unhealthy cells Inflammation: Acute/ Chronic Multiple organ failure; Burns Sepsis; Severe trauma PICS 2 Phases of Systemic Response to Injury - SIRS - CARS The INDUCERS: PAMPs & DAMPS DAMPs - HMGB1 Protein - Complement System - Heat Shock Proteins - Mitochondrial DAMPS - Extracellular Matrix Molecules - S100 Proteins PRRs - TLR - NLR - RAGE - sPRM General Classification of Hormones CNS Regulation of Inflammation in Response to Injury - H-P-A Axis - CRH - ACTH Adrenal Insufficiency Sympathetic Nervous System Adrenaline Insulin Adrenal Medulla OVERVIEW ❑ Inflammatory response to injury- sign to restore tissue function and eradicate invading microorganism. Injuries of limited duration are usually followed by functional restoration with minimal intervention. By contrast, major insults to the host are associated with an overwhelming inflammatory response that without appropriate and timely intervention, can lead to multiple organ failure and adversely impact the patient’s survival. ❑ Trauma - the leading cause of mortality and morbidity for individuals under age 45 - a cellular disruption caused by an exchange with environmental energy that is beyond the body’s resilience which is compounded by cell death due to ischemia/reperfusion. Understanding the complex pathways that regulate the local and systemic inflammatory response following severe traumatic injury is necessary to develop appropriate and targeted therapeutic strategies that will improve outcomes for these patients. Minor host insults, result in a localized inflammatory response that is transient. ❑ Immune system – Prevent/limit infection E.g: Immune compromised people including those with genetic immune disorders, immune debilitating infections like HIV, and even pregnant women who are susceptible to a range of microbes that do not typically cause infections in healthy individuals ❑ DAMPs / Danger Associated Molecular Patterns – danger queues used by the immune system distinguishing from normal healthy cells and unhealthy cells. - Ligand for damaged cells ❑ PAMPs/ Pathogen Associated Molecular Patterns – signals released by infectious microbes - Ligand for microbial components ❑ Unhealthy cells due to: a. Infection b. Cellular damage by non-infectious agents [sunburn/ cancer] NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 1 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT Generally, the extent and effects of chronic inflammation may vary with the cause of the injury and the ability of the body to repair and overcome the damage. STEPS: Inflammation: Acute/ Chronic Inflammation - defense mechanism by which the immune system recognizes and removes harmful foreign stimuli and begins the healing process - in response to 2 kinds of insults: 1. Injury in the epidermal & dermal layer of the skin 2. Contamination of the wound by bacteria Causes Onset Duration of symptoms Examples Types of Inflammation Acute SubChronic Acute Tissue Insidious damage → trauma, microbial invasion, or noxious compounds Rapidly → long-term severe in a inflammation short time Few days 2-6 Months to weeks years Cellulitis Acute pneumonia DM IBD CKD 1. Presence of the 2 insults → Bacteria and other pathogen enter wound. 2. Platelets from blood, release blood-clotting proteins at wound site. Platelets are mobilized to prevent further blood loss on the site of the wound. 3. Mast cells secrete factors that mediate vasodilation and vascular constriction. Delivery of blood, plasma, and cells to injured area increases. Mast cells have a widespread distribution and are seen predominantly at the interface between the host and the external environment. They are immune cells of the myeloid lineage and are present in the connective tissues throughout the body. The activation and degranulation of mast cells significantly modulate many aspects of physiological and pathological conditions in various settings. Mast cells normal physiological functions: Regulate ✓ vasodilation ✓ vascular homeostasis ✓ innate and adaptive immune responses ✓ angiogenesis ✓ detoxification 4. Neutrophils produced by the bone marrow making up the largest fraction of WBCs secrete factors that kill and degrade pathogens. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 2 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT first responders playing the role of the first line of defense against infectious organisms ✓ address foreign invaders by eating them (phagocytosis) or ✓ by taking them up into the cell (endocytosis). 5. Neutrophils and macrophages remove pathogens by phagocytosis. 