Inflammation & Inflammatory Response, Immune system, UCD

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Chap 3 Porth, Immune system, UCD

Inflammation

1. an automatic response to cell injury that: nuetralizes harmful agents & removes dead tissues
2. characterized by elaboration of inflammatory mediators & movement of fluid & leukocyes from vascular system into extravascular tissues
3. An irritation of a tissue caused by infection or injury.

itis

refers to inflammation

Classic physical responses of inflammation

redness, swelling, heat, pain or discomfort & loss of funciton

Manifestations of acute inflammatory response

Immediate vascular changes (vasodilation & increased capillary permeability, influx of inflammatory cells such as neutrophils, & sometimes widespread effects of inflammatory mediators which produce fever & other systemic signs & symptoms

Manifestations of chronic inflammatory response

Due to infiltration with macrophages, lymphocytes, & fibroblasts, leading to persistent inflammation, fibroblast proliferation & scar formation.

Acute inflammation

adaptive response triggered by noxious stimuli & conditions such as infection & tissue injury, short duration, few minutes to several days

chronic inflammation

long duration ,days to years, associated with proliferation of bloodvessel tissue necrosis & fibrosis (scarring)

endolithial cells:

line epithelial lining of bloods vessels, produce antiplatelet & antithrombotic agents, vasodilators & vasoconstictors

platets/thrombocytes

small membrane bound disks, inflammatory mediators

leukocytes/white blood cells

major cellular component of inflammatory response

granulocytes

neutrophils, eosinophils, & basophils - specific cytoplasmic granules & multilobed nucleus

agranulocytes

moncyrtes, macrophages & lymphocytes - lack cytoplasmic granules Have single nucleus

Neutrophils

1) principal leukocytes in acute inflammation
early responders
2) phagocytic, predominate in early inflammatory responses
3) polymorphonuclear
4) Increase in acute infections
5) Ingest bacteria, dead cells & cellular debris
6) short lived & become a componenet of the purulent exudate

Eosinophils

Granular WBC - Weak phagocytes, vascular mediator
1) Protection from infections caused by parasites - Bind on IgE (helminths)
2) Involved in allergic reactions
3) slower reaction (2-3 hrs P/Neutrophils) 2-3% circulation
4) interact w/basophils, long life span, chronic inflammation

Basophils

1) granulocyte that has 2 lobes
2) nonphagocytic
3) releases histamine, prostaglandins, serotonin & leukotrienes; vasoactive mediators
4) associated with allergic responses
5) precurser of mast cell
6) mediated by IgE

Mast cells

1) derived from same stem cells as basophils, but only activated when lodged in tissue sites;
2) release histamine, cytokines, chemotactic facotrs, leukotrienes, prostaglandins when activated

monocyte

Agranulocytic: a relatively large phagocytic white blood cell that circulates in the bloodstream and has a single ovoid nucleus. once these cells migrate into the tissues from the blood, they become macrophages:
produced in bone marrow

macrophages

Develop from monocytes, a type of white blood cell.
1) Either fixed or wandering, Irregular shape with short branching projections.
2) Capable of engulfing bacteria and cellular debris.
3) contibute to initiation of healing process
4) typically arrive at the inflammatory site 24 hours or later after neutrophils

Lymphocytes

A class of white blood cells that consist of small and large lymphocytes. The small lymphocytes bear variable cell-surface receptors for antigen and are responsible for adaptive immune responses. B cells, T cells, NK cells (large granular), of innate immunity

Plasma cells

Devleop from Activated B lymphocytrs & produce antibodies against persistent antigens in inflammatory site

Selectins

Adhesive molecules- (L-selectin on lymphocytes, P selectin and E selectin on endothelial cells)

Adhesive proteins

E-selectin, L-selectin, P-selectin

integrin

30 structurally simiar poteins that promote cell-to-cell & cell-to-extracellular matrix inteactions built into the plasma membrane that interconnects the extracellular matrix and the cytoskeleton.

adhesion molecules

Proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix (ECM).

