ACUTE & CHRONIC INFLAMMATION

ISMET M NUR, dr, SpPA(K), MM

Inflammation is the response of vascularized living tissue to injury Intented to:

Contain

& isolite injury Destroy invading microorganism & inactivate toxins Prepare tissue for healing & repair

Evoked by:
Microbial

infection Physical agents Chemical Necrotic tissue Immune reaction

Inflammation generally characterized by:

Component

of vascular wall response and inflammatory cell response Effects mediated by circulating plasma protein & factors produced by vessel wall or inflammatory cells Termination when the offending agent is eliminated and the secreted mediators are removed

INFLAMMATION
SEQUENCE OF SPECIFIC PHYSIOLOGICAL BEHAVIORS THAT OCCUR IN RESPONSE TO A NONSPECIFIC AGENT.
ACTS TO: 1) NEUTRALIZE OR DESTROY OFFENDING AGENT 2) RESTRICTS TISSUE DAMAGE TO SMALLEST POSSIBLE AREA 3) ALERTS BODY TO TREAT OF TISSUE INJURY 4) PREPARES INJURED AREA FOR HEALING

CAUSES: EXOGENOUS OR ENDOGENOUS TRAUMA, SURGERY, INFECTION, CAUSTIC CHEMICALS, EXTREMES OF HEAT OR COLD, IMMUNE RESPONSES, ISCHEMIC DAMAGE

Acute inflammation:
Early

onset Short duration Involving fluid exudation Polymorphonuclear cells migration

Chronic inflammation:
Later

onset Longer duration Involving lymphocytes & macrophage Inducing blood vessel proliferation & scarring

CARDINAL SIGNS OF ACUTE INFLAMMATION

Heat function

Redness

Swelling

Pain

Loss of

Celsius (30 BC)

Virchow (1902)

INFLAMMATION HOT THING

SIGNS OF INFLAMMATION

DESCRIBED BY CELSUS

ADDED BY VIRCHOW

Acute Inflammation Components

Physiological Responses
Release of soluble mediators

Symptoms

Vasodilation
Increased blood flow Extravasation of fluid (permeability) Cellular influx (chemotaxis) Elevated cellular metabolism

Heat (calor) Redness (rubor) Swelling (tumor) Pain (dolor)

Acute Inflammation Components

Physiological Responses
Release of soluble mediators Vasodilation Increased blood flow Extravasation of fluid (permeability) Cellular influx (chemotaxis) Elevated cellular metabolism Heat (calor) Redness (rubor) Swelling (tumor) Pain (dolor)

Symptoms

Acute Inflammation Components

Physiological Responses
Release of soluble mediators Vasodilation Increased blood flow Extravasation of fluid (permeability) Cellular influx (chemotaxis)

Symptoms

Heat (calor) Redness (rubor) Swelling (tumor) Pain (dolor)

Elevated cellular metabolism

Acute Inflammation Components

Physiological Responses
Release of soluble mediators Vasodilation

Symptoms

Heat (calor)

Redness (tubor)
Increased blood flow Extravasation of fluid (permeability) Cellular influx (chemotaxis) Elevated cellular metabolism

Swelling (tumor)

Pain (dolor)

Acute Inflammation Components

Physiological Responses
Release of soluble mediators

Symptoms

Vasodilation
Increased blood flow Extravasation of fluid (permeability) Cellular influx (chemotaxis)

Heat (calore)
Redness (tubor)

Swelling (tumor)
Pain (dolor)

Elevated cellular metabolism

Edema: excess fluid in interstitial tissue or body cavities Exudate: an inflammatory extravascular fluid that has a high protein concentration and cellular debris, spesific gravity > 1.020 Exudation: extravasation of fluid, proteins,and blood cells from vessels into the interstitial tissue or body cavities Pus: a purulen inflammation exudate rich in neutrophils and cell debris Transudate: extravascular fluid with low protein content, spesific gravity < 1.012

ACUTE INFLAMMATION: SHORT TERM RESPONSE INVOLVES: HEMODYNAMIC CHANGES EXUDATE FORMATION PRESENCE OF GRANULAR LEUKOCYTES CHRONIC INFLAMMATION: PERSISTANT INVOLVES: PRESENCE OF NONGRANULAR LEUKOCYTES RESULTS IN MORE EXTENSIVE SCARRING.

