Acute and Chronic Inflammation

Dr. Omar Emad Ibrahim

PhD in Pathology
Senior Lecturer in Pathology / Histopathology
Consultant Histopathologist
Centre of Preclinical Sciences Studies
Faculty of Dentistry
Universiti Teknology MARA ( UiTM)
Overview of Inflammation

• Why is inflammation essential to humans (organisms)?

• To get rid of damaged or necrotic tissues and foreign invaders, such as
microbes
• How inflammation is fundamental to humans (organisms)?
• This is fundamentally a protective response, designed to rid the
organism of both the initial cause of cell injury (e.g., microbes, toxins)
and the consequences of such injury (e.g., necrotic cells and tissues).
Without inflammation, what can happen to
humans (organisms)?
• Infections would go unchecked
• Wounds would never heal
• Injured tissues might remain permanent festering sores
How inflammation is important in the practice
of medicine ?
• In the practice of medicine the importance of inflammation is that it
can sometimes be inappropriately triggered or poorly controlled
• Is thus the cause of tissue injury in many disorders
By Definition
• Inflammation is a complex reaction in living tissues that consists
mainly of responses of blood vessels and leukocytes.
• The inflammatory response coordinates the reactions of vessels,
leukocytes, and plasma proteins to achieve this goal.
What factors can trigger the vascular & cellular
reaction of inflammation?
• The vascular and cellular reactions of inflammation are triggered by
soluble factors that are produced by various cells or derived from
plasma proteins and are generated or activated in response to the
inflammatory stimulus.
• Microbes, necrotic cells (whatever the cause of cell death) and even
hypoxia can trigger the elaboration of inflammatory mediators, and
thus elicit inflammation
How inflammation will become harmful?
• Inflammation may be harmful in some situations.
• Mechanisms designed to destroy foreign invaders and necrotic
tissues have an intrinsic ability to injure normal tissues.
• When inflammation is inappropriately directed against self tissues or
is not adequately controlled, it becomes the cause of injury and
disease.
Do Inflammation contribute to a variety of
diseases?
• YES, Inflammation may contribute to a variety of diseases that are not
thought to be primarily due to abnormal host responses.
• For instance, chronic inflammation may play a role in:-
• atherosclerosis
• type 2 diabetes
• degenerative disorders like Alzheimer disease,
• and cancer.
• In recognition of the wide-ranging harmful consequences of
inflammation, the lay press has rather melodramatically referred to it
as “the silent killer.”
In clinical medicine, great attention is given to
the damaging consequences of inflammation.
• Inflammatory reactions underlie common chronic diseases, such as:-
1. rheumatoid arthritis
2. Atherosclerosis
3. lung fibrosis
4. life-threatening hypersensitivity reactions to insect bites, drugs, and
toxins.
For this reason our pharmacies abound with anti-inflammatory drugs
Causes of acute inflammation

• The principal causes of acute inflammation are:

• Microbial infections e.g. (bacterial, viral, fungal, parasitic) and
microbial toxins are among the most common and medically
important causes of inflammation,
• Tissue necrosis, e.g. ischaemic infarction.
• Physical agents, e.g. trauma, ionising radiation, heat, cold
• Chemicals, e.g. corrosives, acids, alkalis, reducing agents
• Immune reactions (also called hypersensitivity reactions), e.g.
parasites, tubercle bacilli
What are the three major components of
acute inflammation?
1. Alterations in vascular caliber that lead to an increase in blood flow
2. Structural changes in the microvasculature that permit plasma
proteins and leukocytes to leave the circulation
3. Emigration of the leukocytes from the microcirculation, their
accumulation in the focus of injury, and their activation to eliminate
the offending agent
REACTIONS OF BLOOD VESSELS IN ACUTE
INFLAMMATION
REACTIONS OF BLOOD VESSELS IN ACUTE
INFLAMMATION
• Exudate is an extravascular fluid that has a high protein
concentration, contains cellular debris, and has a high specific gravity.
Its presence is inflammatory reaction.
• Transudate is a fluid with low protein content (most of which is
albumin), little or no cellular material, and low specific gravity. It is an
ultrafiltrate of blood plasma.
What cause heat and redness (erythema) at
the site of inflammation?
• Vasodilation is one of the earliest manifestations of acute
inflammation
• sometimes it follows a transient constriction of arterioles, lasting a
few seconds.
• The result is increased blood flow, which is the cause of heat and
redness (erythema) at the site of inflammation.
• Vasodilation is induced by the action of several mediators, notably
histamine and nitric oxide (NO), on vascular smooth muscle.
REACTIONS OF LEUKOCYTES IN INFLAMMATION

