Tissue Injury, Inflammation, and Repair Flashcards
Exudate
Extravascular fluid with high protein and cellular content, released from the vascular system into the interstitial tissue as a result of increased vessel permeability
Transudate
Extravascular fluid with low protein and cellular content; released from vessels as a result of osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability
Increased vessel permeability
Occurs as a result of the contraction of endothelial cells, signaled by histamine, bradykinin, leukotrienes, PAF, and substance P
Pus
Purulent exudate rich in leukocyte (mostly neutrophils), cellular debris, and often microbes
Leukocyte adhesion
Occurs as a result of TNF and IL-1 release from M1 macrophages; adhesion molecules on leukocytes (L-selectin) and on endothelium (E-selectin) are expressed; low-affinity reactions between adhesion molecules lead to “rolling” of leukocytes along the endothelial wall
Diapedesis
TNF and IL-1 released by M1 macrophages activate endothelial cells in the post-capillary venules to express E-selectin; E-selectin interacts with L-selectin on the surface of neutrophils; neutrophils adhere to the endothelial wall and can slip through gaps in the “leaky” endothelium to enter the underlying connective tissue
Role of Neutrophils in acute inflammation
Neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours; they appear early because they are numerous in the blood, respond rapidly to chemokines, and attach firmly to endothelial adhesion molecules
Neutrophils phagocytose bacteria and tissue debris; they release ROS and proteolytic enzymes
How do neutrophils recognize microbes?
Mannose receptors - recognize molecules found on microbial cell walls
Opsonin receptors - recognize IgG antibodies, C3b component of complement, and other opsonins
How to neutrophils kill microbes?
Neutrophils generate reactive oxygen species (ROS) within their lysosomes, where the phagocytosed materials are segregated; phagocyte oxidase oxidizes NADPH and reduces O2 to the superoxide anion O2-, which is convered into hydrogen peroxide, H2O2, which is converted into hypochloride (OCl-), a potent antimicrobial agent
Histamine
Amine class; Stored as pre-formed molecules within mast cells located in connective tissue adjacent to blood vessels
Release stimulated by cellular trauma, binding of antibodies to mast cells, recognition of anaphylatoxins C3a and C5a, substance P, IL-1
Effects: Vasodilation, increased vascular permeability
Inactivation: Hisaminase
Serotonin
Amine class; Stored as a pre-formed molecule within platelets
Release stimulated when platelets aggregate after contact with collagen
Effects: Increases vascular permeability
Serotonin mediates the linkage between clotting and inflammation
Termination of the acute inflammatory response
Degradation of inflammatory mediators
Neutrophil apoptosis within hours after leaving the blood
Release of anti-inflammatory cytokines (TGF-B and IL-10) from macrophages
Prostaglandins (PGs)
Lipid class; Produced by mast cells, macrophages, endothelial cells, etc. via the action of COX1 and COX2 on arachidonic acid; different prostaglandins are made in the tissues by tissue-speciic enzymes and function in vasodilation, fever, and pain
Production of Prostaglandins & Leukotrienes
Phospholipase A2 enzyme cleaves membrane Arachidonic Acid; arachidonic acid is cleaved by COX1 and COX2 to make Prostaglandins or by 5-lipoxygenase to produce leukotrienes
Thromboxane (TxA2)
A prostaglandin produced by thromboxane synthetase in platelets
Effects: Increases platelet aggregation and vasconstriction
Leukotrienes
Lipid class; Produced by lipoxygenase enzymes from arachidonic acid
Mainly secreted by macrophages & leukocytes
Increase vascular permeability and chemotactic for WBCs
Prostacyclin
A prostaglandin produced by prostacyclin synthetase in vascular endothelium
Effects: Increases vasodilation and vascular permeability, decreases platelet aggregation
Platelet Activating Factor (PAF)
Lipid class; Newly synthesized by platelets as well as all leukocytes and endothelial cells
Effects: Platelet aggregation, vasoconstriction
Lipoxins
Generated from arachidonic acid by the lypoxygenase pathway
Effects: Inhibit leukocyte recruitment, inhibit neutrophil recruitment, negatively regulate leukotrienes
Nitric Oxide (NO)
