Inflammation IaD 2024-2025 PDF

IaD INFLAMMATION Histopathology Division 2024-2025  Intended learning outcomes By the end of this session and the practical session students should be able to: Understand the meaning of inflammation Know the factors that trigger inflammation Recognize its cl...

IaD INFLAMMATION Histopathology Division 2024-2025  Intended learning outcomes By the end of this session and the practical session students should be able to: Understand the meaning of inflammation Know the factors that trigger inflammation Recognize its clinical signs Know the vascular and cellular events that initiate inflammation Perceive the advantages and possible side effects of acute inflammation Recognize the outcome of acute inflammation Understand differences between chronic specific and non-specific inflammation Know types of granulomatous reactions Compare between criteria of acute and chronic inflammation NGU M. Assaf  Intended learning outcomes By the end of this session and the practical session students should be able to: Understand the meaning of inflammation Know the factors that trigger inflammation Recognize its clinical signs Know the vascular and cellular events that initiate inflammation Perceive the advantages and possible side effects of acute inflammation Recognize the outcome of acute inflammation Understand differences between chronic specific and non-specific inflammation Know types of granulomatous reactions Compare between criteria of acute and chronic inflammation NGU M. Assaf  Inflammation Definition Inflammation is a protective response To eliminate the initial cause of cell injury, and consequences of such injury (necrotic cells) To initiate the process of tissue repair Causes Infections Trauma Tissue necrosis Foreign bodies Immune (hypersensitivity) reactions NGU M. Assaf  Inflammation Acute Chronic Rapid onset and short Gradual onset and longer duration (days or weeks) duration (months or years) NGU M. Assaf  Cardinal signs of acute inflammation Words are in Latin NGU Local changes in Acute inflammation v Local tissue damage and release of chemical mediators 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 v The acute Inflammatory Response Vascular phase: Formation of inflammatory fluid exudate Cellular phase: Formation of inflammatory cellular exudate NGU M. Assaf Vascular phase of acute inflammation 1. Transient vasoconstriction: insignificant 2. Arteriolar vasodilatation à é blood flow with engorged capillaries ® makes the inflamed area red (erythema) and hot (warmth) 3. Increased vessel permeability chemical mediators ® contraction of the endothelial cells and widening of the intercellular gaps ® escape of a protein-rich fluid (exudate) in the interstitium. It is predominantly rich in fibrinogen à é osmotic pressure within the extravascular interstitial tissue à é water outflow à fluid exudate à Oedema à Swelling 4. Vascular stasis Local slowing of the circulation in the area due to é blood viscosity resulting from the vascular leakage Important step allowing for leukocyte emigration NGU M. Assaf Dilated vessel Dilated vessel Neutrophils Movement of leukocytes Accumulated RBCs  Inflammatory fluid exudate Functions of Inflammatory Fluid Exudate v Brings Antibodies to site of infection Fibrinogen which changes into fibrin 1. Localization of infection (entangles area of inflammation) 2. Forms a network upon which phagocytic cells move 3. Forms a network upon which fibroblasts move during repair v Vascular Stasis, allowing for leukocyte emigration Response of lymphatic vessels v é lymph flowà drains edema fluid, PNLs and dead tissue from the extravascular space v If viable bacteria exist in the exudates, they may cause inflammation of the lymphatic vessels (lymphangitis) and/or the draining lymph nodes à reactive (inflammatory) lymphadenitis NGU M. Assaf  Lymphangitis on top of infected wound A red streak along the course of lymphatics NGU M. Assaf  Cellular phase of acute inflammation Leukocyte recruitment Deliver leukocytes to the site of injury Activate leukocytes Function of leukocytes Ingest the microbe Kill it Eliminate necrotic tissues and foreign substances NGU M. Assaf  Cellular phase of acute inflammation What is the most common site of cellular events in case of acute inflammation? a. Artery b. Arteriole c. Capillary d. Post- capillary venule e. Vein NGU M. Assaf Cellular phase of acute inflammation What is the most common site of cellular events in case of acute inflammation? a. Artery b. Arteriole Why? Because of the slowest, sluggish circulation and kinking of blood c. Capillary vessels at this point allowing for cellular events to take place. d. Post- capillary venule (WHY?) e. Vein M. Assaf Sequence of events of Leukocyte recruitment (stimulated