Inflammation and Repair

Inflammation
 A response of vascularized tissues that delivers WBCs and
molecules of host defense from the circulation to the sites of
infection and cell damage to eliminate the offending agents
 A protective response that is essential for survival
 Serves to remove the initial cause of cell injury and the
consequences of such injury
 Mediators of inflammation:
o Phagocytic WBCs
o Antibodies
o Complement system
 “-itis” denotes inflammation at the site of an organ
o Conjunctivitis, appendicitis, cirrhosis, arthritis

Steps of Inflammation

Fundamental properties
 Components of the inflammatory response
o Major participants: blood vessels and leukocytes
o Response: dilating and ↑ permeability
o Enables the selected proteins to enter the site of
inflammation or tissue damage
o Circulating WBCs adhere to the endothelial lining of blood
vessels and migrate into tissues
 Harmful consequences of inflammation
o Local tissue damage
o Self-limited and resolve as inflammation abates
o Disorders:
 Misdirection the inflammatory reaction (autoimmune
disease)
 Occurs against normally harmless environmental
substances (allergies)
 Inadequately controlled reaction

 Local and systemic inflammation

o Local: limited to one area (swelling of one part or organ)
o Systemic: whole body is affected (Fever)

 Mediators of inflammation
o Soluble factors produced by various cells or derived from
plasma proteins
 Cytokines, Interleukins, Complements
o Generated or activated in response to the inflammatory
stimulus
o Initiate or amplify the inflammatory response
o Determine the patten, severity, and clinical and pathologic
manifestations of inflammation
 Acute and Chronic Inflammation

Cardinal Signs of Inflammation

Causes of Inflammation
Acute Inflammation
 Rapid host response that serves to deliver leukocytes and
plasma proteins (antibodies) to sites of infection or tissue injury.
 Three major components
1. Dilation of small blood vessels leading to an increase in
blood flow
2. Increased permeability of microvasculature enabling
plasma proteins and leukocytes to leave the circulation
3. Migration of leukocytes form microcirculation:
accumulation in the focus of injury, and activation to
eliminate the offending agent

Reactions of Blood Vessels

 Changes designed to maximize the movement of plasma
proteins and circulating cells out of the circulation
 Escape of fluid, proteins and blood cells from the vascular
system into the interstitial tissue or body cavities: EXUDATION

o Exudate - an extravascular fluid that has a high protein

concentration, contains cellular debris, and has a high
specific gravity, denotes an inflammatory reaction.
o Transudate - a fluid with low protein content (albumin), little
to no cellular material, low specific gravity, an ultrafiltrate of
plasma that results from osmotic or hydrostatic imbalance
 Edema - denotes an excess of fluids in the interstitial tissue or
serous cavities (Exudate vs Transudate)
 Pus - purulent exudate, an inflammatory exudate rich in
leukocytes, debris of dead cells and microbes.

Changes in Vascular Flow and Caliber

1. Vasodilation
 Increases the blood flow causing erythema at the site of
inflammation
 Induced by the action of several mediators: Histamine and
Nitric oxide
2. Increased permeability of microvasculature
 Allows outpouring of protein-rich fluid into the extravascular
tissues.
3. Stasis in smaller blood vessels
  Due to increase in diameter of blood vessels and loss of fluid
-> Increased viscosity of RBCs
 Seen as vascular congestion (localized redness)
4. Leukocytes adhere along vascular endothelium
 Endothelial cells are activated by mediators and express
increased levels of adhesion molecules
 Leukocytes migrate through vascular wall into the interstitial
tissue.

Increased Vascular Permeability

 Hallmark of acute inflammation
 Leads to the escape of protein-rich exudate into the
extravascular tissue, causing edema
 Mechanisms:
1. Contraction of endothelial cells resulting in increased inter-
endothelial spaces
2. Endothelial injury resulting in endothelial cell necrosis and
detachment
3. Increased transporting of fluids and proteins (Transcytosis).
 Occurs in venules and is induced by VEGF (Vascular
Endothelial Growth Factor)

Responses of Lymphatic Vessels

 Lymphatics and lymph nodes filter the extravascular fluids
 Increase in lymphatic flow and helps drain edema fluid that
accumulates
 Cells of the lymphatic vessels proliferate to increase the load of
filtration → Lymphangitis and Lymphadenitis

Leukocyte Recruitment to sites

 WBCs are recruited from the blood vessels into the extravascular
tissue
 Migrate to the site infection or tissue injury
 Activated to perform their specific functions

Mediators of Inflammation
 Properties and General Principles
1. Generated either from cells or from plasma proteins
2. Active mediators are produced in response to various stimuli
3. One mediator can stimulate the release of other mediators 4.
Mediators vary in their range of cellular targets
4. Once activated and released from the cell, most are short-
lived. They quickly decay or are inactivated by enzymes
Phagocytosis and Clearance
 Leukocytes can eliminate microbes and dead cells by
phagocytosis followed by their destruction on phagolysosomes
o Destruction is caused by free radicals (ROS, NO) generated in
activated leukocytes and lysosomal enzymes
o Neutrophils can extrude their nuclear contents to form
extracellular nets that trap and destroy microbes
o Enzymes and ROS may be released into the extracellular
environment
 Also capable of damaging normal tissues (pathologic
consequences of inflammation)
 Anti-inflammatory mediators terminate the acute inflammatory
reaction when it is no longer needed.
Outcomes of Acute Inflammation
Patterns of Acute Inflammation
1. Serous Inflammation
 Marked by the exudation of
cell-poor fluid into spaces
created by cell injury or into
body cavities (peritoneum,
pleura, pericardium)
 Accumulation of fluid:
Effusion
o Pleural effusion
o Pericardial effusion
o Ascites
o Skin blisters from burn or viral infections