Newly synthesized from L-arginine by the enzyme nitric oxide synthase (NOS) in macrophages
Effects: Vasodilation, relaxation of smooth muscle, reduced platelet adhesion
Reactive Oxygen Species (ROS)
Newly synthesized by macrophages and neutrophils; major species are superoxide anion O2-, hydrogen peroxide H2O2, and hydroxyl radical OH-
Effects: destroy phagocytosed microbes
TNF and IL-1
Major cytokines of acute inflammation, produced by M1 activated macrophages
Effects: Endothelial activation, including induction of endothelial adhesion molecules and activation of acute-phase response; fever production; WBC chemotaxis
Chemokines
Small proteins that act as chemoattractants for leukocytes into areas of inflammation
Neutrophil granule contents
Primary and secondary granules contain a wide variety of enzymes
Acid hydrolases degrade bacteria and debris within the phagolysosomes, in which acid pH is maintained; neutral proteases degrade extracellular components (i.e. collagen, basement membrane, etc.) resulting in collateral tissue damage
Cytokines
Newly synthesized by lymphocytes, macrophages, and endothelial cells
Ex: TNF and IL-1 in acute inflammation, IFN-y in chronic inflammation
Substance P
Neuropeptide secreted by sensory nerves, especially in the lung and GI tract;
Effects: Transmission of pain signals, regulation of blood pressure, increased vascular permeability
Role of C3a and C5a in inflammation
C3a and C5a are anaphylatoxins - they stimulate release of histamine from mast cells, causing increased vascular permeability and vasodilation
C5a is also chemotactic for leukocytes
Mechanism of the intrinsic clotting pathway
Factor XII is produced by the liver and circulates in an inactive form in the plasma; Factor XII is activated by contact with negatively charged surfaces (i.e. basement membrane, collagen) and becomes factor XIIa; factor XIIa activates the clotting cascade, leading to production of thrombin; thrombin activates the enzymatic conversion of fibrinogen into fibrin and fibrin split products
Kinin Pathway
Factor XIIa converts plasma prekallikrein into active enzyme kallikrein, which cleaves kininogens to produce Bradykinin
Bradykinin increases vasodilation and vascular permeability, and causes increased transmission of pain
Bradykinin is quickly inactivated by the enzyme kininase
Fibrinolytic System
The fibrinolytic system counterbalances the clotting cacasde by solubizing clots via cleavage of the plasma protein plasminogen to form plasmin, an active protease
Factor XIIa converts plasma prekallikrein to active enzyme kallikrein; kallikrein converts plasminogen to plasmin; plasmin not only solubizes clots by cleaving fibrin to form fibrin split products but also cleaves C3 and C5 of the complement cascade to C3a and C5a, which are anaphylatoxic
Role of C3b in inflammation
C3b is an opsonin - it affixes to microbial cell walls and promotes phagocytosis by neutrophils and macrophages which bear cell surface receptors for the complement fragments
Role of mast cells in chronic inflammation
Mast cells contain on their surface a receptor that binds to the Fc portion of IgE; in immediate hypersensitivity reactions, IgE bound to mast cells causes degranulation and release of histamine and prostaglandins
Mast cells are also activated to release histamine by C3a and C5a components of the complement system
Migration and activation of macrophages in chronic inflammation
Monocytes from the blood migrate into extravascular tissue early in acute inflammation and differentiate into phagocytic macrophages
Macrophages are activated by the classical pathway via IFN-y secreted by Th1 cells; they phagocytose pathogens and secrete TNF and IL-1
Macrophages can be alternatively activated by IL-4 secreted by Th2 cells; these macrophages secrete TGF-B and participate in tissue remodeling, angiogenesis, and scar formation
Role of eosinophils in chronic inflammation
Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections; eosinophils have granules that contain Major Basic Protein, a highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells
Acute Phase Response - Components
Fever Leukocytosis Increased pulse Increased BP Shivering Chills Anorexia Malaise
Fever - Mechanism
Produced in response to pyrogenic substances that stimulate prostaglandin synthesis in the hypothalamus