by chemical mediators & chemo-attractants) Transmigration Margination and Firm adhesion to Migration within between rolling endothelium interstitial tissue endothelial cells NGU M. Assaf  Leukocyte Recruitment Margination, Rolling and adhesion In normal flowing blood, leukocytes are confined to the central (axial) column surrounded by plasma. When blood slowing occurs, some leukocytes (mainly neutrophils and monocytes) fall out of the central column and begin to line the endothelium (margination), and then they tumble on the endothelial surface transiently sticking along the way (rolling), followed by adhesion to the endothelial surface Margination is controlled by chemotactic factors Rolling and pavementing are achieved by adhesion molecules on the surface of leukocytes and endothelial cells in a way like lock and key NGU M. Assaf Leukocyte Recruitment Rolling: Mediators released at site of infection “IL-1 and TNF”à activate endothelial cells à express/ up- regulate surface adhesion molecules (e-Selectin) à leukocytes continuously bind to and detach from these adhesion molecules causing their ROLLING on the surface of endothelial cells NGU M. Assaf Leukocyte Recruitment Adhesion Normally: surface of leukocytes have inactive integrin receptors In inflammation, chemokines (chemo-attractant cytokines) are liberated at sites of infection → a. Expression of endothelial integrin ligands b. Activation of β-integrin receptors on leukocytes à adhere to ligands on surface of endothelial cells → stable attachment of leukocytes on surface of endothelial cells NGU M. Assaf Leukocyte Recruitment Transmigration (extravasation of leukocytes=diapedesis) Leukocytes are squeezed between cells at the intercellular junctions and get out of blood vessels “Secrete collagenase that facilitates crossing basement membrane of blood vessels” They migrate to site of infection/injury (HOW?) Through chemokines that stimulate movement of leukocytes NGU M. Assaf Leukocyte Recruitment Chemotaxis It is the directed movement of the emigrating leukocytes to the organism or particle to be phagocytosed. along a chemical gradient The chemotactic substances in such cases are: a. Bacterial products b. Chemokines c. Complement system components (C5) d. Leukotriene B4 Chemokine receptors on surface of leukocytes are highest at the moving NGU front What is the type of leukocyte emigrating to the site of infection? This depends on the duration of inflammation and the type of stimulus v Duration: 6-24 hours à PNLs (short lived, die by apoptosis) 24-48 hours à monocytes (survive longer) v Type of stimulus: Some infections à continuous PNLs recruitment Viral infectionsà lymphocytes Hypersensitivity reaction (allery, type I)à eosinophils NGU M. Assaf Leukocyte activation When? Once they reach site of infection How? Through microbes, necrotic products & mediators 4 Activation see fig.p.21 Besides stimulating locomotion, chemotactic factors also induce other leukocyte responses, generally referred to as leukocyte activation NGU M. Assaf 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 NGU M. Assaf  Can you think of a disadvantage to leukocyte activation? NGU M. Assaf  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 NGU M. Assaf Types of acute inflammation Acute inflammation Suppurative Non-suppurative Pus formation No pus Localized, Diffuse, e.g., Catarrhal Fibrinous e.g., abscess cellulitis Serous Membranous Allergic Haemorrhagic NGU Acute non- suppurative inflammation Catarrhal inflammation A mild form of acute inflammation affecting the mucous membranes characterized by an exudate with mucus secreted by the irritated mucous membrane, 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 NGU M. Assaf Acute non- suppurative inflammation Fibrinous inflammation Characterized by an exudate rich in fibrin, with a little fluid component Occurs as a result of an injury leading to greater vascular permeability with extracellular leakage of an exudate rich in fibrinogen Sites: Serous membranes as pericardium, pleura and peritoneum Lung alveoli in acute lobar Pneumonia Fate: 1. Resolution: Fibrinous exudate may be degraded by fibrinolysis and removed by macrophages resulting in restoration of the normal tissue structure 2. Organization: Due to failure of complete removal of the fibrin; results in proliferation of fibroblasts and blood vessels, leading to scar formation NGU M. Assaf Acute non- suppurative inflammation Serous inflammation Characterized by excessive clear fluid poor in fibrin and a low inflammatory cell count Examples: Bullae of mild burn NGU M. Assaf Acute non- suppurative inflammation Membranous inflammation A severe form of acute inflammation of mucous membranes characterized by replacement of the normal mucous membrane