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PATHOLOGY
Chronic Inflammation
Chronic inflammation may occur:
• either as a sequel to acute inflammation
(acute inflammationchronic
inflammation), or
• as a primary immune response to a
foreign antigen (usually viral).
Inflammation
A dynamic contunium of change
Resolution (no scar)
Organization (exudatescar *)
Inciting
Stimulus
Acute
Inflammation
Abscess
Chronic-active
Inflammation
Chronic
Inflammation
Resolution with
scarring*
*The longer the stimulus
persists, the greater the
scarring will be.


Chronic inflammation is considered to be
inflammation of prolonged duration (weeks or
months) in which active inflammation, tissue
destruction, and attempts at healing are
proceeding simultaneously.
It may follow acute inflammation, as described
earlier, chronic inflammation frequently begins
insidiously, as a low-grade, flaming, often
asymptomatic response.
Etiology of Chronic Inflammation
 Persistent infections by certain
microorganisms
 Mycobacterium
 Treponema
pallidum
 certain fungi.
Prolonged exposure to potentially toxic
agents, either exogenous or
endogenous (silicosis)
 Autoimmune diseases

Chronic inflammation is characterized
by:



(1) infiltration with mononuclear cells, which
include macrophages, lymphocytes, and
plasma cells, a reflection of a persistent
reaction to injury,
(2) tissue destruction, largely induced by the
inflammatory cells,
(3) attempts at repair by connective tissue
replacement, namely proliferation of
fibroblasts, in particular, fibrosis.
FIBROSIS
There are four components to this
process:
1. Formation of new blood vessels
(angiogenesis)
2. Migration and proliferation of
fibroblasts
3. Deposition of extracellular matrix
4. Maturation and organization of the
fibrous tissue
Fibrosis after chronic bronchitis.
Scarring after chronic inflammation-Lung
Inflammation
Chronic Inflammation – Syphilis
Lymphocytic chronic inflammatory infiltrate in the wall
of the aorta in syphilitic aortitis.
Inflammation
Chronic Inflammation

Histologic features
cells – macrophages,
lymphocytes, and plasma cells
 Tissue destruction by ongoing inflammation,
 Mononuclear

thought to be due to cytokines produced locally by
the mononuclear cells
 Attempts
fibrosis.
at healing, including fibroblasts and
Inflammation
Chronic Inflammation

Monocyte/Macrophages
 They are components of the mononuclear phagocyte
system (MPS), previously known as the
reticuloendothelial system (RES).
• Key cell in chronic and granulomatous inflammation
• Reproduce locally, at the site of injury
• Produce numerous cytokines, which continue to
recruit additional cells, including more macrophages
• May present antigen to T-cells, producing specific
hypersensitivity reactions
The MPS consists of closely related
cells of bone marrow origin, including
blood monocytes, and tissue
macrophages.
 The latter are diffusely scattered in the
connective tissue or clustered in organs
such as the liver (Kupffer’s cells),
spleen and lymph nodes (sinus
histiocytes), and lungs (alveolar
macrophages).





Blood monocytes begin to emigrate early in acute
inflammation, and within 48 hours predominant cell
type.
Extravasation of monocytes is governed by the same
factors involved in neutrophil emigration, namely
adhesion molecules and chemical mediators with
chemotactic and activating properties.
When the monocyte reaches the extravascular tissue
it undergoes transformation into a larger phagocytic
cell, the macrophage.
In addition to performing phagocytosis, macrophages
have the potential of being “activated,” a process that
results in an increase in cell size, increased levels of
lysosomal enzymes, more active metabolism, and
greater ability to phagocytose and kill ingested
microbes.


Activation signals include cytokines (e.g.,
IFN-g) secreted by sensitized T lymphocytes,
bacterial endotoxins, other chemical
mediators, and ECM proteins like fibronectin.
Following activation, the macrophages
secrete a wide variety of biologically active
products that are important mediators of the
tissue destruction, vascular proliferation, and
fibrosis characteristic of chronic inflammation