• The most important leukocytes in typical inflammatory reactions are

the ones capable of phagocytosis, namely neutrophils and
macrophages
• These leukocytes ingest and kill bacteria and other microbes, and
eliminate necrotic tissue and foreign substances
• Leukocytes also produce growth factors that aid in repair
• In most forms of acute inflammation neutrophils predominate in the
inflammatory infiltrate during the first 6 to 24 hours
Neutrophils in tissue
REACTIONS OF LEUKOCYTES IN INFLAMMATION

• In certain bacterial infections the cellular infiltrate is dominated by

continuously recruited neutrophils for several days
• In viral infections, lymphocytes may be the first cells to arrive
• In some hypersensitivity reactions, eosinophils may be the main cell
type
Clinical Examples of Leukocyte-Induced Injury
The cardinal signs of acute inflammation
1. Rubor (redness)
2. Tumor (swelling)
3. Calor (heat)
4. Dolor (pain)
5. Loss of function (functio laesa)
Redness (rubor)

• An acutely inflamed tissue appears red, for example skin affected by

sunburn, cellulitis due to bacterial infection or acute conjunctivitis.
This is due to dilatation of small blood vessels within the damaged
area
Heat (calor)

• Increase in temperature is seen only in peripheral parts of the body,

such as the skin.
• It is due to increased blood flow (hyperaemia) through the region,
resulting in vascular dilatation and the delivery of warm blood to the
area.
Swelling (tumor)

• Swelling results from oedema

• The accumulation of fluid in the extravascular space as part of the
fluid exudate
Pain (dolor)
• For the patient, pain is one of the best-known features of acute
inflammation.
• It results partly from the stretching and distortion of tissues due to
inflammatory oedema and, in particular, from pus under pressure in
an abscess cavity.
• Some of the chemical mediators of acute inflammation, including
bradykinin, the prostaglandins and serotonin, are known to induce
pain.
Loss of function (functio laesa)
• Loss of function, a well-known consequence of inflammation
• was added by Virchow (1821–1902) to the list of features drawn up
by Celsus.
• Movement of an inflamed area is consciously and reflexly inhibited by
pain, while severe swelling may physically immobilise the tissues.
Outcomes of Acute Inflammation

• Complete resolution
• Healing by connective tissue replacement (fibrosis)
• Progression of the response to chronic inflammation
Morphologic Patterns of Acute Inflammation
• The cardinal signs of acute inflammation are modified according to the:-
A. tissue involved
B. the type of agent provoking the inflammation

 Several descriptive terms are used for the appearances, including:-

1. Serous inflammation
2. Fibrinous inflammation
2. Suppurative (purulent) inflammation
3. Membranous inflammation
4. Pseudomembranous inflammation
5. Necrotising (gangrenous) inflammation
Serous inflammation
• Is marked by the outpouring of a thin fluid that may be derived from
the plasma or from the secretions of mesothelial cells lining the
peritoneal, pleural, and pericardial cavities.
• Accumulation of fluid in these cavities is called an effusion.
• The skin blister resulting from a burn or viral infection represents a
large accumulation of serous fluid.
Fibrinous inflammation

• With greater increase in vascular permeability, large molecules such

as fibrinogen pass the vascular barrier
• Fibrin is formed and deposited in the extracellular space
• A fibrinous exudate develops when the vascular leaks are large or
there is a local procoagulant stimulus (e.g., cancer cells)
• A fibrinous exudate is characteristic of inflammation in the lining of
body cavities, such as the meninges, pericardium and pleura.
Fibrinous inflammation

