Lecture 1 (S1-S5)-introduction Lecture 2(S 6- S11)-mechanism & sequences of acute inflammation-vascular changes Lecture 3(S12-S20 (15-2-22)cellular changes in acute inflammation) Lecture 4(S21-S32)concept of scaring, healing fibrosis Lecture 5(S33-LAST) chemical mediators of inflammation

1. Course Code: 514-T(REGULAR SESSION 2022)
CHAPTER 03
(TOPIC: ACUTE AND CHRONIC INFLAMMATION).
COURSE INCHARGE:
Ms Mahrukh Khurshid

2. Chapter 3(topic 1
inflammation)OVERVIEW
 Lecture 1 (S1-S5)-introduction
 Lecture 2(S 6- S11)-mechanism & sequences of acute
inflammation-vascular changes
 Lecture 3(S12-S20 (15-2-22)cellular changes in acute
inflammation)
 Lecture 4(S21-S32)concept of scaring, healing fibrosis
 Lecture 5(S33-LAST) chemical mediators of
inflammation

3. INTRODUCTION:
 white blood cells are also known as leukocyte,made in the bone marrow from
hematopoietic stem cells leukocytes exists in all parts of the body into
connective .tissues lymph and the blood stream.
 They have 2 major types:
 Granulocytes
 Agranulocytes
1.GRANULOCYTES:
 They have visible grains/granules inside the cells. Subtypes are:
 BASOPHILS : Least numerous WBC. It plays all important part in the
inflammatory response of the body like when you sneeze, the inflammatory
response helps you get rid of the irritant in the nose by histamine. It is basophils
which produces and store the histamine and release when needed.
 NEUTROPHILS: The most numerous of all WBCs. Half of it found in the blood
stream and half in the tissues. They are the immune systems first responders. If
bacteria is detected, a chemical signal is sent to the neutrophils and they rush to
the site. They kill germs by phagocytes(cell eating). Besides that they release a
burst of super oxides which kills many bacteria at the same time.
 Eosinophils: They have the ability to poison all the micro-organism with deadly
chemicals. They are also parasites patrol and detected the pressure of harmful
micro-organism will them. They actually act on parasites and worms.

4. 2. AGRANULOCYTES:
 They are free of visible grains under the microscope. Their
subtypes are:
 LYMPHOCYTES: It has three sub types:
T-CELLS: T-cells developed in the thymus gland, have t-cells receptor
on the cells surface. It recognizes the antigen and present it to B-
cells. The T cells destroy the body's own cells that have themselves
been taken over by viruses or become cancerous.
B-CELLS: They mature in the bone marrow cells having B-cells
receptor on the cells surface. The B cells produce antibodies that are
used to attack invading bacteria, viruses, and toxins.
 MONOCYTES: Monocytes have the ability to change into
another cell form called macrophages before facing the germs.
They can actually consume, or munch, on harmful bacteria,
fungi and viruses. Then, enzymes in the monocyte's body kill
and break down the germs into pieces.

5. CONCEPT OF HYDROSTATIC AND ONCOTIC PRESSURE:
 Force that causes outward movement of fluid form capillaries is hydrostatic
pressure
 Force that causes inward movement of fluid form capillaries is oncotic pressure
 Hydrostatic pressure is highest at the arteriolar end of the capillary and lowest at
the venular end.
 When the hydrostatic pressure reaches the capillaries it drops which pushes the
blood content to go into ECF. As the capillaries are leaky and this leakiness is due
to the hydrostatic pressure.
 Essentially, hydrostatic pressure pushes out while osmotic pressure pulls in.
 In the capillaries hydrostatic pressure increases filtration by pushing fluid and
solute OUT of the capillaries, while capillary oncotic pressure (also known as
colloid osmotic pressure/osmotic pressure) pulls fluid into the capillaries and/or
brings fluid from ECF to vessels as it is generated by colloids or protein
(albumin, globulins and fibrinogen - that do not leave the capillary and draw
water).
 Hydrostatic pressure is based on the pressure exerted by the blood pushing
against the walls of the capillaries, while oncotic pressure exists because of the
proteins - like.
 During inflammation , In case of vasodilatation, as more blood flows through
capillaries, they leak which leads to increase in water loss from blood stream into
the interstitial fluid causing edema at a localized level. Vascular shock caused by
septicemia/blood poisoning happens to lose so much water from the blood
stream causing low BP which in compensation increases HR by causing massive
vasoconstriction.

