INFLAMMATION AND REPAIR
Dr. Sheryl Q. Racelis
September 8, 2020
SEM 1 MIDTERMS – TRANS 3
OUTLINE
I. Overview of Inflammation
A. Definitions and General Features
B. Historical Highlights
C. Causes of Inflammation
D. Recognition of Microbes and Damaged Cells
II. Acute inflammation
A. Reactions of Blood Vessels in Acute
Inflammation
B. Leukocyte Recruitment to Sites of Inflammation
C. Phagocytosis and Clearance of the Offending
Agent
D. Termination of the Acute Inflammatory
Response
E. Mediators of Inflammation
F. Morphologic Patterns of Acute Inflammation
G. Outcomes of Acute Inflammation
H. Summary of Acute Inflammation
III. Chronic Inflammation
A. Causes of Chronic Inflammation
B. Morphologic Features
C. Cells and Mediators of Chronic Inflammation
D. Granulomatous Inflammation
IV. Systemic Effects of Inflammation
V. Tissue Repair
A. Overview of Tissue Repair
B. Cell and Tissue Regeneration
C. Organ Regeneration
D. Repair by Connective Tissue Deposition
E. Factors That Influence Tissue Repair
F. Examples of Tissue Repair and Fibrosis
G. Abnormalities in Tissue Repair
VI. References
Legends
 from the book
 take note/ boards/good to know
• General info (from 2022 trans, Doc’s ppt, and additional
references other than the book)
OVERVIEW OF INFLAMMATION
Definitions and General Features
Inflammation
• Response of vascularized tissues to infections and damaged
tissues that brings cell and molecules of host defense from
the circulation to the sites where they are needed, in order to
eliminate the offending agents
• Beneficial host response to foreign invaders and necrotic
tissue but it may also cause tissue damage
• Although in common medical and pay parlance, inflammation
suggests a harmful reaction; it is actually a protective
response that is essential for survival
• Serves to rid the host of both the initial cause of cell injury
(e.g. microbes, toxins) and the consequences of such injury
(e.g. necrotic cells and tissues)
TRANSCRIBERS Calaycay, Caluducan, Fernandez, Usuquen
A. Main Components of Inflammation
o Vascular reaction
o Cellular response
B. Mediators of defense/ inflammatory cells
• Normally circulate in the blood, from which they can be
rapidly recruited to any site in the body include:
o Phagocytic WBCs
o Antibodies
o Complement proteins
• Process of inflammation delivers the above-mentioned cells
and proteins to damaged or necrotic tissues and foreign
invades (e.g. microbes) and activates the recruited cells and
molecules which then function to get rid of the harmful or
wanted substance
• Without inflammation
o Infections would go unchecked
o Wounds would never heal
o Injured tissues might remain permanent festering sores
• Other cells of innate immunity:
o Natural killer cells
o Dendritic cells
o Epithelial cells
o Soluble factors such as the proteins of the complement
system
• Together, these components of innate immunity serve as the
first responders to infection
• Function to eliminate damaged cells and foreign bodies
• Inflammation is triggered by soluble factors that are
o Produced by various cells
o Derived from plasma CHONs
- Generated or activated in response to the inflammatory
stimulus by microbes, necrotic cells (whatever the cause
of cell death), and hypoxia
• Initiate and amplify the inflammatory response and
determine its pattern, severity and clinical and pathologic
manifestations
C. The typical inflammatory reaction develops through a series of
sequential steps:
1.Recognition of the injurious agent
o The offending agent, which is located in extravascular
tissues, is recognized by host cells and molecules.
 The cells involved in inflammation (tissue-resident
sentinel cells, phagocytes, and others) are equipped with
receptors that recognize microbial products and
substances released from damaged cells.
 Engagement of the receptors leads to the production of
mediators of inflammation, which then trigger the
subsequent steps in the inflammatory response.
EDITOR Calaycay 1
 2.Recruit of WBCs and plasma CHONs
o Activated and work together to destroy and eliminate the
offending substance
 When pathogenic microbes invade the tissues, or tissue
cells die, leukocytes (first mainly neutrophils, later
monocytes and lymphocytes) and plasma proteins are
rapidly recruited from the circulation to the extravascular
site where the offending agent is located.
3. Removal of the agent
 Accomplished mainly by phagocytic cells, which ingest
and destroy microbes and dead cells.
4. Regulation (control) of the response
 important for terminating the reaction when it has
accomplished its purpose.
5. Resolution and repair
 consists of a series of events that heal damaged tissue. In
this process the injured tissue is replaced through
regeneration of surviving cells and filling of residual
defects with connective tissue (scarring).
D. Components of Inflammatory Response
• Major participants of inflammatory response:
o Leukocytes
- Get recruited and activated to ingest and destroy
microbes, dead cells, foreign bodies and other unwanted
materials in the tissues
o Blood vessels
- Dilate and increase their permeability -> enabling selected
circulating proteins to enter the site of infection or tissue
damage.
 In addition, the endothelium lining blood vessels also
changes, such that circulating leukocytes adhere and then
migrate into the tissues.
 Leukocytes, once recruited, are activated and acquire the
ability to ingest and destroy microbes and dead cells, as
well as foreign bodies and other unwanted materials in
the tissues.