Acute inflammation caused arteriolar dilatation, increase capillary pressure, reduced osmotic pressure. The net result is an excess of extravasated fluid

LEUKOCYTE NOMENCLATURE

STAGES OF INFLAMMATION
I. NEUROLOGIC RESPONSE - SYMPATHETIC NERVOUS SYSTEM, CAUSES CONSTRICTION OF BLOOD VESSELS II. VASCULAR RESPONSE - INCLUDES TRIPLE RESPONSE A. VASODILATION B. CAPILLARY PERMEABILITY, EDEMA C. PAIN TRIPLE RESPONSE 1) 3-50 SEC. - THIN RED LINE (VASODILATION OF CAPILLARIES) 2) 30-60 SEC. - FLUSH (VASODILATION OF ARTERIOLES) 3) 1-5 MIN - WHEAL (INCREASED VASCULAR PERMEABILITY, EDEMA) WHEAL - PALE, SOFT, SWOLLEN AREAS ON THE SKIN CAUSED BY LEAKAGE OF FLUID FROM THE CAPILLARIES

PATTERNS OF INFLAMMATORY RESPONSE

IMMEDIATE TRANSIENT RESPONSE RESPONSE TO MINOR INJURY IMMEDIATE SUSTAINED RESPONSE RESPONSE TO MORE SERIOUS INJURY, CONTINUES FOR SEVERAL DAYS, DAMAGE TO VESSELS DELAYED RESPONSE INCREASES IN CAPILLARY PERMEABILITY, DELAYED 4-24 HR, RADIATION INJURIES, SUNBURN

III. CELLULAR RESPONSE A. MARGINATION AND PAVEMENTING OF WHITE BLOOD CELLS B. EMIGRATION C. CHEMOTAXIS D. PHAGOCYTOSIS

MARGINATION OF NEUTROPHILS

PAVEMENTING

EMIGRATION OF NEUTROPHILS

Emigration of Neutrophils

Extravasation of Neutrophils

Chemotaxis

Involves binding of chemotactic agents to specific leukocyte surface G proteincoupled receptors, cause increased cytosolic calcium & GTPase activities that polymerize actin & pseudopods that binds the extracellular matrix and can then pull the cells forward

CHEMOTAXIS

Phagocytosis

Involves three steps:

Recognition

& binding. Microorganism coated by opsonin that enhance phagocytosis efficiency by binding leukocyte receptors. Engulfment by encircling pseudopods and enclosure of the particle within an intracellular phagosome Killing & degradation of phagocytosed particles

PHAGOCYTOSIS

PHAGOCYTOSIS

IV. INFLAMMATORY EXUDATES CONTAIN PLASMA, CELLS AND FLUID A. SEROUS LARGELY PLASMA, LOW IN PROTEIN, OCCURS EARLY OR IN MILD INFLAMMATION B. FIBRINOUS LARGE AMOUNTS OF FIBRINOGEN, FORMS A THICK, STICKY MESHWORK. ONLY REMOVED BY FIBROLYTIC ENZYMES. FAILURE OF REMOVAL LEADS TO INFLUX OF FIBROBLASTS AND SCAR TISSUE FORMATION C. PURULENT CONTAINS PUS (REMAINS OF WBCs, PROTEIN AND TISSUE DEBRIS). D. HEMORRHAGIC DAMAGE TO BLOOD VESSELS, OCCURS WITH OTHER FORMS OF EXUDATE. E. CATARRHAL MUCUS HYPERSECRETION THAT ACCOMPANIES INFLAMMATION OF A MUCUS MEMBRANE.

SEROUS EXUDATE

FIBRINOUS EXUDATE

PURULENT EXUDATE

V. RESOLUTION A. INJURED AREA RETURNS TO NORMAL B. MAY PROCEED AND FORM ABSCESSES C. MAY PROCEED TO CHRONIC PHASE

Outcomes of Acute Inflammation

Complete resolution with regeneration of native cells & restoration to normalcy Healing by connective tissue replacement (fibrosis) after substantial tissue destruction Progression to chronic inflammation

CHRONIC INFLAMMATION
SELF PERPETUATING, MAY DEVELOP IN THE COURSE OF RECURRENT OR PROGRESSIVE ACUTE INFLAMMATION OR LOW GRADE IRRITANTS THAT FAIL TO ELICIT AN ACUTE RESPONSE CHRONIC INFLAMMATION IS A PROLONGED PROCESS (WEEKS OR MONTH)

CHRONIC INFLAMMATION
Can occur by: Following acute inflammation because the inciting stimulus persist or normal healing somehow interrupted Repeated bouts acute inflammation Smoldering response without prior acute inflammation due to:
Persistent

infection by intracellular microbes Prolonged exposure to potentially toxic exogenous Immune reactions

