MIM_PRL-08.-Inflammation.pdf

INFLAMMATION S.Y. ‘24 - ‘25 | YL2 - 1ST SEM [PRELIMS] Lecturer: Dr. Anamarie Manangan Permeability increase 1.0 INFLAMMATION ○ histamine cause...

INFLAMMATION S.Y. ‘24 - ‘25 | YL2 - 1ST SEM [PRELIMS] Lecturer: Dr. Anamarie Manangan Permeability increase 1.0 INFLAMMATION ○ histamine causes endothelial cells to loosen, allowing protein and immune cells Refers to the complex biological response of body to exit the bloodstream and migrate to the tissues to harmful stimuli site of infection or injury Primary purpose: ○ Eliminate the cause of cell injury ○ Clear out necrotic cells and tissues 2.3 CHEMOTAXIS & LEUKOCYTE RECRUITMENT damaged from the original insult and the inflammatory process Chemokine release ○ Initiate tissue repair ○ immune cells release chemokines that Crucial component of the immune system’s defense attract other immune cells to the site mechanisms Adhesion and Migration Involves a series of events and processes ○ immune cells (e.g. neutrophils, Inflammatory response – characterized by classic monocytes) adhere to the endothelium and signs and symptoms migrate towards the source of Plays a critical role in the body’s defense against inflammation infections and the healing process after tissue damage 2.4 PHAGOCYTOSIS & DESTRUCTION 2.0 INFLAMMATORY RESPONSE Recognition and Attachment ○ immune cells recognize and adhere to 1. Initiation pathogens through specific receptors 2. Vasodilation and Increased Permeability Engulfment 3. Chemotaxis and Leukocyte Recruitment ○ phagocytes engulf the pathogen or 4. Phagocytosis and Destruction damaged cells 5. Resolution and Tissue Repair Destruction ○ intracellular killing involves enzymes, 2.1 INITIATION reactive oxygen species (ROS), and antimicrobial peptides Detection of threats ○ specialized cells, such as macrophages 2.5 RESOLUTION & TISSUE REPAIR and dendritic cells, detect pathogens or tissue damage Anti-inflammatory signals Recognition molecules ○ release of anti-inflammatory cytokines ○ PRRs on immune cells recognize PAMPs e.g. IL-10 or DAMPs Removal of Debris ○ macrophages clear cellular debris PRRs → Pathogen Recognition Receptors Tissue repair PAMPs → Pathogen Associated Molecular Patterns ○ fibroblasts and other cells contribute to DAMPs → Damage Associated Molecular Patterns tissue healing 2.2 VASODILATION & INCREASED PERMEABILITY Vasodilation ○ histamines and other mediators induce blood vessel dilation → increased blood flow to the affected area trans by el PAGE 1  INFLAMMATION S.Y. ‘24 - ‘25 | YL2 - 1ST SEM [PRELIMS] Lecturer: Dr. Anamarie Manangan Molecular Level Details 3.1 PRO-INFLAMMATORY CYTOKINES Step / Term Details Pattern Recognition Toll like receptors (TLRs) and other Functions: Receptors (PRRs) PRRs recognize PAMPs and DAMPs ○ Induce and promote inflammation ○ Recruit immune cells to sites of infection Activation triggers intracellular signaling cascades or injury ○ Enhance immune responses Mediators of Vasodilation Histamine e.g. & Permeability released from mast cells, triggers vasodilation and increases vascular ○ Interleukin-1 (IL-1) permeability stimulates inflammation, fever, and immune cell activation Prostaglandins lipid mediators that enhance ○ Tumor Necrosis Factor-alpha (TNF-a) vasodilation and contribute to pain promotes inflammation & apoptosis Chemokines small proteins that guide immune cell regulates immune cells movement ○ Interleukin-6 (IL-6) induces acute phase protein Selectins & Integrins adhesion molecules facilitating production and inflammation immune cell binding to endothelial ○ Interleukin-12 (IL-12) cells promotes Th1 cell differentiation Phagocytosis & Opsonization enhances natural killer (NK) cell Intracellular Killing antibodies and complement proteins activity enhance pathogen recognition Phagosome Formation pathogen engulfed into a phagosome 3.2 ANTI-INFLAMMATORY CYTOKINES Respiratory Burst production of ROS within the Functions: phagosome ○ Suppress or dampen the inflammatory response Resolution & IL-10 Anti-inflammatory signals anti-inflammatory cytokine ○ Modulate immune reactions suppressing pro-inflammatory ○ Contribute to the resolution of Resolution of