Figure 2. Components of Inflammatory Responses

E. Harmful Consequences of Inflammation

• Protective inflammatory reactions to infections are often
accompanied by:
o Local tissue damage
o Associated signs and symptoms (e.g. pain and functional
impairment)
• Harmful consequences are self-limited and resolve as the
inflammation abates leaving little or no permanent damage
• In cases wherein normally protective inflammatory reaction
become the cause of the disease, causing a dominant and
injurious damage:
o Autoimmune diseases: inflammatory reaction is
misdirected
o Allergies: occurs against normally harmless
environmental substances
• Inflammatory reactions underlie common chronic diseases such
as:
o Rheumatoid arthritis
Figure 1. Sequence of events in an inflammatory reaction. Sentinel cells o Atherosclerosis
in tissues (macrophages, dendritic cells, and other cell types) recognize o Lung fibrosis
microbes and damaged cells and liberate mediators, which trigger the
vascular and cellular reactions of inflammation.

PATHO – [03] Inflammation and Repair 2

 o Hypersensitivity reactions to insect bites, drugs, and o
If the response fails, the inflammation proceeds to
toxins chronic inflammation
• Anti-inflammatory drugs: which ideally would control the  Chronic inflammation
harmful sequelae of inflammation yet not interfere with its o may follow acute inflammation or arise de novo
beneficial effects o response to agents that are difficult to eradicate, such as
• Inflammation as a silent killer because it may contribute to a some bacteria (e.g., tubercle bacilli) and other pathogens
variety of diseases that are thought to be primarily metabolic, (such as viruses and fungi), as well as self-antigens and
degenerative, or genetic disorders, such as: environmental antigens
o Type II diabetes o longer duration and is associated with more tissue
o Alzheimer disease destruction and scarring (fibrosis)
o Cancer o presence of lymphocytes and macrophages
o proliferation of blood vessels
Table 1. Diseases Caused by Inflammatory Reactions o deposition of connective tissues
Cells and Molecules o more prominent in the reactions of the adaptive immunity
Disorders
Involved in Injury o may coexist with unresolved acute inflammation, as may
ACUTE occur in peptic ulcers
Acute respiratory distress Neutrophils • Termination of inflammation and initiation of tissue repair
syndrome o It is terminated when the offending agent is removed
Asthma Eosinophils; IgE antibodies o Mediators are broken down and dissipated
Glomerulonephritis Antibodies and complement; o Anti-inflammatory mechanisms are activated
neutrophils, monocytes o Tissue repair involves regeneration of the injured tissue
Septic shock Cytokines and deposition of connective tissue scarring.
CHRONIC
Table 2. Features of Acute and Chronic Inflammation
Arthritis Lymphocytes, macrophages;
antibodies? Feature Acute Chronic
Asthma Eosinophils; IgE antibodies Onset Fast: minutes or Slow: days
Atherosclerosis Macrophages; lymphocytes hours
Pulmonary fibrosis Macrophages; fibroblasts Cellular Mainly Monocytes/macrophages
Listed are selected examples of diseases in which the inflammatory response infiltrate neutrophils and lymphocytes
plays a significant role in tissue injury. Some, such as asthma, can present with Tissue injury, Usually mild and Often severe and
acute inflammation or a chronic illness with repeated bouts of acute fibrosis self-limited progressive
exacerbation. Local and Prominent Less
systemic signs
F. Local and Systemic Inflammation
• Local response Historical Highlights
o Largely confined to the site of infection or damage • Egyptian papyrus dated 3000 B.C
• Systemic response o Where clinical features of inflammation were described
o Sepsis: one form of Systemic Inflammatory Response and written in:
Syndrome such as in disseminated bacterial infections ❖ Four Cardinal Signs of Inflammation (Celsus):
causing widespread pathologic abnormalities ▪ Calor (heat)
▪ Rubor (redness)
G. Acute and Chronic Inflammation ▪ Tumor (swelling)
 The distinction between acute and chronic inflammation was ▪ Dolor (pain)
originally based on the duration of the reaction. ▪ Functio laesa (loss of function) – 5th cardinal
 Acute inflammation sign added by Rudolph Virchow (19th century)
o rapid, often self-limited • John Hunter
o response to offending agents that are readily eliminated, o Scottish surgeon
such as many bacteria and fungi, and dead cells o In 1793: “Inflammation is not a disease but a stereotypic
o typically develops within minutes or hours and is of short response that has a salutary effect on the host”
duration (several hours to a few days) • Elie Metchnikoff
o characterized by the exudation of fluid and plasma o Russian biologist
proteins (edema) and the emigration of leukocytes, o In 1880’s: discovered the process of phagocytosis by
predominantly neutrophils observing the ingestion of rose thorns by amebocytes of
o If the offending stimulus is eliminated, the reaction starfish larvae and of bacteria by mammalian leukocytes
subsides, and residual injury is repaired

