Pathology 1.2 LECTURER: Dr.

Bailon
INFLAMMATION AND REPAIR DATE: 06/17/13

OUTLINE OVERVIEW OF INFLAMMATION

I. Definition of Terms  Reaction of vascularized living tissue to local injury
II. Overview of Inflammation  A protective response which is designed to rid the organism of both the
III. Acute Inflammation initial cause of cell injury
A. Cardinal Signs of Acute Inflammation  Body’s principal defenders: plasma proteins, circulating WBCs and
B. Vascular Events of Acute Inflammation tissue phagocytes
C. Cellular Events of Acute Inflammation  Complex reaction in tissues that consists mainly of responses of blood
IV. Mediators of Inflammation vessels and leukocytes
V. Morphologic Patterns of Acute Inflammation  Without inflammation, infection goes unchecked and wound never
VI. Chronic Inflammation heals, injured organs remain injured
VII. Systemic Effects of Inflammation
VIII. Consequence of Defective or Excessive Inflammation  Inflammatory response is closely intertwined with the process of
repair – while it destroys and dilutes walls of the injurious agents, it
OBJECTIVES (from laboratory manual) sets into a motion series of events that try to heal the damaged
 Recognize or indicate the clinical manifestations of inflammation. tissue.
 Define terms used in inflammation  Inflammation may be harmful in some situations - this reaction
commonly underlie chronic diseases such as rheumatoid arthritis,
 Demonstrate knowledge and understanding of the etiopathogenesis of
atherosclerosis and lung fibrosis
inflammation and repair
 Inflammation may contribute to a variety of diseases that are not
 Demonstrate knowledge and understanding of the pathology and
thought to be primarily due to abnormal host responses - it may play
pathophysiology of acute and chronic inflammation
a role in diseases such as type II diabetes, Alzheimer’s disease and
 Demonstrate knowledge and understanding of the course of the
cancer
disorder
CAUSES OF INFLAMMATION
DEFINITION OF TERMS  Microbial Infection
 Edema: o Most common and medically important
o Excess of fluid in interstitial tissues or serous cavities (in between o One of its most important receptors are the Toll-like receptors (TLR)
tissues) which can detect bacteria, viruses, and fungi
o Can be exudates or transudates  Tissue Necrosis
 Exudation: o From ischemia, trauma and physical and chemical injury
o Escape of fluid, proteins and blood cells from the vascular system into o Molecules known to elicit inflammation from necrotic cells (uric acid,
the interstitial tissue or body cavities. ATP, HMGB-1 [DNA-binding protein of unknown function])
 Exudate: o Hypoxia is also an inducer of inflammatory response due to protein
o Inflammatory extravascular fluid with high protein concentration and called HIF-1a
cellular debris and high specific gravity  Physical agents from the thermal extremes or from ionizing radiation,
o Causes alteration in normal permeability of small blood vessel in site of trauma
injury  Chemical agents
 Transudate:  Foreign bodies (splinters, dirt, sutures)
o Fluid with decreased protein concentration (low protein content most o Elicit inflammation because they cause traumatic yissue injury or carry
of which is albumin), little or no cellular material and low specific microbes
gravity  Immunologic Injury
o Ultrafiltrate of blood plasma that results from osmotic or hydrostatic o Normally protective immune system damages the individual’s own
pressure imbalance across the vessel wall without an increase in tissue
vascular permeability
 Pus: The injurious immune responses may be directed against self antigens,
o Purulent exudate causing Autoimmune diseases
o An inflammatory exudate rich in leukocytes (neutrophils) and
parenchymal cell debris and microbes in many cases PATTERNS OF INFLAMMATION
 Acute
Table 1. Difference of exudates and transudate  Subacute (Rarely seen)
Exudate Transudate  Chronic
Capillary Permeability ↑ Normal
Specific Gravity Higher (>1.02) Lower (<1.012) Table 2. Differentiation of Acute and Chronic Inflammation
Protein Content >1.5 g/dL <1 g/dL Acute Chronic
Inflammatory Cells Present Absent Onset Rapid (typically Follows acute
Cause Due to ↑ vascular Due to ↑ minutes) inflammation or be
permeability hydrostatic pressure insidious
and ↓ osmotic Duration Short (weeks or Longer (months to
pressure days) years)
Inflammatory Edema Present Absent
Predominant cells Polymorphonuclear Lymphocytes, plasma
(e.g. neutrophils) cells, macrophages,
fibroblasts
Fibrosis/angiogenesis Absent Present
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 Loss of fluid and increase vessel diameter leads to slower blood flow &
ACUTE INFLAMMATION increased viscosity of blood  STASIS (vascular congestion or localized
 Rapid host response that serves to deliver leukocytes and plasma proteins redness).
to tissue injury/site of infection  Finally, the accumulation of neutrophils along vascular endothelium will
occur. Also, endothelial cells are activated by mediators and express
CARDINAL SIGNS OF ACUTE INFLAMMATION high level of adhesion molecules
1. Redness
 due to vasodilatation, mediated by certain indicators of inflammation B. Increased Capillary Permeability
 Vasodilation mediated by prostaglandins (PGE and prostacyclin)  Structural changes in the microvasculature permit the plasma proteins
resulting to hyperemia (increased blood flow) and leukocytes to leak out of the vessels and leave the circulation.
2. Swelling  This is a hallmark of acute inflammation which results to edema.
 Increased vascular permeability
 Mediated by vasoactive amines (i.e., histamine and serotonin) , C3a, MECHANISMS:
C5a, bradykinin, various leukotrienes (i.e., C4, D4, E4), and platelet 1. Endothelial cell contraction resulting in increased interendothelial
activating factor PAF – all of which contribute to edema spaces (gaps are widened)
3. Heat  Elicited by histamine, bradykinin, leukotrienes, neuropeptide
 Warmth due to hyperemia substance P, etc.
4. Pain  One of the most common mechanism of vascular leakage
 Increased pressure exerted by edema and stimulation of pain-sensitive  Also known as the immediate transient response (occurs rapidly,
nerve endings by prostaglandin & bradykinin short-lived 15-30mins).
5. Loss of function (“Functio Laesa”) 2. Direct endothelial injury resulting in endothelial cell necrosis and
 Due to pain and immobility detachment which is rapid and may be long-lived
 For example in tonsillitis, it becomes difficult to swallow because the  Immediate sustained response (for several hours until the
