6 N1 Lecture 6 Inflammation; chemical mediators.pdf

Lecture 6 Acute Inflammation; Chemical mediators Dr Mohammad Shahid Iqbal M.D Assistant Professor of Pathology 1 Learning Outcomes By the end of this lecture, the students must be be able to 1. Define phagocytosis and explain the steps of phagocytosis 2. Enumerate the cell derived and plasma derived...

Lecture 6 Acute Inflammation; Chemical mediators Dr Mohammad Shahid Iqbal M.D Assistant Professor of Pathology 1 Learning Outcomes By the end of this lecture, the students must be be able to 1. Define phagocytosis and explain the steps of phagocytosis 2. Enumerate the cell derived and plasma derived chemical mediators of inflammation 3. Discuss about cytokines and their role in inflammation 4. Discuss the sources, and roles of various chemical mediators 2 Phagocytosis ‘’Process of engulfment of solid particulate material e.g., bacterial, necrotic tissue or foreign material. by phagocytic cells ‘’ Type of phagocytic cells: Neutrophils, Macrophages Three steps : 1) Recognition and attachment. 2) Engulfment 3) Killing or degradation Classifications: Inflammation can be Acute or Chronic. Differences between Acute and Chronic Inflammation Acute Inflammation Chronic Inflammation Onset/ Duration. Immediate reaction of tissue to injury. Rapid: hours to weeks. Immunity Innate Predominant Cell Type / Cellular infiltrate Tissue injury, Fibrosis Local & systemic signs Outcome Mainly Neutrophils. Persisting reactions of tissue to injury. Slow Response: weeks/ months/ years. Cell mediated Monocytes/ Macrophages & lymphocytes. Often sever & progressive. Less Prominent. Tissue destruction, fibrosis, necrosis. Response Usually mild & self limiting Prominent. Resolution, abscess formation, chronic inflammation. Components & Events of Acute Inflammation Acute inflammation has 4 major components: 1) Vascular Changes: Alteration in Vascular caliber with increased blood flow thus called Vasodilation. 2) Microvascular Changes: Alteration in permeability of microvasculature. Plasma proteins & WBC leakage (Increased Vascular Permeability). 3) Cellular Events: Emigration, accumulation & activation of WBCs in the site of Injury (cellular recruitment and activation). 4) Mediators, derived from plasma proteins and cells. Principles of Mediators Inflammatory mediators are chemical substances that trigger certain processes in an inflammatory reaction. Mediators are differentiated according to their origin: (A) Cell-derived mediators. (B) Plasma-derived mediators. Principles of Mediators Initially bind to specific receptors and act. Stimulate the release of other mediators Can act on one or few target cell types. Once activated these are short lived. Potentially harmful. Active Mediators Active Mediators are produced and released in response to various Injurious stimuli such as: Microbial products. Substances released from necrotic cells. Proteins of the complement, kinin, and coagulation systems which activated by microbes and damaged tissues. - Ensures that inflammation is normally triggered only when and where it is needed. Roles of Mediators Multifunctional Effects on: ▪ The blood vessels. ▪ Inflammatory cells ▪ Other cells in the body EFFECTS OF MEDIATORS Effects of mediators 1. Vasodilation. 2. Vasoconstriction. 3. Altered vascular permeability. 4. Activation of inflammatory cells. 5. Chemotaxis. 6. Cytotoxicity. 7. Degradation of tissue. 8. Pain. 9. Fever. (A) Cell -derived mediators ▪ May be pre-formed and stored in granules of platelets and leukocytes (histamine)…or… ▪ May be synthesized as needed. (A) Cell-derived mediators 1. 2. 3. 4. 5. Vasoactive amines (Histamine). Arachidonic Acid derivatives (Prostaglandins & Leukotrienes). Platelet-Activating Factor. Cytokines. Nitric Oxide. (A) Cell-Derived Mediators of Inflammation: 1. Vasoactive amines (Histamine) The most notable example is Histamine. Source: mast cells, basophils & platelets. Effects: (1) vasodilatation (2) venular permeability increase (3) endothelial activation. (A) Cell-Derived Mediators of Inflammation: 2. Arachidonic Acid (AA) Metabolites (Prostaglandins & Leukotrienes). Prostaglandins (PGI2, PGD2 & PGE2). - Mediate vasodilation, pain, fever. Leukoterines (LTB4, LTC4, LTD4 & LTE4). - Mediate increased vascular permeability, chemotaxis, leukocytes adhesion & activation. Source: mast cells & leukocytes (mainly by neutrophils). Involved in all stages of inflammation. (A) Cell-Derived Mediators of Inflammation: 3. Platelet- Activating Factors (PAF) Source: produced by mast cells and other leukocytes (mainly neutrophils). Effects: (1) Vasodilation. (2) Increased vascular permeability. (3) Leukocyte adhesion. (4) Oxidative burst. (5) Chemotaxis. (6) Induced platelet degranulation. (A) Cell-Derived Mediators of Inflammation: 4. Cytokines Cytokines are proteins produced by many cell types that modulate the functions of other cell types. Source: produced by activated lymphocytes and macrophages that modulate the function of other cell types. Involved both in acute and chronic inflammation Cytokines include: ▪ Lymphokines – cytokines produced by lymphocyte. ▪ Monokines - cytokines produced by monocytes/ macrophages. ▪ Interleukins (IL) - cytokines that act between the leukocytes (more than 15 types). ▪ Interferons (INF) – inhibit replication of viruses within the cells and activates macrophages and natural killer (NK) cells. ▪ Growth factors. ▪ Tumor necrosis factors – kill tumor cells but also stimulate adipose and muscle catabolism leading to weight loss. Important Note/ Tumor necrosis factor alpha (TNFa) and IL-1 are key cytokines in acute inflammation. Cytokines Effects: (A) Cell-Derived Mediators of Inflammation: 5. Nitric Oxide (NO) Nitric oxide (NO) is a potent vasodilator. Source: Soluble gas produced by endothelial cells & macrophages. Nitric oxide acts as a regulator of inflammation, actively reducing the effect of other proinflammatory mediators. Role of Cell- mediators in different Reactions of Inflammation (B) Plasma protein-derived mediators ▪ Circulate in an inactive form. ▪ Must be transformed into an active form by an activator. ▪ Numerous, specific and non-specific. ▪ All activators have natural in-activators to maintain balance. (B) Plasma protein-derived mediators Three interrelated systems are involved in several aspects of inflammation: Proteins are derived from plasma 1. Complement 2. Bradykinin 3. Factor XII References 1. Robbins and Cotran Pathologic Basis of Disease; 10th ed. 2021 2. HarshMohan Textbook of Pathology. 7th edition. 26 Thank You 27