Acute inflammation triggers

Infections, immune reactions, mechanical , chemical agents, trauma, chemical, tissue necrosis from any cause

LAD I and II, Leukocyte Adhesion deficiency

Inability of cell to control adhesion of selectins w/immune system
Contibute to pathogenesis of RA (excessive expression of cell adhesion)

rubor

redness

calor

heat

dolor

pain

tumor

swelling

functio laesa

loss of function

acute phase response elicits:

cardinal signs of inflammation: rubor, tumor, calor, dolor, functio laesa as well as fever, anorexia, hypertension, increased heart rate, corticoid steroid and ACTH release occur during this phase.

vascular stage of acute inflammation

increased blood flow: vasodilation

structural change of acute inflammation

increased vascular permeability: plasma proteins leave circulation

cellular stage of acute inflammation

emigration of leukocytes from microcirculation & accumulation at injury site

First line of defense: Immune system

Innate/natural immunity - responds early & rapidly; very effective

2nd line of defense: Immune system

Inflammation (immunity) - functions immediately as an effective barrier to microbes

3rd line of defense

adaptive/acquired immunity -resonds less rapidly, but more effectively. Use of lymphocytes, antibodies

physical & mechanical barriers:

The skin, linings of GI, Genitourinary & respiratory tracts:
Act by:
Sloughing off of cells
coughing & sneezing
flushing
vomiting
mucus & cells

Biomechanical barriers

Synthesized & secreted saliva, tears, ear wax, sweat & mucus
anitmicrobial peptides
normal bacterial flora

Inflammatroy response: 2nd line of defense triggers

Caused by a variety of materials:
Infection, mechanical damage, ischemia, nutrient deprivation, temperature,extremes, radiation, etc.
Local manifestations

Inflammatory mediators

Compounds which stimulate inflammation

Histamine:

1) first mediator of inflammation,
2) released from mast cells & damaged tissue.
3) Causes vasodilation & increased capillary permeability

Inflammatory agents

histamine, prostaglandins, leukotrienes

Plasma protein systems

Complement system
Coagulation System
Kinin system

Proenzymes

Inactive enzyme

MAC (membrane attack complex) complement actions

Cell lysis, including bacterial & altered blood cells

C3a, C5a, complement actions

activates basophils & mast cells, vascular permeability, release of inflammatoroy mediators that produce smooth muscle contraction, changes in endothelial cells to enhance migration of phagocytes

C3a complement actions

anaphylatoxin bronchospasm, mast cell degranulation

C3b-opsonization-

opsonization- coating of particles (microbes) for more efficient recognition by phagocytes

35b67 complement actions

Chemotaxis (complement actions)

C5a complement actions

Neutrophil activation

Coagulation clotting systems

Forms a fibrinous meshwork at an injured or inflamed site:
1) prevent spread of infection
2) keeps microorganisms & foreign bodies at site of greatest inflammatory cell activity
3) forms a clot tht stops bleeding
4) provides a framework for repair & healing

Fibrin

main substance in an insoluble protein

Kinin system

1) functions to activate & assist inflammatory cells
2) primary kinin is bradykinin
3) causes:
a. dilation of blood vessels
b. pain
c. smooth muscle contraction
d. vascular permeability
e. leukocyte chemotaxis

Classic Manifestations of Inflammation:

Local: pain, swelling, warmth, redness, LOF
Systemic: fever, leukocytosis, malaise

Vascular stage:

Prostaglandins & leukotrienes affect blood vessels
arterioles & venules dilate
increase blood flow to injured area
redness & warmth result
capillaries become more permeable
allows exudate to escape into tissues
swelling & pain result

What mechanism causes the redness associated with the inflammatory process?

Prostaglandins & leukotrienes cause vasodilation, which brings more blood to the injured/affected area as well as redness/erythema & warmth.

Serous

watery fluids, low in protein, early inflammation

hermorrhagic

red blood cells present due to damage to capillary beds & blood vessels, indicates bleeding

fibrinous

fibrinogen, thick & sticky meshwork, clotted exudate, indicates more advanced inflammation

Membranous

on mucous membrane, necrotic cells on fibropurulent exudate

purulent

pus, WBC's, proteins & tissue debris, indicates a bacterial infection

pyogenic

pus forming

abcess

localized area of inflammation containing purulent exudate

ulceration

site where epithelial surface (skin or GI) becomes necrotic & eroded

Cellular stage:

WBC enters injured tissue:
destroys infective organisms
remves damaged cells
releases more inflammatory mediators to control further inflammation & healing

Duties of leukkocytes:

1) enter injured area
2) express adhesive proteins
3) attach to blood vessel lining
4) squeeze between the cells
5) follow inflammatory mediators to injured area
6) release many inflammatory mediators @ injured area

Leuckocytes release these inflammatory mediators @ injured area:

Histamine & seratonin
platelet activating factor
cytokines: colony stimulating factors; interleukins (IL), interferons, tumor necrosis factor (TNF)
Nitric Oxide (NO)

Which leukocytes participate in the acute inflammatory response?
a. eosinophils
b. monocytes
c. neutrophils
d. all of the aobve
e. a & c

e. a & c
Granulocytes & monocytes play a role in the acute phase of the immune reponse. Eosinophils & neutrophils are granuloctes, so all of the leukocytes listed participate.

