INFLAMMATION AND REPAIR

CARDINAL SIGNS OF INFLAMMATION

WHAT IS INFLAMMATION?
a. A protective response
b. Suggests a harmful reaction
c. Serves to rid the cause of injury
d. All of the above

• response of vascularized tissues to infections and

tissue damage that brings cells and molecules of host
defense from the circulation to the sites where they
are needed, to eliminate the offending agents.
• serves to rid both the cause and consequence of cell
injury
• initiates the process of repair

WHAT ARE THE MEDIATORS OF DEFENSE?

 Leukocytes
 Complement proteins
 Antibodies

SEQUENTIAL STEPS OF A TYPICAL INFLAMMATORY TRUE OR FALSE?

REACTION  Inflammation is protective (True)
1. The offending agent, which is located in  Inflammation can also become the cause of disease
extravascular tissues, is recognized by host cells and (True)
molecules.  Inflammation is terminated when the offending
2. Leukocytes and plasma proteins are recruited from agent is eliminated (True)
the circulation to the site where the offending agent
is located. WHAT HAPPENS AFTER INFLAMMATION?
3. The leukocytes and proteins are activated and work
together to destroy and eliminate the offending
substance.
4. The reaction is controlled and terminated.
5. The damaged tissue is repaired.
• After inflammation has achieved its goal of
eliminating the offending agents, it sets into motion
TWO TYPES OF INFLAMMATION
the process of tissue repair.
ACUTE
• The injured tissue is replaced through regeneration
• Onset: Fast (within minutes or hours)
of surviving cells and filling of residual defects with
• Duration: short (hours or a few days)
connective tissue (scarring).
• Main characteristics: exudation of fluid and plasma
proteins (edema)
CAUSES OF INFLAMMATION
• Infiltrates: mostly Neutrophils (PMNs)
1. Infections: bacterial, viral, fungal, parasitic and
• Tissue injury: mild and self-limited
microbial toxins
• Local/systemic signs: Prominent
2. Tissue necrosis:
 Ischemia (reduced blood flow, e.g.,
CHRONIC
myocardial infarction)
• Onset: Slow
 Trauma
• Duration: Longer
 Physical and chemical injury (e.g., thermal
• Main characteristics: tissue destruction
injury, as in burns or frostbite; irradiation;
• Infiltrates: monocyte/macrophages, lymphocytes
exposure to some environmental chemicals).
• Tissue injury: severe, progressive, with fibrosis
3. Foreign bodies (splinters, dirt, sutures)
• Local/systemic signs: Less
4. Immune reactions (also called hypersensitivity):
autoimmune and allergic diseases
CARDINAL SIGNS OF INFLAMMATION
STEPS OF INFLAMMATORY RESPONSE
1. Recognition of injurious agent
2. Recruitment of leukocytes
3. Removal of the agent
4. Regulation/control of the response
5. Resolution/Repair

Calor, Rubor, Tumor, Dolor, Functio Laesa

 2. Endothelial injury: resulting in endothelial cell
necrosis and detachment.
3. Transcytosis: increased transport of fluids and
proteins through the endothelial cell.

EXUDATE
 High protein content
 may appear as yellow, turbid, purulent
 contains cellular debris, WBC and RBC
 inflammatory edema
 due to inflammation and increased blood vessel
permeability
 high specific gravity
 seen in pus cells, Infections, Malignancies

TRANSUDATE
 low protein content (mostly albumin)
 appearance: clear, colorless
 few cells
 non-inflammatory edema
 due to increased hydrostatic pressure or decreased
colloid osmotic pressure
 low specific gravity
1. RECOGNITION OF INJURIOUS AGENT
 e.g., Congestive heart failure, Liver disease
• first step in inflammatory responses is the
recognition of microbes and necrotic cells by cellular
STASIS
receptors and circulating proteins.
• engorgement of small vessels jammed with slowly
1. Cellular receptors for microbes
moving red cells
• Phagocytes, dendritic cells, Toll-like receptors
• due to slower blood flow, concentration of red cells
recognize pathogen-associated molecular patterns
in small vessels, and increased viscosity of the blood
(PAMPs) in microbesproduction and expression of
• Microscopically seen as vascular congestion.
membrane proteins (cytokines, etc.)
Grossly: Localized redness (erythema)
2. Sensors of cell damage
• Cytosolic receptors recognize damage-associated
2 RECRUITMENT OF LEUKOCYTES
molecular patterns (DAMPs)  activates
• key function: eliminating the offending agent
inflammasome  production of interleukins etc.
• most important leukocytes in typical inflammatory
3. Circulating proteins
reactions: neutrophils and macrophages
• Complement system, collectins
(phagocytes)
• PMNs: fast recruited, rapid, transient
response
ACUTE INFLAMMATION
• Macrophages: slow-responders, long-lived,
prolonged response
ACUTE INFLAMMATION: MAJOR COMPONENTS
• The journey of leukocytes from the vessel lumen to
1) Vasodilation/dilation of small vessels: leading to an
the tissue is a multistep process that is mediated and
increase in blood flow
controlled by adhesion molecules and cytokines.
2) Increased permeability of the microvasculature
enables plasma proteins and leukocytes to leave the
EMIGRATION OF LEUKOCYTES
circulation
3) Emigration of the leukocytes accumulates in the site
of injury, and their activation attempts to eliminate
the offending agent