Fibrinous pericarditis. A, Deposits of fibrin on the

pericardium
Suppurative or purulent inflammation; abscess

• Is characterized by the production of large amounts of pus or

purulent exudate consisting of :-
1. Neutrophils
2. liquefactive necrosis
3. oedema fluid
 Certain bacteria (e.g., staphylococci) produce this localized
suppuration and are therefore referred to as pyogenic (pus-
producing) bacteria
Suppurative or purulent inflammation; abscess

• Abscesses : are localized collections of purulent inflammatory

tissue caused by suppuration buried in a tissue, an organ, or a
confined space.
• They are produced by deep seeding of pyogenic bacteria into a tissue
• Once pus begins to accumulate in a tissue, it becomes surrounded by
a ‘pyogenic membrane’ consisting of sprouting (new buds) capillaries,
neutrophils and occasional fibroblasts
• Such a collection of pus is called an abscess
• Bacteria within the abscess cavity are relatively inaccessible to
antibodies and to antibiotic drugs
Antibioma is a chronic abscess formed because of incomplete
treatment of an infection by using antibiotics without incision and
drainage
Abscesses
Ulcers

• Is a local defect, or excavation, of the surface of an organ or tissue

that is produced by the sloughing (shedding) of inflamed necrotic
tissue
• Ulceration can occur only when tissue necrosis and resultant (a force)
inflammation exist
• It is most commonly encountered in:-
1. The mucosa of the mouth, stomach, intestines, or genitourinary tract
2. The skin and subcutaneous tissue of the lower extremities in older
persons who have circulatory disturbances that predispose to extensive
ischemic necrosis.
Ulcers
 SYSTEMIC EFFECTS
OF INFLAMMATION
• Inflammation, even if localized, is associated with cytokine
induced systemic reactions.

• That are collectively called the acute-phase response.

 SYSTEMIC EFFECTS
OF INFLAMMATION
• Anyone who has suffered through a severe bout of a viral illness
(e.g., influenza) has experienced the systemic manifestations of
acute inflammation.

• These changes are reactions to cytokines whose production is

stimulated by bacterial products and by other inflammatory
stimuli.

• The cytokines TNF, IL-1, and IL-6 are important mediators of the
acute-phase reaction; other cytokines, notably interferons, also
contribute.
Fever
Fever
Fever
• Characterized by an elevation of body temperature, usually by 1°C to
4°C.
• One of the most prominent manifestations of the acute-phase
response, especially when inflammation is associated with infection.
• Substances that induce fever are called pyrogens and include
bacterial products (exogenous pyrogens, e.g., LPS).
• Cytokines principally IL-1 and TNF (called endogenous pyrogens).
• Exogenous pyrogens act by stimulating immune cells to release IL-1
and TNF
• Which upregulate cyclooxygenases, the enzymes that synthesize
prostaglandins
Fever
• Among the cells that respond to IL-1 and TNF are
1. vascular cells of the hypothalamus
2. 2. perivascular cells of the hypothalamus.

• Prostaglandins released by these cells, especially PGE ,

2

stimulate the production of neurotransmitters by the

hypothalamus.
• That reset the body’s steady-state temperature to a higher level
by reducing heat loss (via vasoconstriction).
Fever
• Increasing heat generation (through effects on brown fat and
skeletal muscle).
• NSAIDs, including aspirin, reduce fever by inhibiting
prostaglandin synthesis.
• An elevated body temperature has been shown to help
amphibians ward off microbial infections.
• It is assumed that fever is a protective host response in
mammals as well.
Pathophysiology of fever

• https://www.youtube.com/watch?v=R1b33YZ3jso
PATHOGENESIS OF FEVER
• PYROGENS
• The term pyrogen (Greek pyro, “fire”) is used to describe any
substance that causes fever.
• Exogenous pyrogens are derived from outside the patient
• most are microbial products, microbial toxins, or whole
microorganisms (including viruses).
• PYROGENIC CYTOKINES
• Cytokines are small proteins (molecular mass, 10,000–20,000
Da) that regulate immune, inflammatory, and hematopoietic
processes
• Chronology of
events required
for the induction
of fever. AMP,
• adenosine 5-
monophosphate
; IFN, interferon;
IL, interleukin;
PGE ,2

prostaglandin
• E ; TNF, tumor
2

necrosis factor.
Acute-phase Proteins

• Elevated levels of acute-phase proteins, which are plasma

• proteins, mostly synthesized in the liver,
• whose plasma concentrations may increase several hundred–
fold as part of the response to inflammatory stimuli.
• Three of the best known of these proteins are
1. C-reactive protein (CRP)
2. Fibrinogen
3. Serum amyloid A (SAA) protein
Acute-phase Proteins

