INFLAMMATION, TISSUE REPAIR AND FEVER

Part 2: The Immune System Prepared by: Mae Michelle F. Aguilar RNAdvanced PathophysiologyUSI – Graduate School MAN MS

A PROTECTIVE RESPONSE intended to eliminate the initial cause of cell injury as well as necrotic cells and tissues resulting from that injury.

THE INFLAMMATORY RESPONSE

Inflammatory conditions are named with adding the suffix –itis

Two Basic PatternsACUTE CHRONIC

ACUTE INFLAMMATION

The early reaction of local tissues and their blood vessels to injury. Typically occurs before the immune response.

Can be triggered by: infections, immune reactions, blunt and perforating trauma, physical or chemical agents and tissue necrosis.

CARDINAL SIGNSFirst Century AD , Roman physician Celsus described the local reaction to injury.

RUBOR (Redness) TUMOR (Swelling) CALOR (Heat) DOLOR (Pain)

2nd Century AD, Greek physician Galen added the 5th cardinal sign

• Functio laesa (loss of function)

SYSTEMIC MANIFESTATIONS

Occurs as chemical mediators produced at the site of inflammation gain entrance to the circulatory system.

TWO COMPONENTS: VASCULAR STAGE AND CELLULAR STAGE

Acute-phase Response

VASCULAR STAGE

Momentary vasoconstriction followed rapidly by vasodilation.

Vasodilation causes Hyperemic Response: Area becomes congested causing redness and warmth.

Accompanied by an increase in vascular permeability with outpouring of protein-rich fluid (exudates) into the extravascular spaces.

Loss of proteins reduces capillary osmotic pressure and increases interstitial osmotic pressure.

Accompanied with an increase in capillary pressure causes outflow of fluid and its accumulation in tissues and spaces produce swelling, pain and impaired function.

Fluid moves out of the vessels, stagnation of flow and clotting of blood occurs.

CELLULAR STAGEMarked by the movement of WBCs or leukocytes into the area of injury

GRANULOCYTESMONOCYTES

GRANULOCYTES

Characterized by their cytoplasmic granules. Three Types: Neutrophils, Eosinophils, Basophils

Neutrophils are the primary phagocyte that arrives early at the site of inflammation.

Their cytoplasmic granules contain enzymes and other antibacterial substances that are used in destroying and degrading the engulfed particles

Contains oxygen dependent metabolic

pathways that generate toxic oxygen and nitrogen products that destroy pathogens.

Called polymorphonuclear neutrophils (PMNs) or segmented neutrophils (segs)

Increases greatly during an inflammatory process especially during bacterial infections.

After release from the bone marrow, neutrophils have a lifespan of 10 hours.

LEUKOCYTOSIS

EOSINOPHILS

Stain red with acid dye eosin

Increased in the blood during allergic reactions and parasitic infections.

Granules contain proteins that are highly toxic to large parasitic worms that cannot be phagocytize.

Plays an important role in allergic reactions by controlling release of specific chemical mediators.

BASOPHILSStains blue with basic dye, contains histamine and other bioactive mediators of inflammation.

MAST CELLS – resides in connective tissue throughout the body.

Monocytes are the largest of the circulating WBC and constitute 3 % and 8 % of total back leukocytes.Life span is longer that granulocytes. Arrive at the inflammatory site within 24 hours and by 48 hours Monocytes and macrophages are the predominant type Also plays a role in chronic inflammation

MONONUCLEAR PHAGOCYTES

LEUKOCYTE RESPONSE

PHAGOCYTOSIS

THREE DISTINCT STEPSAdherence plus opsonizationEngulfmentIntracellular Killing

OPOSONIZATION – Enhanced binding of an antigen due to antibody or complement Intracellular killing of pathogens is accomplished by lysosomal enzymes and oxygen-dependent mechanisms.

Plasma-derived Mediators

Major mediators: Kinins, Bradykinins - causes increased capillary permeability and painProteins of the Complement System – cascade of plasma proteins that plays an important role in immunity and inflammation

Complement System contribute to inflammation1. Causes vasodilation and increasing vascular permeability2. Promoting leukocyte activation, adhesion and chemostaxis3. Augmenting Phagocytosis

Cell-derived Mediators HISTAMINE AND SEROTONIN

Found in mast cells of connective tissues and blood basophils and platelets.