VASODILATION
• main mediator: histamine
• one of the earliest manifestations of acute
inflammation, and may be preceded by transient
vasoconstriction.
• Arterioles  capillary beds  increase in blood flow
(heat and redness)

INCREASED PERMEABILITY OF VASCULATURE (heat-swelling

• results in outpouring of protein-rich fluid (an
exudate) into the extravascular tissues.

• Mechanisms:
1. Retraction of endothelial cells: resulting in opening
of inter-endothelial spaces. (Most mechanism)
 4 REGULATION/CONTROL OF RESPONSE
Termination of the acute inflammatory response:
 Inflammation declines after the offending agents are
removed
 The mediators of inflammation are produced in rapid
bursts, only as long as the stimulus persists, have
short half-lives, and are degraded after their release.
o Neutrophils have short half-lives in tissues
and die by apoptosis within hours to a day or
two after leaving the blood.

MEDIATORS OF ACUTE INFLAMMATION

• Mediators may be produced locally at the site of
inflammation or may be derived from circulating
inactive precursors that are activated at the site of
inflammation.
 Cell-derived mediators in acute
inflammation: tissue macrophages, dendritic
cells, and mast cells. Also, platelets,
neutrophils, endothelial cells, and most
epithelia.
 Plasma-derived mediators: complement
proteins
• Mediators are produced only in response to various
molecules that stimulate inflammation.
• Most mediators are short-lived.
• One mediator can stimulate the release of other
mediators.
3 REMOVAL OF THE OFFENDING AGENT
• Phagocytosis: Three sequential steps: MEDIATORS OF ACUTE INFLAMMATION
1. Recognition and attachment of the particle
to be ingested by the leukocyte
2. Engulfment, with subsequent formation of a
phagocytic vacuole
3. Killing or degradation of the ingested
material
• The killing of microbes and the destruction of
ingested materials are accomplished by reactive
oxygen species (ROS), reactive nitrogen species, and
lysosomal enzymes
• Neutrophils can extrude their nuclear contents to
form extracellular nets that trap and destroy
microbes.

TRUE OR FALSE?
 The mechanisms that function to eliminate microbes
and dead cells also are capable of damaging normal
tissues.

LEUKOCYTE-MEDIATED TISSUE INJURY

In some circumstances, leukocytes that are meant to destroy
offending agents also damage normal tissues (pathologic
consequences of inflammation).
• Tissues at or near the site of infection suffer
collateral damage.
• In some infections that are difficult to eradicate, the
prolonged host response contributes more to the
pathology than does the microbe itself. (e.g., TB,
Hepatitis)
• In certain autoimmune diseases, where the
inflammatory response is inappropriately directed
against host tissues.
• In some allergic diseases and drug reactions, the host
“hyper-reacts” against usually harmless
environmental substances.

MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION
 Morphologic hallmarks of acute inflammatory
reactions are dilation of small blood vessels and
accumulation of leukocytes and fluid in the
extravascular tissue.
1. Serous Inflammation
2. Fibrinous Inflammation
3. Purulent (Suppurative) Inflammation
4. Ulcer
SEROUS INFLAMMATION
 marked by the exudation of cell-poor fluid into
spaces created by injury to surface epithelia or into
body cavities lined by the peritoneum, pleura, or
pericardium.
 serous fluid is not infected by destructive organisms
and does not contain large numbers of leukocytes
 e.g. blisters, effusion
  area of damage is converted to fibrous tissue
FIBRINOUS INFLAMMATION
 develops when the vascular leaks are large or there
is a local procoagulant stimulus.
 characteristic of inflammation in the lining of body
cavities, such as the meninges, pericardium, and
pleura.
 e.g. fibrinous pericarditis
  Hypersensitivity diseases
PURULENT INFLAMMATION
 characterized by pus, an exudate consisting of
neutrophils, the liquefied debris of necrotic cells, and
edema fluid.
 Abscess – localized collection of pus
 seen in bacterial infections that cause liquefaction
necrosis, e.g. Staph infections, brain abscess
ULCER
 local defect, or excavation, of the surface of an organ
or tissue that is produced by the sloughing
(shedding) of inflamed necrotic tissue
OUTCOMES OF ACUTE INFLAMMATION
COMPLETE RESOLUTION
 injury is limited or short-lived
 little tissue destruction from acute inflammation
 damage cells regenerate
 cellular debris and microbes are removed
SCARRING/ FIBROSIS
 If there is substantial tissue destruction
 tissues involved are incapable of regeneration
 exudation cannot be adequately cleared
CHRONIC INFLAMMATION
 when acute inflammatory response cannot be
resolved
CHRONIC INFLAMMATION
• response of prolonged duration (weeks or months)
• inflammation, tissue injury, and attempts at repair
coexist, in varying combinations
• may follow acute inflammation, or may begin
insidiously, without any signs of a preceding acute
reaction.
• Causes:
 Persistent infections
 Prolonged exposure to potentially toxic
agents, either exogenous or endogenous
 Other disease such as Alzheimer’s disease,
Metabolic syndrome, T2 diabetes
MORPHOLOGIC FEATURES IN CHRONIC INFLAMMATION
c
a. Infiltration with mononuclear cells, which include
macrophages, lymphocytes, and plasma cells
b. Tissue destruction
c. Attempts at healing
 Angiogenesis (proliferation of small blood
vessels)
 Fibrosis
CELLS AND MEDIATORS OF CHRONIC INFLAMMATION
• Macrophages: dominant cells in most chronic
inflammatory reactions
 life span of tissue macrophages is several
months or years.
 macrophages often become the dominant
cell population in inflammatory reactions
within 48 hours of onset.
 Kupfer cells (liver)
• Sinus histiocytes (spleen and LN)
• Microglia (CNS)
• Alveolar macrophages (Lungs)
PATHWAYS OF MACROPHAGE ACTIVATION
CELLS AND MEDIATORS OF CHRONIC INFLAMMATION
• Lymphocytes: often present in chronic inflammation
 granulomatous inflammation
o Lymphocytes and macrophages interact in a
bidirectional way, resulting in a cycle of
cellular reactions that fuel and sustain
chronic inflammation.
• Other cells:
o Eosinophils: abundant in immune reactions
mediated by IgE and in parasitic infections
o Mast cells: participate in both acute and
chronic inflammatory reaction; involved in
hypersensitivity reactions; release histamine
and prostaglandin
o Neutrophils: “acute on chronic”
inflammation; induced either by persistent
microbes or by cytokines and other
mediators produced by activated macro-
phages and T lymphocytes.
GRANULOMATOUS INFLAMMATION
• form of chronic inflammation characterized by
collections of activated macrophages, often with T
lymphocytes, and sometimes associated with central
necrosis.
o Epithelioid cells: activated macrophage
resembling epithelial cells
o Multinucleate giant cells: fusion of activated
macrophages
o Granuloma formation
• 2 types of granuloma:
o Immune granulomas
o Foreign body granulomas
• e.g. Tuberculosis, Sarcoidosis, Leprosy, Crohn’s
disease
Typical tuberculous granuloma showing an area of central
necrosis surrounded by multiple multinucleate giant cells,
epithelioid cells, and lymphocytes.
TISSUE REPAIR
• Repair of damaged tissues occurs by two types of
reactions:
1. Regeneration by proliferation of residual
(uninjured) cells and maturation of tissue
stem cells
2. Deposition of connective tissue to form a
scar
REPAIR BY REGENERATION
• Depends on the type of tissue and severity of injury
• Intrinsic proliferative capacity of tissues:
o Labile tissues: continuously dividing cells,
constant turnover of new cells as long as
stem cells are preserved
- hematopoietic cells, many surface
epithelium (oral cavity, vagina, and
cervix), cuboidal epithelia of
exocrine organs, columnar
epithelium of the GI tract, uterus,
and fallopian tubes; and transitional
epithelium of the urinary tract.
o Stable tissues: quiescent cells with minimal
proliferative activity
- parenchyma of liver, kidney and
pancreas
o Permanent tissues: terminally differentiated
and non-proliferative
- neurons, cardiac muscle cells
• Liver regeneration
o It is triggered by cytokines and growth
factors produced in response to loss of liver
mass and inflammation.
o In different situations, regeneration may
occur by proliferation of surviving
hepatocytes or repopulation from progenitor
cells.
REPAIR BY SCARRING
• if injured tissues are incapable of complete
restitution
• “patches” rather than restores tissue
STEPS IN SCAR FORMATION

• Granulation tissue: proliferation of fibroblasts and

new thin-walled, delicate capillaries in a loose
extracellular matrix, often with admixed
inflammatory cells, mainly macrophages
• Scar or fibrosis: composed of largely inactive,
spindle-shaped fibroblasts, dense collagen,
fragments of elastic tissue, and other ECM
components
• Angiogenesis: process of new blood vessel
development from existing vessels

HEALING OF SKIN WOUNDS

• Healing by primary intention
 Primary union
 Epithelial regeneration with minimal scarring
 Clean incision approximated by suture

• Healing by secondary intention

 Secondary union
 Larger wounds that heal by a combination of
regeneration and scarring
 Involves wound contraction because of
presence of myofibroblasts

ABNORMAL TISSUE REPAIR

• Defects in healing: chronic wounds
• Excessive scarring
 hypertrophic scar vs. keloid
 exuberant granulation
 contractures

Which picture shows Hypertrophic scar? Keloid?

Differentiate.