6. CONCEPT OF TRANSUDATE AND EXUDATE:
 The escape of blood cells fluids, proteins from the
vascular system to the interstitial fluid body cavities is
known as exudation which is an inflammation fluid out
of inflammatory response.
 The difference between the exudate and transudate is
Exudate has intermediate to high cell content, large
molecule(fibrinogen), high protein, high albumin and
likely to clot being viscous in nature. Transudate has low
cellular content, watery component of plasma, low
protein, low albumin and unlikely to clot.

7. INFLAMMATION
 It is a series of defensive biological reactions to harmful
agents that lead to different cardinal signs of
inflammation
 Cardinal signs:
 dotor - pain
 calor - heat
 rubor - redness
 tumor – swelling
 functiolessa – loss of function

8.  Inflammation is not a specific process it goes after
anything like bacteria or bee stings in the same way.
 EXAMPLE: Bee stings you, your body recognizes it as a
foreign particle. It signals + release chemicals
(histamine) to cause vasodilatation + leaky vessels to
infiltrate more WBCs to the affected site. Not only WBC
but fluid loss from vessels also occurs to the interstitial
fluid causing swelling. Swelling presses neighboring
cells causing pain. Histamine causes arteriolodilation
and bronchioconstriction.

9. TYPES OF INFLAMMATION
 Acute inflammation
 Chronic inflammation

10. ACUTE INFLAMMATION
 It’s a rapid response to an injurious agents that serves to deliver mediators --- leukocytes
and plasma proteins to the site of injury. It may occur over seconds, minutes, hours and
days.
 Causes: Physical, Chemical injuries, foreign bodies(splinters, dirt, sutures, inflection,
immune reactions etc.
MANIFESTATION OF ACUTE INFLAMMATION:
 Vascular changes
 Leukocytes events/ Cellular events.
A. VASCULAR CHANGES
 Vascular changes can be seen in terms of vasodilatation and vascular permeability.
 In inflammation blood vessels undergo a series of changes that are designed to maximize
the movement of plasma proteins out of the circulation and into the site of injury.
 Vasodilatation is one of the early manifestations of acute inflammation which follows a
transient constriction of arteriole lasting a few seconds. Vasodilatation is what erythema
(redness)and heat to the injured/inflamed area. It is mediated by mediators such as nitric
oxide, histamine , bradykinin or vascular smooth muscles.

11.  Vasodilatation followed by increased vascular permeability as the
capillary hydrostatic pressure increases, and there is also escape of
plasma proteins into the ECF (endothelial contraction allowing
proteins to escape between cells). Consequently, much more fluid
leaves the vessels than is returned to them. The net escape of
protein-rich fluid is called exudation; hence, the fluid is called an
exudate in the ECF.
 There are two mechanisms of increase in vascular permeability.
Either chemical mediators of acute inflammation may cause
retraction of endothelial cells, leaving intercellular gaps (chemical
mediated vascular leakage). Or toxins and physical agents may
cause necrosis of vascular endothelium, leading to abnormal
leakage (injury induced vascular leakage).
 The loss of fluid from vasculature allows increased concentration
of RBC + increased blood viscosity and slower blood flow in the
vessel known as stasis.
 This causes edema we know that, but it is somehow beneficial also
as it dilutes the irritant + lowers its effects and let
antibiotics(natural)to come to the site of injury. Leukocytes
infiltration produces lactic acid which lowers pH that in turn
decreases bacterial growth. Release fibrin serves for repair.

12. b. CELLULAR EVENTS:
 An important function of inflammation is the delivery
of leukocytes to the site of injury. Leukocytes ingest, kill
microbes and get rid of necrotic tissues and foreign
substance.
 On the other hand, leukocytes may also induce tissues
damage and prolong inflammation and damage the
normal host tissues by the leukocytes enzymes.
 white blood cells get out of the circulation and into the
area where they are needed by the following sequence:
 Margination:
 Adhesion:
 Emigration:
 chemotaxis:
 Phagocytosis.