Pyrogens may be exogenous (i.e. bacterial products) or endogenous (i.e. cytokines such as IL-1 and TNF released from activated leukocytes)
Pyrogens increase COX1 and COX2 activity converting arachidonic acid into prostaglandins; in the hypothalamus, prostaglandins stimulate the production of neurotransmitters which re-set the body’s thermostat to a higher level
Leukocytosis
Occurs as part of the acute phase response
Cytokines (TNF and IL-1) stimulate accelerated release of immature leukocytes from the bone marrow
Bacterial infections cause neutrophilia
Viral infections cause lymphocytosis
Asthma, allergy, and parasitic infections cause eosinophilia
Formation of blood clot
Wounding causes the rapid activation of coagulation pathways leading to the formation of a clot containing fibrin, fibronectin, and complement components; the clot stops bleeding and serves as a scaffold for migrating cells attracted by local chemokines
Within 24 hours, neutrophils appear at the margins of the wound, releasing proteolytic enzymes that clean out debris and bacteria
Formation of Granulation Tissue
Fibroblasts and vascular endothelial cells proliferate to form a specialized tissue called granulation tissue, characterized by the processes of angiogenesis and fibroblast proliferation
Scar formation, Wound Contraction, and Recovery of Tensile Strength
Granulation tissue scaffolding is converted into avascular scar tissue composed of fibroblasts, collagen, elastin, and other ECM components
Wound contraction results from the formation of a network of myofibroblasts at the edges of the wound; these cells have characteristics of smooth muscle and contract int he wound tissue to draw the edges closer together
Recovery of tensile strength is mostly due to the accumulation of type I collagen
Systemic factors affecting wound repair
Nutrition - protein and Vitamin C deficiencies
Metabolic Status - Diabetes Mellitus
Circulatory status - arteriosclerosis, venous stasis
Hormones - glucocorticoids
Local factors that affect wound healing
Infection - persistent tissue injury and inflammation
Mechanical stress - may compress blood vessels and seperate the edges of the wound
Foreign bodies
Size, location, and type of wound
Hypertrophic and Keloid Scar Formation
Hypertrophic scar - accumulation of excessive amounts of collagen giving rise to a raised scar
Keloid scar - scar tissue grows beyond the boundaries of the original wound and does not regress
Fibrosis
Excessive deposition of collagen as a result of chronic inflammation
Alternatively activated macrophages produce TGF-B, which causes increased fibroblast migration and proliferation, increased synthesis of collagen, and decreased degradation of ECM components due to inhibition of MMPs
Coagulative (Ischemic) Necrosis
The dead cell remains a “ghost-like remnant” of its former self; occurs in stages:
Pyknosis - the cell nucleus shrinks and stains darkly
Karyorrhexis - fragmentation of the pyknotic nucleus
Karyolysis - complete break down and disappearance of the nucleus
Classically seen following MI
Liquefactive Necrosis
Dead cell dissolves away as lysosomal hydrolases digest cellular components
Commonly seen in the brain and spleen, and with acute infection
Caseous Necrosis
Seen only in tuberculosis infection; the central portion of an infected lymph node becomes necrotic due to toxic levels of mycobacteria, producing a soft, whitish-grey tissue
Fat Necrosis
Leakage of lipases from dead cells attack triglycerides in surrounding adipose cells and generate free fatty acids and calcium soaps with a chalky white appearance
Classically seen in the pancreas following acute infection
Burns - Partial vs. Total Thickness
Partial Thickness burns affect the epidermis but not the dermis
Total thickness burns involve complete destruction of the epidermis and dermis, including dermal appendages (i.e. hair shaft) and the stem cells found in these areas
Hyperthermia - Exertional vs. Classic
Exertional Hyperthermia - may lead to rhabdomyolysis (breakdown of skeletal muscle fibers), lactic acidosis, disseminated intravascular coagulation (DIC), and acute tubular necrosis (ATN)
Classic heat stroke - typically seen in hot, humid weather affecting young, old, and ill patients; may lead to respiratory alkalosis 2/2 hyperventilation, hypotension, and coma
How does the body neutralize ROS?
