Unit 3: Inflammation

1. Name the cardinal signs of inflammation

  • Redness, Heat, Swelling and Pain, loss of function

2. Describe the purpose of the acute inflammatory response

First line of defense against an injury (which can be physical or chemical to infectious)

Process of Acute Inflammation

  1. Vascular Changes

    a. vessels dilate to increase blood flow to the area

    b. vessels become more permeable to allow plasma proteins to leave the circulation and enter the injured site

  2. Cellular response

    a. emigration of leukocytes from the microcirculation to the site of injury

3. Describe the role vascular changes, cellular responses, and chemical mediators have in the acute inflammatory response.

Vascular Injury

  • Occurs in the microcirculation (capillaries, arterioles and venules) which vasodilate and results in more blood in the area

  • Transient vasoconstriction occurs first

  • Active dilation of arterioles, capillaries, and venules are caused by chemical mediators (Histamine) from necrotic cells

    • Mast cells contain granules that hold histamine (causes capillary dilation)

  • Increased flow to the blood = HYPEREMIA and is the reason the inflamed tissue looks red

  • Acute inflammation causes edema (epiithelium is damaged, increased fluids and protein molecules will pass into extravascular space)

  1. Initial endothelial cell contraction induced by histamine widens intercellular junctions. Transient, occuring primarily in venules. Retraction of endothelial cells mediated by Tumour necrosis factor and IL-1 can also occur

  2. Direct injury from burns or infection results in endothelial cell necrosis and detachment (leakage of plasma from vessels)

  3. Leukocyte-mediated endothelial injury occurs as neutrophils release proteolytic enzymes and toxic oxygen species which further causes endothelial cell injury and detachment.

  4. Increased transcytosis or fluid movement occurs with increased permeability

  5. Newly forming immature blood vessels are “leaky” and are a cause of increased vascular permeability

Stasis = flow of blood slowing due to viscous movement of fluid to the interstitial space

4. Describe how and why inflammatory exudate form, and the differences between the various types of exudate

  • Inflammatory exudate or exudation = the process of increased movement of fluid, larger protein molecules and cells out of the vasculature due to increased vascular permeability. The fluid in the tissues/tissue surface = exudate

  • Transudate = fluid which leaves vessels due to increased hydrostatic presure (fails to return due to low osmotic pressure)

  • HOW ARE THESE DIFFERENT, HOW ARE THESE THE SAME?

    • Exudate = more like plasma, formed with increased permeability, more proteins and neutrophils, yellow/white/pink (Peritonitis, infection)

      • NOTE fibrin is found in exudates but not transudates

      • appears as pink staining meshwork on interstitial space

        • shipping fever caused by infection and characterized by aundant fibrin production (seen in stressed cattle which are stressed by transportation and have respiratory viral infection)

    • Transudate = ultrafiltrate of plasma (more watery less protein), formed with normal vascular permeability, clear colourless, fewer cells and proteins (Ascites, fluid)

5. Describe the differences between granulocytes and mononuclear cells and their role in inflammation.

Vascular changes = transit for inflammatory cells to reach the site and do the work of inflammation

Inflammatory cells = Leukocytes (white blood cells) which are derived from Myeloid cells in the bone marrow (move out when they are mature)

Two arms of the myeloid cells are Granulocytes (holes) and Mononuclear (smooth and rounded)

  • Granulocytes = neutrophils, basophils and eosinophils

  • Neutrophil = white blood cell that arrives en masse early on in inflammation. They are motile, capable of phagocytosis (enzymes that can degrade bacteria). Function is phagocytosis of microorganisms. Think Angry Sperm that protects against infection

  • Eosinophils = hypersensitivity responses and have their own enzymes that are usually for parasitic diseases

  • Mononuclear = lymphocytes, plasma cells, monocytes, macrophages

  • Usually used in the chronic stages of inflammation

  • Lymphocytes = attracted to the site by other cells, can develop into plasma cells (that have antibodies)