13. i. MARGINATION:
 In normal blood flow RBC and WBC generally travel along the central
axis of the blood vessel. As in inflammation, vasodilatation causes blood
to slow the flow(hemostasis), so WBC margin themselves along the
periphery of the endothelial blood vessel margination.
 On the other hand RBCs clump together due to vasodilation + increased
vascular permeability --- rouleax so RBCs help displace WBC to
marginate.
ii. ADHESION:
 Margination is followed by assembling WBCs firmly aka
adhesion/Rolling.
 This process is achieved by selectin/CAMs{cells adhesion molecules}
found on the surface of endothelial cells + leukocytes.
 At first ‘selectin’ (CAMs) lightly bind leukocytes with endothelium and
later. ICAMs (inter cellular adhesion molecules) of endothelial cells and
intergrins of neutrophils (leukocyte) bind them.
iii. EMIGRATION/DIAPEDESIS:
 Leukocytes leave the blood vessel to enter the interstitial fluid by
inserting pseudopodium like cytoplasmic projection which helps widen
the endothelial pores. It takes 2-10 minutes.

15. iv. CHEMOTAXIS:
 From the ECF, the movement of leukocytes to the damaged area is called chemotaxis
mediated by substances called chemoattractants or chemotactic factors, they diffuse from
the area of tissues damaged. Generally chemoattractants bind to the receptors on
leukocytes and activates secondary messengers system which causes increased Ca+ influx
resulting in increased activity of the cell.
 Second messenger are molecules that pass the signal from receptor on cell surface to target
molecules inside the cell. They amplify the signal strength and cause some kind of changes
in the activity of the cell. They are component of cell signaling pathway. For eg: Ca+, nitric
oxide are the example of second messenger system.
 The chemoattractants/chemokines are as follows:
 Leukotriene B4 (LT-B4)
 Platelatefactor 4(PF4)
 Components of complement system(C3 , C5 in particular)
 Cytokines (interleukines 1L-1, 1L-5, 1L-6)
 Solute bacterial products
 Monocyte chemoattract protein(MCP-1)
 Chemotactic Factor for CD4 + T-cells
 Eotaxinchemotactic for eosinophil
 There are specific receptors for each of the above chemokines. They not only induce
leukocytes activation but also includes the production of the arachidonic acid metabolites,
secretion/degranulation of lysosomal enzymes, generation of oxygen metabolites,
increased intracellular calcium etc.

17. v. PHAGOCYTOSIS:
 It is the process of engulfment of solid particles by the cells phagocytes. There are microphages
(neutrophils in acute inflammation) and marcophages (monocytes in chronic inflammation).
 The process of phagocytosis involves 4 stages.
 RECOGNITION AND ATTACHEMENT STAGE (OPSONIZATION): The phagocytes
recognize and attach to foreign bodies by chemokines (usually released by damaged
tissues). There are naturally occurring factors ”opsonins” in the serum which coat
bacteria and the phagocytes have specific receptors for oposnins for attachment.
 ENGULFEMENT STAGE: In this stage phagocytes engulf the opsonins by forming
pseudopods around oposonins enveloping it into vacuole which eventually causes
membrane breakage of phagocytes to let the opsonin inside the cytoplasm where
lysosomes fuse with the vacuole and form phagosomes/phagolysosomes.
 DEGRANULATION STAGE: In this stage phagocytes secret certain enzymes like IL2,
IL3, TNF, arachidonic acid metabolites ,leukotrienes, platelet activating factor and
oxygen metabolites into the phagosome/phagolysosome.
 KILLING/DEGRADATION STAGE: After secreting the above mentioned enzymes,
bacteria get killed by hydrolytic enzymes(antimicrobial agents)of phagocytes by 2
ways.
 Oxygen Dependent Mechanism: Activated phagocytes has NADPH-oxidase present in the CM
of phagosome which reduces oxygen to super oxide ion and converted into hydrogen peroxide
having bactericidal properties. The dead MO are degraded by lysosomal enzymes.
 Oxygen Independent Mechanism: Some agents secreted by phagocytes into phagosome do not
need oxygen to have bactericidal properties like lysosome hydrolases, permeability increasing
factors, defensins and cationic proteins.

