Lecture 2.1 - Acute Inflammation PDF

What is inflammation?: ◦Inflammation is a rapid response to injury of vascularised living tissue. Its purpose is to deliver defensive materials (white blood cells and fluid containing plasma proteins) to a site of injury. ◦The response of living tissue to injury ◦Vascular an...

What is inflammation?: ◦Inflammation is a rapid response to injury of vascularised living tissue. Its purpose is to deliver defensive materials (white blood cells and fluid containing plasma proteins) to a site of injury. ◦The response of living tissue to injury ◦Vascular and cellular ‣ Accumulation of exudate (fluid) and neutrophils (main inflammatory cells involved in the process) in tissue ◦Controlled by a variety of mediators ‣ Derived from plasma or cells ◦Protective ‣ But can cause local and systemic complications What causes inflammation?: ◦Foreign bodies (splinters, dirt, sutures) ◦Immune reactions ◦Infections (bacterial, viral, parasitic) and microbial toxins ◦Trauma (blunt and penetrating) ◦Physical and chemical agents (thermal injury, e.g. burns or frostbite, irradiation, environmental chemicals) What are the clinical signs?: ◦Vasodilation of blood vessels = RUBOR ◦Loss of function - this enforces rest and reduces the chance of further damage What changes occur in vessels and surrounding tissues?: ◦Changes in blood flow ◦Movement of fluid into tissue - vascular phase ‣ Starling’s law: Fluid movement controlled by balance between: ◦Hydrostatic pressure (pressure exerted on vessel wall by fluid - pushes fluid away…)  ◦Oncotic pressure (pressure exerted by plasma protein within a vessel - draws fluid towards…) These pressures exist in vessels and the interstitial ◦Increased capillary hydrostatic pressure = increased fluid flow out of vessel ◦Increased interstitial oncotic pressure = increased fluid flow out of vessel In acute inflammation: ◦Vasodilation = increased capillary hydrostatic pressure ◦Increased vessel permeability = loss of plasma proteins into interstitium (increased interstitial oncotic pressure) ◦Net flow of fluid OUT of vessel INTO interstitium ◦OEDEMA (swelling - TUMOUR) Movement of fluid OUT of the vessel - Net movement ◦Increased viscosity of blood ◦Reduced flow through vessel = STASIS Types of interstitial fluid: ◦EXUDATE: ‣ Occurs in inflammation ‣ Increased vascular permeability ‣ Protein rich (delivering proteins to area of injury) ◦TRANSUDATE: ‣ Fluid loss due to increased capillary hydrostatic pressure or reduced capillary oncotic pressure ‣ No change of vascular permeability - therefore less protein present ‣ Occurs in heart failure/hepatic failure/renal failure - systemic problems Mechanisms of increased vascular permeability: ◦Endothelial contraction (gaps between endothelial cells) ‣ Histamine, leukotrienes  ◦Endothelial cytoskeleton reorganisation (change of shape increases the gaps between them) ‣ Cytokines IL-1 beta, TNF alpha ◦Direct injury: ‣ Chemical, toxic burns ◦Leucocyte dependent injury: ‣ Enzymes and toxic oxygen species from leucocytes ◦Infiltration of inflammatory cells into tissue - cellular phase ‣ Chemical mediators at each step ‣ Neutrophil: The primary white blood cell involved in acute inflammation Trilobed nucleus A granulocyte Chemotaxis and neutrophil infiltration: ◦Stasis causes neutrophils to line up at the edge of blood vessels along the endothelium = MARGINATION ◦Neutrophils then roll along endothelium, sticking to it intermittently = ROLLING ◦Then stick more avidly - use of adhesion molecules = ADHESION ◦Followed by EMIGRATION of neutrophils through blood vessel wall Adhesion molecules: ◦Selectins: ‣ On endothelial cell surface ‣ Upregulated by chemical mediators ◦Integrins: ‣ On neutrophil surface ‣ Bind to receptors on endothelial surface Inflammatory infiltrate:  How do neutrophils move through the interstitium?: ◦Chemotaxis: ‣ Movement along a chemical gradient of chemoattractants Bacterial peptides, C5a, LTB4 IL8 Rearrangement of neutrophil cytoskeleton Pseudopod formation What do neutrophils do?: ◦Phagocytosis: ‣ Phagosomes fuse with lysosomes ‣ Produce secondary phagolysosomes How do inflammatory cells limit damage?: ◦Removal of toxins and pathogenic organisms ◦Removal of necrotic tissue ◦Release of chemical mediators stimulates and regulates further inflammation ◦Stimulates pain ‣ Encourages rest and limits risk of further damage Why is acute inflammation effective?: ◦Vascular phase ‣ Exudation of fluid into interstitium (oedema) ‣ Dilute toxin effect ◦Cellular phase ‣ Infiltration of neutrophils ‣ Kills pathogens How does oedema limit damage?: ◦Dilutes toxins ◦Delivers plasma proteins to area of injury  ‣ Fibrin (mesh limits spread of toxin) ‣ Inflammatory mediators - stimulates and regulate further inflammation ‣ Immunoglobulins - regulates the process ◦Increased lymphatic draining from area of injury ‣ Delivers antigens to lymph nodes (inducing adaptive immune response) Chemical mediators: ◦A vast array of chemicals that contribute to the inflammatory process ‣ Overlapping functions ‣ Varying chemical structures ‣ Some circulate in an inactive state