Inflammation inflammation negative feedback mechanisms to e.g. prevent excessive inflammation ○ Interleukin-10 (IL-10) ** most forms of inflammation are exaggerated because of the anti-inflammatory humoral amplification systems with production of pro-inflammatory suppress immune responses mediators inhibits the production of ** act as secondary messengers to induce synthesis and expression pro-inflammatory cytokines of specific adhesion molecules on endothelial cells and white cells ○ Transforming Growth Factor-beta (TGF-B) cell growth, differentiation, and ** PMNs play a central role in the acute inflammatory response immune responses, often with anti-inflammatory effects 3.0 CYTOKINES 3.3 REGULATORY CYTOKINES Signaling molecules that play a crucial role in cell communication Categorized based on their functions Functions: ○ Pro-inflammatory cytokines ○ Control and balance immune responses ○ Anti-inflammatory cytokines ○ Maintain immune homeostasis ○ Regulatory / Immunoregulatory cytokines ○ Prevent excessive inflammation or immune reactions trans by el PAGE 2  INFLAMMATION S.Y. ‘24 - ‘25 | YL2 - 1ST SEM [PRELIMS] Lecturer: Dr. Anamarie Manangan e.g. Redundancy & Pleiotropy ○ Interleukin-2 (IL-2) ○ Multiple cytokines may have similar or stimulates T cell proliferation and overlapping functions → redundancy in the regulatory T cell development system ○ Interleukin-4 (IL-4) ○ Pleiotropy promotes B cell growth and a phenomenon wherein a single antibody class switching, involved cytokine can exert diverse effects in allergy and parasite defense on different cell types or ○ Interferon gamma (IFN-γ) processes activates macrophages Cellular crosstalk enhances antigen presentation ○ The cytokine network facilitates contributes to immune defenses communication between different immune against intracellular pathogens cells, including T cells, B cells and ○ Interleukin-17 (IL-17) macrophages at mucosal surfaces; regulates ○ Crosstalk → crucial for coordinating the inflammatory responses overall immune response Homeostasis maintenance 4.0 CYTOKINE NETWORK ○ The cytokine network contributes to maintaining immune system homeostasis, ensuring a balanced response to various Refers to the intricate and dynamic system of challenges while avoiding excessive interactions among various cytokines in the inflammation or immunodeficiency immune system Dysregulation & Disease Cytokines ○ Imbalances or dysregulation within the ○ signaling molecules that play a central role cytokine network are associated with in regulating immune responses and various diseases communication between cells e.g. overproduction of pro Cytokine network inflammatory cytokines → can ○ concept that emphasizes the contribute to autoimmune interconnectedness and complexity of diseases, chronic inflammation, these signaling molecules, illustrating how and tissue damage they influence each other’s production, Therapeutic Targets activity and functions ○ Understanding the complexity of the cytokine network has important 4.1 KEY FEATURES OF CYTOKINE NETWORK implications for therapeutic interventions ○ Targeting specific cytokines or modulating their activity can be a strategy for treating Interdependence conditions where the cytokine network is ○ Cytokines often act in a network where the dysregulated presence or actions of one cytokine can influence the expression or effects of others → creates a finely tuned system 5.0 CARDINAL SIGNS OF INFLAMMATION that can quickly adapt to changing conditions Set of classic indicators that characterize the body’s Feedback loops response to tissue injury, infection or other harmful ○ Many cytokines are involved in feedback stimuli loops, where the production of one These signs are commonly taught in medical and cytokine is regulated by the presence or biological sciences and include: activity of another → helps maintain ○ Rubor (redness) balance and prevent excessive or ○ Calor (heat) prolonged immune response ○ Tumor (swelling) ○ Dolor (pain) ○ Functio Laesa (loss of function) trans by el PAGE 3  INFLAMMATION S.Y. ‘24 - ‘25 | YL2 - 1ST SEM [PRELIMS] Lecturer: Dr. Anamarie Manangan Cardinal Signs of Inflammation ○ increased