PATHO – [03] Inflammation and Repair 3

 o Purpose of inflammation: to bring phagocytic cells to the Recognition of Microbes and Damaged Cells
injured area to engulf invading bacteria • First step in all inflammatory reactions
• George Bernard Shaw • The cells and receptors that perform this function of
o In his play “The Doctor’s Dilemma,” in which one recognizing invaders evolved as:
physician’s cure-all is to “stimulate the phagocytes!” Sir o Adaptation of multicellular organisms to the presence of
Thomas Lewis, studying the inflammatory response in microbes in the environment
skin, established the concept that chemical substances, o Responses they trigger are critical for the survival of the
such as histamine (produced locally in response to injury), organisms
mediate the vascular changes of inflammation A. Cellular Receptors
• Sense the presence of foreign substances
Causes of Inflammation • Plasma membrane: for extracellular microbes
1. Infections • Endosomes: for ingested microbes
o Bacterial, viral, fungal, parasitic infections and toxins • Cytosol: for intracellular microbes
o Most common and medically important cause of • Toll-like receptors (TLRs): where family of best defined of
inflammation receptors belong to.
o Elicit varied inflammatory response from acute to chronic
• trigger the production of molecules involved in inflammation
and from localized to systemic
• expressed on many cell types, including:
o Outcomes are determined largely by the type of
▪ Epithelial cells: through which microbes enter from the
pathogen and by characteristics of the host that remain
external environment
poorly defined
▪ Dendritic cells, macrophages, and other leukocytes:
which may encounter microbes in various tissue
2. Tissue necrosis
• Engagement of receptors triggers production of molecules
o Elicits inflammation regardless the cause of cell death
involved in inflammation, including:
which includes:
o Adhesion molecules on endothelial cells
o Ischemia: reduced blood flow, the cause of
o Cytokines and other mediators
myocardial infarction
o Trauma
B. Sensors of Cell Damage
o Physical and chemical injury
• All cells have cytosolic receptors (i.e.: NOD-like receptors
▪ E.g. thermal injury (burns or frostbite);
(NLRs)) that recognize molecules that are liberated or altered
irradiation; exposure to some
as a consequence of cell damage.
environmental chemicals
o Example of these molecules are:
o Molecules released from the necrotic cells trigger
▪ Uric acid: DNA breakdown product
inflammation
▪ ATP: released from damaged mitochondria
3. Foreign Bodies
▪ Reduced intracellular K+: loss of ions due to plasma
o May elicit inflammation by themselves or because they
membrane injury
cause traumatic tissue injury or carry microbes
▪ DNA: when not sequestered in the nuclei
o Can be exogenous or endogenous
 These receptors activate a multiprotein cytosolic complex
o Endogenous substances:
called the inflammasome, which induces the production of the
o Urate crystals: can cause gout
cytokine interleukin-1 (IL-1). IL-1 recruits leukocytes and thus
o Cholesterol crystals: can cause inflammation in
induces inflammation.
atherosclerosis
 Gain-of-function mutations in the genes encoding some of the
o Lipids: can cause inflammation in obesity-
receptors are the cause of rare diseases grouped under
associated metabolic syndrome
autoinflammatory syndromes that are characterized by
4. Immune Reactions/ Hypersensitivity
spontaneous IL-1 production and inflammation; IL-1 antagonists
o It is when normally protective immune system damages
are effective treatments for these disorders
individuals on tissues
 Inflammasome has also been implicated in inflammatory
o Autoimmune diseases: immune response is directed
reactions of the following:
against self-antigens
▪ Urate crystals: the cause of gout
o Allergies: a reaction against normal substances in the
▪ Lipids: metabolic syndrome and obesity-
environment
associated type 2 diabetes
o These are harder to cure because the inflammation is
▪ Cholesterol crystals: atherosclerosis
persistent
▪ Amyloid deposits in the brain: Alzheimer
o The inflammation of this kind is usually elicited by
disease
cytokines produced by T-lymphocytes