18. FATE OF ACUTE INFLAMMATION:
1. HEALING:
 During the healing process, damaged cells capable of
proliferation regenerate.
 Different types of cells vary in their ability to regenerate.
 Some cells, such as epithelial cells, regenerate easily, whereas
others, such as liver cells, do not normally proliferate but can be
stimulated to do so after damage has occurred.
 Still other types of cells are incapable of regeneration.
 For regeneration to be successful, it is also necessary that the
structure of the tissue be simple enough to reconstruct. For
example, uncomplicated structures such as the flat surface of
the skin are easy to rebuild, but the complex architecture of a
gland is not.
 In some cases, the failure to replicate the original framework of
an organ can lead to disease.
 This is the case in cirrhosis of the liver, in which regeneration of
damaged tissue results in the construction of abnormal
structures that can lead to hemorrhaging and death.

19. 3. SUPPURATION
 The process of pus formation, called suppuration, occurs when
the agent that provoked the inflammation is difficult to eliminate.
 Pus is a viscous liquid that consists mostly of dead and dying
neutrophils and bacteria, cellular debris, and fluid leaked from
blood vessels.
 The most common cause of suppuration is infection with the
pyogenic (pus-producing) bacteria, such as Staphylococcus and
Streptococcus.
 Once pus begins to collect in a tissue, it becomes surrounded by a
membrane, giving rise to a structure called an abscess. Because an
abscess is virtually inaccessible to antibodies and antibiotics, it is
very difficult to treat. Sometimes a surgical incision is necessary to
drain and eliminate it. Some abscesses, such as boils, can burst of
their own accord. The abscess cavity then collapses, and the tissue
is replaced through the process of repair
4. CHRONIC INFLAMMATION:
 The acute inflammation may lead to chronic inflammation if the
causative agent is no neutralized.

20. 2. REPAIR:
 Repair, which occurs when the normal tissue architecture cannot be
regenerated successfully, results in the formation of a fibrous scar.
 Through the repair process, endothelial cells give rise to new blood
vessels, and cells called fibroblasts grow to form a loose framework of
connective tissue.
 This delicate vascularized connective tissue is called granulation tissue.
 As repair progresses, new blood vessels establish blood circulation in the
healing area, and fibroblasts produce collagen that imparts mechanical
strength to the growing tissue.
 Eventually a scar consisting almost completely of densely packed
collagen is formed.
 The volume of scar tissue is usually less than that of the tissue it
replaces, which can cause an organ to contract and become distorted.
 For example, scarring of the intestines can cause the tubular structure to
become obstructed through narrowing. The most dramatic cases of
scarring occur in response to severe burns or trauma.

21. SCARRING/FIBROSIS OF INTESTINE

23. CHRONIC INFLAMMATION
 If the agent causing an inflammation cannot be eliminated, or if there is
some interference with the healing process, an acute inflammatory
response may progress to the chronic stage.
 Repeated episodes of acute inflammation also can give rise to chronic
inflammation.
 The physical extent, duration, and effects of chronic inflammation vary
with the cause of the injury and the body’s ability to ameliorate the
damage.
 In some cases, chronic inflammation is not a sequel to acute
inflammation but an independent response.
 Some of the most common and disabling human diseases, such
as tuberculosis, rheumatoid arthritis, and chronic lung disease, are
characterized by this type of inflammation.
 Chronic inflammation can be brought about by infectious organisms
that are able to resist host defenses and persist in tissues for an extended
period. These organisms include Mycobacterium tuberculosis (the
causative agent of tuberculosis), fungi, protozoa, and metazoal parasites.
 Other inflammatory agents are materials foreign to the body that cannot
be removed by phagocytosis or enzymatic breakdown. These include
substances that can be inhaled, such as silica dust, and materials that
can gain entry to wounds, such as metal or wood splinters.