motion swallowing is limited due to the pain experienced damaged vessels are thrombosed or repaired
 Delayed prolonged response (e.g., sunburn; type IV
3 MAJOR COMPONENTS hypersensitivity reaction)
1. Alterations in vascular calibre (vasodilation) that lead to an increase in 3. Leukocyte mediated endothelial injury through the release of
blood flow (causing erythema and warmth) reactive oxygen species (ROS) and proteolytic enzymes
2. Structural changes in microvasculature that permits plasma proteins and  Associated with late stages of inflammation
leukocytes to leave the circulation  Occurs in venules, pulmonary capillaries
3. Emigration of the leukocytes from microcirculation, accumulation in  Long- lived
focus of injury and activation to eliminate offending agent. 4. Increased transcytosis, which is the increased transport of fluids &
proteins
VASCULAR EVENTS OF ACUTE INFLAMMATION  Once there is an increase in vascular permeability, the proteins
Presence of offending agent/obnoxious stimuli within the blood vessels go out into the interstitial
↓ tissue/extravascular space
Brief period of vasoconstriction (arterioles)  The combination of increased hydrostatic pressure INSIDE the
↓ vessel and increased osmotic pressure OUTSIDE the vessel will
Vasodilatation draw water from the intravascular to the extravascular
↓ compartment. The fluid will now contain bigger molecules (i.e.,
Increase in blood flow protein), hence there is now a completion of the formation of an
↓ exudates
Increase in hydrostatic pressure (capillaries, venules)  Process involve channels consisting of interconnected, uncoated
↓ vesicles and vacuoles called the vesicovacuolar organelle located
Fluid goes out of the blood vessel, and into the extravascular close to intercellular junction
space/interstitial tissue  Induced by VEGF (vascular endothelial growth factor) which
↓ functions to promote leakage by increasing the number and
Because there is still no increase in vascular permeability, all the fluid will go perhaps the size of these channels
out hence known as TRANSUDATE
↓ C. Increased vascular permeability (Vascular Leakage)
Eventually there will be increase in capillary permeability  leads to formation of exudates.
(caused by many factors, but mainly by endothelial cell contraction)
 Increased vascular permeability also leads to hemoconcentration
within the blood vessel.
A. Vasoactive Changes (Caliber and Flow)
 Decrease in intravascular osmotic pressure with increase in hydrostatic
 Initially there is a brief period of vasoconstriction (in seconds) of pressure due to vasodilation
arterioles which is the natural response of the body to an injurious
 Hemoconcentration will increase blood viscosity thus leading to STASIS
stimulus or agent.
o Disrupts normal axial flow
 Vasodilation (one of the earliest manifestations of acute inflammation) o Normal axial flow refers to bloodstream with the formed elements of
of the arterioles (to capillary beds) would then occur, resulting to the blood occupying the center of the bloodstream, and the fluid
increased blood flow – a hallmark of early hemodynamic change – orthoplasma occupying the periphery of the bloodstream.
causing heat and redness. This is induced notably by histamine & Nitric o When there is stasis, this is lost.
Oxide. o Finally, when this occurs, the cellular events of inflammation take
 There will be an increase in hydrostatic pressure of the capillary place.
venules.
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 PATHOLOGY 1.2
 Responses of Lymphatic vessels
o The system of lymphatics and lymph nodes filters and polices the
extravascular fluids
o In inflammation lymph flow is increased and drains edema fluid
o Increased load (leukocyte, cell debris, and microbes) leads to
proliferation of blood vessels
 Chemotactic factors:
CELLULAR EVENTS OF ACUTE INFLAMMATION
Note: Neutrophils predominate in inflammatory infiltrate during first 6-24 hours, and
Two main events: EXTRAVASATION and PHAGOCYTOSIS
are replaced by monocytes in 24-48 hours.
Figure 1. Cellular Events
I. EXTRAVASATION – Journey of leukocytes from the vessel lumen to the
interstitial tissue. Divided into following steps:
1. From the normal axial flow, the formed elements of the blood, which
are the LEUKOCYTES, will be displaced in the periphery of the
bloodstream. This process is called MARGINATION.
2. When the leukocytes go out in the bloodstream, it will ROLL OVER into
the endothelial space, and this is mediated by Selectins P and E.
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3. Adhesion: There are certain chemicals known as
CHEMOKINES/CYTOKINES that are bound to proteoglycans and this
increases the affinity of INTEGRINS. This activation by the chemokines
will cause these leukocytes to adhere more firmly to the endothelial
surface.
4. Diapedesis/Transmigration: When the leukocytes have secured the
area well and have clenched in their particular endothelium, they are
now able to insinuate between the inter-endothelial spaces through
the action of PECAM-1 or CD31, so they can enter/penetrate the
basement membrane of the blood vessels and go out in the
extravascular component of interstitial tissue.
5. After this, the leukocytes are now exposed to the matrix (extracellular)
and at the same time at the area of the injury. There are chemical
mediators known as CHEMOTACTIC FACTORS which will attract these
leukocytes towards the site of injury. The unidirectional movement of
leukocytes toward the site of injury is called the CHEMOTAXIS.
o Bacterial products
 Most common exogenous agents
 Includes peptides that possess an N-formylmethionine terminal
amino acid
o Complement components (C5a) [endogenous]
o Arachidonic acid metabolites (LTB4) [endogenous]
o Cytokines (IL-8) [endogenous]
Reading Assignment
Table 2-1. Endothelia-Leukocyte Adhesion Molecules
Note: L-selectin is expressed weakly on neutrophils. It is involved in the binding
of circulating T-lymphocytes to the high endothelial venules in lymph nodes and
mucosal lymphoid tissues, and subsequent “homing” of lymphocytes to these
tissues.
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Figure 2. Receptor that will activate leukocytes and their responses
 Receptors that recognize external stimuli and deliver signals that will
activate leukocytes to engulf the offending agents and cause
phagocytosis as well as amplify the inflammation process: (Figure 2)
o Receptors for microbial products (Toll-like or TLRs): Present on cell
surface and in endosomal vesicles of leukocytes
o GPCR – Found on neutrophils, macrophages which recognize N-
formylmethionyl residues on bacterial peptides; others recognize