PATHO – [03] Inflammation and Repair 4

 C. Other Cellular Receptors
• Leukocytes: express receptors for the Fc tails of the antibodies
and for complement proteins
o These receptors recognize microbes coated with
antibodies and complement (the coating process is called
opsonization) and promote ingestion and destruction of
the microbes as well as inflammation
D. Circulating Proteins
• Complement system: reacts against microbes and produces
mediators of inflammation
• Mannose-binding lectin: circulating protein that recognizes
microbial sugars and promotes ingestion of the microbes and
the activation of the complement system
• Collectins: also bind to and combat microbes
• Classical pathway: recognizes pathogen’s surface
• Lectin pathway: mannose-binding lectin binds to mannose on
pathogen surface
• Alternative pathway: recognizes antigen-antibody complexes

ACUTE INFLAMMATION
• Initial, rapid response to infection and tissue damage
• Typically develops within minutes to hours Figure 3. Changes in vascular flow and caliber
• Short-lived, lasts for several hours or a few days
• More prominent in the reactions of the innate immunity C. Increased Vascular Permeability
• Its main characteristics are: • Increased permeability of post-capillary venules: a
o Exudation of fluid and plasma proteins (edema) hallmark of acute inflammation
o Leukocyte migration, predominantly neutrophils (PMN)
• If the inflammation achieves its desired goal, it subsides.
• If the response fails, the inflammation proceeds to chronic
inflammation.

 Three Major Components:

• Vasodilation, leading to an increase in blood flow
• Increased permeability of the microvasculature enabling
plasma proteins and leukocytes to leave the circulation
• Emigration of 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

A. Changes in Blood Flow and Permeability
• Both are designed to maximize the movement of plasma
proteins and leukocytes out of the circulation into the site
of injury

B. Changes in Vascular Flow and Caliber

• Histamine: primarily induce vasodilation
• Vasodilation: one of the earliest manifestations of acute
inflammation; first affects the arterioles leading to the
opening of new capillary beds

Figure 4. Principal mechanisms of increased vascular permeability in

inflammation and their features and underlying causes

PATHO – [03] Inflammation and Repair 5

 1. Contraction of endothelial cells resulting in increased
inter-endothelial spaces
• The most common mechanism of vascular leakage
• Mediated by histamine, bradykinins, and
leukotrienes
• Called as the Immediate Transient Response
o Because it occurs rapidly after exposure to
mediators, usually short-lived (15-30 minutes)
• Delayed prolonged leakage
• In mild injury such as burns, irradiation, ultraviolet
radiation, and exposure to certain bacterial toxins
• Vascular leakage begins after a delay of 2 to 12 hours
and lasts for several hours or even days

2. Endothelial injury resulting endothelial necrosis and

detachment
• Direct damage to the endothelium is encountered in
severe injuries such as:
o Burns
o Induced by the actions of microbes and
microbial toxins that target endothelial cells
• Neutrophils that adhere to the endothelium during
inflammation may also injure the endothelial cells
and thus amplify the reaction.
• Leakage starts immediately after injury → edema
and is sustained for several hours until the damaged
vessels are thrombosed or repaired

3. Transcytosis
• Increased transport of fluids and proteins through
the endothelial cell
• VEGF (Vascular Endothelial Growth Factor):
promotes vascular leakage
• Exudation: process by which fluid, proteins, and Figure 5. Normal, exudate and transudate
blood cells from the vascular system escapes into
the interstitial tissue or to the body cavities D. Responses of Lymphatic Vessels and Lymph Nodes
• Lymphatic vessels
Table 3. Exudate vs. Transudate
o Also participate in acute inflammation
Exudate Transudate o System of lymphatics and lymph nodes: filters and
Extravascular fluid Ultra-filtrate of polices the extravascular fluid
blood plasma o Normally drain the small amount of extravascular fluid
CHON High Low (mostly that has seeped out of capillaries
concentration albumin) o In inflammation:
Content Cellular debris Little or no cellular › Lymph flow is increased and help drain edema from
material injured tissues
› Leukocytes and cell debris, as well as microbes, may
Implication Increase in the Osmotic or
find their way into lymph
permeability of small hydrostatic
o Lymphatic vessels proliferate to handle increased work
blood vessels imbalance across
load.
triggered by some sort the vessel wall o Lymphangitis: secondarily inflamed lymphatics
of tissue injury and an without an increase o Lymphadenitis: when lymph nodes become enlarged and
ongoing inflammatory in vascular o lymph follicles undergo hyperplasia
reaction permeability o Reactive or Inflammatory Lymphadenitis: constellation of
Other feature Low specific gravity pathologic changes which involves inflamed lymph nodes
which are often enlarged because of hyperplasia of the
lymphoid follicles and increased numbers of lymphocytes
 Edema: denotes an excess of fluid in the interstitial tissue or and macrophages
serous cavities, can be both an exudate and transudate
 Pus: purulent exudate rich in leukocytes and cell debris