by a false membrane composed of necrotic tissue & fibrin Virulent bacteria localized on the surface of mucous membranes à secreting exotoxins à mucosal necrosis and marked submucosal inflammation à false membrane composed of necrotic mucosal patches, fibrin and acute inflammatory cells Examples: § Bacillary dysentery: mucous membrane of intestine § Diphtheria: Throat infection An adherent, dense, grey pseudo- membrane covering the tonsils is NGU M. Assaf classically seen in diphtheria Acute non- suppurative inflammation Allergic inflammation Immune reaction rich in blood and tissue eosinophils Haemorrhagic inflammation A cellular exudate rich in red blood cells due to associated damage of blood vessels Examples: small pox and haemolytic streptococcal infections NGU M. Assaf Types of acute inflammation Acute inflammation Suppurative Non-suppurative Pus formation No pus Localized, Diffuse, e.g., Catarrhal Fibrinous e.g., abscess cellulitis Serous Membranous Allergic Haemorrhagic NGU Acute Suppurative Inflammation Definition: Acute inflammation characterized by pus formation (due to liquefactive necrosis). Causative organism: pyogenic organisms as Staphylococcus aureus, Streptococcus haemolyticus, gonococci, E.coli,..…… Localized (abscess, carbuncle) OR diffuse (cellulitis) Mechanism of pus formation: q Pyogenic organisms cause: a) Remarkable necrosis b) Attraction of a huge number of neutrophils c) Death of many neutrophils due to high virulence of the bacteria q Dead neutrophils (pus cells) release their proteolytic enzymes à liquefaction of necrotic tissue & fibrin. The liquefied material mixed with pus cells & fluid exudate form a turbid creamy fluid called pus NGU M. Assaf Abscess A type of localized suppurative inflammation characterized by a cavity containing pus Sites: Ø Any organ in the body as lung abscess and brain abscess Ø Small abscess related to a hair follicles (furuncle) Staph aureus à coagulase enzyme àmassive fibrin deposition àlocalized NGU M. Assaf Abscess Early, two zones: Later, progressive liquefaction starts at the margin of necrotic tissueà three zones: A) central zone of necrosis A) A central necrotic core. B)peripheral zone of inflammation C) A mid zone of pus showing many neutrophils, dilated B) Peripheral zone of inflammation (pyogenic capillaries and fibrin (pyogenic membrane) membrane) B B C A A NGU M. Assaf  Lung abscess What are the characteristic features seen? A central liquefactive necrosis Surrounded by fibrinous wall What are the components of pus? 1. Liquefied necrotic tissue 2. Bacteria & their toxins 3. Inflammatory exudateà (pus cells [dead PNLs], PNLs, macrophages, red cells and fluid) NGU M. Assaf What are the characters of pus? It is a thick alkaline fluid It does not clot on standing It is usually yellowish (greenish when caused by bacillus pyocyeneus) It is usually odourless (offensive when caused by E. coli) Fate of abscess Small abscess: Pus is may be absorbed, followed by healing. Large abscess: Since absorption of pus occurs at a very slow rate, a big abscess (if not surgically incised) à pointing & rupture (spontaneous evacuation) à healing (fibrosis) NGU M. Assaf  Carbuncle Large suppurative lesion Multiple communicating deep subcutaneous abscesses, opening on skin by multiple openings Usually in diabetics with low resistance to infection. Most common site: back of neck and scalp NGU M. Assaf Cellulitis Acute diffuse suppurative inflammation of loose CT (e.g. orbit, pelvis,…) Causative organisms: usually streptococcus haemolyticus (produces streptokinase liquefying fibrin and hyaluronidase liquefying cement substance à rapid spread of infection) Morphology: pus is thin, slowly forming Extensive necrosis of tissues with overlying red, hot, edematous skin Fate: resolution or progression à bacteremia/ toxemia NGU M. Assaf 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) NGU M. Assaf  What is the difference between the two lesions? What is your diagnosis? NGU M. Assaf Fate of acute inflammation Factors that modify outcome Intensity and nature of injury Host response Tissue affected Resolution: it occurs when inflammation is limited, tissue damage is minimal and the tissue is capable of replacing necrotic cells Scarring and fibrosis: in case of substantial tissue destruction and in tissues that do not regenerate. Chronicity: occurs if the injurious agent could not be eliminated completely. NGU M. Assaf  INJURY INJURY Bacterial infection Viral infection Toxins Autoimmune Trauma Chronic infection Acute inflammation Progression Chronic inflammation Healing Resolution Abscess Healing Fibrosis NGU M. Assaf NGU M. Assaf  Conclusion NGU M. Assaf  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 leads to increased blood flow secondary to arteriolar