In chronic inflammation macrophage accumulation
persists, mediated by different mechanisms, each
predominating in different types of reactions:
1. Continued recruitment of monocytes from the circulation, which
results from the steady expression of adhesion molecules and
chemotactic factors. (most important source for macrophages)
Chemotactic stimuli for monocytes C5a; cytokines of the IL-8
family (chemokines) produced by activated macrophages and
lymphocytes (MCP-1 for monocytes); certain growth factors
(PDGF and TGF-b); fragments from the break-down of collagen,
fibronectin and fibrinopeptides.
2. Local proliferation of macrophages after their emigration from
the bloodstream.
3. Immobilization of macrophages within the site of inflammation.
Indeed, certain cytokines (macrophage inhibitory factor) and
oxidized lipids can cause such immobilization

Lymphocytes: Lymphocytes are mobilized in
both antibody- and cell-mediated immune reactions
and also, for reasons unknown, in non-immune
mediated inflammation.


Lymphocytes of different types (T, B) or states (naive,
activated or memory T cell) use various adhesion
molecules (VLA-4/VCAM-1 and ICAM-1/ LFA-1
predominantly) and chemical mediators (largely
cytokines) to migrate into inflammatory sites.
Lymphocytes can be activated by contact with
antigen. Activated lymphocytes produce cytokines
(formerly called as: “lymphokines”), and one of these,
IFN-g is a major stimulator of monocytes and
macrophages.

Plasma cells: They produce antibody directed either
against persistent antigen in the inflammatory site or
against altered tissue components.

Eosinophils: They are characteristic of immune reactions
mediated by IgE and of parasitic infections.
Like neutrophils, they use adhesion molecules and
chemotactic agents (derived from mast cells, lymphocytes,
or macrophages) to exit the blood.
Eosinophils are phagocytic and undergo activation.
Their granules contain major basic protein (MBP), a highly
cationic protein that is toxic to parasites but also causes
lysis of mammalian epithelial cells. They may thus be of
benefit in parasitic infections but contribute to tissue
damage in immune reactions.



Plasma cells
Types of Chronic Inflammation
1. Non-granulomatous Chronic
Inflammation
a) Chronic viral infections
b) Chronic autoimmune diseases
c) Chronic chemical intoxications
d) Chronic nonviral infections
e) Allergic inflammation and metazoal
infections,
2. Granulomatous Chronic
Inflammation
Non-granulomatous
Chronic Inflammation



Characterized by the accumulation of sensitized
lymphocytes (specifically activated by antigen),
plasma cells, and macrophages in the injured
area.
These cells are scattered diffusely throughout
the tissue, however, and do not form
granulomas.
Scattered tissue necrosis and fibrosis are
common.
Classification of non-granulomatous
chronic inflammation:
a) Chronic viral infections
b) Chronic autoimmune diseases
c) Chronic chemical intoxications
d) Chronic nonviral infections
e) Allergic inflammation and metazoal
infections
a) Chronic viral infections:
 Persistent infection of parenchymal cells by viruses
 main components are a B cell response and a T cell
cytotoxic response.
 The affected tissue shows accumulation of
lymphocytes and plasma cells that produce cytotoxic
effects on the cell containing the viral antigen,
causing cell necrosis.
 This cytotoxic effect is mediated either by killer T
lymphocytes or by cytotoxic antibody acting with
complement.
 Ongoing parenchymal cell necrosis is associated with
repair characterized by fibroblast proliferation and
deposition of collagen.
b) Chronic autoimmune diseases:
 immune response mediated by cytotoxic
antibody and killer T cells occurs in several
autoimmune diseases.
 The antigen involved is a host cell molecule
that is perceived as foreign by the immune
system.
 The pathologic result is similar to the nongranulomatous chronic inflammation seen in
chronic viral infections, with cell necrosis,
fibrosis, and lymphocytic and plasma cell
infiltration of the tissue.
c) Chronic chemical intoxications:
 Persistent toxic substances such as alcohol
produce chronic inflammation, notably in the
pancreas and liver.
 The toxic substance is not antigenic, but by
causing cell necrosis it may result in
alteration of host molecules so that they
become antigenic and evoke an immune
response.
 The features of cell necrosis and repair by
fibrosis in such cases dominate the features
of the immune response.
 In many cases of alcoholic chronic
pancreatitis, the lymphocytic and plasma cell
infiltration is slight.
d) Chronic nonviral infections:
 specific type of non-granulomatous chronic inflammation is
seen with certain microorganisms;
 (i) survive and multiply in the cytoplasm of macrophages
after direct phagocytosis
 (ii) evoke a very ineffective T cell response.
 accumulation of large numbers of foamy macrophages in
the tissue. The macrophages are present diffusely in the
tissue without aggregating into granulomas.
 The ability of the macrophage to kill the organism is limited
because of the poor T cell response, permitting the
organisms to multiply in the cell.
 large numbers of organisms are present in the cytoplasm
of the macrophages. The main defense appears to be
direct phagocytosis by the macrophages. Variable
numbers of plasma cells and lymphocytes may be present.
 Accumulation of infected macrophages in the tissue
causes nodular thickening of the affected tissue, a clinical
feature that is typical of this type of chronic inflammation.
e) Allergic inflammation and metazoal infections:
 Eosinophils are present in acute hypersensitivity
reactions and accumulate in large numbers in tissues
subject to chronic or repeated allergic reactions.
 Eosinophils may have evolved as a defense against
infection with various metazoal parasites.
 Eosinophils respond chemotactically to complement
C5a and factors released by mast cells and in turn
release a variety of enzymes and basic proteins.
 Eosinophils bear high-affinity Fc receptors for IgA and
low-affinity receptors for IgE.
 Eosinophils are derived from a bone marrow precursor
in common with mast cells and basophils,
 play a role in modulating histamine release or histamine
catabolism.
 Mast cells and basophils have high-affinity Fc receptors
for IgE.
Chronic Granulomatous
Inflammation