chemokines, C5a, platelet activating factor, prostaglandins and
leukotrienes.
o Opsonin Receptors – Include antibodies (IgG), complement proteins
(C3) and lectins (mannan-binding lectin)
o Cytokine Receptors – Interferon-γ (IFN-γ) – major macrophage
activating cytokine; secreted by NK cells and by antigen-activated T-
lymphocytes during adaptive immune responses.
II. PHAGOCYTOSIS – Ingestion of particulate matter (tissue debris, bacteria
whether living/dead, foreign bodies) by phagocytic cells
 Neutrophils and monocytes - are the most important phagocytic cells
 Has three sequential steps:
1. Recognition and attachment
2. Engulfment
3. Microbial killing and degradation
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Figure 3. Phagocytic Events
1. Recognition and attachment
o Microbes bind to phagocyte receptors
o Phagocytic receptors:
 Mannose receptors
o A lectin that binds terminal mannose and fucose of
glycoproteins and glycolipids
o Recognize microbes and not host cells
 Scavenger receptors (sr)
o Bind and mediate endocytosis of oxidized or acetylated LDL
receptor particles that can no longer interact with the
conventional LDL receptor
o Macrophage sr & macrophage integrins [Mac-1 (CD
11b/CD18)]: Also bind microbes for phagocytosis
 Receptors for opsonins
o Opsonization: The process of coating a particle by opsonins
to target it for ingestion; Facilitates phagocytosis
o 3 major opsonins:
1. Fc fragment of Immunoglobin G (Naturally occurring Ab
against the ingested particle)
2. C3b from complement activation via immune or non-
immune mechanisms
3. Plasma lectins – Mannan-binding lectin (MBL)
 Certain microbes require recognition and attachment
2. Engulfment
o Once the microbe is attached, it will be engulfed and will become
a PHAGOSOME. This a vesicle that encloses the particle (after
being bound to phagocyte receptors)
o After this, the phagosome will fuse with lysosomal membrane and
granules, and it will become PHAGOLYSOSOME.
o DEGRANULATION occurs next, where granules from lysosome are
discharged into phagolysosome
 Regurgitation – Sometimes, when the membrane has not
completely diffused, and there is already degranulation and
release of lysosomal enzymes, these enzymes can leak out and
produce regurgitation, causing tissue damage
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3. Microbial Killing and Degradation
A. OXYGEN-DEPENDENT Microbial Killing
(H2O2 Myeloperoxidase and Halide System)
o Most effective/efficient bactericidal system of neutrophils;
most effective method of killing
o Main mechanism
o Mostly by Reactive Oxygen Species (Superoxide formation of
Hypochlorite [used in various chemicals used for cleaning like
Zonrox, Chlorox] and OH radicals), as well as reactive nitrogen
species (NO Peroxynitrite)
o Reactive Oxygen Species (ROS) – Generated due to activation
of NADPH oxidase which oxidizes NADPH which then reduces
oxygen to superoxide anion. The superoxide anion is then
converted to hydrogen peroxide.
o H2O2 is converted to hypochlorite by myeloperoxidase (MPO) in
presence of halide (Cl-)
o Hypochlorite – Potent antimicrobial agent, destroys by
halogenation or by oxidation of proteins and lipids
o NO – Produced from arginine by nitric oxide synthase; it reacts
with superoxide to generate free radical peroxynitrite which
damages lipids, proteins and nucleic acids of microbes
B. OXYGEN-INDEPENDENT Microbial Killing
o Less effective
o Mediated by bacterial permeability increasing protein (BPI)
[binds bacterial endotoxin], lysozyme [hydrolyzes muramic acid
N-acetylglycosamine bond], lactoferrin, major basic protein
(MBP) [cationic protein of eosinophils, cytotoxic to parasites],
defensins [arginine-rich granule peptides], cathelicidins
 Other Functional Responses of Activated Leukocytes
o Macrophages
 Produce growth factors that stimulate proliferation of endothelial
cells and synthesis of collagen and enzymes that remodel connective
tissues
 Can be activated through:
1. CLASSICALLY ACTIVATED Macrophages
 Respond to microbial products and T-cell cytokines such as
IFN-γ, have strong microbiocidal activity
 Give rise to ROS and various interleukin and chemokines and
will result in microbial killing (Phagocytosis) and pathologic
inflammation
2. ALTERNATIVELY ACTIVATED Macrophages
 Respond to cytokines IL-4 AND IL-13, mainly involved in tissue
repair and fibrosis.
 Give rise to IL-10 and TGF-B which have anti-inflammatory
effects and is also involved in wound repair and fibrosis
Figure 4. Responses of Macrophages
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TYPES OF INFLAMMATORY CELLS
Figure 5. Types of Inflammatory cells
 Viral infections – Lymphocytes (First 24 hours)
 Hypersensitivity reactions – Eosinophils
1. Neutrophils
 Cells are the common inflammatory cells found in acute response
 Manifested in the first 6-24 hours after injury
 Exceptions:
o Pseudomonal infections: Neutrophils for 2-4 days
o Viral infections: Lymphocytes
o Hypersensitivity reactions: Eosinophils
2. Monocytes, Macrophages
 Replaces neutrophils after 1-2 days (Dominant in chronic inflammation)
 Components of mononuclear phagocyte system
 Accumulate in response to
o Continued recruitment of monocytes from the circulation
o Local proliferation (mitosis) of macrophages after emigration
o Prolonged survival and immobilization of macrophages within
inflamed tissue
 Examples of macrophages: Kupffer cells (liver), Sinus histiocytes (spleen
and lymph nodes), Alveolar macrophages (lungs), Microglia (central
nervous system)
 Activated macrophages eliminate injurious agents and initiate process
of repair
 Activated macrophages induce tissue destruction (one of hallmarks of
chronic inflammation)
3. Lymphocytes
 Predominant cells in viral infections
 Associated with chronic inflammation together with monocytes-
macrophages and plasma cells
 Mobilized in antibody and cell-mediated immunologic reaction and in
non-immunologic reaction
 Involve in cytokine production
 Activated lymphocyte (Activated by contact with antigen)Produces
lymphokines  Stimulates monocyte chemotaxis + activation of
macrophages  Activated macrophages produce monokines 
Monokines influence T- and B-cell functions
 Types of Lymphocytes:
o B lymphocytes
 Gives rise to plasma cell
 Plasma cell is responsible for antibody production & delayed
hypersensitivity
o Effector Cells which consists of
 Mixed lymphocytes reactive cells
 Cytotoxic killer cells
 Helper T Cells
o T Lymphocytes have both
 Regulatory Cells
 Suppressor Cells
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 PATHOLOGY 1.2