6. Macrophages secrete hormones called cytokines that attract immune system cells to the site and activate cells involved in tissue repair. Macrophages - specialized cells involved in the detection, phagocytosis, and destruction of bacteria and other harmful organisms. - present antigens to T- cells and initiate inflammation by releasing molecules known as cytokines that activate other cells. - originate from blood monocytes that leave the circulation to differentiate in deferent tissues. ✓ There is a substantial heterogeneity among each macrophage population which most probably reflects the required level of specialization within the environment in a given tissue. This heterogeneity is reflected in their morphology, the types of pathogens they can recognize, as well the levels of the inflammatory cytokines they produce. Cytokines IL [interleukins] & TNF [tissue necrosis factor] – produce ROS {NO} killing phagocytosed bacteria. 7. Inflammatory response continues until the foreign material is eliminated and the wound is repaired. Multiple Organ Failure A local inflammatory response always occurs in relation to trauma and severe injury or multiple traumas evoke a system inflammatory response caused by hormonal metabolic and immunological mediators and is associated with the hemodynamic response. Case: A subset of these patients will die within 24 hours of hospital admission, succumbing to overwhelming tissue injury and immediate organ damage. A second subgroup of patients who suffer a major host insult succumb to secondary organ damage remote from the injury site and die later (weeks) in their hospital course form an increasing percentage of the in-hospital traumarelated deaths. HENCE, A dysregulated, overwhelming systemic inflammatory response to the injury/hemorrhage and associated ischemia/reperfusion events → implicated as the cause of multiple organ failure in these patients ➔ + linked to immune suppression that increases the risk of infectious complications and poor outcome. Sepsis ; Severe Trauma A systemic inflammatory response to a confirmed or suspected infection. Infection → fever, chills, rapid breathing, confusion, extreme pain/ discomfort → untimely treatment ➔ organ failure & death - So, the initial injury and subsequent operative treatments promote a proinflammatory response which is exaggerated and may cause organ injury like acute respiratory distress syndrome or multiple organ failure. Meanwhile, an anti-inflammatory response is involved in reducing the potentially harmful effects of the proinflammatory response and enhances susceptibility to secondary infections which increases the risk of sepsis and septic complications. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 3 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT Traumatic injury → activates innate immune system ➔ systemic inflammatory response (SIR) : (a) acute pro-inflammatory response [from innate immune system recognition of ligands] (b) anti-inflammatory response [modulates the proinflammatory phase & direct a return to homeostasis] → limit damage ➔ restore homeostasis. Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) - Characterized by extended length of stay in the ICU, complicated post-discharge courses, and failure to regain/recover to their preinjury status. - Linked to persistent inflammation and suppressed host protective immunity. Degree and duration of dysregulated acute inflammatory response – common denominator on the survivors of severely injured patients in all cases. Case: Patient diagnosed with acute appendicitis and with the following vital signs; BP of 120/80, RR: 25, PR: 110. Patient has decreased urine output and with history of febrile episodes with a current temperature of 38.5. Identify the clinical spectrum of the disease. Is the patient having an infection? Is the patient in septic shock? Convalescence period – mediated by the counter regulatory anti- inflammatory response syndrome - period following SIRS after injury Severe inflammation may lead to acute multiple organ failure and early death after injury. A lesser inflammatory response followed by an excessive counter regulatory anti-inflammatory response syndrome may induce a prolonged immunosuppressed state that can also be deleterious to the host. Normal recovery after injury requires some period of systemic inflammation followed by a return to homeostasis, accompanied by the suppression of the adaptive immunity. 2 Phases of Systemic Response to Injury 1. SIRS / Systemic inflammatory response Syndrome - Pro-inflammatory phase - characterized by activation of cellular processes designed to restore tissue function and eradicate invading microorganisms 2. CARS: Compensatory anti- inflammatory response syndrome - Anti-inflammatory phase or counter - regulatory phase in preventing excessive pro-inflammatory activities and in restoring homeostasis. Sepsis Life threatening organ dysfunction caused by a dysregulated host response to infection. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Septic shock Subset of sepsis with circulatory and cellular/metabolic dysfunction associated with a higher risk of mortality. Page 4 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT In uncomplicated trauma patients with systemic inflammatory response, it is temporary, predictable, and is well balanced between pro and anti-inflammatory mediators. If the patient is exposed to major severe trauma, an initial exaggerated proinflammatory response may be observed. - The INDUCERS: PAMPS & DAMPS produced as a consequence of tissue damage or cellular stress as systemic inflammation following trauma is sterile. ❑ PAMPS / Pathogen Associated Molecular Patterns - Exogenous ligand Ex. In bacterial infection a. Toll-like receptors b. NOD-like receptors c. C-type lectin Clinical features of the injury-mediated SIR: increased body temperature, heart rate, respirations, and white blood cell count SIMILAR to infection. ❑ DAMPS / Damage Associated Molecular Patterns / Alarmins - Endogenous ligands - Immunologically active - Released passively from necrotic/ damaged cells; actively from physiologically stressed cells - interact with specific cell receptors that are located both on the cell surface and intracellularly. - ATP, NO, Fatty Acids MOA: Release of DAMPs → outside the cell → activation of innate immune cells + recruitment + activation of antigen presenting cells ➔ host defense. Trauma DAMPs structurally diverse endogenous molecules that are immunologically active. Most common ways of monitoring Pts: - monitoring vital signs and laboratory tests. Degree of the SIR following trauma is PROPORTIONAL to injury severity ➔ independent predictor of subsequent organ dysfunction & resultant mortality. The systemic inflammatory response is required for tissue repair and as evolved in all mammals to optimize the healing potential of an organism. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 5 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT I. HMGB1 Protein / High Mobility Group Box 1 Protein - The best characterized DAMP with significant preclinical evidence for post trauma release, as well as a direct link to the systemic inflammatory response. - It is a constitutively expressed, non-histone chromosomal protein that participates in a variety of nuclear events, including DNA repair and transcription. (1) released passively: from damaged or necrotic cells and is detected rapidly in the circulation within 30 minutes post injury. (2) released actively: from immune-competent cells stimulated by bacterial-derived lipoproteins (e.g., PAMPS-endotoxin) or by inflammatory cytokines (e.g., tumor necrosis factor and IL-1). - Abundant non-histone component of chromatin known for its 2 binding domains (HMGB1 box A and box B) - Main characteristic is as architectural factor for its ability to recognize and bind with high affinity to distorted DNA and its ability to induce kinks in linear DNA fragments. - Correlated to cancer progression, elevated expression occurred in certain types of primary tumor including melanoma, colon, prostate, pancreatic and breast cancers. - In majority of cases, it is associated with invasion and metastasis In normal tissues: Protein: Soluble form Tumor cell: Insoluble and membrane bound The HMGB1 Protein Signaling Pathway Inflammatory signaling can redirect HMGB1 to the cytosol in both monocytes and macrophages, as a result of post translational modification. Main signaling pathway is activated through the interaction of HMGB1 with its receptor for advance glycation end products (RAGE) elevated expression of RAGE and HMGB1 is not always a prerequisite of poor prognosis of tumor development The data concerning HMGB1 protein and RAGE in various tissues and tumor cells reflect the overall production of the proteins. However, they do not refer to their cellular localization and there is no direct evidence for the formation of a stable complex between them. In studies, they have investigated the subcellular distribution of HMGB1 and RAGE in various organs compared to ascites and tumor cells. HMGB1 forms a stable complex with RAGE only in their protein extract derived from the cancer cells predominantly in the membrane fraction. Pro-inflammatory cytokine and receptors are found on the myeloid cells and receptor target ion endothelial and somatic cells. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 6 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT The diverse pro-inflammatory biological responses that result from HMGB1 signaling include: -The release of cytokines and chemokines from macrophage/monocytes and dendritic cells. -Neutrophil activation and chemotaxis. -Alterations in epithelial barrier function, including increased permeability. -Increased pro-coagulant activity on platelet surfaces; among others. HMGB1 binding to TLR4 triggers proinflammatory cytokine release mediates “sickness behavior.” the that Importantly, shifts between the redox states have been demonstrated and indicate that redox state dynamics are important regulators of HMGB1. HMGB1 levels in human subjects following injury correlate with the: a. Injury Severity Score b. Complement activation c. Increases in circulating inflammatory mediators such as tumor necrosis factor Injury Severity Score Sample Once outside the cell, HMGB1 has been shown to