Inflammation and Repair pdf - نظري

Unit 2: Inflammation and Repair

Definition

Is a protective response intended to eliminate the initial
cause of cell injury as well as the necrotic cells and tissues
resulting from the original insult.

Acute inflammation

Causes (Stimuli for Acute Inflammation)



Infection



Trauma



Physical injury from thermal extremes or from ionizing

radiation



Chemical injury



Immunologic injury



Tissue death. Inflammatory changes occur in viable tissue

adjacent to necrotic areas

Processes

1)  Recognition of the injurious agent,
2)  Recruitment of leukocytes,
3)  Removal of the agent,
4)  Regulation (control) of the response, and
5)  Resolution (repair).

Cardinal signs



Rubor (redness caused by dilation of vessels)



Dolor (pain due to increased pressure exerted by the

accumulation of interstitial fluid and to mediators such as
bradykinin)



Calor (heat caused by increased blood flow)



Tumor (swelling due to an extravascular accumulation of

fluid)



Functio laesa (loss of function)

Types

1- Acute
2- Chronic

Components of inflammation

A) Vascular changes.
B) Cellular events.

Vasoactive changes



These changes begin with a brief period of

vasoconstriction, followed shortly by dilation of
arterioles, capillaries, and postcapillary venules.



The resultant marked increase in blood flow to the

affected area is clinically manifest by redness and
increased warmth of the affected area.



Transudate: is an ultrafiltrate of blood plasma and

contains little protein.



Exudate: interstitial fluid with high concentration of

plasma protein.



Increased capillary permeability

 This results in leakage of proteinaceous fluid, which

causes edema.

 Causes
1) Endothelial changes that vary from contraction of

endothelial cells in postcapillary venules, with widening
of interendothelial gaps.

2) Endothelial damage involving arterioles, capillaries & venules

Unit 2: Inflammation and Repair

Cellular Events: Leukocyte Recruitment &

Activation (Cellular response of leukocytes)

1- Emigration 2- Chemotaxis.
3- Phagocytosis. 4- Intracellular microbial killing

1) Emigration



Is the passage of inflammatory leukocytes between the

endothelial cells into the adjacent interstitial tissue.



Through many steps:

 Margination occurs as leukocytes localize to the outer

margin of the blood flow adjacent to the vascular
endothelium.

 Pavementing occurs as leukocytes line the endothelial

surface.

 Rolling is mediated by the action of endothelial selectins

loosely binding to leukocytes, producing a characteristic
"rolling" movement of the leukocytes along the
endothelial surface.

 Adhesion occurs as leukocytes adhere to the endothelial

surface and is mediated by the interaction of integrins on
leukocytes binding to immunoglobulin-family adhesion
proteins on endothelium.

 Transmigration is the movement of leukocytes across

the endothelium and is mediated by platelet endothelial
cell adhesion molecule-1 (PECAM-1) on both leukocytes
and endothelium

Adhesion molecules



Adhesion molecules play an important role in acute

inflammation.



They are of three families: selectins, immunoglobulin-

family adhesion proteins, and integrins.

 Selectins
o These molecules are induced by the cytokines interleukin-

1 (IL-1) and tumor necrosis factor (TNF).

o L-selectins are expressed on neutrophils and bind to

endothelial mucin-like molecules such as GlyCam-1.

o E- & P-selectins are expressed on endothelial cells and

bind to sialyl-Lewis X on the surface of leukocytes.

 Immunoglobulin-family adhesion proteins
o Intercellular adhesion molecules 1 and 2 (ICAM-1 and

ICAM-2) are expressed on endothelial cells and bind to
integrin molecules on leukocytes.

o Vascular cell adhesion molecules (VCAMs) similarly are

expressed on endothelial cells and bind to integrin
molecules on leukocytes.

 Integrins.

Examples include leukocyte MAC-1, and VLA-4which
bind to endothelial immunoglobulin-family adhesion proteins

2) Chemotaxis



Process by which leukocytes are attracted to and move

toward an injury.



This process is mediated by diffusible chemical agents.



Movement of leukocytes occurs along a chemical gradient.



Chemotactic factors for neutrophils

1)  Products from bacteria
2)  Complement components, especially C5a
3)  Arachidonic acid metabolites, especially leukotriene

B4 (LTB4)and kallikrein

Unit 2: Inflammation and Repair

3) Phagocytosis



It is the ingestion of particulate material (e.g., tissue

debris, living or dead bacteria, other foreign cells) by
phagocytic cells. Neutrophils and monocytes-
macrophages are the most important phagocytic cells.

Anatomic changes during phagocytosis



Phagocytosis is characterized morphologically by

internalization of the attached opsonized particle by
pseudopodial extensions from the surface of the
leukocyte, which enclose the foreign particle, forming an
internalized vesicle, the phagosome.