• Synthesis of these molecules in hepatocytes is stimulated

• by cytokines:

1. Especially IL-6 (for CRP and fibrinogen)

2. IL-1 or TNF (for SAA)
Acute-phase Proteins

• Many acute-phase proteins, such as CRP and SAA, bind to

microbial cell walls.
• They may act as opsonins and fix complement.
• They also bind chromatin, possibly aiding in clearing necrotic
cell nuclei.
Systemic Effects of Inflammation
Acute-phase Proteins
• Fibrinogen binds to red cells and causes them to form stacks
(rouleaux) that sediment more rapidly at unit gravity than do
individual red cells.
• This is the basis for measuring the erythrocyte sedimentation rate
(ESR) as a simple test for the systemic inflammatory response, caused
by any stimulus
The normal range is 0-22 mm/hr
for men and 0-29 mm/hr for
women.
Acute-phase Proteins

• Acute-phase proteins have beneficial effects during acute

inflammation.
• Prolonged production of these proteins (especially SAA) in
states of chronic inflammation causes secondary amyloidosis.
• Elevated serum levels of CRP have been proposed as a marker
for increased risk of myocardial infarction in patients with
coronary artery disease.
• It is postulated that inflammation involving atherosclerotic
plaques in the coronary arteries may predispose to thrombosis
and subsequent infarction.
Acute-phase Proteins

• Two other liver proteins that are released in increased amounts as

part of the acute phase response often lead to altered blood counts:
1. Hepcidin is a small protein that reduces the availability of iron to
erythroid progenitors in the bone marrow; over time, this effect may
lead to the anaemia of chronic inflammation.

2. Thrombopoietin, the major growth factor for megakaryocytes

(platelet precursors) in the bone marrow, is also upregulated and as a
result systemic inflammation may be associated with an elevated
platelet count (thrombocytosis).
Leukocytosis
• The leukocyte count usually climbs to 15,000 or 20,000 cells/
mL.
• sometimes it may reach extraordinarily high levels of 40,000 to
100,000 cells/mL.
• These extreme elevations are sometimes called leukemoid
reactions
• because they are similar to the white cell counts observed in
leukemia,from which they must be distinguished.
Leukocytosis
• Is a common feature of inflammatory reactions, especially those
induced by bacterial infections.
• The leucocytosis occurs initially because of accelerated
release of granulocytes from the bone marrow
• caused by cytokines, including (TNF and IL-1)
• therefore associated with a rise in the number of both mature
and immature neutrophils in the blood, referred to as a shift to
the left.
Leukocytosis
• Most bacterial infections induce an increase in the blood
neutrophil count, called neutrophilia.
Leukocytosis / Neutrophilia
Leukocytosis
• Viral infections, such as infectious mononucleosis, mumps,
and German measles, cause an absolute increase in the
number of lymphocytes (lymphocytosis).
Leukocytosis / Lymphocytosis
Leukocytosis
• In some allergies and helminth infestations, there is an
increase in the absolute number of eosinophils, creating
eosinophilia.
Leukocytosis / Eosinophilia
Leukopenia
• Certain infections typhoid fever
• Infections caused by some viruses, rickettsiae, and certain
protozoa)
• are associated with a decreased number of circulating white
cells (leukopenia)
• In part because of sequestration of activated leukocytes in
vascular spaces and tissues.
Other Manifestations of the Acute-
phase Response
• Increased pulse and blood pressure
• Decreased sweating, mainly because of redirection of blood
flow from cutaneous to deep vascular beds, to minimize heat
loss through the skin
• Rigors (shivering), chills (search for warmth)
• Anorexia, somnolence, and malaise
• Probably because of the actions of cytokines on brain cells.
Other Manifestations of the Acute-
phase Response
Other Manifestations of the Acute-
phase Response
• In severe bacterial infections (sepsis), the large amounts of bacteria and their
products in the blood stimulate the production of enormous quantities of several
cytokines:
• Notably TNF and IL-1.
• High blood levels of cytokines cause various clinical manifestations such as:
• Disseminated intravascular coagulation
• hypotensive shock
• Metabolic disturbances, including insulin resistance and hyperglycemia.

