inflammation part i

Inflammation is a protective response What is the aim of inflammation? • To eliminate the initial cause of cell injury, as well as clearing away necrotic cells and tissues resulting from the original insult • To initiate the process of tissue repair ○ By recruiting immune cells and other mediators to the site of injury What are the tissue elements involved in inflammation? • Host cells (e.g. neutrophils, macrophages, lymphocytes) • Blood vessels • Proteins and other mediators (e.g. cytokines) ○ e.g., Acute-Phase Proteins like C-Reactive protein (CRP) that gets released from the liver in acute inflammation or infection (humoral immunity) How does inflammation accomplish its protective mission? • Dilutes, destroys/neutralizes harmful agents • Stimulates factors that lead to healing and repair at the sites of injury How Do Cells Recognize the Presence of Harmful, Infectious Agents? Microbes & Dead Cells release unique signals that differentiate them from normal tissues Phagocytes, Dendritic cells & Some other cells express receptors that sense the presence of infectious pathogens and substances released from dead cells Classification of Inflammation Acute: • Suppurative (Pus formation) • Non-Suppurative (No pus formation) Chronic: • Specific • Non-Specific Acute Inflammation Acute inflammation is an immediate response of tissue to injurious agents Function: • Delivers Leukocytes and Mediators to the site of injury through the blood stream Factors that Modify Outcome: • Intensity and Nature of injury • Host Response • Tissue Affected Factors that Trigger Acute Inflammation: • Infections • Trauma • Tissue Necrosis • Foreign bodies • Immune (Hypersensitivity) reactions Cardinal Signs of Acute Inflammation: • Redness (Rubor) • Heat (Calor) • Pain (Dolor) • Swelling (Tumor) • Loss of Function (Functio Laesa) • Cellulitis (Acute Skin Infection commonly caused by Streptococcus Pyogenes or Staphylococcus Aureus) Acute Phase Response to Inflammation: • Fever [especially with infections] • Acute Phase Proteins: ○ like C-Reactive Protein [mostly synthesized in the liver] show increased plasma level in response to inflammatory stimuli • Leukocytosis ○ Especially with bacterial infections • Other features: ○ Increased heart rate and blood pressure rigors (shivering) ○ Chills (search for warmth) Reactions of Acute Inflammation: • Vascular • Cellular Vascular Changes in Acute Inflammation 1. Transient Vasoconstriction: ○ Brief and insignificant narrowing of blood vessels. 2. Arterial Vasodilation: ○ Expansion of arteries, leading to increased blood flow ○ Capillaries become engorged with blood 3. Increased vessel permeability: A. Protein-Rich Fluid moves into the extracellular tissue § Cause of Swelling (Edema) B. Increased concentration of RBCs (more RBCs present in the affected area) Increased vessel permeability leads to: • Protein-Rich fluid moves from the vessels into the extravascular tissue • Increasing Osmotic Pressure within the extravascular interstitial tissue • Increased water outflow out of blood vessels • Formation of Exudate (Protein-Rich Fluid) • Leading to Edema (Swelling) Increased Concentration of RBCs in the Flowing Blood: • Increased Blood Viscosity • Slow circulation • • Formation of Fluid Exudate Formation of Fluid exudate in Inflammation occurs through: • Increased Vascular Permeability • Direct Cell injury The Function of Inflammatory Fluid Exudate Includes: 1. Dilutes Toxins 2. Bringing Fibrinogen, which forms a Fibrin Network: ○ Facilitates the movement of white blood cells (PNLs) to the site of injury ○ Entangles the area of inflammation ○ Provides a framework for the proliferation of fibroblasts to initiate repair 3. Transports Antibodies to the site of infection Response of Lymphatic Vessels Increased Lymph Flow: • Drains Edema Fluid • Drains PNLs and Dead Tissue from the Extravascular Space (Note: PNLs mean Polymorpho-Nuclear Leukocytes) In Severe Infections, lymphatic vessels transport the microbe, which could help in its dissemination which can cause lymphangitis Lymphangitis: • Lymphatic Vessels infected with the microbe Reactive (Inflammatory) Lymphadenitis: • They could spread the infection to the draining lymph nodes Cellular Events in Acute Inflammation Most Common Site: • Post-Capillary Venule Leukocyte Recruitment (Cellular Event in Acute Inflammation) Leukocyte Recruitment is Stimulated by: • Chemical Mediators • Chemo-Attractants What is the most important function of inflammatory response? • Deliver leukocytes to the site of injury • Activate leukocytes The Function of Leukocytes: • Ingest the microbe • Kill it • Eliminate necrotic tissue and foreign substances Sequence of Events of Leukocyte Recruitment: 