This is a distinctive pattern of chronic
inflammatory reaction in which the
predominant cell type is an activated
macrophage with a modified epithelial-like
appearance (epithelioid cells) .
Granuloma: aggregation of macrophages
that are transformed into epitheloid cells
surrounded by a collar of mononuclear
leukocytes, principally lymphocytes and
occasionally plasma cells .
 The cells in a granuloma are:

 macrophages
and/or histiocytes (principal),
 lymphocytes (principal),
 fibroblasts,
 giant cells.
•
•
•
A cellular mechanism for dealing with
indigestible substances
The principal cells involved in
granulomatous inflammation are
macrophages and lymphocytes
Epithelioid histiocytes are the hallmark
of granulomatous inflammation
A granuloma is an abnormal structure built
from at least two activated macrophages
adhering to one another.
 Such macrophages are called epithelioid
cells.
 Epithelioid cells have

 abundant
pink cytoplasm,
 indistinct borders,
 elongated, euchromatin-rich, reticulated
nuclei.

There are two types of granulomas:
 Foreign
body granulomas incited by
relatively inert foreign bodies.
 Immune granulomas Two factors
determine the formation of immune
granulomas:
The presence of indigestible particles of
organisms (e.g., the tubercle bacillus)
 T cell-mediated immunity to the inciting agent.

Granulomas with suppuration


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With pus in their centers,
stellate microabscesses.
Bacterial diseases with a propensity to involve
lymph nodes:
 lymphogranuloma
 cat
venereum,
scratch fever,
 brucellosis,
 plague,
 tularemia,
 glanders-melioidosis,
 listeria,
 camphylobacter,
 yersinia infection.
Granulomas with caseation necrosis

Typical of certain fungal and mycobacterial
infections:
 histoplasmosis,
 blastomycosis,
 coccidioidomycosis,
 tuberculosis,
 leprosy,
 atypical
mycobacteria.

Granulomas can contain syncytial giant cells
(polykaryons):
Langhans giant cells (in the necrotizing
granulomas: tuberculosis)
 nuclei

Foreign body giant cells (in the non-necrotizing
granulomas: foreign body granuloma)
 with

arranged in a horseshoe around the edge
nuclei dispersed more or less evenly
Asteroid bodies (in the non-necrotizing
granulomas: foreign body granuloma,
sarcoidosis)
 altered

cytoskeletal components in the shapes of stars
Schaumann bodies (in the non-necrotizing
granulomas: sarcoidosis)
 laminated
calcified nuggets; "conchoid bodies“.
Granulomatous Inflammation
•
•
•
Immunity may be judged by its effect on the
invading organism, but an adverse effect on
the host is generally termed hypersensitivity.
Destruction of tissue is primarily via the action
of killer T cells (CD8+), directed by
macrophages.
Products of activated T lymphocytes are
important in transforming macrophages into
epitheloid cells and multinucleated giant
cells.
Granulomatous diseases***