• This clinical triad is known as septic shock and is one form of a severe, often
fatal disorder referred to as systemic inflammatory response syndrome
• it is discussed in more detail in Shock Chapter 4.
 KEY CONCEPTS
• SYSTEMIC EFFECTS OF INFLAMMATION
• Fever: cytokines (TNF, IL-1) stimulate production of prostaglandins in
hypothalamus.

• Production of acute-phase proteins: C-reactive protein, others; synthesis

stimulated by cytokines (IL-6, others) acting on liver cells.

• Leukocytosis: cytokines (CSFs) stimulate production of leukocytes from

precursors in the bone marrow.

• In some severe infections, septic shock: fall in blood pressure, disseminated

intravascular coagulation, metabolic abnormalities; induced by high levels of TNF
and other cytokines.
Four Your Info…..
• Bacteraemia is the presence of bacteria in the blood.

• Viraemia is the presence of viruses in the blood.

• Fungaemia is the presence of fungi or yeasts in the blood.

• Parasitaemia is the presence of parasites in the blood.

 Consequences of Defective or
Excessive Inflammation
• To summarize the clinical and pathologic consequences of too much or too
little inflammation:-
1. Defective inflammation
 typically results in increased susceptibility to infections
associated with delayed wound healing

2. Excessive inflammation
 is the basis of many types of human disease
Allergies
autoimmune diseases
Chronic Inflammation

• Chronic inflammation is inflammation of prolonged duration (weeks

or months) in which inflammation, tissue injury, and attempts at
repair coexist
• Rheumatoid arthritis, atherosclerosis, tuberculosis, and pulmonary
fibrosis and purely degenerative, such as Alzheimer disease
• It has also been implicated in the progression of cancer ???
Causes of Chronic Inflammation

• Persistent infections by microorganisms that are difficult to

eradicate, such as mycobacteria, and certain viruses, fungi, and
parasites
• Immune-mediated inflammatory examples of such diseases are
rheumatoid arthritis and multiple sclerosis
• Prolonged exposure to potentially toxic agents, either exogenous or
endogenous. Atherosclerosis by endogenous toxic plasma lipid
components
 Granulomatous Inflammation
• Granulomatous inflammation is a distinctive pattern of
chronic inflammation that is encountered in a limited number of
infectious and some noninfectious conditions
• A granuloma is a cellular attempt to contain an offending agent that is
difficult to eradicate.
• In this attempt there is often strong activation of T lymphocytes leading
to macrophage activation
• Tuberculosis is the prototype of the granulomatous diseases
• But sarcoidosis, cat-scratch disease, leprosy, brucellosis, syphilis, some
mycotic infections are also included
Granulomatous Inflammation

• The prototype of the immune granuloma is that caused by infection

with Mycobacterium tuberculosis
• In this disease the granuloma is referred to as a tubercle
• It is often characterized by the presence of central caseous necrosis
 Definition:

• Granulomatous inflammation is a distinctive pattern of

chronic inflammatory reaction.
• It is a protective response to chronic infection or foreign
material, preventing dissemination and restricting
inflammation.
• Some autoimmune diseases such as rheumatoid
arthritis and Crohns disease are also associated with
granulomas.
Granulomatous inflammation
• A granuloma is a microscopic aggregation of activated macrophages
that are transformed into epithelium-like cells surrounded by a collar
of mononuclear leukocytes, principally lymphocytes and occasionally
plasma cells.
 Granulomatous inflammation
• Epithelioid cells fuse to form giant cells containing
20 or more nuclei.
• The nuclei arranged either peripherally (Langhans-
type giant cell) or
• haphazardly (foreign body-type giant cell).
• These giant cells can be found either at the
periphery or the center of the granuloma.
Slide 3.41