signal via the Toll-like receptors (TLR2, TLR4, TLR9), the receptor for advanced glycosylation end products (RAGE), CD24, and others. The activation of TLRs by HMGB1 occurs mainly in myeloid cells, whereas RAGE is thought to be the receptor target for HMGB1 in endothelial cells. The biologic function of HMGB1 is regulated by its redox state. Example: A thiol at C106 is required for HMGB1 to promote macrophage TNF release, while a disulfide bond between C23 and C45 confers proinflammatory properties. With all three cysteines in the thiol (reduced) state, HMGB1 loses its DAMP function, but gains the capacity to serve as a chemotactic mediator. LEGEND:  APACHE - Acute Physiology and Chronic Health Evaluation  SOFA - Sequential Organ Failure Assessment Score  SIRS - Systemic Inflammatory Response Syndrome Score  PATI - Penetrating Abdominal Trauma Index  ICISS - ICD-based Injury Severity Score  TMPM-ICD9 - Trauma Mortality Prediction Model  TRISS - Trauma Related Injury Severity Score  ASCOT - A Severity Characterization of Trauma  ICISS - International Classification of Diseases Injury Severity Score NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 7 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND. METABOLIC SUPPORT Complement System - Functions: Enhances ability of the antibodies and phagocytic cells to clear microbes and damaged cells from an organism. - Promotes inflammation and attacks the pathogen’s cell membrane. Characteristics: - Part of innate immune system, non-adaptable and doesn’t change over the course of individual’s lifetime. - Can be recruited and be brought into action by antibodies generated by the adaptive immune system. - Consists of a number of small proteins found in the blood which is synthesized by the liver that circulates as inactive precursors or pro-proteins. - When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. - Over 30 proteins and protein fragments make up the complement system including serum proteins and cell membrane receptors. - Account for 10% of globulin fraction of blood serum. II. Heat Shock Proteins “Stress proteins” - - - - Large and diverse family of intracellular proteins expressed during times of inflammation and oxidative stress or following tissue injury. Very highly conserved across species. Function as molecular chaperones to monitor and maintain appropriate protein folding. Capable of binding foreign proteins and thereby function as intracellular chaperones for ligands such as bacterial DNA and endotoxin. Presumed to protect cells from the effects of traumatic stress and when released by damaged cells, alert the immune system of the tissue damage by activating both innate and acquired immunity. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 8 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT - Released from intact cells via a nonclassical secretory pathway, both via “secretory lysosomes” as well as the exosome pathway. MOA: Once outside the cell, free HSPs can bind to pattern-recognition receptors (PRR) as well as other cell surface receptors to modulate the inflammatory response. In the context of massive cell damage or large exosome release, HSPs may serve as proinflammatory DAMPs. In contrast, HSPs released by active secretion may exert anti-inflammatory immune dampening signals. III. Mitochondrial DAMPs Mitochondrial proteins and/or DNA can act as DAMPs by triggering an inflammatory response to cellular necrosis and stress. Mitochondrial DNA (mt DNA) released from damaged or dysfunctional mitochondria leads both to inflammasome activation and activation of the stimulator of interferon gene pathway (STING). CIRP / Cold Inducible RNA-binding Protein stress induced protein DAMPS will act as ligands that will connect to its receptor to activate the complement system which will induce the formation of proinflammatory and anti-inflammatory cytokines. This will react on the damage tissues and return it to homeostasis. IV. T cells, macrophages and dendritic cells (e.g., plasma cystoid). Potent activators of the pathway include cell DNA that has leak from the nucleus of the host cell perhaps following cell division or as a consequence of cell damage. Essential for protecting the cell against a variety of pathogens even against the development of cancer by promoting anti tumor immune responses. Release of mitochondrial DNA and formyl peptides from damage or dysfunctional mitochondria has been implicated in the activation of the macrophage inflammasome, a cytosolic signaling complex that responds to stress. STING / Stimulator of Interferon Gene Pathway Signaling molecule associated with the endoplasmic reticulum. Essential for controlling the transcription of numerous host defense genes including type 1- INF and pro inflammatory cytokines following the recognition of aberrant DNA species or cyclic dinucleotides in the cytosol of the cell. Amino acid protein consisting of several transmembrane regions that is express in various