24.  The hallmark of chronic inflammation is the
infiltration of the tissue site by macrophages,
lymphocytes, and plasma cells (mature antibody-
producing B lymphocytes).
 Monocytes infiltration which are inactive in the blood
vessel, once they reach the site of injury become
activated and termed as macrophage. As monocytes are
in damaged tissue they survive for several months. On
activation, macrophages release biologically acute
substance acids, O2 metabolities, cytokines etc.
 These products bring about nercosis(tissue
destruction), angiogenesis(neovasculation)and
fibrosis(repair).
 These cells are recruited from the circulation by the
steady release of chemotactic factors.

25. MANIFESTATION OF CHRONIC INFLAMMATION
 Infiltration of leukocytes(macrophages, lymphocytes and
plasma cells).
 Tissue destruction by the products of the inflammation
cells.
 Healing
 Repair, involving angiogenesis and fibrosis

26. A. LEUKOCYTE INFILTRATION:
 Once the monocytes are activated, aka histiocytes. Macrophage activation occurs
by either of the two pathways.
 CLASSICAL ACTIVATION: Classical activation of macro phages induced by
bacteria products(endotoxin), interferon gamma(IFN-gamma) from T-
lymphocytes. Classically activated macrophages produce lysosomal enzymes,
NO (Nitric oxide) and ROS (Reactive oxygen species) which increased the killing
ability of the MO and secret cytokine that stimulate inflammation.
 ALTERNATE ACTIVATION: Alternate activation of macrophages is induced by
cytokines like IL-4 and IL-13 produce by T-lymphocytes and eosinophil.
Macrophages activated by this pathway are not actively microbicidal instead,
their role is in tissue repair. They secret growth factor which promote
angiogenesis and fibrosis. Usually macrophages infiltration starts off with
classical activation with microbicidal activities followed by tissue repair via
alternate pathway
 After the stimulus is dead by macrophages, macrophages then die or wander off
into lymphatic.
 Lymphocytes are also seen at the site of injury in chronic inflammation, both T
and B cells reach where B-type developed into plasma cells and which secret
antibodies and CD4+T lymphocytes are activated to secret cytokines.

27. B. TISSUE DESTRUCTION:
 The chemicals released by inflammatory cells or inflammatory cell itself may damage
tissue as in the form of granulomatous inflammation.
 A granuloma is a condition which is characterized by non cancerous inflammation in the
tissue which does not give any sign or symptoms and all are revealed upon x-rays
accidently. (Frequently occur in lungs but can occur anywhere in the body).
 Usually granuloma occurs when activated macrophages appear as large cells (epitheliod
epithelial cell like)under the microscope with enhanced ability to secrete lysozymes but
decreased phagocytic activity.
 Basically macrophages (aka histiocytes) are the cells that define a granuloma where
macrophages fuse to form giant cells. The macrophages in granuloma are known as
epitheliods.
 Giant cells are of two types, Langhans type and foreign body type.
 Langhans type is the giant cell formed from the fusion of macrophages with nuclei in the
periphery of the cells as in TB.
 While foreign body type giant cells also formed from the fusion of macrophages with
scattered nuclei throughout the cell as in splinters, sutures, breast implants.
 Basically the granuloma formation builds up the cell mediated immunity to the causative
agents.
 T-lymphocytes liberate lymphokines which activate and attract more macrophages w/c
undergoes epitheliod (granuloma) formation. Granuloma of TB has central caseous
necrosis. In granulomatous inflammation; though it walls off the causative agent but
cannot eradicate(phagocyte)it which by way of repairing give rise to fibrosis and
angiogenesis which end up causing tissue dysfunction. RECALL SCARRING/FIBROSIS

28. C. HEALING:
 Replacement of injured tissues with normal tissues is
regeneration. It occurs epithelia able to divide proliferate
such as skin, liver or intestine or where the injury is not
severe enough.
D. REPAIR:
 If the damage is extensive and occur in tissue incapable of
regeneration. So repair occurs by the positioning of the
connective tissues or fibrosis which forms scar. It just give
the structural stability to the damaged tissue alerts its
function somehow, still somehow function may usually be
performed. If fibrosis developed in tissue spaces where
exudate is present(during inflammation)it is called
organization.
 Scar formation includes two main processes that occurs, are:
 Fibrosis
 Angiogenesis.