in blood ‣ Released by: Activated inflammatory cells Platelets Endothelial cells Chemical mediators at each step: ◦Vasodilation - histamine serotonin, prostaglandins, nitric oxide ◦Increased vascular permeability - histamine, bradykinins, leukotrienes, C3a and C5a ◦Chemotaxis - C5a, LTB4, TNF-alpha, IL-1 beta, IL8, bacterial peptides ◦Fever - prostaglandins, IL-1 beta, TNF-alpha, IL-6 ◦Pain - bradykinin, substance P, prostaglandins Local complications: ◦Swelling: ‣ Blockage of nearby tubes and ducts (bile duct/intestines) ◦Exudate: ‣ Compression of organs ‣ E.g. cardiac tamponade ◦Pain and loss of function: ‣ Muscle atrophy ‣ Psycho-social consequences of chronic pain Systemic complications: ◦Fever: ‣ Endogenous pyrogens (prostaglandins, IL-1 beta, TNF alpha) - chemical mediators ‣ Act on hypothalamus to alter baseline temperature control ◦Pain: ‣ IL6 produced by the immune system causes systemic muscle pain. ◦Leucocytosis (increased production of white cells) ‣ IL-1 beta and TNF alpha act on bone marrow to increase production ‣ Bacterial infection = more neutrophils ‣ Viral infection = more lymphocytes ‣ Clinical use: can measure blood levels of these via FBC (full blood count) - can also detect what type of blood cells are present  ◦Acute phase proteins: ‣ Release of proteins from inflammatory cells: C-reactive protein (commonly used blood marker; is an opsonin) Alpha 1 antitrypsin Haptoglobin Fibrinogen Serum amyloid A protein ◦Cause “acute phase response” ‣ Malaise, reduced appetite, altered sleep, tachycardia ◦Septic shock: ‣ Overwhelming infection ‣ Huge release of chemical mediators ‣ Widespread vasodilation ‣ Hypotension, tachycardia ‣ Multi-organ failure ‣ Death Sequelae: ◦What happens after acute inflammation? ‣ Complete resolution ‣ Continued acute inflammation with chronic inflammation -> abscess ‣ Chronic inflammation and fibrous repair, with some tissue regeneration (replaced by scar tissue) ‣ Death Complete resolution: ◦All changes gradually reverse: ‣ Resolution is absolutely vital Neutrophils no longer marginate Vascular permeability returns to normal Vessel calibre ◦Therefore: ‣ Exudate drains away via lymphatics ‣ Fibrin is degraded ‣ Neutrophils die, break up and get phagocytosed ‣ Damaged tissue may be able to regenerate, if architecture is preserved ‣ Mediators are diluted/inactivated/degraded Clinical examples: ◦Appendicitis: ‣ Blocked men (commonly faecolith) ‣ Accumulation of bacteria, increased pressure, reduced blood flow  Normalappendix Appendilitis ◦Pneumonia: ‣ Many causative organisms: Streptococcus pneumoniae, Haemophilus influenzae ‣ Signs and symptoms: Shortness of breath, fever, cough, sputum production, chest pain ‣ Risk factors: Smoking, pre-existing lung condition (COPD, asthma, malignancy) ◦Bacterial meningitis: ‣ Inflammation of the meninges ‣ Caused by a variety of pathogens Group B streptococcus E.coli Neisseria meningitidis ‣ Clinical signs: Neck stiffness, fever, photophobia, altered mental state ‣ Rapidly fatal Abscess: ◦An accumulation of dead and dying neutrophils ◦With associated Liquefactive necrosis ◦Causes compression of surrounding structures and nerves: ‣ Pain blockage of ducts Inflammation of serous cavities: ◦Variety of causes: ‣ Exudate pours into serous cavity: Ascites - abdominal distension  Pleural effusion - shortness of breath Pericardial effusion - cardiac impairment Disorders of acute inflammation: ◦Rare disorders ◦Illustrate the complex mechanisms of acute inflammation ‣ Hereditary angio-oedema: This is an extremely rare autosomal dominant condition in which sufferers have an inherited deficiency of C1-esterase inhibitor (a component of the compliment system). Patients have attacks of non-itchy cutaneous angio-oedema (rapid oedema of the dermis, subcutaneous tissue, mucosa and submucosal tissues). They also experience recurrent abdominal pain which is due to intestinal oedema. There is often a family history of sudden death which is due to laryngeal involvement. ‣ Alpha-1 antitrypsin deficiency: This is an autosomal recessive disorder with varying levels of severity in which there are low levels of alpha-1 antitrypsin, a protease inhibitor which deactivates enzymes released from neutrophils at the site of inflammation. Patients with the disorder develop emphysema as proteases released by neutrophils within the lung act unchecked and destroy normal parenchymal tissue. Liver disease also occurs as the hepatocytes produce an abnormal version of the protein which is incorrectly folded. It polymerises and cannot be exported from the endoplasmic reticulum. This causes hepatocyte damage and eventually cirrhosis. ‣ Chronic granulomatous disease: In this genetic condition phagocytes are unable to generate the free radical superoxide. Bacteria are phagocytosed but the phagocytes cannot kill them as they can’t generate an oxygen burst. This results in many chronic infections in the first year of life. Numerous granulomas and abscesses affecting the skin, lymph nodes, and sometimes the lung, liver and bones occur, however they are ineffective at eliminating the infectious agents.