  • Monocytes = present in the blood but migrate into tissues where they are then MACROPHAGES

  • The white blood cell = Monocyte/Macrophage system

  • Macrophages = greatest role in acute inflammation (BIG GUNS) and are phagocytes

    • ingest microorganisms and clean up cellular debris

    • secrete substances such as pyrogen or complement components

Leukocyte Recruitment

  1. Margination, Rolling and Adhesion of Leukocytes

    • Margination = increased contact between the leukocytes and endothelium

      • roll along the endothelial surface and mediated by selectin (select the leukocytes they want to marginate within the vessel)

    • Adhesion = leukocytes stick to the vessell wall due to integrins

      • Integrins = integrate leukocytes into tissues

  2. Transmigration of Leukocytes

    • Diapedesis = the process of neutrophils leaving blood vessels by squeezing through intercellular junctions

      • Facilitated by PECAM-1 an adhesion molecule

    • Neutrophils pass through basement membrane by degradation with collagenases and move into tissues

  3. Chemotaxis

    • Inflammatory cells attracted to tissue = Chemotaxis

    • C3a and C5a, leukotrine and cytokines are chemotactic substances which are chemical mediators

    • Chemotactic substances binds to receptors on the leukocyte surfaces → increased calcium → assembly of intracellular contractile elements → allow leukocytes to move (pseudopods extended) → induce leukocyte activation

  4. Leukocyte Activation

    • receptor families activate leukocytes

    • soluble tissue molecules bind foreign substances and activate the leukocytes

    • Innate Immunity = process of induction of acute inflammatory response through receptors and factors

      • LEADS TO:

        • Phagocytosis

        • Upregulation of mechanisms for degradation and killing of microbes

        • Production of inflammatory mediators

  5. Phagocytosis and Pathogen Degradation

    • Phagocytic cells recognize and attach to the particle or agent

      • Nonspecific = intert particles

      • Specific = with antibody

    • Collectins = carb binding lectins found in plasma bind microbial cell walls as opsonins

      • Leukocytes have receptors for IgG (antibody), complement and collectins

      • Opsonization = enhanced phagocytosis

    • Once recognized and bound, the particle is engulfed and forms a vacuold within the phagocytes cytoplasm

    • Stimulates increase in o2 dependent metabolism in leukocytes, increasing Oxidative radicals and killing pathogens. They are then fused with lysosomes (the pathogens are fused) which release enzymes and acid hydrolaxes to further kill and digest

Histamine + Serotonin cause vasodilation and increased permeability in the immediate phase of the acute inflammatory response.

What effects do plasma proteases have?

  • Initial activation by Factor XII

  • Bradykinin (final product of kinin system) - causes increased vascular permeability and mediates pain (XII → prekallikrein → kallikrein (turns kininogen to bradykin))

  • Fibrin increases vascular permeability and are chemotactic for neutrophils. Thrombin enhances leukocyte adhesion to endothelial cells

Activated Factor XIIa initiates which four systems that are involved in the inflammatory response?

  1. Kinin System

  2. Coagulation cascade

  3. Complement System

Bradykinin, C3a and C5a are important mediators of what?

  • Increased vascular permeability

  • C3a and C5a stimulate histamine release from cells

What does C5a mediate

  • chemotactic activator for phagocytic cells

  • activates lipoxygenase pathway of arachidonic acid metabolism

List and describe thrombin’s several roles (3pts)

  • enhance leukocyte adhesion to endothelial cells

  • produces fibrin

Lysosomal Constituents

  • Neutrophils generate toxic oxygen-based free radicals (damage and increased vascular permeability) + degrade microorganisms

  • Porteases degrade constituents of extracellular matrix

Arachidonic acid metabolism

  • unsaturated fatty acid which when released by phospholipases lead to the production of Prostaglandins, lekotrienes and lipoxins (Eicosanoids)

  • Eicosanoids are synthesized at inflammatory sites and also effect hemostasis

Platelet Activating Factor

  • generated from cell membranes by phospholipase A

  • causes platelet aggregation and activation, vasodilation and increased vascular permeabiltity, other features of inflammation