2. Fibrinous Inflammation
 Fibrin deposition (fibrinous exudate)
in the extracellular space because of
leakage of fibrin from the blood
vessels.
 Often leads to scarring or fibrosis
 Meninges, Pericardium, and Pleura

3. Suppurative or Purulent Inflammation

 Production of large amounts of pus
or purulent exudate (neutrophils,
liquefactive necrosis, and edema
fluid)
 Pyogenic - occurs when certain
bacteria produces the suppuration
(Staphylococcus)
 Abscess - localized collections of
purulent inflammatory tissue
 o Produced by deep seeding of pyogenic bacteria
o May become walled off and ultimately replaced by
connective tissue

4. Ulcers
 A local defect or excavation on the surface of an organ or
tissue that is produced by the shedding of inflamed necrotic
tissue
 can occur only when tissue necrosis and resultant
inflammation exist on or near a surface

Chronic Inflammation
 Inflammation of prolonged duration (weeks or month)
 May follow an acute inflammation or may start insidiously as a
low-grade, smoldering response without any manifestations of an
acute reaction
 Causes:

Morphologic Features
1. Infiltration with Mononuclear cells (macrophages,
lymphocytes and plasma cells)
2. Tissue destruction (Hallmark of chronic inflammation)
3. Attempts at healing by connective tissue replacement of
damaged tissue, accomplished by angiogenesis and fibrosis.

Role of Macrophages
 Macrophage - dominant cellular player in chronic inflammation
 Begin to migrate into extravascular tissues early in inflammation
 Monocytes undergo transformation into macrophage →
activation
Role of Lymphocytes
 Activation of T and B lymphocytes
o Amplify and propagate chronic inflammation
o Secretion of cytokines and CD4 Tcells promote inflammation
o Activated B-cells and antibody producing plasma cells
produces specific antibodies for persistent foreign antigens of
self-antigens

 Other cells in chronic inflammation

o Eosinophils have granules that contain major basic protein
that is toxic to helminths but may also injure host epithelial
cells
o Mast cells are widely distributed in connective tissues,
secrets numerous cytokines that will drive inflammation
o Neutrophils

Granulomatous Inflammation
 A distinct pattern of chronic inflammation that is encountered in
a limited number of infectious and non-infectious conditions
 A cellular attempt to contain an offending agent that is difficult
to eradicate.
o Strong activation of T lymphocytes → Macrophage activation
 Causes of granuloma:
o Tuberculosis
o Leprosy
o Sarcoidosis
o Brucellosis
o Cat-scratch disease
o Syphilis
o Lymphogranuloma inguinale
o Irritant lipids (silicon breast implant)
 “Granuloma”
 Chronic inflammation consisting
of a microscopic aggregation of
macrophages that are
transformed into epithelium-like
cells (epithelioid cells)
 Surrounded by a collar of
mononuclear leukocytes:
lymphocytes and few plasma
cells.
2 types of Granuloma
A. Foreign Body Granuloma
 Incited by foreign bodies: talc, silicon, sutures
  Normally does not incite specific inflammatory or immune
response
 Foreign material are usually identified at the center of the
granuloma
 Examples:
o Suture granuloma
o Breast implant granuloma
B. Immune Granuloma
 cause by variety of agents capable of inducing cell-mediated
immune response
 Mycobacterium tuberculosis or Sarcoidosis
 Central caseous necrosis
 Example:
o Tuberculous granuloma
o Sarcoidosis

Systemic Effects of Inflammation

1. Fever
 Elevation of body temperature
 Most prominent manifestation of acute-phase
response
 Pyrogens - substances responsible for fever,
stimulated by prostaglandin
2. Acute-phase proteins
 Mostly synthesized by the liver
 CRP, Fibrinogen, Serum Amyloid A protein, IL-6 and IL-
1, TNF 3. Leukocytosis
 WBC >15,000 cells/uL

Consequences of Defective or Excessive Inflammation

 Defective Inflammation
o Increased susceptibility to infections
o Delayed wound healing
 Excessive Inflammation
o Hypersensitivity Reactions
o Atherosclerosis and Ischemic Heart Disease
o Neurodegenerative diseases (Alzheimer disease)

Tissue Repair
Overview of Tissue Repair
 Repair: restoration of tissue architecture and function after an
injury
 2 process of repair of damaged tissue:
1. Regeneration
 o Damaged tissues are replaced
o Essentially return to normal state
o May occur by proliferation of differentiated cells
2. Connective tissue deposition
o Scar formation
o Occurs if injured tissues are incapable of regeneration or
if the supporting structures are severely damaged to
support regeneration
o Repairs by laying down connective tissue (fibrous tissue)
o “Fibrosis”

Cell and Tissue Regeneration

 Controlled by the rate of cell proliferation, differentiation and
death by apoptosis.
 Terminally differentiated cells - cells that are not capable of
replication
 Cell proliferation is driven by signals by growth factors and from
the extracellular matrix

Tissue Proliferative Activity

Repair by Connective Tissue Deposition
 Deposition of collagen and other ECM components causing the
formation of scar
 Occurs when tissue injury is severe or chronic and results in
damage of both parenchymal and stromal cells

Factors affecting tissue repair

 Infection
 Diabetes
 Nutritional status
 Glucocorticoids (Steroids)
 Mechanical factors
 Poor perfusion
 Foreign bodies
 Type and extent of tissue injury
 Location of injury

Abnormalities in Tissue Repair

Ulcerations

Hypertrophic Scar and Keloid

Contracture