o Cytotoxic natural killer cells  Leukotriene is produced by lipoxygenase enzymes, 5-lipoxygenase,

o Null Cells predominant in neutrophils and is more potent than histamine in
 Activated T-lymphocytes produce cytokines which also recruits IFN-γ - a increasing vascular permeability
powerful activator of macrophages. This could make inflammatory  Lipoxins inhibit leukocyte recruitment and cellular components of
reaction chronic and severe inflammation

4. Eosinophils
 Cells are seen in allergic reactions (IgE-mediated) and parasitic
infections
 Orange to reddish granules
 Granules contain Major Basic Protein (MBP) toxic to parasites and
cause lysis of epithelial cells resulting in tissue damage in
hypersensitivity reactions

5. Plasma Cells
 Develop from activated B lymphocytes
 Produce antibody (Ab) against the antigens in inflammatory site or
versus altered tissue component
 May assume features of lymphoid organs (called tertiary lymphoid
organs) together with lymphocytes and antigen-presenting cells
 Seen in synovium of patients with rheumatoid arthritis

6. Basophils
Figure 7. Arachidonic acid metabolism.
 Prominent dark purple cytoplasmic inclusion
*Dr. Bailon spent some time discussing this diagram so study this
accordingly.*
7. Mast Cells
 Participate in both acute and chronic inflammatory reactions 3. Platelet-activating factor (PAF)
 Express the receptor (FcεRI) that binds the Fc portion of IgE antibody
 Specialized cells with cytoplasmic granules (histamine) 4. Reactive Oxygen species
 Histamine is released by the cytoplasmic granules in response to type I  Causes endothelial cell damage, injury to other cell types, inactivation
hypersensitivity reactions of antiproteases

MEDIATORS OF INFLAMMATION 5. Nitric Oxide (NO)

 Dual actions in inflammation:
o Contributestovascular reaction (Promotion of vasodilation)
o Inhibits the cellular component of inflammatory responses