Superoxide radicals (O2-) are neutralized by the enzyme superoxide dismutase (SOD), which generates H2O2
H2O2 itself is a reactive species that is neutralized by catalase
Glutathione Peroxidase neutralizes ROS
Early changes seen in injured cells
- Cell Membrane - Lipid peroxidation, cell swelling
- Mitochondria - Swelling
- ER - Swelling, leading to detachment of polyribosomes from rough ER and decreased protein synthesis
- Nucleus - decreased synthesis of rRNAs in the nucleolus
Classic Pathway of Necrosis
Irreversible changes in the cell membrane occur leading to Ca2+ influx across the plasma membrane and from stores in the ER; intracellular Ca2+ activates Ca2+ dependent proteases and lipases; the mitochondrial membrane permeability transition pore (MTP) is opened, with a loss of the ability of the mitochondria to make ATP; the cytoplasm and mitochondria swell and eventually burst, releasing intracellular contents
IFN-y
Produced by Th1 and Th17 cells; activates M1 macrophages
IL-17
Produced by Th17 cells; recruits neutrophils and monocytes
Critical Features of Acute Inflammation
Vasodilation - causes erythema (redness) and warmth
Increased vascular permeability - causes swelling
Inflammatory cell infiltrate - neutrophils predominate
Abscess
An accumulation of inflammatory fluid that develops within a confined space, forming a new cavity; neutrophils predominate
Empyema
An accumulation of inflammatory infiltrate located within an anatomic space or cavity (i.e. pleural empyema, subdural empyema); neutrophils predominate early but macrophages & lymphs also seen
Cellulitis
An inflammatory infiltrate located in the skin (epidermis, dermis) - usually bacterial (staph or strep) but may be inflammatory
Involvement of the deep fascia is called “necrotizing fasciitis”
Granuloma
Accumulation of inflammatory infiltrate within the parenchyma (i.e. lung, liver, spleen) forming a rounded, nodular structure; contains macrophages, lymphocytes, and plasma cells
Epitheloid / Giant Macrophages predominate
May be mineralized and so visible on X ray
Functions of Macrophages - Key Processes & Chemical Mediators
- Removal of injured tissue and debris - phagocytosis, collagenase, elastase
- Anti-microbial activity - ROS
- Chemotaxis and proliferation of fibroblasts (repair) - TGF-B
- Angiogenesis - VEGF
- Deposition and remodeling of ECM: TGF-B, MMPs
Chemical mediators of vasodilation
Prostaglandins
NO
Histamine
Chemical Mediators of Vascular Permeability
Histamine and Serotonin C3a and C5a via their actions as anaphylatoxins Bradykinin Leukotrienes PAF Substance B
Chemical Mediators of Fever
IL-1, TNF
Prostaglandins
Chemical Mediators of Pain
Prostaglandins
Bradykinin
Substance B
Chemical Mediators of Tissue Damage & Microbicide
ROS
Lysosomal enzymes of leukocytes
C3a and C5a
Complement cascade components produced in the liver
Effect: Anaphylatoxic; bind receptors on Mast cells, triggering release of Histamine leading to vasodilation, increased vascular permeability, and WBC chemotaxis
Bradykinin
Plasma protein derived from proteolysis of kininogens by Kallikrein proteases
Functions: Vasodilation, increased vascular permeability, pain
Inactivation: Kininases
Hereditary Angioedema
Caused by a deficiency in the C1 esterase inhibitor (C1-INH) enzyme; C1-INH is responsible for down-regulating the complement pathway
Characterized by pathologic inflammation/edema
Histologic changes seen with acute MI
Injury Phase - Cytoplasmia eosinophilia, loss of myocyte nuclei
Acute phase - PMN infiltrate
Chronic Phase - Foamy macrophages, increased fibroblasts, neovascularization
Repair Phase - Fibroblasts surrounded by lots of collagen fibers, some lymphocytes
What are the histologic criteria for the diagnosis of cirrhosis?
- Fibrosis
- Regenerative nodules
- Alteration in architecture / blood flow