  • At high levels causes vasoconstriction

Cytokines

  • products of lymphocytes and macrophages

  • modulate the function of other cells

  • IL-1 and TNF

    • produced by macrophages, dendritic cells and T-lymphocytes (TNF)

    • secretion is stimulated by a variety of inflammatory mediators and injurious stimuli

    • induce endothelial activation and hence expression of selectins and integrins

    • activate fibroblasts (IL-1) and neutrophils (TNF)

    • Induce systemic acute phase responses (fever, lethargy etc)

NSAIDS = act by decreasing inflammation (in the case of spinal cord injury)

Corticosteroids = block the conversion of cell membrane phospholipids to arachidoinic acids, decrease vasodilation and permeability and decreasing the immune response (Prednisone)

6. Describe the possible local and systemic outcomes of acute inflammation

  • Local signs of acute inflammation = redness, heat, swelling and pain

    • heat only at the bodies surface

Localized Pain

  • mediators of inflammation in the arachidonic cascade are responsible for pain

  • bradykinin, histamine and serotonin signal pain through changes in permeability

  • Bradykinin = also sensitizes the nerve endings

Systemic signs of Inflammation = Fever, nausea and malaise (general feeling of illness and discomfort), changes in peripheral white blood cell count, changes in plasma proteins

  • ALSO KNOWN AS ACUTE PHASE REACTION

  • Fever and Hypothermia

    • pyrogens induce fevers, and can be endogenous or exogenous

    • Endogenous pyrogens are generated in accute inflammation from neutraphils (IL-1 and IL-6 and TNF. (enter blood stream and go to brain affecting temperature of the body)

  • Changes in peripheral white blood cell count

    • neutrophils = most important inflammaotry cell type in acute inflammation (first responders)

    • Left shift = presence of immature neutraphils in the blood (released from bone marrow before mature)

    • Leukocytosis = increased total white blood cell count

    • Neutropenia = neutrophils decreased

    • Leukopenia = decrease in total wbc count

  • Changes in plasma proteins

    • increased levels of plasma proteins (acute phase reactants) which include C-reactive protein, fibrinogen, haptoglobin and alpha 1-antitrypsin

    • nonspecific indication of presence of inflammation

OUTCOMES OF ACUTE INFLAMMATION

  • Resolution

    • clearance of injurious stimuli

    • clearance of mediators and acute inflammatory cells

    • replacement of injured cells

    • normal function

  • Suppurative inflammation

    • replacement of cells by regeneration and scar formation

    • influx of neutrophils into the area, leading to liequefactive necrosis of the tissue and PUS

    • Abscess = formed when an area of suppurative inflammation becomes walled off by fibrous tissues

    • Can lead to systemic signs and healing OR chronic inflammation and sepsis if the bacteria escapes and causes spread of bacteria

  • Sepsis or Septicemia

    • not be effective in destroy8ing the causative agent and the infectious agent spreads or disseminates

    • SEPSIS = spread of toxins or bacteria via the bloodstream

    • If the spread is serious and causes marked cytokine release it can cause death

  • If local acute inflammation can’t be resolved over a short period of time it progresses to chronic inflammation

7. Describe how and why chronic inflammation develops and what characterizes the different types of chronic inflammation.

Chronic inflammation is characterized by;

  • some degree of immune response, indicated by the presence of mononuclear cell types such as plasma cells and lymphocytes

  • infiltration and accumulation of macrophages which mediates phagocytosis

  • healing of tissue through the development of granulation tissue, characterized by tissue fibrosis and angiogenesis

  • ongoing tissue injury and necrosis

Chronic inflammation is the result of;

  • continued inflammatory response + immune response against a persistent injurious agent

    • bacteria, fungi, viruses

  • When an antigen is introduced and persists, T and B cells transform into effector T cells or plasma cells

    • these characterize chronic inflammation

Granulomatous Inflammation

  • What three things characterize granulomatous inflammation?