Released when there is trauma and immune reactions involving binding of immunoglobulin E (IgE) antibodies to mast cells.

Histamine causes dilatation of arterioles and increases permeability of venules.

Serotonin is a performed mediator, found in platelets, that has actions similar to those of histamine .

ARACHIDONIC ACID METABOLITES

Injured tissue, Inflammatory

mediators

Cell membrane phospholipids

Arachidonic acid

Lipoxygenase pathway Cyclooxygenase

pathway

Leukotrinenes(LTC4, LTD4, LTE4)

Prostaglandins(PGI2, PGF2a

Thromboxane(TxA2)

Smooth muscle contractionConstricts pulmo airwaysIncreases microvascular permeability

Vasodilation and bronchoconstrictionInhibits inflammatory cell function

VasoconstrictionBronchoconstrictionPromotes platelet function

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Corticosteroid Medication

Aspirin, NSAIDs

PLATELET ACTIVATING FACTOR (PAF)

Synthesized by all inflammatory cells, endothelial cells and injured tissue cells.Causes Platelet Aggregation and enhances functions of neutrophils and monocytes.A potent eosinophil chemoattractant.A potent vasodilator

CYTOKINES

Include colony stimulating factors that direct the growth of immature marrow precursor cells and the interleukins (IL), Interferons (IFN) and Tumor necrosis factor (TNF)

NITRIC OXIDE

Relaxes vascular smooth muscle, reduces platelet aggregation and adhesion.

Regulator of leukocyte recruitment and aids in killing microbes by Phagocytic cells.

MANIFESTATIONS OF INFLAMMATION

LOCAL MANIFESTATIONSSerous exudates – watery fluids low in protein content that result from entering the inflammatory site.

Are You SEROUS?!!!

Hemorrhagic exudates- severe tissue injury that damages blood vessels.

Fibrinous exudates- contains large amounts of fibrinogen and form a thick and sticky meshwork.

Membranous or Psudomembranous – necrotic cells in fibropurulent exudate

Purulent or suppurative exudates – contains pus, which is composed of degraded white blood cells, proteins and tissue debris.

Abscess- localized area of inflammation containing a purulent exudate.

Ulceration – a site of inflammation where an epithelial surface has become necrotic and eroded, often associated with subepithelial inflammation.

SYSTEMIC MANEFESTATIONS

ACUTE PHASE RESPONSEALTERATIONS IN WBC Count (Leukocytosis or Leukopenia)FEVERSystemic inflammatory response (Sepsis or septic shock)

ACUTE-PHASE RESPONSE

Begins hours or days of the onset of inflammation or infection.

Changes in plasma proteins, increased ESR, fever, increased leukocyte count, skeletal muscle catabolism, and negative nitrogen balance.

Due to release of cytokines (IL -1, IL- 6 and TNF-α)

Fever

Increased number of immature neutrophils

Release of cytokines IL-1, IL- 6 and TNF- α which affect the thermoregulatory center in the hypothalamus

IL – 1 and other cytokines stimulate the bone marrow.

Lethargy

Produces amino acids that can be used in immune response and tissue repair

IL-1 and TNF – α effects on the CNS

Skeletal muscle catabolism

Increased ESR Liver dramatically increases synthesis of acute-phase proteins such as fibrinogen and C-reactive protein.

Acute phase proteins dampen the repulsive effect of like charges on red blood cells causing them to clump or aggregate, forming stacks (rouleau formations)

C REACTIVE PROTEIN (CRP)

The classic acute phase reactant. Low levels of CRP in the body, which rises when there is an acute inflammatory response.Function is protective, binds to the surface of invading microbes and targets them for destruction through complement and phagocytosisHas an anti-inflammatory function.

Interest has focused on the use of CRP as a predictor of risk for cardiovascular events in persons with atherosclerotic heart disease.

WHITE BLOOD CELL RESPONSELEUKOCYTOSIS – increase in WBC especially when caused by a bacterial infection.

15,000 to 20,000 cells/μl (4,000-10,000 cells/ μl)

“shift to the left” in WBC differential count refers to the increase in immature neutrophils seen in severe infections

Bacterial infections – neutrophilia Parasitic and allergic responses – eosinophiliaViral infections – neutropenia and an increase in lymphocytes (lymphocytosis)Infections in persons with debilitating diseases such as cancer – Leukopenia.