PATHO – [03] Inflammation and Repair 6

 o Presence of red streaks near a skin wound
› For clinicians, it is a telltale sign of an infection in the
wound
› Follows the course of the lymphatic channels and is
diagnostic of lymphangitis
Leukocyte Recruitment to Sites of Inflammation
• Changes in blood flow and permeability lead to an influx of
leukocyte in the tissues
• Role of leukocytes: perform the key function of eliminating the
offending agents
• Neutrophils and macrophages
o Most important leukocytes which are capable of
phagocytosis
• Leukocytes
o Ingest and digest necrotic tissues and destroy bacteria
and other microbes
o Also produce growth factors that aid in repair
o Strong activation can cause nearby tissue damage and
prolonged inflammation
A. Margination, Rolling, and Adhesion to the Endothelium
• Chemokines: are adhesion molecules and cytokines which
mediates and controls the journey of leukocytes from the
vessel lumen to the tissue
Leukocyte Adhesion to the Endothelium
• Red cells flow in the center of the blood vessel and displace
the leukocytes beside the wall of the endothelium.
• Due to stasis, more leukocytes are displaced to the
• periphery
• Margination: process of leukocyte redistribution
• Leukocytes adhere transiently into the endothelium,
detaching and binding again thus rolling in the endothelial
wall.
• Cells finally comes to a rest and adhere to the wall
• The attachment of leukocytes to endothelial cells is mediated
by complementary adhesion molecules on the two cell types
whose expression is enhanced by cytokines.
• Cytokines are secreted by sentinel cells in tissues in response
to microbes and other injurious agents, thus ensuring that
leukocytes are recruited to the tissues where these stimuli are
present.
• Selectins and integrins
o Two major molecules that play a role in leukocyte rolling
and adhesion
1. Selectins
• Mediates initial rolling interactions
• Three types:
o L-Selectin – expressed by leukocytes
o E-Selectin – expressed by the endothelium
o P-Selectin – expressed by platelets
• Ligands for selectins are sialylated oligosaccharides
bound to mucin-like glycoprotein backbones.
• The expression of selectins and their ligands is
regulated by cytokines produced in response to
infection and injury.
• Tissue macrophages, mast cells, and endothelial
cells that encounter microbes and dead tissues
PATHO – [03] Inflammation and Repair
respond by secreting several cytokines, including
tumor necrosis factor (TNF), IL-1, and chemokines
(chemoattractant cytokines).
• They have low affinity to the leukocyte, thus easily
disturbed by blood flow, promoting rolling of the
leukocyte.
• TNF and IL-1
o Induce expression of numerous adhesion
molecules
o Within 1 to 2 hours, the endothelial cells begin to
express E-selectin and the ligands for L-selectin
• Histamine and thrombin
o Stimulate redistribution of P-selectin from
normal intracellular stores in endothelial cell
granules (called Weibel-Palade bodies) to the
cell surface
• Leukocytes
o Express L-selectin at the tips of their microvilli
and also express ligands for E- and P-selectins, all
of which bind to the complementary molecules
on the endothelial cells
2. Integrins
• Family of heterodimeric leukocyte surface protein
that forms a firm adhesion
• TNF and IL-1 induce endothelial expression of
ligands for integrins, mainly:
o Vascular cell adhesion molecule 1 (VCAM-1):
ligand for the β1 integrin VLA-4
o Intercellular adhesion molecule-1 (ICAM-1):
ligand for the β2 integrins LFA-1 and Mac-1
• Leukocytes: normally express integrins in low-
affinity state
• Chemokines: from the injured cell activate the
rolling leukocyte and convert VLA-4 and LFA-1
integrins to a high-affinity state
• Firm integrin-mediated binding of the leukocytes
to the endothelium at the site of inflammation
• Done in combination of cytokine-induced
expression of integrin ligands on the
endothelium and increased integrin affinity
on the leukocytes results
• Once leukocyte stops rolling, it spreads out on the
endothelial surface.
B. Leukocyte Migration to the Endothelium