Phagosomes fuse with cytoplasmic lysosomes and form

phagolysosomes.



Phagolysosome formation is associated with leukocytic

degranulation.

Opsonization



This process facilitates phagocytosis. It is the coating of

particulate material by substances referred to as opsonins,
which immobilize the particles on the surface of the
phagocyte.



The most important opsonins are immunoglobulin G

(IgG) subtypes and C3b, a complement component.



Fragments opsonized by IgG are bound to phagocytic

cells by cell-surface receptors for the Fc portion of the
IgG molecule.



Fragments opsonized by C3b bind to cellular receptors for

C3b.

Intracellular microbial killing

Is mediated within phagocytic cells by oxygen-dependent
and oxygen-independent mechanisms.



Oxygen-dependent microbial killing

Is the most important intracellular microbicidal process
which mediated by formation of free radicals like
superoxide anion (O2·-), hydrogen peroxide (H2O2) and
hydroxyl radical (OH·).



Oxygen-independent microbial killing

 This process is much less effective than oxygen-

dependent microbial killing.

 This process is mediated by proteins, such as lysozyme,

lactoferrin, and cationic proteins, such as defensins

 Types of inflammatory cells

1) Neutrophils are the most prominent inflammatory cells in

foci of acute inflammation during the first 24 hours.
Important causes of neutrophilia (increased neutrophils in
the peripheral blood) include bacterial infections and
other causes of acute inflammation, such as infarction.
The early release of neutrophils into the peripheral blood
in acute inflammation is from the bone marrow
postmitotic reserve pool. There is often an increase in the
proportion of less mature cells such as band neutrophils.
After 2–3 days, neutrophils are replaced mainly by

2) Monocytes-macrophages, which are capable of

engulfing larger particles, are longer-lived, and are
capable of dividing and proliferating within the inflamed
tissue. Important causes of monocytosis (i.e., increased
number of monocytes in the peripheral blood) include
tuberculosis, brucellosis, typhus, and salmonella infection.

3) Lymphocytes are the most prominent inflammatory cells

in many viral infections and, along with monocytes-
macrophages and plasma cells, are the most prominent
cells in chronic inflammation. Lymphocytosis (i.e., an
increased number of lymphocytes in the peripheral blood)
is most often caused by viral infections such as influenza,
mumps, rubella, and infectious mononucleosis and certain
bacterial infections such as whooping cough and
tuberculosis.

4) Eosinophils are the predominant inflammatory cells in

allergic reactions and parasitic infestations. The most
important causes of eosinophilia include allergies such as
asthma, hay fever, and hives and also parasitic infections.
Other causes include polyarteritis nodosa & Hodgkin
lymphoma.

5) Mast cells and basophils are sources of histamine.

Important causes of basophilia include chronic
myelogenous leukemia.

Unit 2: Inflammation and Repair

Neutrophils (polymorphonuclear leukocytes, PMNs) in tissue.
PMN infiltration typifies the early stages of acute inflammation.

Outcome of acute inflammation

1) Resolution of tissue structure and function often occurs

if the injurious agent is eliminated.

2) Tissue destruction and persistent acute inflammation



Abscess. This is a cavity filled with pus (neutrophils,

monocytes, and liquefied cellular debris).
 It is often walled off by fibrous tissue and is relatively

inaccessible to the circulation.

 It results from tissue destruction by lysosomal

products and other degradative enzymes.

 It is usually caused by bacterial infections, often by

staphylococci.



Ulcer. This is the loss of surface epithelium.

This can be caused by acute inflammation of epithelial
surfaces (e.g., peptic ulcer, ulcers of the skin).



Fistula. This is an abnormal communication between two

organs or between an organ and a surface.



Scar. This is the final result of tissue destruction, with

resultant distortion of structure & in some cases, altered
function.

3) Conversion to chronic inflammation



This change is marked by the replacement of neutrophils &

monocytes with lymphocytes, plasma cells & macrophages.



It often includes proliferation of fibroblasts& new vessels,

with resultant scarring and distortion of architecture.

 It is important to remember that there are both

good and bad aspects to acute inflammation



The Good.

Dilution of toxins

  Entry of antibodies
  Transport of drugs
  Fibrin formation (traps microbes, serves as a matrix

for granulation tissue)

 Delivery of nutrients & oxygen
 Stimulation of immune response



The Bad.

Swelling (can occlude airways, raise intra-cranial pressure
and so on)

 Inappropriate inflammatory response.
 Digestion of normal tissues

Unit 2: Inflammation and Repair

Lecture 2 - chemical mediators and regulators of inflammation

Unit 2: Inflammation and Repair

Lecture 3 – Chronic Inflammation & Systemic effects of Inflammation

Chronic Inflammation

Unit 2: Inflammation and Repair

Systemic effects of Inflammation

Unit 2: Inflammation and Repair