6. Cytokines and Chemokines

 Cytokines (IL-1 & TNF) induce systemic acute-phase responses
associated with infection or injury
 Chemokines has 2 main functions:
o Stimulate leukocyte recruitment ininflammation
o Control normal migration ofcells
 4 major groups: C-X-C, C-C, C & CX3C chemokines

7. Lysosomal Constituents of Leukocytes

 Acid proteases – Degrade bacteria within phagolysosomes
Figure 6. Chemical mediators of inflammation  Neutral proteases – Degrade extracellular components

CELL-DERIVED MEDIATORS 8. Neuropeptides

 Neurokinin A and Substance P
1. Vasoactive amines: Histamine and Serotonin o Some functions: Transmission of pain signals, regulation of BP &
 Histamine is the principal mediator of immediate transient phase of increasing vascular permeability
increased vascular permeability
 Serotonin is stimulated when platelets aggregrate with collagen,
thrombin, ADP, antigen-antibody complexes

2. Arachidonic Acid Metabolites: Prostaglandins, Leukotrienes and

Lipoxins
 Prostaglandins is produced by COX-1 and COX-2
 Most important: PGE2, PGD2, PGF2α, PGI2 (Prostacyclin) & TXA2
(Thromboxane)

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 PATHOLOGY 1.2

 Biologic functions:
a. Inflammation [C3a,C5a,C4a]
b. Phagocytosis [C3b]
c. Cell lysis [MAC]

2. Coagulation and Kinin systems

 Kinins are vasoactive peptides derived from plasma proteins called
kininogens by proteases called kallikreins
 Activated Hageman factor (Factor XIIa) initiates four systems involved
in inflammatory response:
a. Kinin system [Produces vasoactive kinins]
b. Clotting system [Thrombin formation]
c. Fibrinolytic system [Produces plasmin and degrades fibrin]
d. Complement system [Produces anaphylatoxins]

Table 4. Role of Mediators in Different Reactions of Inflammation

Principal
Mediator Actions
Sources

Figure 8. Principal Local and Systemic Actions of TNF and IL-1 CELL-DERIVED
Mast cells,
Vasodilation, increased vascular
Table 3. Action of Principal Mediators of Inflammation Histamine basophils,
permeability, endothelial activation
Role in Inflammation Mediators platelets
Prostaglandins Vasodilation, increased vascular
Serotonin Platelets
permeability
Nitric oxide
Vasodilation Mast cells,
Histamine Prostaglandins Vasodilation, pain, fever
Leukocytes
Histamine and serotonin Increased vascular permeability,
Mast cells,
Leukotrienes chemotaxis, leukocyte adhesion and
C3a andC5a (by liberating vasoactive leukocytes
activation
amines from mast cells, other cells)
Vasodilation, increased vascular
Increased vascular Bradykinin
Platelet- Leukocytes, permeability, leukocyte adhesion,
permeability Leukotrienes C4,D4,E4 activating factor mast cells chemotaxis, degranulation,
PAF oxidative burst

Substance P Reactive oxygen

Leukocytes Killingof microbes, tissue damage
TNF, IL-1 species
Chemotaxis,
Chemokines Endothelium, Vascularsmooth muscle relaxation,
leukocyte Nitric oxide
C3a,C5a macrophages killing of microbes
recruitment and
activation Leukotriene B4 Local endothelial activation
Macrophages,
(expression of adhesion molecules),
Fever IL-1,TNF Cytokines endothelial
fever/pain/anorexia/hypotension,
Prostaglandins (TNF, IL-1) cells,
decreased vascular resistance
Pain Bradykinin mast cells
(shock)
Lysosomal enzymes of leukocytes
Tissue damage Reactive oxygen species Nitric oxide Leukocytes,
activated Chemotaxis,leukocyte activation
Chemokines
macrophages
*Dr. Bailon said that we should MEMORIZE this table.

PLASMA PROTEIN-DERIVED MEDIATORS PLASMA PROTEIN–DERIVED

Complement Plasma
1. Complement system products (produced in Leukocyte chemotaxis and
 Critical steps in complement activation: (C5a, C3a,C4a) liver) activation, vasodilation (mast
o Proteolysis of C3. Plasma cell stimulation)
o Cleavage of C3 can occur in 3 pathways: Kinins (produced in
a. Classical pathway liver) Increased vascular permeability,
b. Alternative pathway smooth muscle contraction,
c. Lectin pathway Proteases vasodilation, pain
o All lead to formation of C3 convertase, which splits C3 into distinct Plasma
activated
fragments, finally culminating into formation of membrane attack (produced in
during Endothelial activation, leukocyte
complex (MAC) liver) recruitment
coagulation

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FACTORS THAT MODIFY INFLAMMATORY RESPONSE MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION

1. Nature and intensity of injury  Based on the nature of exudates

2. Site and tissue affected  Hallmarks of inflammation
3. Host’s response a. Dilation of small blood vessels
 Nutrition b. Slowing of blood flow
 Adequacy of CVS c. Accumulation of leukocytes and fluid in the extravascular tissue
 Drug treatment
 Other diseases (D.M., cancer) SEROUS INFLAMMATION
 Previous immunity to agent
 Fluids predominate
SECOND LINE OF DEFENSE IN ACUTE INFLAMMATION: MPS and Lymphatics  Marked by the outpouring of a thin fluid that may be derived from the
plasma or from the secretions of the mesothelial cells lining the
 When there is inflammation, the body try to contain it. peritoneal, pleural and pericardia cavities
o MPS - Mononuclear Phagocyte System  Effusion: accumulation of fluid in the cavities
o Lymphangitis - Inflammation of lymph vessels  Example: skin blisters form a burn, TB, pleuritis or viral infection
o Reactive or inflammatory lymphadenitis – inflammatory response of
the lymph nodes
o Bacteremia – Bacteria in blood (Heart valves, meninges, kidneys, and
joints)
o Sepsis – characterized by bacteria and its toxic products in blood;
produces signs and symptoms in the patient

OUTCOME OF ACUTE INFLAMMATION

Figure 10. Serous inflammation. Low-power view of a cross-section of a skin

blister showing the epidermis separated from the dermis by a focal collection
of serous effusion.