Other inflammatory mediators:

kinins
coagulation & fibrinolysis proteins
complement system
C-reactive protein

Leukocytes release interleukins & tumor necrosis factor during the acute phase response which

affects thermoregulatory center - fever
affects CNS - lethargy
causes skeletal muscle breakdown

During the acute phase response, the liver makes fibrinogen & C-reactive protein which:

facilitate clotting
bind to pathogens
moderate inflammatory responses

Fever during the systemic manifestations of inflammation, is:

caused by exogenous & endogenous pyrogens
act directly on the hypothalmus

An increased number of circulating leukocytes

leukocytosis

Systemic manifestations of Inflammation:

Fever
leukocytosis
Increased plasma protein synthesis (C-reactive, fibrinogen, haptoglobin, amyloid, ceruloplasmin)

Acute phase reactants synthesised during inflammation

C-reactive protein, fibrinogen, haptoglobin, amyloid, ceruloplasmin, etc.

Body temperature is controlled through negative feedback loops. T/F

True, when body senses a change out of the norm, it activates mechanisms that oppose that change (vasodilation & sweating with increased temperatures; vasoconstriction & shivering with decreased temperatures. This is known as negative feedback.

Vasodilation & sweating occur

with increased body temperatures/fevers

Vasoconstriction & shivering occur

with decreased body temperatures

White blood cell response to inflammation

Inflammatory mediators cause WBC production
WBC count rises
Immature neutrophils released into blood

During chronic inflammtion, macrophages:

Accumulate in the damaged area & keep releasing inflammatory mediators

With non specific chronic inflammation:

fibroblasts proliferate
scar tissue forms

During Granulomatous inflammation:

Macrophages mass together around foreign bodies
Connective tissue surronds & isolates the mass

Chronic inflammation of 2 wks or longer

is often related to an unsuccessful acute inflammatory response

Characteristics of chronic inflammation include:

dense infiltration of lymphocytes & macrophages
granuloma formation
epithelioid cell formation
giant cell formation

Ulcerative colitis:

involves the colon & rectum & only the mucosal layer is affected.

The hallmark sign & symptom of Ulcerative Colitis is:

Bloody diarrhea & lower abdominal cramps

There is an increased risk of cancer after

8-10 years of ulcerative colitis disease

Assessment of ulcerative colitis disease:

Number of stools/day
hematocrit
sed rate
albumin level

Albumin

Plasma protein that maintains the proper amount of water in blood

Crohn Disease signs & symptoms

Intermittent bouts of fever, diarrhea, & RLQ pain
may have RLQ mass, tenderness
Can affect any portion of GI tract

To DX Crohn disease

Uper GI series with small bowel follow thru plus either colonoscopy or barium enema

Treatment for crohn disease

stop smoking, drugs similar to UC

Crohn disease can be found:

any portion of GI tract
30% small bowel
50% small & large bowel
15-20% large bowel

Treatments of IBD (Inflammatory Bowel Disease)

Corticosteroids
Sulfasalazine
Mesalazine
Aminosalicylates
Antibiotics
Surgery

Acute pancreatitis leads to

Deep abdominal pain
hypocalcemia
digestion of elastic tissue
inactivation of surfactant in the lung which can cause pulmonary edema & the development of acute respiratory distress syndrome
Glucose intolerance

Symtpoms of acute pancreatitis

Nausea
vomiting
GI bleeding & ulcers
hematemesis

Treatment for acute pancreatitis includes:

fluids & electrolytes
collid treatments for shock
demerol for pain
nasogastric suctionto rest digestive system
vasoconstrictor drugs if shock

Acute Pancreatitis is defined as:

acute autodigestion of the pancreas
40-60% are associated with ETOH abuse, gallstones & other billary diseases
Also associated with trauma to abdomen, hyperlipidemia & certain types of drugs

Activation of enzymes in acute pancreatitis:

Serum amylase is one of first to increase
serum trypsin
serum phoshoipase A
serum elastase

Tissue Repair is stimulated by

growth factors stimulate local cells to divide

Tissue organization is

controlled by the extra cellular matirx

Tissue regeneration

Injured tissue is replaced by the same kind of cells

fibrous tissue repair:

injured tissue is replaced by connective tissue

Granulation tissue leads to

scar tissue

immune resonse

The collective, coordinated response of the cells & molecules

anitigens

elicit adaptive immune repsonses - memory of the substance is developed so repeat exposure to same microbe produces quicker & more vigorous response

Humoral immunity

mediated by antibodies which are produced by B lymphocytes

Cell mediated immunity

defends against intracellular microbes, such as viruses, provided by T lymphocytes.