29. i. FIBROSIS:
 It’s a pathological condition associated with repair in chronic
inflammation where excessive deposition of ECM(extracellular
matrix) impair tissue/organ architecture occur and malfunction
which eventually results in tissue/organ failure.
 In response to injury, this is called scarring, basically fibrosis acts
to deposit connective tissues.
 The fibrosis process basically initiated when macrophages release
certain chemicals that stimulate fibroblast like TFG-beta(pro-
fibrotic mediator)released by macrophages or by any damaged
tissue between cells gaps i.e interstitium.
 Other mediators include CTGF, Platelets derived growth
factor(PDFG), IL-4, all these initiate signal transduction pathway.
 Examples of fibrosis:
 Pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation induced lung
injury post cancer(lung).
 Cirrhosis(liver)
 MI, atrial fibrosis(heat)
 Arterial stiffen(vessel).

30.  Let’s get the concept of ECM(extra cellular matrix)straight here:
we know that connective tissue are one of the type tissue in our
body like epithelial, nervous, muscle and connective
tissues(collagen),fibrosis connective tissue(tendons, ligaments),
cartilage, bone, adipose tissue, blood. The cells of connective
tissue include fibroblast, adipocyte, macrophages, mast cells.
 The connective tissue is found in between other tissues anywhere
in the body including the nervous tissue.
 Now about ECM, our cells are not tightly joined together, they
have some space too in between i.e ECF which is filled with
complex network ECM, which is a physiologically active
component of the body, which helps guide the division, growth
and the development of the cells/tissues.
 ECM is made of proteoglycans, minerals, water, fibrosis proteins.
ECM can be seen in for example in between the bones as synovial
fluid, corneal fluid in the eye which helps transmit light in your
eye ball.
 Two main classes of molecule found in ECM are fibrosis proteins
and proteoglycans. Fibrosis protein comprise collagen, elastin,
fibronectin, laminin produced by fibroblast while proteoglycans
provide hydration to the tissue such as mucus.

31.  Now we will talk about the concept of signal transudation pathway. It is a process
in which a signal is conveyed to trigger a change in the activity or state of a cell
which involves ligand binding to a receptor(protein) on the cells which given rise
to a cascade of biochemical events along a signaling pathway which target a
molecule or reaction inside the cell.
 So in a nut shell fibrotic cascade starts initial epithelial damage to eventual
myofibroblast induction mediated by chemicals released by
macrophages(already discussed).
ii. ANGIOGENESIS:
 Angiogenesis is the development of new blood vessel from an existing vascular
network. It is usually associated with increased capillary permeability that sreves
to supply plasma components to the ECF such as recruitment of leukocytes,
platelets, mast cells, all of which are capable of producing large quantities of
proangiogenic factors VEGF(vascular endothelial growth factor),FGF(fibroblast
growth factor),cytokines.
 Hypoxia is also considered as a stimulus to angiogenesis and inflammation
resulting in the accumulation of leukocytes and growth factor. Lets get to see
their example in skeleton muscles. Where we see muscular adaptation post
strenuous exercise which also includes the development of a additional
capillaries(angiogenesis). Since strenuous exercise depends on adequate oxygen
supply, so hypoxia occurring within muscle during the exercise may provide the
stimulates to angiogenesis for greater O2 supply.
 https://www.hindawi.com/journals/mi/2016/2053646/

32. EXTRACELLULAR MATRIX

33. CHEMICAL MEDIATORS OF INFLAMMATION:
 Although injury starts the inflammatory response,
chemical factors released upon this stimulation bring
about the vascular and cellular changes outlined above.
The chemicals originate primarily from blood plasma,
white blood cells (basophils, neutrophils, monocytes,
and macrophages), platelets, mast cells, endothelial
cells lining the blood vessels, and damaged tissue cells.
 They are broadly classified into 2 classes:
 Mediators released by cells
 Mediators released by plasma.