FIBRINOUS INFLAMMATION

 A greater increase in vascular permeability causes large molecules such as

fibrinogen to pass the vascular barrier
 Fibrin is formed and deposited in the extracellular space
 Characteristic of inflammation in the lining of body cavities–meninges,
pericardium, pleura
 More of plasma proteins (fibrinogen) and fibrin (thread-like or solid
amorphous eosinophilic coagulum)
 Histologically, fibrin appears as an eosinophlic meshwork of threads or an
amorphous coagulum
Figure 9. Outcomes of Acute Inflammation
 Fibrin can be removed by cleaving of macrophage or fibrinolysis
 If fibrin is no removed, it may stimulate the ingrowth of fibroblasts and
 Complete Resolution
blood vessels, leading to scarring
o Clearance of injurious stimuli
 E.g. bread and butter pericarditis of RHD (inner surface of pericardium);
o Involves removal o fcellular debris and microbes by macrophages, and
meninges
resorption of edema fluid by lymphatics
o Injury must be short-lived or when there has been little tissue
destruction and the damaged parenchymal cells can regenerate
o Restoration of the site of acute inflammation to normal
 Healing By CT Replacement (Fibrosis or Scarring)
o After substantial tissue destruction
o Involves tissues that are incapable of regeneration, or when there is
abundant fibrin exudation in tissue or serous cavities (pleura,
peritoneum) that cannot be adequately cleared
o Organization: CT grows into the damaged/exudated area converting it
into a mass of fibrous tissue
o Collagen deposition
o Loss of function
 Progression to Chronic Inflammation
Figure 11. Fibrinous pericarditis. A. Deposits of fibrin on the pericardium.
o When the acute inflammatory response can not be resolved due to:
B. A pink meshwork of fibrin exudate (F) overlies the pericardial surface (P).
 Persistence of the injurious agent
 Interference with the normal process of healing

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 PATHOLOGY 1.2

SUPPURATIVE / PURULENT INFLAMMATION

 Production of large amounts of pus or purulent exudate consisting of

neutrophils, liquefactive necrosis & edema fluid
 Pyogenic bacteria: pus producing
 Ex: Acute appendicitis
 Abscesses:
o Localized collections of pus (neutrophils, necrotic cells and edema fluid)
buried in tissue, organ or a confined space. Usually caused by pyogenic
organisms Figure 14. Duodenal ulcer
 Central region: A mass of necrotic leukocytes and tissue cells

Figure 15. Crater of duodenal ulcer with an acute inflammatory exudate in

Figure 12. Purulent inflammation. A. Multiple bacterial abscesses in the
lung, in a case of bronchopneumonia. B. The abscess contains neutrophils
and cellular debris, and is surrounded by congested blood vessels.
MEMBRAMOUS INFLAMMATION
 Necrosis of mucosa and inflammatory exudate remain attached as surface
membrane
 E.g. Membranous enterocolitis - congested edematous and yellowish
 E.g. Diphteria - diphteric membrane that may contain toxins.
Figure 13. Thinning of intestinal mucosa
ULCERS
 A local defect, or excavation, of the surface of an organ or tissue
 Produced by the sloughing/shedding of the inflamed necrotic tissue
 Occurs when necrosis/inflammation exist on/or near surface
 Found in:
o Mucosa of the mouth, stomach, intestines, or genitourinary tract
o Skin and subcutaneous tissue of the lower extremities
 Intense polymorphonuclear infiltration and vascular dilation in the
margins of the defect
 Best exemplified by peptic ulcer of stomach and duodenum
 Prolonged ulcers develop
o Fibroblastic proliferation
o Scarring
o Accumulation of lymphocytes, macrophages & plasma cells
the base.
Acute ulcer - base of ulcer have a necrotic tissue, neutrophilic infiltrates,
edema, blood vessels widely congested  rupture may produce bleeding
CHRONIC INFLAMMATION
 Inflammation of prolonged duration (weeks or months) in which
inflammation, tissue injury, and attempts at repair coexist, in varying
combinations
 Causes:
1. Persistent infections by microorganisms difficult to eradicate (TB,
T.pallidum, virus, fungi, parasites)  Delayed hypersensitivity rxn 
Granulomatous reaction
2. Prolonged exposure to non-degradable toxic substances - Asbestosis,
silicosis, atherosclerosis [by endogenous toxic plasma lipids]
3. Immune-mediated inflammatory disease: immune excessive and
inappropriate activation of the immune system leading to chronic
inflammation.
a. Autoimmune diseases (immune rxn against own tissues evoked by
autoantigens) − Rheumatoid arthritis, multiple sclerosis, SLE
b. Unregulated immune response against microbes − Inflammatory
bowel disease
c. Immune rxn against environmental allergens − Bronchial asthma
HISTOLOGIC HALLMARKS OF CHRONIC INFLAMMATION
1. Mononuclear cell infiltration (including macrophages, lymphocytes, and
plasma cells.)
2. Tissue destruction (induced by the persistent offending agent or by
inflammatory cells)
3. Attempts at healing by CT replacement of damaged tissue by
proliferation of small blood vessel (angiogenesis) and, in particular,
fibrosis