endothelial and epithelial cell types as well as in hematopoietic cells such as NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 9 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT V. Extracellular Matrix Molecules Proteoglycans, in particular, have also been shown to activate the intracellular inflammasomes that triggers sterile inflammation. These molecules, which consist of a protein core with one or more covalently attached glycosaminoglycan chains, can be membrane bound, secreted, or proteolytically cleaved and shed from the cell surface. Various proinflammatory cytokines and chemokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β are downstream effector molecules of biglycan/TLR2/4 signaling. Among these, the mechanism of bi- glycan – mediated autonomous synthesis and secretion of mature IL-1β is unique. VI. S100 Proteins Group of calcium-binding proteins that participate in the regulation of intracellular calcium. Released passively from damaged cells; actively via nonclassical protein secretion mechanisms. Extracellular S100A8/A9 functions as an endogenous agonist to bind TLR4 and RAGE, serving as a strong proinflammatory mediator. Can induce both inflammatory cytokine production and activation of leukocyte migration, as well as promote apoptosis and autophagy in distinct cell types. Surface and cytoplasmic receptors that mediate the innate immune response to microbial infection have also been implicated in the activation of sterile inflammation. Genes have been identified that are dysregulated acutely both in response to a microbial ligand administered to human volunteers and in response to traumatic injury. PRRs / Pattern Recognition Receptors (Germ-line encoded) - Class of receptors important for sensing damaged cells and cell debris thru DAMPs or PAMPs as ligands. Ligand is a molecule and an antibody hormone or drug that binds to a receptor. I. TLR / Toll- like Receptors - Transmembrane proteins - Several TLR w/ distinct ligands (components of pathogens) - Expressed on both immune and nonimmune cells. - TLR4 - first human TLR identified Now, more than 10 human TLR family members have been identified, with distinct ligands that include lipid, carbohydrate, peptide, & nucleicacid components of various pathogens. Inflammasome-activated cytokines (IL-1 beta and IL-18) - potent proinflammatory molecules that promote key immune responses essential to host defense. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 10 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT II. NLR / Nucleotide- binding oligomerization domain- Like Receptor - Intracellular PRR - Sense endogenous DAMPs and exogenous PAMPs for innate immune activation - Associated with inflammasome in leukocytes NLR family pyrin domain-containing 3 (NLRP3) - the best characterized of the NLRs. - highly expressed in peripheral blood leukocytes. - forms the key “sensing” component of the larger, multiprotein inflammasome complex. When phagocytosed DAMPs are sensed by NLRP3, leads to release of the self- repression. Caspase-1 – the key effector of the NLRP3 inflammasome. Assembly of the caspase-1 products → Formation of IL-1 converting enzyme (ICE) → Cleaves IL-1β, IL-18, and IL-33 pro- forms → Formation of IL-1β, IL-18, and IL-33 active & mature forms ➔ Cell secretion = Auto activation of pro- caspase-1 to caspase-1 Inflammasome-activated cytokines IL-1β & IL-18 - potent proinflammatory molecules promoting key immune responses essential to host defense. III. - RAGE / Receptor for Advanced Glycation End-products Transmembrane receptor Highly conserved across species A member of the immunoglobulin superfamily that is constitutively expressed at high levels in the lung, with low/absent expression in other adult cell types. However, proinflammatory stimuli and the presence of RAGE ligands can increase RAGE expression on immune cells such as neutrophils, macrophages, and lymphocytes. RAGE soluble form / sRAGE - composed only of the extracellular domain which can bind to and sequester RAGE ligands without consequent signaling events. The multi- receptor advanced glycation end products or RAGE of the immunoglobulin super family is expressed on multiple cell types implicated in the immune inflammatory response and in atherosclerosis. Multiple studies have elucidated that the ligand RAGE interaction on cells such as monocytes, macrophages, endothelial cells mediate cellular migration and upregulation of pro inflammatory and pro thrombotic molecules. IV. - - Soluble Pattern Recognition Molecules [sPRM] molecularly diverse group of molecules that share a conserved mode of action defined by: a. Complement activation b. Agglutination c. Neutralization d. Opsonization Synthesized at sites of injury & inflammation by macrophages & dendritic cells. Stored by neutrophils & release them rapidly following activation. Epithelial tissues [liver] as reservoir source for systemic mass release. Pentraxins – best described of the