34. 1. MEDIATRS RELEASED BY CELLS:
 VASOACTIVE AMINES – e.g. (histamine, serotonin) : One of the best-known chemical
mediators released from cells during inflammation is histamine, which triggers vasodilation
and increases vascular permeability. Stored in granules of circulating basophils and mast
cells, histamine is released immediately when these cells are injured.
 ARACHIDONIC ACID METABOLITES(EICOSANOIDS) – e.g. (prostaglandins,
thromboxane, prostacyclin, leukotrienes) : The prostaglandins are a group of fatty acids
produced by many types of cells. Some prostaglandins increase the effects of other
substances that promote vascular permeability. Others affect the aggregation of platelets,
which is part of the clotting process. Prostaglandins are associated with the pain and fever of
inflammation. Anti-inflammatorydrugs, such as aspirin, are effective in part because
they inhibit an enzyme involved in prostaglandin synthesis. Prostaglandins are synthesized
from arachidonic acid, as are the leukotrienes, another group of chemical mediators that
have vasoactive properties
 LYSOSOMAL COMPONENTS : released from neutrophils. Many cytokines secreted by cells
involved in inflammation also have vasoactive and chemotactic properties.
 PLATELET ACTIVATING FACTOR: they increase vascular permeability, help leukoctes to
adhere to the endothelium, bronchoconstriction.
 CYTOKINES – e.g. (interleukin 1, Tissue necrotic factor alpha & beta, interferon)
 NITRIC OXIDE AND O2 METABOLITES: They cause vasodilatation and bactericidal in
nature.

35. 2. MEDIATORS RELEASED BY PLASMA CELLS (PROTEASES):
 They include activation and interaction of 4 interlinked system of proteins.
 Each of these system has its inhibitors and accelerators on plasma
 System: kinin, clotting fibrynolytic and complement system.
 Factor (xii)(hageman factor) leaks through endothelial gap in inflammation
plays an important role in interaction of all 4 system. Contact of factors xii with
basement membrane or bacterial endotoxins which leads to activation of
clotting, fibrinolytic and kinin system. The end products of these 3 system
activate complement system.
 Activated complement proteins serve as chemotactic factors for neutrophils,
increase vascular permeability, and stimulate the release of histamine from mast
cells. They also adhere to the surface of bacteria, making them easier targets for
phagocytes.
 The kinin system, which is activated by coagulation factor XII, produces
substances that increase vascular permeability. The most important of the kinins
is bradykinin, which is responsible for much of the pain and itching experienced
with inflammation. The coagulation system converts the plasma prein
fibrinogen into fibrin, which is a major component of the fluid exudate.
 There is activated by plasminogen activator(that cause fibrinolysis) which breaks
fibrin and gives off fibrinopeptides or fibrin split products which increased
vascular permeability and are chemotactic for leukocytes.

36. SYSTEMIC EFFECTS OF INFLAMMATION
 Fever
 Leukocytosis
 Cachexia
 Lymphangiogenesis
 Shock
 Anemia
 ESR
 Amyloidosis

37. 1. FEVER:
 Fever or pyrexia is somehow beneficial as in its great for killing
off pathogens.
 It is triggered by a proteins IL-1 secreted by macrophages in
response to a pathogen which then cause a release or synthesis
of prostaglandin-E, it is a lipid compound that signals
hypothalamus of your brain(thermoregulatory center)to raise
the body temperature
 Prostaglandins are lipid in nature when any cell is injured or
suffers trauma, it disrupts the phospholipids membrane and a
chemical process converts some of these phospholipids into PG.
 So greater the injury more of these triggers released causing
high fever even to a greater extent. So fever somehow enhances
the immune response like increased the WBC production and
increased their chemical release plus decreased the bacterial
multiplication, as bacteria grow in optimal pH and temperature.
Many of the bacteria that get you sick as in cold, flu, pneumonia
disease are in your lungs and lungs are the coolest part as every
time you exhale you lose some heat so fever make lungs a little
hotter than they are to get rid of the bacteria/virus living in your
lungs.