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PATTERNS OF CHRONIC INFLAMMATION 2. Immune granuloma

 Unsoluble particles induce cell-mediated immune response
Non-granulomatous  Causes:
 Diffuse proliferation of chronic inflammation cells (macrophage, 1. Infectious agents
lymphocytes, plasma cells) , fibroblasts and collagen  Bacterial – TB, SY, leprosy, cat-scratch disease (GM – bacillus)
 Fungal – Cryptococcus, Coccidioides immitis
Granulomatous  Parasitic – Schistosomiasis
 A distinctive pattern of chronic inflammation that is encountred in a 2. Inorganic materials and dusts – Silicosis, berylliosis, irritant lipids
limited number of infectious and some noninfectious conditions; a 3. Uknown etiology – sarcoidosis (eg, Crohn disease)
cellular attempt to contain an offending agent that is difficult to
eradicate. Table 4. Examples of Diseases with Granulomatous Inflammation
o Granulomas: a focus of chronic inflammation consisting of a Disease Cause Tissue Reaction
microscopic aggregation of macrophages that are transformed Tuberculosis Mycobacterium Caseating granuloma
into epithelium-like cells surrounded by a collar of mononuclear tuberculosis (tubercle): focus of activated
leukocyte, principally lymphocytes and occasionally plasma cells. macrophages (epitheloid
o Nodular collections of specialized macrophages referred to as cells), rimmed by fibroblasts,
epitheliod cells (modified macrophages resembling epithelial cells) lymphocytes, histiocytes,
surrounded by a rim of lymphocytes, multinucleate giant cells, +/- occasional Langhans giant
caseous necrosis cells; central necrosis with
amorphous granular debris;
Histologically: Epitheloid cells have pale pink granular cytoplasm, indistinct acid-fast bacilli
cell boundaries; nucleus: less dense, oval or elongate, folding of nuclear Leprosy Mycobacterium Acid-fast bacilli in
membrane; may fuse to form giant cells leprae macrophages: noncaseating
granulomas
Syphilis Treponema Gumma: microscopic to
pallidum grossly visible lesion,
enclosing wall of histiocytes;
plasma cell infiltrate; central
cells necrotic without loss of
cellular routine
Cat-scratch Gram- negative Rounded or stellate
disease bacillus granuloma containing central
granular debris and
recognizable neutrophils;
Figure 16. Histologic section of granuloma in TB giant cells uncommon
Sarcoidosis Unknown etiology Noncaseating granulomas
with abundant activated
macrophages
Crohn’s disease Immune reaction Occasional noncaseating
(inflammatory against intestinal granulomas in the wall of the
bowel disease) bacteria self- intestine, with dense chronic
antigens inflammatory infiltrate

Figure 17. Granulomatous formation in the lungs

 How Granulomas Arise:

o Formation involves activation of macrophages by interactions with
T lymphocytes
o Macrophage present poorly digestible antigen to CD4+ lymphocytes.
o Interaction with the antigen specific T-cell receptor of these cells
triggers the release of cytokines (esp. Interferon), which mediate the
transformation of monoctyes and macrophages to epitheliod and giant
cells (Langhan’s)

o 2 types:
1. Foreign body
 Talc, sutures, fibers are large enough to produce phagocytosis by a
single macrophage
 Do no incite specific inflammatory rsponses

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 PATHOLOGY 1.2

Figure 20. Macrophage-lymphocyte interactions in chronic inflammation.

Activated T cells produce cytokines that recruit macrophages (TNF, IL-17,
chemokines) and others that activate macrophages (IFN-y).Activated
Figure 18. The sequence of events in primary pulmonary tuberculosis,
macrophages in turn stimulate T cells by presenting antigens via cytokines
commencing with inhalation of virulent Mycobacterium tuberculosis
(IL-12).
organisms and culminating with the development of cell-mediated immunity
to the organism. A. Events occurring in the first 3 weeks after exposure. B. SYSTEMIC EFFECTS OF INFLAMMATION
Events thereafter. The development of resistance to the organism is Acute Phase Response or Systemic Inflammatory Response (SIRS)
accompanied by the appearance of a positive tuberculin test. γ-IFN,
 Collective term for systemic changes associated with acute
interferon-γ; iNOS, inducible nitric oxide synthase; MHC, major
inflammation
histocompatibility complex; MTB, M. tuberculosis; NRAMP1, natural
 Caused by reactions to cytokines whose production is stimulated by
resistance-associated macrophage protein; TNF, tumor necrosis factor.
bacterial products
 The acute phase response consists of several changes namely:
1. Fever
ROLE OF MACROPHAGE IN CHRONIC INFLAMMATION
2. Acute Phase Proteins
3. Leukocytosis
 Its products serve to: 4. Other responses
o Eliminate injurious agents such as microbes
o Initiate the process of repair I. Fever
o Responsible for much of the tissue injury in chronic inflammation
 Due to pyrogens that enter the blood and act on thermoregulatory
 Activation of macrophages result in increased levels of lysosomal enzymes center in the hypothalamus
and reactive oxygen and nitrogen species, among others
Infections, toxins, immune complexes, neoplasia