and capillary bed dilation (àerythema and warmth) This is followed by increased permeability of post-capillary venules resulting in an exudate of protein-rich extravascular fluid (à edema) Cellular events of acute inflammation are 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; or extensive destruction of the tissue resulting in scarring NGU M. Assaf  Chronic inflammation NGU M. Assaf Chronic inflammation Definition: Inflammation of prolonged duration, in response to persistent stimuli, in which active inflammation, tissue injury and healing proceed simultaneously Chronic inflammation arises in one of two ways: v May follow acute inflammation due to failure of defense mechanisms. v The response may be chronic from the start due one of the following: Infection with resistant organisms e.g., Mycobacterium tuberculosis Non-living irritants as foreign bodies e.g., silica particles Autoimmune disease NGU M. Assaf  Chronic inflammation Main chronic inflammatory cells Macrophages Lymphocytes Plasma cells +/- Eosinophils, Mast cells Macrophages [phagocytic& antigen presenting] Phagocytosis: destroy foreign invaders and necrotic tissues Formation of giant cells which have greater phagocytic activity, e.g., foreign body giant cells (engulfing foreign bodies) and Langhans giant cells (in case of T.B) Secrete cytokines & Growth factors Activate T- lymphocytes NGU M. Assaf Cells involved in chronic inflammation T- helper lymphocytes [CD4+ T- cells] and their role in chronic inflammation +++ TH1 IFN-𝛾 Macrophages CD4+ IL-4, IL-5& +++ TH2 T- cells IL-13 Eosinophils +++ TH17 IL-17 neutrophils NGU M. Assaf +++ = recruit & activate Characteristics of chronic inflammation 1. Infiltration by mononuclear cells (macrophages, lymphocytes, plasma cells) 2. Repair by fibrosis 3. Thick- walled blood vessels Compare these characteristics with findings in acute inflammation NGU M. Assaf  Compare acute and chronic inflammation Acute Inflammation Chronic Inflammation Onset Fast and sudden Slow and gradual Duration Short (days) Prolonged (months/years) Nature Mild or severe Usually mild Fluid exudate Abundant Scanty or absent Blood vessels Dilated and thin walled Thick walled with narrow lumen (endarteritis obliterans) Cells PNLs and macrophages Lymphocytes, plasma cells, macrophages and giant cells Tissue destruction Mild Marked Fibrosis Absent Present Cardinal signs Present Absent NGU M. Assaf Types of chronic inflammation Non- Unresolved acute inflammation specific De novo (in some types of cell injury) Granulomatous inflammation Specific ( specific pattern of tissue response with characteristic/ SPECIFIC histology NGU M. Assaf Granuloma Granulomas are, microscopically, composed of: Nodular aggregates of macrophages with a variable mixture of lymphocytes, plasma cells, giant cells & sometimes neutrophils The macrophages commonly change into larger eosinophilic cells called epithelioid cells ±central necrosis, e.g., caseous necrosis in TB NGU M. Assaf Examples of granulomatous lesions Immune mediated granulomas Tuberculosis (Mycobacterium tuberculosis) Infectious Leprosy (Mycobacterium lepra) granulomas Syphilis (Treponema pallidum “ a spirochete”) Non- infectious Sarcoidosis Foreign body granulomas NGU M. Assaf  Granuloma Formation Type IV hypersensitivity, where stimulated T lymphocytes release cytokines that attract large numbers of macrophages Persistent and/or non-degradable antigens Ag is presented by APC in association with MHC II to naïve CD4 Th cells → differentiation into Th1 cells IL-12 is produced by macrophages and dendritic cells which derives differentiation of naïve CD4 Th1 and induces T cells to secrete INF-γ, TNF and IL-2 IL-2: proliferation of T-cells INF-γ: activates macrophages and undergo transformation into epitheliod cells and giant cells TNF: acts on endothelium to ++ expression of adhesion molecules, so facilitate adhesion of monocytes and lymphocytes NGU M. Assaf Fate of a granuloma Persist for a long time May slowly resolve and disappear May become fibrotic and heal by scar tissue May coalesce and destroy surrounding tissues forming cavities filled with necrotic material, e.g., chronic fibrocaseous tuberculosis NGU M. Assaf Conclusion 1. Inflammation can be classified into acute and chronic, where chronic inflammation is either non- specific or specific 2. Acute inflammation is characterized by clinical cardinal signs 3. The cardinal signs are related to both vascular and cellular events 4. Chronic specific inflammation is a granulomatous type of inflammatory reaction characterized by specific histological features. NGU M. Assaf  Suggested reading Robbins Basic Pathology; Tenth edition (2017) Cumar, Abbas and Aster; Elsevier/ Saunders (Chapter 3, Inflammation and repair) NGU M. Assaf