CHRONIC INFLAMMATION
Typified by: Infiltration with mononuclear inflammatory cells (macrophages, lymphocytes, plasma cells) Tissue destruction induced by persistent injury & inflammatory cells Attempts at healing by connective tissue replacement

CHRONIC INFLAMMATION

A. NONSPECIFIC CHRONIC INFLAMAMTIONDIFFUSE ACCUMULATION OF MACROPHAGES AND LYMPHOCYTES AT INJURY SITE MACROPHAGES FROM 3 SOURCES: 1) RECRUITMENT 2) LOCAL PROLIFERATION 3) PROLONGED SURVIVAL
B. GRANULOMATOUSGRANULOMA FORMATION MASSING OF MACROPHAGES SURROUNDED BY LYMPHOCYTES, ASSOCIATED WITH FOREIGN BODIES

GRANULOMA FORMATION

GIANT FOREIGN BODY CELL

Chemical mediators of Inflammation

INFLAMMATORY MEDIATORS:
1) HISTAMINE 1st mediator of initial inflammatory response, causes dilation of arterioles and an inc. in permeability of capillaries and venules. 2) SEROTONIN Causes vasodilation and inc. vascular permeability

INFLAMMATORY MEDIATORS
3) PLASMA PROTEINS a) BRADYKININ Causes an inc. in capillary permeability and pain, may inc. leukocyte chemotaxis b) COMPLEMENT COMPONENTS Make up 10% of circulating serum proteins, chemotactic to neutrophils and monocytes, complement cascade can damage bacteria c) COAGULATION SYSTEM Responsible for making a fibrous network at the site of a lesion to trap exudate, microorganisms, and foreign bodies, stops bleeding and provides a framework for repair to begin.

COMPLEMENT CASCADE
Classic Pathway Antigen Antibody complex Alternative Pathway Bacterial cell walls (endotoxin)

Activated C1
C4 C2 C3 Inflammation Chemotaxis Analphylatoxins C3b C5b C3a C5a C5 C6 C7 C8 C9

C3b

Factors B and D Properdin

Antigen opsonization Membrane attack Complex and cell lysis

EFFECTS OF COMPLEMENT

COAGULATION CASCADE
Extrinsic Pathway Injured cells X Intrinsic Pathway Collagen or other activators Xa

XIIa
Va Phospholipi d Thrombin

XII

Prothrombin

Fibrinogen

Fibrin + Fibrinopeptide monomer

Fibrin polymer

INFLAMMATORY MEDIATORS
4) PROSTAGLANDINS AND OTHER PRODUCTS OF THE CYCLOOXYGENASE PATHWAY Derived from arachidonic acid, contribute to vasodilation, capillary permeability, pain and fever 5) LEUKOTRIENES Derived from arachidonic acid via the lipoxygenase pathway,most contribute to inc. vascular permeability, can induce bronchoconstriction, transient wheal and flare response, Slow Reacting Substance of Anaphylaxis

Generation of Arachidonic Acid Metabolites & their roles in Inflammation

Generation of Arachidonic Acid Metabolites & their roles in Inflammation (continued)

6) WHITE BLOOD CELL PRODUCTS a. NEUTROPHILS - LTs, PROTEASES, REACTIVE OXYGEN INTERMEDIATES, THROMBOXANE A2, PGE2, HYDROLASES b. MONOCYTES/ MACROPHAGES REACTIVE OXYGEN AND NITROGEN INTERMEDIATES, LTs, IL-1, IL-6, TNF-, COLONY STIMULATING FACTORS

c. LYMPHOCYTES 1. T HELPER CELLS - IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, -INTERFERON, COLONY STIMULATING FACTORS, TUMOR NECROSIS FACTOR - 2. T CYTOTOXIC CELLS TUMOR NECROSIS FACTOR - , PERFORINS 3. B CELLS - IMMUNOGLOBULIN
T CELL MEDIATED KILLING

d. MAST CELLS HISTAMINE, SEROTONIN, LTB4, PROSTAGLANDINS, PLATELET ACTIVATING FACTOR, NEUTROPHIL CHEMOTACTIC FACTOR (IL-8), EOSINOPHIL CHEMOTACTIC FACTOR e. EOSINOPHILS CONTROL MEDIATORS THAT ARE RELEASED BY MAST CELLS

The roles of activated macrophages in chronic inflammation

Consequences of defective or excessive inflammation

Defective inflammation typically result in increased susceptibility to infections & delayed healing of wounds and tissue damage. Excessive inflammation is the basis of many categories of human disease, ex. Allergies and autoimmune diseases. Inflammation also play critical role in cancer, neurodegenerative diseases, atherosclerosis.

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