LYMPHADENITIS – painful, palpable nodes are commonly associated with INFLAMMATORY process, non painful lymph nodes are characteristics of NEOPLASMS

CHRONIC INFLAMMATION

Self perpetuating and lasts for weeks, months or even years.

A result of a recurrent or progressive acute inflammatory response or from failure of the acute response.

CHARACTERISTICS

Infiltration of MACROPHAGES AND LYMPHOCYTES instead of neutrophils

Proliferation of fibroblasts instead of exudates.

Agents: low grade fever, persistent irritants that are unable to penetrate deeply or spread rapidly. (i.e. talc, asbestos, silica)

Viruses, fungi, bacteria, larger parasites of moderate to low virulence.

Presence of injured tissue such as that surrounding a healing fracture.

NON SPECIFIC CHRONIC INFLAMMATION

Diffuse accumulation of macrophages and lymphocytes at the site of the injury.

Leads to fibroblast proliferation, then scar formation that replaces connective tissue or the functional parenchymal tissues of the involved structures.

A, Chronic inflammation in the lung, showing all three characteristic histologic features: (1) collection of chronic inflammatory cells (*), (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3) replacement by connective tissue (fibrosis, arrows).

GRANULOMATOUS INFLAMMATIONGranuloma is a small 1-2 mm lesion in which there is massing of macrophages surrounded by lymphocytes.

Also called Epithelioid cells.

Associated with foreign bodies such as splinters, sutures, silica, and asbestos and microorganisms that cause tuberculosis, syphilis and sarcoidosis, deep fungal infections and brucellosis.

TISSUE REPAIR & WOUND HEALING

TISSUE REPAIR

A response to tissue injury and represents an attempt to maintain normal tissue structure and function.

TISSUE REGENERATIONFIBROUS TISSUE REPAIR

Tissue Regeneration

Replacement of injured tissue with cells of the same type.

Three types:LABILE cells – continues to divide and replicate throughout life. i.e. Surface epithelial cells of skin, oral cavity, vagina and cervix, Columnar epithelium of GI, uterus, and fallopian tubes. Transitional epithelium of bone marrow and urinary tract.

STABLE CELLS – normally stops dividing when growth ceases.

PERMANENT OR FIXED CELLS – cannot undergo mitotic division. i.e. Nerve cells, skeletal muscle cells, cardiac muscle cells.

FIBROUS TISSUE REPAIR

Severe or persistent injury with damage to both the parenchymal cells and extracellular matrix (ECM).

Repair by replacement of connective tissue, process involving generation of granulation tissue and formation of scar tissue.

GRANULATION TISSUE

Glistening red, moist connective tissue that contains newly formed capillaries, proliferating fibroblasts and residual inflammatory cells.

Development involves Angiogenesis (growth of new capillaries) and Fibrogenesis (formation of scar tissue.)

Fibrogenesis involves the influx of activated fibroblasts.

Fibroblasts secrete components of the ECMFibronectin, hyaluronic acid, proteoglycans, collagen.

Scar formatio: 1. Emigration and proliferation of fibroblasts into sites of injury 2. deposition of ECM by these cells

Collagen synthesis – important to development of the strength in wound healing.

Regulation of the Healing Process

Chemical mediators and Growth factorsChemical mediators of the inflammatory responseGrowth factors control proliferation, differentiation and metabolism of cells during wound healingContribute the generation of ECM, stimulate angiogenesis and assist in inflammatory processesExamples of GF: PDGF, FGF, EGF

EXTRACELLULAR MATRIX (ECM)Provides turgor to soft tissue and rigidity to bone.ECM must be intact for restoration of normal structure.

WOUND HEALING

Factors affecting wound healing:

MalnutritionBlood flow and oxygen deliveryImpaired inflammatory or immune responseWound separation, infection and foreign bodies

TEMPERATURE REGULATION AND FEVER

Body temperature Maintained at 36.0 -37.5 ˚C Regulated by the thermoregulatory center in the hypothalamus. FEVER – increase in body temperature due to resetting of the hypothalamic thermoregulatory set point as a result of endogenous pyrogens released from host macrophages or endothelial cells. An adaptive response to bacterial and viral infections or to tissue injury. The growth rate of microorganisms is inhibited and immune function is enhanced.