• Also called transmigration or diapedesis
• Occurs mainly in postcapillary venules
• Chemokines act on the leukocyte and stimulate the cell to
migrate in the inter-endothelial spaces.
• CD31 or PECAM-1
o Platelet endothelial cell adhesion molecule
o A member of the immunoglobulin superfamily
o An adhesion molecule is present in the intercellular
junction
• Leukocytes pierce the membrane by producing collagenases
and enter the extravascular tissue
• Leukocyte adhesion deficiency
o Type 1: defect in synthesis of B2 chain
o Type 2: absence of Sialyl-Lewis X
7
 Phagocytosis and Clearance of the Offending Agent
• Recognition of microbes or necrotic tissue lead to leukocyte
activation.
o Increase in cytosolic Ca++
o Activation of enzymes such as Protein Kinase A and
Phospholipase A2
• Most important functional responses for destruction of
microbes and other offenders
o Phagocytosis and intracellular killing
• Phagocytosis (3 steps)
1. Recognition and attachment of particle to be ingested
Figure 6. Multistep process of leukocyte migration through blood vessels
2. Engulfment
3. Killing or degradation dependent on polymerization
C. Chemotaxis of Leukocytes
A. Recognition and Attachment
• Migration in the tissue towards a chemical gradient
• Process wherein leukocytes move in the tissues toward the 1. Mannose Receptors
site of injury • Lectin that binds to terminal mannose and fructose
• Both exogenous and endogenous substances can produce residues of glycoproteins and glycolipids
chemotaxis. • These sugars are typically found in microbial cell
• Exogenous: walls.
o Bacterial products that contain N-formylmethionine • Mannose receptors recognizes microbes and not
• Endogenous: host cells
o Cytokines (those on chemokine family: IL-8) 2. Scavenger Receptors
o Complement proteins (C5a) • Binds and mediate endocytosis of oxidized or
o Arachidonic acid metabolites (leukotriene B4) acetylated LDL particles that can no longer interact
• All bind to the G-protein coupled receptor of the with conventional LDL receptors.
leukocyte  Phage scavenger receptors bind a variety of
• Results to an increase in intra-cytosolic Ca++ microbes in addition
o Macrophage integrin (Mac-1) may also bind
• Induce polymerization of actin at the leading edge of the
microbes
cell
3. Receptors for Opsonins
• Localization of myosin filaments at the back
• Opsonized bacteria coated with antibodies
• This results to an overall movement of the leukocyte to
 Enhance phagocytosis efficacy
the stimulus.
• Product of the complement system
B. Engulfment
 Nature of Leukocyte Infiltrate Varies with the Age of the
Inflammatory Response and Type of Stimulus • Extensions of the pseudopods flow around it and the
• Acute Inflammation plasma membrane pinches off to form a phagosome that
o Neutrophils: respond more quickly to encloses the particle.
cytokines and adhere better on the • The phagosome fuses with lysosomal granules resulting
endothelial wall in discharge of the granule’s contents into the
o Short-lived phagolysosome.
o 6 to 24 hours
• Chronic Inflammation C. Intracellular Destruction of Microbes and Debris
o Monocytes: can survive longer and can • Production of reactive oxygen species (ROS), reactive
multiply in the tissue nitrogen species, and lysosomal enzymes
o Long-lived • All of these are sequestered inside the lysosome.
o 24-48 hours  Accomplished by ROS (also called reactive oxygen
• Some exceptions intermediates) and reactive nitrogen species, mainly
o Pseudomonas infections derived from nitric oxide (NO), and these as well as
› Predominantly neutrophils for several lysosomal enzymes destroy phagocytosed debris
days
o Viral infections 1. Reactive Oxygen Species
› First cells to arrive are lymphocytes. • Produced by rapid oxidation of NADPH by NADPH
› Hypersensitivity reactions: dominated Oxidase (phagocyte oxidase). In the process,
by activated lymphocytes superoxide ion is produced.
o Allergic reactions • In neutrophils, they have hydrogen peroxide and
› Main cell types are eosinophils their azurophilic granules contain
myeloperoxidase.