blood flow to the affected area → redness and warmth Sign Definition Increased vascular permeability Rubor Cause: ○ mediators: including histamine and (redness) increased blood flow to the affected bradykinin → enhance the permeability of area blood vessels Explanation: ○ allow proteins (e.g. antibodies, clotting blood vessels dilate (vasodilation) factors) and fluid to exit the bloodstream Calor Cause: → swelling (edema) (heat) increased blood flow and metabolic Endothelial activation activity in the affected area ○ endothelial cells lining blood vessels Explanation: express adhesion molecules vasodilation and influx of immune cells ○ facilitates the attachment and rolling of lead to increase in temperature at the WBCs (leukocytes) along the vessel walls site of inflammation Chemotaxis Tumor Cause: ○ chemokines are released, guiding (swelling) accumulation of fluid (edema) in the leukocytes to the site of inflammation affected tissue ○ leukocytes adhere to the endothelium and Explanation: migrate towards the chemotactic signals increased vascular permeability allows proteins and fluids to leak into the tissue → swelling 6.2 CELLULAR PHASE Dolor Cause: (pain) release of inflammatory mediators, Margination & Rolling tissue damage, and pressure on nerves ○ leukocytes (primary neutrophils) move to Explanation: the periphery of blood vessels inflammatory mediators, such as (margination) and roll along the vessel prostaglandins and bradykinins, sensitize nerves → pain; tissue walls damage and accumulation of fluid can ○ adhesion molecules on leukocytes interact exert pressure on nerves, contributing with receptors in endothelial cells to the sensation of pain Adhesion & Transmigration Function Laesa Cause: ○ Firm adhesion (loss of function) protective response to prevent further leukocytes adhere tightly to the damage endothelium through integrin Explanation: interactions in severe inflammation, the affected ○ Transcription tissue may lose normal function temporarily → a protective mechanism leukocytes squeeze through the aimed at minimizing movement or vessel wall (diapedesis) and stress on the injured area to facilitate move towards the site of injury or healing infection Chemotaxis & Activation 6.0 PHASES OF INFLAMMATION ○ chemotactic signals guide leukocytes to the source of inflammation ○ leukocytes become activated, enhancing Vascular Phase their ability to phagocytose pathogens or Cellular Phase damaged cells Phagocytosis & Destruction 6.1 VASCULAR PHASE ○ phagocytes (neutrophils & macrophages) engulf and digest pathogens or cellular Vasodilation debris ○ mediators such as histamine and ○ intracellular killing → involves the release prostaglandins induce the relaxation of of enzymes and reactivate ROS blood vessel walls trans by el PAGE 4  INFLAMMATION S.Y. ‘24 - ‘25 | YL2 - 1ST SEM [PRELIMS] Lecturer: Dr. Anamarie Manangan Resolution & Tissue Repair Ulcerative Inflammation ○ anti-inflammatory signals (e.g. IL-10) are occurs near an epithelium released resulting in necrotic loss of tissue from the surface, ○ macrophages play a role in removing Ulcer exposing lower layers with debris and other cells contribute to tissue subsequent excavation in the repair and resolution of inflammation epithelium 7.0 COMPONENTS OF PLASMA CASCADE 8.1 OUTCOMES OF ACUTE INFLAMMATION SYSTEM Depends on the particular circumstances and will Complement system be determined by the tissue in which the injury has ○ promotes opsonization, chemotaxis, and occurred agglutination and produces the MAC ○ Resolution Kinin system ○ Fibrosis ○ generates proteins capable of sustaining ○ Abscess formation vasodilation and other physical ○ Chronic inflammation inflammatory effects Resolution Coagulation or clotting cascade ○ Inflammatory response must be actively ○ forms a protective protein mesh over sites terminated when no longer needed to of injury prevent unnecessary bystander damage to Fibrinolysis system tissues ○ acts in opposition to the coagulation ○ Failure of resolution → results to chronic system → to counterbalance clotting and inflammation and cellular destruction generate other inflammatory mediators Mechanisms Involved