1. Margination and Rolling 2. Firm Adhesion to Endothelium 3. Transmigration between Endothelial cells 4. Migration within Interstitial Tissue 1. Margination: ○ Normally Leukocytes occupy the center of the blood stream (central axis) ○ In inflammation: Slowing of blood stream causing leukocytes to leave the central axis to become at the periphery of the blood stream "Margination" ○ 1.2. Rolling: ○ Mediators released at site of infection "IL-1 and TNF" ○ Activate endothelial cells ○ Express/ up-regulate surface adhesion molecules (e-Selectin) ○ Leukocytes continuously bind to and detach from these adhesion molecules causing their ROLLING on the surface of endothelial cells ○ 2. Adhesion To Endothelium: • Normally: ○ Surface of leukocytes have inactive Integrin receptors • In Inflammation: ○ Chemokines (chemo-attractant cytokines) are liberated at sites of infection leading to: § Expression of Integrin Ligands § Activation of β-Integrin receptors on leukocytes → adhere to ligands on surface of endothelial cells • End Result: ○ Stable attachments of leukocytes on surface of endothelial cells 3. Transmigration Between Endothelial Cells: ○ Extravasation of Leukocytes = Diapedesis ○ Leukocytes are squeezed between cells at the intercellular junctions ○ They get out of blood vessels § "Secrete Collagenase that facilitates crossing basement membrane of blood vessels" ○ They migrate to site of infection/injury through chemokines that stimulate movement of leukocytes Chemotaxis: • Movement of Leukocytes from blood to site of infection/injury along a chemical gradient • The chemotactic substances in such cases are: ○ Bacterial Products ○ Leukotriene B4 ○ Chemokines ○ C5 (Complement System Components) • Chemokine receptors on surface of leukocytes are highest at the moving front ○ Types of Leukocytes Emigrating to the Site of Infection This Depends on the: • Duration of Inflammation • Type of stimulus Duration of Inflammation: • 6 - 24 hours: ○ PNLs § Short lived § Die by Apoptosis • 24 - 48 Hours: ○ Monocytes (Survive longer) Type of Stimulus: • Some Infections: ○ Continuous PNLs Recruitment • Viral Infections: ○ Lymphocytes • Hypersensitivity Reactions: ○ Eosinophils Leukocyte Activation Leukocytes are activated once they reach site of infection through: • Microbes • Necrotic Products • Mediators Steps of Phagocytosis: 1. Recognition & Attachment of pathogen to leukocyte 2. Engulfment 3. Organism inside a Phagosome 4. Fusion of lysosome containing enzymes with phagosome forming a Phagolysosome 5. Killing and degradation of ingested pathogen by enzymes & ROS Disadvantage of Leukocyte Activation: • Once leukocytes are activated, they are unable to distinguish between the pathogen and the normal surrounding tissue of the host • Leukocyte-Dependent Tissue Injury triggers lots of acute and chronic diseases Types of Acute Inflammation Acute Non-Suppurative Inflammation: • No Pus formation • e.g. Catarrhal Inflammation in Rhinitis • Subtypes: ○ Catarrhal ○ Fibrinous ○ Serous ○ Membranous ○ Allergic ○ Hemorrhagic Acute Suppurative Inflammation: • Pus Formation ○ Cause: Pyogenic Organisms • Two Subtypes: ○ Localized: § Abscess (common organism: Staphylococcus Aureus) ○ Diffuse: § Cellulitis Catarrhal Inflammation (Non-Suppurative Inflammation) A mild type of acute inflammation affecting the mucous membranes characterized by excess mucous secretion • e.g. catarrhal rhinitis, bronchitis Fate: • Mucous Membranes return to normal after few days ○ Sometimes Progress to Give a Mucopurulent discharge secondary to Pyogenic infection Fibrinous Inflammation (Non-Suppurative Inflammation) Occurs as a result of an injury leading to greater vascular permeability with extracellular leakage of an exudate rich in Fibrinogen Sites: • Serous Membranes e.g.: ○ Pericardium ○ Pleura ○ Peritoneum • Lung Alveoli ○ Acute Lobar Pneumonia Fate: • Resolution: ○ Fibrinous Exudate may be degraded by Fibrinolysis and Removed by Macrophages ○ Resulting in Restoration of the Normal Tissue structure • Organization: ○ Due to failure of complete removal of the fibrin ○ Results in Proliferation of Fibroblasts and Blood vessels, leading to Scar Formation Serous Inflammation (Non-Suppurative Inflammation) Characterized by formation of Clear Fluid with a Low Inflammatory cell count Examples: • Bullae of Mild Burn • Membranous Inflammation (Non-Suppurative Inflammation) An acute, non-suppurative inflammation of mucus surfaces characterized by formation of Pseudo-Membranes Where and When? • Mucous Membranes of Intestine in Bacillary Dysentery • Throat in Diphtheria infections (Remember IM 101: Diphteria are among the common bacteria that cause disturbed fat metabolism as mentioned in the degeneration