PRMs C-reactive protein / short pentraxin – first PRM to be identified, produced solely in the liver. Serum amyloid protein (SAP) – has 51% sequence similarity to human CRP - contains the pentraxin molecular signature. CRP and SAP plasma levels - low (≤3 mg/L) under normal circumstances. However, CRP is synthesized by the liver in response to interleukin-6, increasing serum levels more than a 1000-fold ➔ CRP is considered part of the acute-phase protein response in humans ➔ C-reactive protein has been studied as a marker of the proinflammatory response in many clinical settings, including appendicitis, vasculitis, and ulcerative colitis. CRP and SAP are ancient immune molecules that share many functional properties with antibodies: they bind bacterial polysaccharides, ECM components, apoptotic cells, and nuclear materials, as well as all three classes of Fcγ receptors (FcγR) Both molecules also participate in the activation and regulation of complement pathways. In this way, short pentraxins can link immune cells to the complement system. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 11 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT PTX3 - Long pentraxin family member in the sterile inflammatory response associated with cellular response. - Produced by various cells in peripheral tissues, including immune cells. PTX3 plasma concentrations increase rapidly in various inflammatory conditions, including sepsis. PTX3 concentrations at admission were associated with injury severity, while higher PTX3 serum concentrations 24 hours after admission correlated with lower probability for survival. General Classifications of Hormones Polypeptides Cytokines Glucagon Insulin Amino Acids Epinephrine Serotonin Histamine Fatty Acids CNS Regulation of Inflammation in Response to Injury Glucocorticoids Prostaglandins Leukotrienes NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 12 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT Sensory & motor neurons – receive & integrate information to generate a coordinated response. Soluble mediators & direct neural projections – transmit information to regulatory areas in the brain as CNS receives information against injuryinduced inflammation. CNS via autonomic signaling – integral role in regulating the inflammatory response that is primarily involuntary. HOW? DAMPs and inflammatory molecules convey stimulatory signals to the CNS via multiple routes. E.g. Soluble inflammatory signaling molecules from the periphery can reach neurons and glial cells directly through the fenestrated endothelium of the circumventricular organs (CVO) or via a leaky blood-brain barrier in pathological settings following a traumatic brain injury. In addition, inflammatory stimuli can interact with receptors located on the brain endothelial cells to generate a variety of proinflammatory mediators (cytokines, chemokines, adhesion molecules, proteins of the complement system, and immune receptors) that directly impact the brain parenchyma. Autonomic Nervous System (ANS) – regulates: HR, BP, RR, GI motility & body temperature; inflammation in a reflex manner [patellar tendon reflex] HOW? Site of inflammation → afferent signals → hypothalamus →relays opposing antiinflammatory messages ➔reduce inflammatory mediator by immunocytes. Hypothalamic-Pituitary-Adrenal axis + release of systemic glucocorticoids = potent signaling countered response to inflammation. Inflammatory reflex – composed of the axons from the visceromotor component of CN X - feeds back to the periphery to regulate inflammatory signaling events. Information regarding peripheral inflammation and tissue damage can also be signaled to the brain via afferent neural fibers, particularly those of the vagus nerve. These afferent fibers can interconnect with neurons that project to the hypothalamus to modulate the HPA axis. Vagal stimulation reduces heart rate, increases gut motility, dilates arterioles, causes pupil constriction, and regulates inflammation. Unlike humoral anti-inflammatory mediators, signals discharged from the vagus nerve are targeted at the site of injury or infection. Neuro-Endocrine Response to Injury Two Principle of Host Response to Injury 1. HPA axis = Glucocorticoid hormones release 2. Sympathetic Nervous System = Catecholamines release Cholinergic Anti- Inflammatory Pathway Acetylcholine - primary neurotransmitter of the parasympathetic system. - reduces tissue macrophage activation. - Cholinergic stimulation directly reduces tissue macrophage release of the proinflammatory mediators, tumor necrosis factor (TNF) alpha, interleukin IL-1 and IL-18, and the high mobility group protein. But not the anti-inflammatory cytokine interleukin IL-10. The attenuated inflammatory response induced by cholinergic stimuli was further validated by identification of acetylcholine or nicotinic receptors on tissue macrophages. CNS inflammatory stimuli - behavioral changes, increased sleep, lethargy, reduced appetite, and fever. Vagus nerve – influential in mediating afferent sensory input. Dorsal motor nucleus [CN X] – produces vagal nerve impulses - modulate cells in the brain stem from which efferent preganglionic parasympathetic originate. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 13 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT I. Hypothalamic- Pituitary- Adrenal Axis Traumatic injury results in complex neuroendocrine signaling from the brain that serves to enhance immune defense and rapidly mobilize substrates necessary to meet essential energy and structural needs. Virtually every hormone of the HPA axis influences the physiologic response to injury and stress, but some with direct influence on the inflammatory response or immediate clinical impact. Direct neural input via afferent vagal fibers that interconnect with neurons projecting to the hypothalamus can also trigger CRH release. CRH acts on the anterior pituitary to stimulate the secretion of adrenocorticotropin hormone (ACTH) into the systemic circulation. The cytokines that act on the hypothalamus are also capable of stimulating ACTH release from the anterior pituitary so that marked elevations in ACTH and in cortisol can occur that are proportional in magnitude to the injury severity. Additionally, pain, anxiety, vasopressin, angiotensin II, cholecystokinin, vasoactive intestinal peptide, and catecholamines all contribute to ACTH release in the injured patient. ACTH acts on the zona fasciculata of the adrenal glands to synthesize and secrete glucocorticoids. Cortisol is the major glucocorticoid in humans and is essential for survival during significant physiologic stress. The resulting increase in cortisol levels following trauma have several important antiinflammatory actions. A. CRH / Corticotrophin- Releasing Hormone Injury → PVN [paraventricular nucleus of the hypothalamus] → secretes CRH [corticotrophinreleasing hormone] → mediates circulation of cytokines TNF-α, IL-1β, IL-6, and the type I interferons (IFN-α/β) = innate response. Cytokines IL-2 and IFN-γ - produced as a result of the adaptive immune response. - capable of increasing cortisol release. B. ACTH / Adrenocorticotrophic Hormone Injury → pain, anxiety, vasopressin, angiotensin II, cholecystokinin, vasoactive intestinal peptide, and catecholamines → Anterior pituitary gland → release ACTH This receptor is regulated by the stressinduced protein heat shock protein (HSP) maintaining the glucocorticoid receptor in the cytosol. On ligand binding, HSP is released, and the receptor-ligand complex is transported to the nucleus for DNA transcription. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 14 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT Ligand binding to receptor will have anti- inflammatory effects. It inhibits the TLR ligation (pro-inflammatory). Upon ligand binding, the glucocorticoid receptor is activated and can employ a number of mechanisms to modulate proinflammatory gene transcription and signaling events with a net anti-inflammatory effect. Because it is lipid soluble, cortisol can diffuse through the plasma membrane to interact with its receptor, which is sequestered in the cytoplasm in a complex with heat shock proteins. Adrenal Insufficiency Adrenal insufficiency represents a clinical syndrome highlighted largely by inadequate amounts of circulating cortisol and aldosterone. Classically, adrenal insufficiency is described in patients with atrophic adrenal glands caused by exogenous steroid administration who undergo a stressor such as surgery. These patients subsequently manifest signs and symptoms such as tachycardia, hypotension, weakness, nausea, vomiting, and fever. Critical illness may be associated with a relative adrenal insufficiency such that the adrenal gland cannot mount an effective cortisol response to match the degree of injury. LABORATORY FINDINGS: Hypoglycemia – fr decreased gluconeogenesis Hyponatremia – fr impaired renal tubular Na resorption Hyperkalemia – fr decreased kaliuresis Adrenal insufficiency – exogenous steroid - Tachycardia, hypotension, weakness, nausea, vomiting, fever Relative Adrenal insufficiency – gland cannot mount an effective cortisol response to match the degree of injury - critically ill patient - - - C. MIF / Macrophage Inhibiting Factor A proinflammatory cytokine expressed by a variety of cells and tissues, including the anterior pituitary, macrophages and Tlymphocytes. Inhibit immunosuppressive effect of cortisol on immunocytes. Upregulate expression of TLR4 in macrophages. D. Ghrelin Ligand for GH-secretagogue receptor 1a Appetite stimulant secreted by stomach Glucose homeostasis, lipid metabolism Cholinergic anti-inflammatory pathway NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 15 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT E. Growth Hormones & Insulin- Like Growth Factors - - B. Insulin A hormone secreted by the pancreas. Mediates an overall host anabolic