Mycobacterial
infections:

 tuberculosis
 leprosy

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Fungal diseases
Sarcoidosis
Lymphogranuloma
inguinale
Foreign body
granuloma

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Chronic
granulomatous
disease
Crohn’s disease
Leishmaniasis cutis
Berylliosis
Brucellosis
Syphilis
Inflammation
Granulomatous Inflammation
Fibroblasts
Lymphocytes
Macrophages, Epithelioid
Cells, and Giant Cells
Caseous Necrosis
Caseating Granuloma
Non-caseating
Granuloma
Langhans giant cells
Asteroid bodies
Schaumann bodies
Inflammation
Granulomatous Inflammation


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Tuberculous lung, showing
massive destruction by
granulomatous inflammation.
This type of response is simply
the best the body can do,
since the inciting organism
cannot be removed.
Mycobacteria may live for
years, perhaps even a lifetime,
within granulomas.
FUNCTION & RESULT OF CHRONIC
INFLAMMATION
 Chronic inflammation serves to contain and
remove an injurious agent that is not easily
eradicated by the body. Containment and
destruction of the agent are largely
dependent on immunologic reactivity,
whether these are achieved by
 (1) direct killing by activated lymphocytes,
 (2) interaction with antibodies produced by
plasma cells, or
 (3) activation of macrophages by
lymphokines produced by T lymphocytes.



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Persistent tissue destruction, with damage to both
parenchymal cells and stromal framework, is a
hallmark of chronic inflammation.
As a consequence, repair cannot be accomplished
solely by regeneration of parenchymal cells, even in
organs whose cells are able to regenerate.
Attempts at repairing tissue damage then occur by
replacement of non-regenerated parenchymal cells
by connective tissue, which in time produces fibrosis
and scarring.
The process is granulation tissue and is
fundamentally similar to that occurring in the healing
of wounds, but because the injury is persistent, and
the inflammatory reaction ebbs and flows, the events
are less predictable.
Granulation Tissue
Formation of new blood vessels
(angiogenesis)
 Migration and proliferation of fibroblasts
 Deposition of extracellular matrix
 Maturation and organization of the fibrous
tissue, also known as remodeling.

Granulation Tissue
The process of repair begins early in
inflammation.
 Sometimes as early as 24 hours after
injury, fibroblasts and vascular endothelial
cells being proliferating to form (by 3 to 5
days) the specialized type of tissue
(granulation tissue) that is the hallmark
of healing.


The term granulation tissue derives from
its pink, soft, granular appearance on
the surface of wounds, but it is the
histologic features that are
characteristic:
 The

proliferation of new small blood vessels
New vessels originate by budding or sprouting
of pre-existing vessels, a process called
angiogenesis or neovascularization.
 The
proliferation of fibroblasts.


Several factors can induce angiogenesis,
notably basic fibroblast growth factor (FGF)
and vascular endothelial growth factor (VEGF
or vascular permeability factor [VPF ]).
Migration of fibroblasts to the site of injury
and their subsequent proliferation are
undoubtedly triggered by growth factors,
 such
as PDGF, EGF, FGF, and TGF-b, and the
fibrogenic cytokines, derived in part from
inflammatory macrophages.

Some of these growth factors also stimulate
synthesis of collagen and other connective
tissue molecules.
These new vessels have leaky
interendothelial junctions, allowing the
passage of proteins and red cells into
the extravascular space.
 Thus, new granulation tissue is often
edematous.

Characteristics of acute and chronic
inflammation
ACUTE
CHRONIC
Vascular changes
Vasodilation and
Increased permeability
Minimal
Cellular infiltrates
Polymorphs
Mononuclear
Stromal changes
Minimal separation
due
to edema
Cellular proliferation
Fibrosis
Inflammation
Acute vs. Chronic Inflammation

Acute inflammation
 Accumulation
of fluid and plasma components
in the affected tissue
 Intravascular stimulation of platelets
 Presence of polymorphonuclear leukocytes
(PMNs)

Chronic inflammation
 Lymphocytes,
macrophages
plasma cells, and
MIXED ACUTE & CHRONIC
INFLAMMATION

