Inflammation (2024-25) - Prof Simon Whawell - PDF

Inflammation Simon A. Whawell [email protected] Learning outcomes Identify tissue responses to injury and microbial attack Explain inflammation as a protective mechanism Recognise the molecular mechanism of inflammation Distinguish between acute and chronic inflammation W...

Inflammation Simon A. Whawell [email protected] Learning outcomes Identify tissue responses to injury and microbial attack Explain inflammation as a protective mechanism Recognise the molecular mechanism of inflammation Distinguish between acute and chronic inflammation What is inflammation? Protective response to challenge designed to eliminate/limit a cause of cell/tissue injury Challenge may be internal or external Destroy microorganisms, foreign material, subsequent dying cells Cascade with complex mediators, tightly regulated Vascular & cellular responses Cells & molecules brought to site of tissue damage Key initiator of healing/repair Can be acute or chronic Classic signs of inflammation Latin inflammare – set of fire Roman physician Celsus. 1st century AD Rubor Tumour Calor Dolor Functio laesa (added latter) Types of inflammatory challenge Physical agents: trauma, heat/cold, radiation Chemical agents: toxic, irritant, harmful Infective agents: e.g. viruses, fungi, bacteria, parasites & their toxins Immunological agents: cell mediated and antigen-antibody reactions, hypersensitivity, autoimmune Inflammatory responses Acute (rapid) inflammation – innate immune system Vascular changes Release of preformed inflammatory mediators from cells Serotonin from platelets - vasoconstriction initially to restrict blood loss Histamine from mast cells – vasodilator to get more blood to site Initiation of cascades through activation of plasma components Kinin cascade forms bradykinin – vasodilation, increases vascular permeability Fibrinolytic system activates complement system Synthesis of new inflammatory mediators  Inflammatory mediators Arachidonic acid released from Membrane phospholipid disrupted phospholipid Phospholipase A2 membranes Converted into prostaglandins Arachidonic acid by cyclooxygenase pathway Lipoxygenase Cyclooxygenase Include prostacyclin – vasodilation Reaction take place in Leukotrienes Prostaglandins inflammatory cells & Thromboxanes endothelium Leukotrienes: chemotactic & increase vascular permeability Inflammatory mediators Cytokines & chemokines Pro-inflammatory Interleukin-1 Tumour necrosis factor α Induce production of other cytokines Interleukin-8 Monocyte chemotactic protein (MCP) Attract neutrophils, monocytes, lymphocytes Vascular changes Vascular system crucial in inflammation Initial vasoconstriction to reduce blood loss Vasodilation Brings inflammatory cells to the site (there are some resident in the tissue) Leukocyte emigration & accumulation in the site of injury  Normal Vascular changes Altered vascular permeability Endothelial vessel lining becomes ‘leaky’ Contraction of endothelial cells Osmotic pressure of interstitial fluid increases Extravasation & deposition of plasma fluid and proteins Oedema (swelling) Exudate Cellular events: recruitments of leucocytes Volume of blood increased, flow rate reduced Initial low affinity interaction with endothelium (rolling) Chemokines activate adhesion molecules on leucocytes & endothelium Firm adhesion then extravasation out of Cellular events Neutrophils first cells to infiltrate Activated by bacterial LPS, products of other cells Secrete chemokines to attract monocytes and macrophages Both neutrophils & macrophages are phagocytic Neutrophils generate oxygen free radicals toxic to cells Complement cascade Key part of innate immunity C3a & C5a important inflammatory mediators Binding to antigens as part of phagocytosis (opsonisation) Assemble membrane attack complex resulting in cell lysis  Phagocytosis Cellular process for ingesting & eliminating foreign bodies, microorganisms, apoptotic (dead) cells Neutrophils & macrophages are ‘professional’ phagocytes Recognition Receptors e.g PAMPs Opsonins e.g antibody, complement Ingestion Early then late phagosome formation Phagolysosome formation Exocytosis Resolution of acute inflammation Resolution Cytokines have short half life Immune cells apoptose (die) when not needed Anti-inflammatory cytokines released (IL-4, IL-10) If acute inflammation is not resolved it may become chronic Infection/foreign body may persist Defective control of inflammatory reactions e.g. autoimmune disease Fibroblast proliferation & scar formation Circulating markers e.g. C-reactive protein Acute vs. Chronic inflammation Inflammatory pain Normally innocuous stimuli produce pain (Hyperalgesia). Activation of nociceptive sensory neurons by inflammatory mediators Depolarization of sensory nerve endings in the periphery generate action potentials that travel to the spinal cord Inflammatory mediators can also reduce the threshold of activation of nociceptive sensory neurons (peripheral sensitisation) Sensitisation maintained by increased production of Timeline - depending on nature of insult & tissue Venous leg ulcers Wound healing stages: Haemostasis Inflammation Proliferation Remodelling Signals from one phase control the next Ulcers -‘stuck’ in the inflammatory phase Underlying disease - venous hypertension (damaged valves) Skin more fragile & open wounds more likely to become infected Histological inflammation Acute Chronic Can detect inflammation microscopically due to large cell infiltrate Acute: largely multilobed neutrophils Chronic: monocyte/macropha ge, lymphocytes, plasma cell Periodontal disease Subgingival plaque Chronic inflammation Heightened host response Inflammation activates bone degrading cells (osteoclasts) Loss of alveolar bone may eventually lead to tooth loss  When control goes wrong…… Cytokine storm Systemic inflammatory syndromes Elevated circulating cytokines & immune cell hyperactivation Tumour inflammation Complex relationship to cancer progression Tumour associated neutrophils and macrophages ‘Inflammageing’ Increase in proinflammatory markers with age Summary Inflammation essential body protective response to threat Complex cascade involving cellular & vascular changes Multiple inflammatory mediators act as messengers and attractants Short or long term (acute/chronic) Tightly regulated – if not serious disease can result (See Immunology teaching) Resources https://www.youtube.com/watch?v=LaG3nKGotZs https://www.youtube.com/watch?v=yIMz9pkT9xQ https://teachmephysiology.com/immune-system/immun e-responses/acute-inflammation/ Physiology, immunology, pathology text books