state through hepatic glycogenesis and glycolysis, peripheral glucose uptake, lipogenesis, & protein synthesis. Action is anabolic Hyperglycemia & insulin resistance - hallmarks of injury and critical illness due to the catabolic effects of circulating mediators, including catecholamines, cortisol, glucagon, and growth hormone. Growth hormone (GH)neurohormone expressed primarily by the pituitary gland that has both metabolic and immunomodulatory effects; - GH promotes both protein synthesis and insulin resistance while enhancing the mobilization of fat stores. GH secretion is upregulated by hypothalamic GH–releasing hormone and downregulated by somatostatin. II. Sympathetic Nervous System A. Aldosterone A mineralocorticoid released by the zona glomerulosa of the adrenal cortex. - It binds to the mineralocorticoid receptor (MR) of principal cells in the collecting duct of the kidney where it can stimulate expression of genes involved in sodium reabsorption and potassium excretion to regulate extracellular volume and blood pressure → acting on the renal mineralocorticoid receptor of the distal convoluted tubules ➔ Retain sodium and eliminate potassium & hydrogen ions. - Stimulated by ACTH, ANG II, decrease intravascular volume, hyperkalemia. DEFFICIENCY: hypertension and hyperkalemia EXCESS: Edema, hypertension, hypokalemia, & metabolic alkalosis - Although there is an increase in insulin production at the same time, severe stress is frequently associated with insulin resistance, leading to decreased glucose uptake in the liver & the periphery contributing to acute hyperglycemia. Hormones and inflammatory mediators associated with the stress response inhibit insulin release. In conjunction with peripheral insulin resistance following injury, this results in stress induced hyperglycemia and is in keeping with the general catabolic state immediately following major injury. In a healthy individual, insulin exerts a global anabolic effect by promoting hepatic glycogenesis and glycolysis. Glucose → lipogenesis & protein synthesis → adipocytes → injury → insulin release SUPPRESSED → normal / excessive insulin production [despite Hyperglycemia]. Hyperglycemia occurs via mobilization of glucose from the liver via glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. To compound the resulting hyperglycemia, insulin release is decreased mainly through the stimulation of α-adrenergic pancreatic receptors. Hyperglycemia contributes proinflammatory response and mitochondrial dysfunction. to the to further Activated lymphocytes express insulin receptors and activation enhances T-cell proliferation and cytotoxicity. Tight control of glucose levels in the critically-ill has been associated with significant reductions in morbidity and mortality. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 16 | 18 PCC SOM 2026 SURGERY 1 P.02.02.01 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT Adrenal Medulla - A modified sympathetic ganglion. Postganglionic neurons lack axons. NE and E are secreted in response to alarm signals from the CNS into the bloodstream for distribution throughout the body. Acetylcholine signaling to the resident chromaffin cells ensures that a surge of epinephrine (EPI) and norepinephrine (NE) release into the circulation takes place in a ratio that is tightly regulated by both central and peripheral mechanisms. The hypermetabolic state observed following severe injury is attributed to the activation of the adrenergic system. NE and E are increased 3-4-fold in times of trauma found in plasma immediately following injury with elevations lasting 24-48 hours before returning towards baseline levels. In the liver, it promotes glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. It also causes decreased insulin release but increases glucagon secretion. Peripherally, epinephrine increases lipolysis in adipose tissues and induces insulin resistance in skeletal muscles. This collectively, like cortisol, epinephrine enhances leukocyte demarginalization with resultant neutrophilia and lymphocytosis. Injury-induced activation of the sympathetic nervous system results in secretion of acetylcholine from the preganglionic sympathetic fibers innervating the adrenal medulla. Catecholamine release almost immediately prepares the body for the “fight or flight” response with well-described effects on the cardiovascular and pulmonary systems, and on metabolism. Hyperglycemia, insulin release is decreased mainly through the stimulation of α-adrenergic receptors. Catecholamines - Inhibit production of TNF-α - Enhance production of anti-inflammatory cytokine IL-10 - Proinflammatory cytokine regulation - Reestablish and maintain the systems’ homeostasis, including the innate immune system. NOTE TAKER: Chomenwey, Domingo, Mariano, Martinez, Medrano, Padagas, Santiago Page 17 | 18 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 antiinflammatory 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 1 | 18