Because acute and chronic inflammation
represent different types of host response
to injury, features of both types of
inflammation may coexist in certain
circumstances, as in chronic suppurative
inflammation and recurring acute
inflammation.
Chronic Suppurative
Inflammation

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
The surrounding viable tissue responds with a
longstanding inflammatory process in which areas of
suppuration (liquefied necrotic tissue and neutrophils)
alternate with areas of chronic inflammation
(lymphocytes, plasma cells, macrophages) and
fibrosis.
Such a pattern occurs in chronic suppurative
osteomyelitis and pyelonephritis.
If the area of suppuration localizes to an abscess that
remains over a long period, a fibrous wall of
increasing thickness forms.
The difference between an acute and a chronic
abscess lies in the thickness of the fibrous wall; both
forms are filled with pus.
"chronic
abscess" with
elements of
both acute and
chronic
inflammation.
Seen here in
the right middle
lung lobe is just
such a chronic
abscess.
Recurrent Acute Inflammation



Repeated attacks of acute inflammation may occur if
there is a predisposing cause, eg, in the gallbladder
when there are gallstones.
Each attack of acute inflammation is followed by
incomplete resolution that leads to a progressively
increasing number of chronic inflammatory cells and
fibrosis.
Depending on the time of examination, the picture may
be mainly that of chronic inflammation or of acute
superimposed on chronic inflammation. The terms
subacute inflammation and acute-on-chronic
inflammation are also used to denote this pattern.


mixed
inflammation
is typical of
repeated or
recurrent
inflammation
a diagnosis
of "acute
and chronic
cholecystitis"
or "acute
and chronic
cervicitis"
can be
made.
Morphologic Patterns

The severity of the reaction, its specific cause, and
the particular tissue and site involved all introduce
morphologic variations in the basic patterns of acute
and chronic inflammation:
1.
Serous inflammation
Fibrinous inflammation
Suppurative or Purulent inflammation
Necrotizing inflammation
Hemorragic inflammation
2.
3.
4.
5.
1. Serous Inflammation


Serous inflammation is marked by the
outpouring of a thin fluid that, depending on
the size of injury, is derived from either the
blood serum or the secretions of mesothelial
cells lining the peritoneal, pleural, and
pericardial cavities (called effusion).
The skin blister resulting from a burn or viral
infection represents a large accumulation of
serous fluid, either within or immediately
beneath the epidermis of the skin.
Types of Serous Inflammation
Vesicle (blister): an elevation (<1 cm) of
the epidermis containing watery liquid
(herpes labialis).
 Bulla (large blister): an elevation (>1 cm)
of the epidermis containing watery liquid
(bullous pemphigoid, sunburn).
 Catarrh: inflammation of a mucous
membrane (especially affecting the nose
and air passages- rhinitis catarrhalis)

2. Fibrinous Inflammation




With more severe injuries and the resulting
greater vascular permeability, larger molecules
such as fibrin pass the vascular barrier.
A fibrinous exudate develops when the vascular
leaks are large enough or there is a procoagulant
stimulus in the interstitium (e.g., cancer cells).
A fibrinous exudate is characteristic of
inflammation in body cavities, such as the
pericardium and pleura.
Histologically, fibrin appears as an eosinophilic
meshwork of threads, or sometimes as an
amorphous coagulum.
Fibrinous exudates may be removed by
fibrinolysis, and other debris by
macrophages (resolution).
 But when the fibrin is not removed it
may stimulate the ingrowth of fibroblasts
and blood vessels and thus lead to
scarring.

 Conversion
of the fibrinous exudate to scar
tissue (organization) within the pericardial
sac will lead either to opaque fibrous
thickening of the pericardium and
epicardium in the area of exudation or,
more often, to the development of fibrous
strands that bridge the pericardial space.
3. Suppurative or Purulent
Inflammation
This form of inflammation is characterized
by the production of large amounts of pus
or purulent exudate consisting of
neutrophils, necrotic cells, and edema fluid.
 Certain organisms (e.g., staphylococci)
produce this localized suppuration and are
therefore referred to as pyogenic (pusproducing) bacteria.