Exogenous pyrogenes (bacterial products e.g. LPS)

Stimulate WBC to release endogenous pyrogenes (IL-1 & TNF)

Increased cyclooxygenase that converts arachidonic acid into PG

Increased PG synthesis (especially PGE2) in vascular & perivascular cells of
hypothalamus

Stimulate production of neurotransmitter (cAMP)

cAMP reset temperature set point at higher level

Fever

 Characterized by an increase in body temperature usually by 1 - 4 °C

 This is produced in response to PYROGENS
Figure 19. The Roles of activated macrophages in chronic inflammation.
o Pyrogens stimulate prostaglandin synthesis in the vascular and
Macrophages are activated by nonimmunologic stimuli such as endotoxin or
perivascular cells of hypothalamus
by cytokines from immune-activated cells (particularly IFN-y). The products
 Bacterial products, such as LPS (exogenous pyrogens) stimulate
made by activated macrophages that cause tissue injury and fibrosis are
leukocytes to release of cytokines, such as IL-1 and TNF (endogenous
indicated.
pyrogens) that increase the enzymes (cyclooxygenases) that convert
Arachidonic acid into Prostaglandin.
 NSAIDs (Ex: aspirin) diminish fever by inhibiting PG synthesis

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 PATHOLOGY 1.2

II. Acute Phase Proteins  In severe bacterial infection (aka Sepsis), large amounts of organisms and
 These are plasma proteins, mostly found in the liver, that increase in LPS in blood increase production of cytokines, which then result to:
concentration as response to inflammatory stimulus o Change in the nature of the host response
 3 most common acute-phase proteins: o Results in IV coagulation, cardiovascular failure and metabolic
1. C-reactive protein (CRP) disturbance
2. Fibrinogen o Septic shock
o Bind RBCs and forming stacks (rouleaux) that sediment more o Triad of DIC, hypoglycaemia and CVS failure
rapidly than inidividual RBC o ARDS (Adult Respiratory Distress Syndrome)
o Basis for measuring Erythrocyte Sedimentation rate for systemic o Multiple Organ Failure
inflammatory response.
3. Serum amyloid A (SAA) CONSEQUENCES OF DEFECTIVE OR EXCESSIVE INFLAMMATION
o Replace apolipoprotein A (component of high-density
lipoprotein) – results to altered targetting of HDL from liver cells Defective Inflammation
to macriphages, which can be used as energy-producing lipids.  Results in increased susceptibility to infections
o Prolonged production causes secondary amyloidosis  Inflammation response is central component of innate immunity
o Synthesized by hepatocyes and up-regulated by cytokines  Associated with delayed wound healing
o IL-6 for CRP and fibrinogen  Inflammation needed for removal of damaged tissues and debris,
o IL-1 or TNF for SAA and provides stimulus to start process of repair
o CRP and SAA can both act to 1.) bind to microbial cell walls – to act
as opsonins and fix complement; 2.) bind chromatin, possibly aiding Excessive Inflammation
in the clearing of necrotic cell nuclei.  Allergies
o Hepcidin – another acute-phase CHON; reduce availability of iron  Autoimmune diseases
and are responsible for the anemia associated with chronic  Cancer
inflammation.  Atherosclerosis
 Ischemic heart
III. Leukocytosis
 Alzheimer disease
 Commonly found in bacterial infections  Other chronic infectious and metabolic diseases
 Characterized by extreme elevations of WBC reffered to as
Leukemoid reaction.
o Reaching usually to 15,000 – 20,000 cells/µL, or in extraordinary Edited by: Natz
extent, up to 40,000 – 100,000 cells/µL.
o Even having similar WBC counts, it is different to Leukemia.
 Occurs initially because of accelerated release of cells from bone
marrow post mitotic reserve pools
o Resulting to increase in the number of more immature neutrophils
in the blood (aka Shift to the Left)
 Prolonged infection causes proliferation of leukocyte precursors
from the bone marrow, caused by increased production of colony-
stimulating factors.
o Bone marrow output is increased to compensate for the loss of
WBCs in the inflammatory response
 Neutrophilia - Increase in neutrophil count in the blood
 Eosinophilia - Increase in eosinophil count in the blood
o Found in bronchial asthma, allergy and parasitic infections
 Lymphocytosis - Increase in lymphocyte count in the blood
o Found in viral infections such as infectious mononucleosis, mumps
and German measles
 Leukopenia - decrease number of circulating white cells
o Associated with typhoid fever and infections caused by some
viruses, rickettsia, and protozoa

IV. Other Acute Phase Responses

 Increase ESR (Erythrocyte sedimentation rate)
o Basis: Fibrinogen binding to RBCs
 Increase Blood Coagulability due to increased Sticky platelets,
coagulation factors
 Other manifestations: Increase pulse and BP, decreased sweating
(due to redirection of blood flow from cutaneous to deep vascular
beds, to minimize heat loss through skin), rigors (shivering), chills
(search for warmth), anorexia, somnolence and malaise.

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