cell injury lecture) Pathogenesis: • A More Severe type of Acute Inflammation • Causative organisms are localized on the surface of mucous membranes --> Secrete Exotoxins -> Necrosis of the Superficial part of the Mucosa Exotoxins (Bacteriology: Structure IAD 102) • Secreted by living organisms both Gram-Positive (mainly) and Gram-Negative • Staphylococcus Aureus • Cl. Tetanus • Proteins • Every toxin has specific action Pseudo-Membrane: • An adherent, dense, grey pseudo-membrane covering the tonsils is classically seen in Diphtheria • Components: ○ Fibrin Network entangling the Necrotic Tissue, PNLs and organisms • Allergic Inflammation (Non-Suppurative Inflammation) Immune reaction Rich in Blood and Tissue Eosinophils Hemorrhagic Inflammation (Non-Suppurative Inflammation) A Cellular Exudate Rich in RBCs due to damage of blood vessels Examples: • Smallpox • Hemolytic Streptococcal Infections ----- Acute Suppurative Inflammation It is an acute inflammation characterized by Pus Formation Pyogenic Micro-Organisms: • Staphylococcus Aureus • Streptococcus Hemolyticus • Gonococci • E. Coli Localized: • Abscess • Carbuncle Diffused: • Cellulitis ○ (Helwan Notes) Bacterial skin infection that can spread to other parts of the body. ○ Caused by Hemolytic Streptococci which secretes Fibrinolysis & Hyaluronidase Abscess Cellulitis Type Localized Suppuration Diffused Suppuration Causative Staphylococcal Aureus Hemolytic Streptococci Organism Enzymes Coagulase Fibrinolysis & Hyaluronidase Pus Rapid (48 Hours) Slow Thick Thin Yellow (Can be Green by Bacillus Pyocyeneus) Sanguineous (Bright Red) Abscess (Localized Acute Suppurative Inflammation) Acute localized suppurative inflammation draining pus from one opening Sites: • Any organ in the body (e.g. lung abscess, brain abscess) • Small abscess in relation to hair follicles (furuncle) Early Stage Abscess: • Staphylococcus Aureus -> Coagulase -> Massive Fibrin Deposition -> Localized • Two Zones: ○ Pyogenic Membrane: § "Vascular Phenomenon" § Zone of Inflammation: □ PNLs □ Dilated Blood Vessel □ Fibrin Network ○ The Other Zone contains organisms that have released bacterial toxins that eventually lead to Central Necrosis • Late Stage Abscess: • Three Zones: ○ Granulation Tissue ○ Pyogenic Membrane § Contains Proteolytic enzymes ○ Necrotic Zone Liquefaction § Pus • Lung Abscess: • A Central Liquefactive Necrosis surrounded by Fibrinous Wall • Components of Pus: • Liquefied Necrotic Tissue • Bacteria & Their Toxins • Inflammatory Exudate: ○ Fluid ○ Pus Cells (dead PNLs) ○ PNLs ○ Macrophages ○ RBCs Characteristics of Pus: • Thick Alkaline Fluid • Does NOT clot on Standing • It is usually Yellowish ○ Greenish when caused by Bacillus Pyocyeneus • Odorless ○ Offensive when caused by E. Coli Carbuncle (Localized Acute Suppurative Inflammation) Large Suppurative Lesion • Usually in Diabetics with low resistance to infection (Helwan Notes) Carbuncles are clusters of abscesses connected deeply subcutaneous, causing deeper scarring • Appears more in immuno-deficient people. (Helwan Notes) Furuncle is a skin abscess caused by staphylococcal infection, which involves a hair follicle and surrounding tissue. Most Common Site: • Back of Neck & Scalp Morphology: • Multiple cavities which communicate with each other and open through multiple points in the skin Cellulitis Acute Diffuse Suppurative Inflammation of Loose CT • e.g. Orbit, Pelvis Causative Organisms: • Usually Streptococcus Hemolyticus • Produces Streptokinase Liquefying Fibrin and Hyaluronidase liquefying cement substance • Rapid Spread of Infection Morphology: • Pus is thin, slowly forming • Extensive Necrosis of Tissues with Overlying Red, Hot, Edematous Skin Fate: • Resolution or Progression • Could lead to Bacteremia/Toxemia Fate of Acute Inflammation Conclusion Inflammation is a defensive host response to foreign invaders and necrotic tissue, but it is itself capable of causing tissue damage The vascular changes in acute inflammation lead to increased blood flow secondary to arteriolar and capillary bed dilation (→erythema and warmth) • This is followed by increased permeability of post-capillary venules resulting in an exudate of protein-rich extravascular fluid (→ edema) Cellular events of acute inflammation: • Primarily involving leukocytes that pass through steps of margination, rolling, adhesion, transmigration and chemotaxis • All these steps are controlled by cytokines and chemokines • Phagocytosis, killing, and degradation of the offending agent follow. The outcome may be: • Removal of the exudate with restoration of normal tissue architecture (resolution) • Transition to chronic inflammation • Extensive destruction of the tissue resulting in scarring