Abscess: focal localized collections of purulent
inflammatory tissue caused by suppuration buried in
a tissue, an organ, or a confined space (fruncle,
dental abscess)
Phlegmon: a purulent inflammation and infiltration
of connective tissue without collection (acute
appendicitis)
Pustule: a small circumscribed elevation of the skin
containing pus and having an inflamed base
(subcorneal pustular dermatosis)
Empyema: the presence of pus in a body cavity (as
the pleural cavity; called also pyothorax).




Abscesses are produced by deep seeding of
pyogenic bacteria into a tissue.
An abscess has a central region that appears
as a mass of necrotic white cells and tissue
cells.
There is usually a zone of preserved
neutrophils about this necrotic focus, and
outside this region vascular dilatation and
parenchymal and fibroblastic proliferation
occur, indicating the beginning of repair
(pyogenic membrane).
In time, the abscess may become walled off
by connective tissue that limits further spread.
4. Necrotizing inflammation


An ulcer is a local defect, or excavation, of the
surface of an organ or tissue that is produced by
the sloughing (shedding) of inflammatory necrotic
tissue.
Ulceration can occur only when an inflammatory
necrotic area exists on or near the surface. It is
most commonly encountered in
 (1)
inflammatory necrosis of the mucosa of the mouth,
stomach, intestines, or genitourinary tract, and
 (2) subcutaneous inflammations of the lower extremities
in older persons and diabetics who have circulatory
disturbances that predispose to extensive necrosis.
Ulcerations are best exemplified by the
peptic ulcer of the stomach or
duodenum.
 During the acute stage, there is intense
polymorphonuclear infiltration and
vascular dilatation in the margins of the
defect.
 With chronicity, the margins and base of
the ulcer develop fibroblastic
proliferation, scarring, and the
accumulation of lymphocytes,
macrophages, and plasma cells.

A Cavern is a hollow defect within a
solid organ, which is produced by the
sloughing of inflammatory necrotic
tissue.
 It is most commonly encountered in
Cavitaty tuberculosis due to the Caseous
necrosis.

Pus is either an exudate or an area of
liquefaction necrosis containing
neutrophilic leukocytes and necrotic debris.
 The preferred adjective to describe things
with lots of pus is purulent.
 To produce pus is to suppurate.
 Pus which literally fills an important body
cavity is called an empyema.


Color of pus:
 Pus
always has a yellow-green tinge because of
myeloperoxidase.
 Classic yellow pus (as in a staphylococcal boil) also
includes some lipid from necrotic tissue.
 Pseudomonas bacteria make a dye which imparts a
blue-green fluorescence to pus.
Inflammation
Systemic Manifestations of Inflammation
•
Fever - clinical hallmark of inflammation
•
•
•
•
Endogenous pyrogens: IL-1 and TNF-a
Leukocytosis - may be neutrophils,
eosinophils, or lymphocytes
Leukopenia - rare
Acute Phase Reactants - non-specific
elevation of many serum proteins - will
markedly increase the “red-cells
sedimentation rate (ESR)”
Leukocytosis and Leukopenia
 Mediators  increased production and
early release of neutrophils from the bone
marrow  Increased neutrophils in the
blood stream  Leukocytosis,
 the
presence of young neutrophils is called a
left shift.

Bone marrow inhibition  Leukopenia
 viral
infections,
 unusual bacterial infections (typhoid,
rickettsial disease).
Inflammation
Systemic Manifestations of Inflammation
•
Shock – most common in Gram-negative
septicemia (bacteria in the bloodstream),
although it can occur with Gram-positive
bacteremia
•
•
Lipopolysaccharide (LPS or endotoxin) of
Gram-negatives can produce symptoms of
shock when injected into animals
TNF-a can produce a similar syndrome.
Complications and sequelae

Acute inflammation
 Serous


inflammation
Catarrh (asphyxia, diarrhea)
Perifocal edema (brain)
 Suppurative/purulent
inflammation




Pyemia/septicemia
Fistulization
Empyema
Pressure (brain)
 Ulcer



Perforation (stomach, bowel)
Bleeding (stomach, bowel)
Stenosis (stomach, bowel).

Chronic
inflammation
 Scar
and Keloid
 Stenosis (heart
valves, GI, urinary,
ect.)
 Failure (heart valves)
 Obstruction (urinary,
GI, biliary, respiratory,
ect.)
 Adhesion (periton,
pleura)
 Amyloidosis (kidney,
liver, adrenal, spleen).