PATHO – [03] Inflammation and Repair 8

 • Halogenation: in the presence of halides, such as • Other granules contain:
Cl, converts H2O2 to hypochlorite, an active o Defensins: cationic arginine-rich granule
ingredient of bleach, which is an efficient peptides toxic to microbes
bactericidal agent. o Cathelicidins: antimicrobial proteins
• H2O2 can also be converted to a hydroxyl radial o Lysozymes: hydrolyzes muramic acid in
(OH). NAG component of bacterial cell wall
• Respiratory burst: oxidative reaction of o Lactoferrin: iron-binding protein
neutrophils triggered by activating signals to o Major basic protein: cationic protein of
produce ROS eosinophils, toxic to most parasites
• ROS are produced within lysosome and
phagolysosome
• ROS are implicated in tissue damage
accompanying inflammation
• Antioxidant mechanisms of the body
o Superoxide dismutase → converts superoxide
to H2O2
o Catalase → converts H2O2 to H2O and O2
o Glutathione peroxidase → H2O2 detoxifier
o Ceruloplasmin
o Transferrin

2. Reactive Nitrogen Species

• Nitric oxide (NO) is a gas produced from arginine
via nitric oxide synthase.
• Three different types of nitric oxide synthetase:
o eNOS → endothelial NOS; maintenance of
vascular tone
o nNOS → neuronal NOS; neurotransmitter
o iNOS → induced NOS; involved in microbial
killing
• NO reacts with superoxide to form peroxynitrite
(ONOO), a highly reactive free radical.
• NO also relaxes vascular smooth muscle and
promotes vasodilation
3. Lysosomal Enzymes
• Neutrophils have two main types of granules:
1. Smaller specific (secondary)
o Lysozymes, collagenases,
gelatinases, lactoferrin, plasminogen
activator, histamine, alkaline
phosphatase
2. Larger specific (primary)
o Myeloperoxidase, bactericidal
factors, defensins, acid hydrolases,
neutral proteases (e.g. elastase,
cathepsin G, non-specific
collagenases, proteinase-3)
• Acid proteases: degrade bacteria and debris
within phagosomes
• Neutral proteases: capable of degrading
extracellular components; can also degrade c3,
producing amphylatoxins and release a kinin-
like peptide from kininogens
 The destructive effects of lysosomal enzymes
can potentiate further inflammation by
damaging tissues if unchecked
 Harmful proteases are normally controlled by
antiproteases
Figure 7. Stages of phagocytosis
D. Neutrophil Extracellular Traps
• Extracellular fibrillar networks that provide a high
concentration of antimicrobial substances at sites of
infection
• Prevent the spread of microbes by trapping them in the
fibrils
• NETs are produced by neutrophils in response to pathogens
and inflammatory mediators
• The extracellular traps consist of a viscous meshwork of
nuclear chromatin that binds and concentrates granule
proteins such as antimicrobial peptides and enzymes
• NETs have also been detected in the blood during sepsis
E. Antioxidant Mechanisms of the Body
• Superoxide dismutase: converts superoxide to H2O2
• Catalase: converts H2O2 to H2O at O2
• Glutathione peroxidase
• Ceruloplasmin and transferrin
F. Leukocyte-Mediated Tissue Injury
• In some infections which are hard to eradicate (e.g.
tuberculosis and viral diseases), the prolonged host
response contributes more and amplifies the pathology
than the microbe itself.
• Adjacent normal tissues may suffer collateral damage.
• Inappropriately directed against host tissues à autoimmune
• Excessive reaction against usual harmless substances à
allergy
• The mechanism by which leukocytes damage normal tissue
is the same as the mechanism involved in antimicrobial
defense

PATHO – [03] Inflammation and Repair 9

 • If phagocytes encounter materials that cannot be easily Table 6. Genetic defects in leukocyte function
ingested, such as immune complexes deposited on Disease Defect
immovable flat surfaces (e.g. glomerular basement Leukocyte Adhesion Def 1 Mutation in B chains of CD11 and
membrane), the inability of the leukocytes to surround and CD18 integrins
ingest these substances (frustrated phagocytosis) triggers Leukocyte Adhesion Def 2 Mutation in fucosyl transferase
strong activation, and the release of large amounts of
Chronic Granulomatous Decrease oxidative burst
lysosomal enzymes into the extracellular environment.
Disease
G. Other Functional Response of Activated Leukocytes Myeloperoxidase Defect myeloperoxidase H2O2
Chediak Higashi Mutation affecting protein
• Cytokines are produced to amplify or limit the inflammatory
reaction. Syndrome involved in lysosomal
• Growth factors are also secreted to stimulate the membrane traffic
proliferation of endothelial cells and fibroblasts.
• Synthesis of collagen and enzymes that remodel connective Table 7. Acquired defects in leukocyte function
tissue. Disease Defect
• Cells of adaptive immunity also contribute to acute Bone Marrow Suppression Production of leukocyte
inflammation via production of cytokine IL-17 secreted by Diabetes, Malignancy, Adhesion and chemotaxis
TH17 cells. Sepsis and Chronic Dialysis
• Absence of TH17 can make the individual susceptible to Leukemia, Anemia, Sepsis, Phagocytosis and microbicidal
fungal and bacterial infections and develop skin abscesses Diabetes and Malnutrition
that do not present with warmth or redness (cold-abscess).