38. 2.LEUKOCYTOSIS:
 It is also known as increased/high WBC count in the
blood triggered by epinephrine and corticodteriods.
They force the WBCs(neutrophils esp)to release from
bone marrow to reach at the site of inflammation. So
inflammation also results in leukocytes.
3.CACHEXIA:
 It is the wasting away of body fat and muscle as a result
of chronic disease/inflammation.it is triggered by an
inflammatory mediator TNF-a(tissue necrotic factor-
alpha)which cause your body to improperly utilize fat
and other nutrients from your dirt and the person ends
upon losing weight.

39. 4.LYMPHANGIOGENESIS:
 It is a proliferation of lymphatic capillaries in inflamed
tissues, occurs in both types of inflammation. It is usually
mediated by inflammatory mediators such as PG or
cytokines which may lead to lymphatic capillaries. We know
the function of lymphatic system is that defense the
immune system. The lymph is very similar to blood plasma,
it contain lymphocytes and WBCs, waste, debris together
with bacteria. The spleen, thymus all the lymphoid organs
of the immune system. The lymphatic drainage from all over
the body like head, limbs, body cavity, thorax, abdomen and
pelvic cavities all empty into the lymphatic ducts which
drain into subclavian veins to eventually enter into the
venous circulation. So yourlymphatic system is responsible
for the removal of interstitial fluid form the tissue(form
leaky capillaries). Similarly the lymphatic system regulates
the inflammatory response by the transport of leaked fluid,
leukocytes and antigen-presenting cells from the ECF
around the inflammatory induced edema.

40. 5.SHOCK:
 Sepsis is defined as life threatening organ dysfunction
caused by poor regulation of infection by host body.
This condition leads to dangerously low BP and
abnormalities in cellular metabolism. It can occur in
any part of the body but most commonly in the lungs,
brain, urinary tract, skin, abdominal organs. It can also
cause multiple organ dysfunction syndrome(MODS). In
this condition, abnormal distribution of blood flow in
the smallest blood vessel is seen that result in ischemia
and organ dysfunction because we know that there are
mediators such as cytokine which increased
vasodilatation, increased capillary permeability so
eventually low blood pressure.

41. 6.ANEMIA:
 Anemia is a condition which accounts for lower count of
RBC or the amount of HB in the RBC that prevents the body
cells from getting enough O2. HB is an iron rich protein that
gives red color to the RBC, such anemia is iron deficiency
anemia. On the other hand, Anemia of inflammation that
occurs with chronic or long term illnesses or infections. It is
usually confused with iron deficiency anemia because in
both anemias, levels of iron circulating in the blood are low.
Iron in the body is found both circulating in blood and
stored in the body tissue. Circulating iron is necessary for
RBC production. So in iron deficiency anemia, low blood
iron levels occur due to depleted levels of stored iron in body
tissue. While in inflammation iron stores are normal/high
but still it gives depleted levels of iron in the blood because
the inflammation interferes with the body’s ability to use
stored iron and absorb iron from the diet so the RBCs can’t
absorb and use iron efficiently. This is basically mediated by
cytokines released in inflammation which interferes with
the absorption of iron from the diet.

42. 7.ESR:
 It stands for erythrocyte sedimentation rate which is the rate
at which the RBCs sediment in a period of an hour. It’s a
common hematology test and is a non-specific measure of
inflammation. To perform this test, anticoagulated blood is
placed in an upright tube and the rate at which RBCs fall in
measured in mm/hour. When an inflammatory process is
present, the proportion of fibrinogen makes RBCs to stick to
each other.(Rouleaux)
8.AMYLOIDOSIS:
 It is a condition in which abnormal deposition of a protein
amyloid builds up in tissues and organs which effects the
shape and functions of the tissue/organ. It occurs usually in
chronic inflammatory diseases like RA, TB, and Ulcerative
colitis. Amyloid fibers are formed by clumping of normal
soluble body proteins in the ECF.

43. Chapter summary

45. REFERENCES
 Kumar V, Cotran RS, Robbins SL. Robbin’s Basic
Pathology. 8th Ed. W. B. Saunders Publishers; 2007