in Resolution 8.0 MORPHOLOGIC PATTERNS OF INFLAMMATION Mechanism Details Short half life of mediators Production and release of TGF-B Granulomatous - Tuberculosis From macrophages IL-10 - Leprosy - Sarcoidosis Production of anti-inflammatory - Syphilis mediators: lipoxins, resolvins, maresins, and neuroprotectins Downregulation of Upregulation of anti-inflammatory pro-inflammatory molecules molecules such as the IL-1 receptor (e.g. leukotriene) antagonist or the soluble TNF Fibrinous receptor - Cancer - Pseudomembranous colitis Apoptosis of pro-inflammatory cells Desensitization of receptors Increased survival of cells in Downregulation of receptor activity regions of inflammation due by high concentration of ligands to their interaction with the Large amount of pus (with extracellular matrix (ECM) Cleavage of chemokines by matrix neutrophils, dead cells, fluids metalloproteinases (MMPs) might & abscess); can have lead to production of Staphylococcal infection anti-inflammatory factors Serous Inflammation copious effusion of non-viscous serous fluid, commonly produced by Skin blisters mesothelial cells of serous membranes, but may be derived from blood plasma trans by el PAGE 5  INFLAMMATION S.Y. ‘24 - ‘25 | YL2 - 1ST SEM [PRELIMS] Lecturer: Dr. Anamarie Manangan 9.0 UNCONTROLLED INFLAMMATION Systemic effects: ○ Infectious organism may spread to other parts of the body via the circulatory and the lymphatic systems ○ When inflammation overwhelms the host systemic inflammatory response syndrome is diagnosed ○ When it is due to infection leads to sepsis ○ Vasodilation and organ dysfunction leads to septic shock and death 10.0 CYTOKINE STORM 10.1 CYTOKINE STORM (CONT.) Loosely used interchangeably with cytokine release syndrome (CRS) A life threatening condition that requires ICU care ○ With the same clinical phenotype but associated with high mortality different characteristics Characterized by: ○ As a result of therapy → symptoms are ○ Overwhelming systemic inflammation delayed (days or weeks after treatment) ○ Hyperferritinemia ○ Severe case of CRS – cytokine storm ○ Hemodynamic instability ○ Cytokine storm – immediate onset ○ Multi-organ failure Uncontrolled immune response resulting in Attributed to the action of the pro-inflammatory continuous activation and expansion of immune cytokines like IL-1, IL-6, IL-8, IFN-y and TNF-a cells, lymphocytes, and macrophages which Anti-inflammatory cytokines (IL-10 and IL-1 receptor produce immense amounts of cytokines antagonist) are elevated in the serum of patients experiencing cytokine storm Has been reported in several viral infections: 10.1 CAUSES OF CYTOKINE STORM ○ Influenza viruses H5N1 virus Infections: H1N1 virus ○ Viral respiratory infections COVID-19 e.g. H5N2 influenza, SARS CoV-1, SARS-CoV SARS CoV-2, CMV, and Group A MERS-CoV Streptococcus ○ Both pro-inflammatory cytokines (e.g. IL-1, Non-infectious: IL-6, and TNF-a) and anti-inflammatory ○ Graft versus Host disease 9GVHD0 cytokines (e.g. IL-10 and IL-1 receptor ○ Drugs antagonist) are elevated ○ Adverse effect of some monoclonal ○ IL-6 and TNF-a antibody medications, as well as adoptive main contributors to the interplay T cell therapies – infusion reaction of the cytokine storm May also be associated with the following: ○ Hemophagocytic lymphohistiocytosis ○ Epstein Barr virus associated hemophagocytic lymphohistiocytosis ○ Systemic or non-systemic juvenile idiopathic arthritis-associated macrophage activation syndrome ○ NLRC4 macrophage activation syndrome ○ Cytokine release syndrome and sepsis trans by el PAGE 6  INFLAMMATION S.Y. ‘24 - ‘25 | YL2 - 1ST SEM [PRELIMS] Lecturer: Dr. Anamarie Manangan ** It was proposed that the immune system cytokine network may also communicate with the central nervous system (CNS) cytokine network, especially when the blood brain barrier (BBB) is compromised. ** Microglia and IL-1 activation → can cause increased ROS production, phagocytosis, apoptosis, and increased cytokine expression within the CNS, leading to neural tissue damage through neuroinflammation, increased oxidative stress and excitotoxicity, and dysfunction in synaptic pruning. trans by el PAGE 7