Cellular elements of the blood: RBC's WBC's, platelets

derived from hematopoietic stem cells in bone marrow

Myeloid progenitor is precurser to:

monocytes/macrophages, granulocytes & dendritic cells of innate immune system which are produced in bone marrow.

Phagocytic cells

monoctyes/macrophages, granulocytes, dendritic cells

dendritic cells

cell with long fingerlike processes

Lymhoid progenitor in the bone marrow is precurser to:

lymphocytes (B&T) & natural killer cells.

naive lymphocyte

mature B or T lymhocyte that has not previously encountered antigen or is not progeny of antigen-stimulated mature lymphocyte

B lymphocytes

cells capable of producing antibodies, mediate humoralimmunity

T lymphocytes

Cell-mediated immunity; antigen receptors recognize peptide fragments of proteing antigens

Helper T cells

Help B lymphocytes produce antibodies & help phagocytic cells destroy ingested pathogens

cytotoxic T cells

kill or lyse intracellular microbes

CD proteins

Cluster of differentation, numerical, defines particular cell type or staged of cell differentiation & are recognized by cluster/group of antibodies

CD4 Helper cells

measures progressionof HIV infection

Natural Killer Cells NK

recognize & kill tumor cells, abnormal body cells & cells infected with intracellular pathogens (viruses & intracellular bacteria)

Central Lymphoid organs

bone marrow & thymus provide environment for immune cell production & maturation

Peripheral Lymphoid Organs

lymph nodes, spleen, tonsils, appendix, Peyer patches of intestine, mucosa associated lymphoid tissues in respiratory, GI tract, & reproduction systems

Lymph channels, blood vessels & capillaries

Immune cells circulate through these various tissues & organs to seek out and destroy foreign material.

Thymus, fully functional @ birth

generates mature immunocometent T lymphocytes which express appropriate receptors

Thymic selection

abiltiy of T cells to recognize foreign antigens & distinguish self from non self; process of maturation

B cell maturation

occurs in bone marrow; here cells multiply, mature & acquire immunoglobulin (Ig) signalining molecules & cell markers that distinguish self from nonself

lymph

fluid which drains from the epithelia, connective tissues, & most parenchymal organs

T lymphocytes, B lymhocytes

_____are more abundant in paracortex of lymph node; ____ are more abundant in follicles & germinal centers located in outer cortex of lymh node.

specialized areas of lymph node

outer cortex
paracortex
inner medulla

Spleen

secondary lymphoid organ
filters antigens from blood
comprised of red and white pulp

red pulp

well supplied with arteries & area where senescent & injured RBC's are removed

white pulp

contains concentrated areas of B & T lymphocytes permeated by macrophages & dendritic cells

mucosa-associated lymphoid tissues (MALT)

Nonencapusulated clusters of lymphoid tissue located around membranes lining respiratroy, digestive & urogenital tracts

Cytokines

short acting soluble protein molecules which provide cell-to-cell communication; mediate actions of immune systems cells

Interleukins (ILs)

made by leukocytes & act on leukocytes

Interferons (IFNs)

interfere with virus multiplication

pleiotropsim

ability of cytokine to act on a different cell type

chemokines

cytokines that stimulate migration & activation of immune & inflammatory cells

CC chemokines

2 cysteines located adjacent to each other; attract mononuclear leukocytes to sites of chronic inflammation

CXC chemokines

2 cysteines separated by amino acie; attract neutrophils to sites of acute inflammation

Chemokines receptors

CCR1, R = receptor, 1 = number of gene

Colony stimulating factors (CSF)

cytokines that stimulate bone marrow pluripotent stem & progenitor or precursor cells to produce large number of erthrocytes, platelets, lymphocytes, neutrophils, moncytes, eosinophils, basopils & dendritic cells

toll-like receptors

transmembran receptor involved in activation pathway for pathogen snesors of innate immunity (Drosophila)

Opsonins

coating materials which bind particles (microbes) for efficient recognition by phagocytes
acute-phase proteins
lectins
complement

Complement system

1) Can destroy pathogens directly, increased phagocytosis, destruction & clearance of pathogen from the body
2) Activates or collaborates with every other component of the inflammatory response, enhances inflammatory response
3) Pathways: classical, lectin, alternative

3 phases of complement system reaction

1. initiation or activation
2. amplification of inflammation
3. membrane attack response

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