    • activated macrophages with a large amount of foamy cytoplasm

      • not as effective at phagocytosis, better at secreting lysosomes

    • presence of rough ER (secretory)

    • T cells produce lymphokines that cause macrophages to remain in the area

  • What are some differential diagnoses for granulomatous inflammation?

    • Tuberculosis

    • Atypical bacteria

      • Mycobacteria spp (tuberculosis and leprosy)

      • Treponema pallidum (syphilis)

      • Brucella spp (Brucellosis)

    • Fungal pathogens within tissues

    • Parasites within tissues

    • Inert foreign bodies

    • Immune-mediated diseases

  • How does Granulomatous Inflammation Develop?

    • When the causal agent is phagocytosed but survives and persist within the macrophages

    • When phagocytosis of a causal agent is impaired

Non-Granulomatous Chronic Inflammation

  • any inflammation without epithelioid cells

  • characterized by the presence of sensitized lymphocytes, plasma cells and macrophages through the affected tissue + necrosis and fibrosis

Caused By:

  1. Chronic viral infections - cells persistently infected with viruses evoke a B cell +T cell cytotoxic and lead to necrosis. Presence of lymphocytes and plasma cells, necrosis and fibrosis

  2. Other chronic infections - microorganisms = ineffective T cell response and foamy macrophages that do not form granulomas

  3. Chronic Autoimmune Disease - similar response to the chronic infection, but directed against self-antigens

  4. Allergic conditions and parasitic infections - eosinophils and mononuclear cells accumulate in tissues

  5. Chronic toxic diseases - alcohol consumption causes necrosis of cells of the liver and pancreas resulting in antigenic + immune response

8. Describe how chronic inflammation develops in response to non-antigenic agents such as foreign material.

Foreign Body Granulomas

  • i.e. sutures, porcupine quills or wood slivers

  • develop when inert(no inflammatory response) and non-antigenic (no immune response) enters a tissue and is too large to be phagocytosed by a single macrophage

  • Macrophages congregate around the material and attempt to remove it by nonimmune phagocytosis

Osteomyelitis

  • result of infection of bone with pyogenic bacteria

  • Hematogenous = carried to the bone by the bloodstream (children and growing animals are susceptible due to the cartilage on growing bone)

  • Secondary = bacteria develop secondary to extension from a wound or adjacent site of infection

  • Progresses through acute and chronic phases (second one is more likely). Causes ischemia of bone.

  • Necrosis of bone and disruption of blood results in a sequestra (fragment of devitalized bone) that persists despite attempts to clear it out

9. Describe the significance of amyloid deposition in tissues.

  • Amyloidosis = diseases characterized by the deposition of similar appearing, abnormally folded insoluble proteins termed amyloid in the interstitium of tissues

  • Amyloid = beta-pleated fibrillar protein

    • Derived from Serum amyloid associated (AA), non-immunoglobulin protein which is produced in the liver during inflammatory processes (presence of amyloid in some chronic inflammations)

    • Immunoglobulin light chains (AL amyloid) produced by plasma cell or B cell tumors

    • Amyloid AB (Beta) characterizes the cerebral plaque lesions of alzheimer disease

  1. Systemic amyloidosis = involvement of several organ systems

    a. Primary amyloidosis (AL) associated with cancer called multiple myeloma (neoplasm of plasma cells) which are abnormal and form AL

    b. Systemic = amyloid depositions which occur widely in the body, in association with chronic inflammatory diseases (Secondary/Reactive)

  2. Localized = localized deposition within a single tissue or organ

    a. alzheimer and localized deposition of amyloid plaques

    b. amyloid depositions seen in endocrine tumours derived from peptide hormones

  3. Familial = rare, inherited disorder in which amyloid is deposited locally in organs such as the heart, kidney or nervous tissue

Functional Problems

  • deposited in interstitial tissue and causes the tissue to become enlarged and firm

  • nutrients may not diffuse as readily and tissue function is affected