Table 4. Clinical examples of acute leukocyte injury Termination of the Acute Inflammatory Response
Disease Molecules and Cell Involved • The host defense system has the capacity to cause tissue injury;
Acute Respiratory Neutrophils therefore, tight control systems are needed to minimize the
Distress Syndrome damage.
Acute Transplant Lymphocytes, Ab’s and complement • Inflammation declines when offending agents are removed
through the production of mediators in rapid bursts, only as
Rejection
long as the stimulus persists, have short half-lives, and are
Asthma Eosinophil, IgE, Ab’s degraded after their release (neutrophils die by apoptosis after
Glomerulonephritis Neutrophils, monocytes, AB’s and a few hours after leaving the blood).
complement • Stop signals are produced as inflammation develops.
Septic Shock Cytokines • Active termination mechanisms:
Lung Abscess Neutrophil o Switch in the type of arachidonic acid metabolite
produced, from proinflammatory leukotrienes to anti-
inflammatory lipoxins
Table 5. Clinical examples of chronic leukocyte injury
o Liberation of anti-inflammatory cytokines, including
Disease Molecules and Cell Involved transforming growth factor-β (TGFΒ) and IL-10, from
Arthritis Lymphocyte and macrophage macrophages and other cells
Asthma Eosinophil, IgE, Ab’s o Other control mechanisms: neural impulses (cholinergic
Atherosclerosis Macrophage and lymphocyte discharge) that inhibit production of TNF in
macrophages
Chronic Transplant Lymphocyte and cytokines
• Mediators of inflammation are produced in rapid burst, as long
Rejection
as stimulus persists.
Pulmonary Fibrosis Macrophage and fibroblast • Short half-lives
• Degraded after their release
H. Defects in Leukocyte Function • Production of anti-inflammatory lipoxins, anti-inflammatory
• Inherited defect in leukocyte adhesion → defect of integrin cytokines, anti-inflammatory lipid mediators
and selectin ligands → recurrent bacterial infection • The inflammatory reaction itself triggers a variety of stop
• Inherited defect in phagolysosome function such that of signals that actively terminate the reaction.
Chediak Higashi syndrome
• Inherited defects in microbicidal activity → chronic Mediators of Inflammation
granulomatous disease → inherited defects in the genes • Substances that initiate and regulate inflammatory reactions
encoding components of phagocyte oxidase • Can either be secreted by cells or generated from plasma proteins
• Acquired deficiencies • Most important mediators are:
o Marrow suppression o Vasoactive amines
o Mast cells and macrophages o Lipid products (prostaglandins and leukotrienes)
o Cytokines (including chemokines)
o Products of complement activation
• These mediators induce various components of the
inflammatory response typically by distinct mechanism.
• Thus, inhibiting each has been therapeutically beneficial.

PATHO – [03] Inflammation and Repair 10

 • It can either be secreted by cells or generated from plasma
proteins:
o Cell-derived molecules
▪ Sequestered in intracellular granules
▪ Can be synthesized de novo
▪ Major cell types are the sentinels that detect
invaders and damage in tissues which are:
 Macrophages, dendritic cells, and mast cells:
major cell types that produce mediators of
acute inflammation that detect invaders and
damage in tissues
o Plasma-derived molecules (complement protein)
▪ Produced mainly in the liver
▪ Present in circulation as inactive precursor
▪ Must be activated by a series of proteolytic cleavage
• These mediators are produced as a response to a stimulus
which include microbial products and substances from necrotic
cells.
• Some stimuli trigger well-defined receptors and signaling
pathways.
• The usual requirement for microbes or dead tissues as the
initiating stimulus ensures that inflammation is normally
triggered only when and where it is needed.
• Most of these mediators are short-lived (they quickly decay,
inactivated by enzymes, scavenged or inhibited).
• A system of checks and balances regulated mediator actions
• One mediator can stimulate the release of another.
• Complement activation can stimulate histamine release →
cytokine TNF acts on endothelial cell → TNF can stimulate and
produce IL-1 and many chemokines
• Such cascades can provide mechanisms for amplification
A. Vasoactive Amines
• Two major amines are histamine and serotonin
• Both are stored as preformed molecule
1. Histamine
• Richest source are the mast cells, also found in
basophils and platelets
• Principal mediator of the immediate transient phase
of increased vascular permeability
• Also causes contraction of some smooth muscle
• Mast cells secrete histamine due to various stimuli
o Physical injury
o Binding of antibodies to mast cells –
products of complement called
anaphylatoxins
• Neuropeptides (substance P) and cytokines (IL-8)
• Binding of antibodies to mast cells
• Histamine causes dilation of arterioles and increases
the permeability of venules
• Histamine binds to H1 receptors to increase vascular
permeability and produce inter-endothelial gap
2. Serotonin
• 5-hydroxytryptamine
• Present in platelets and certain neuroendocrine
cells
• Primarily functions as a neurotransmitter
• It is a potent vasoconstrictor, but its importance in
inflammation is unclear
PATHO – [03] Inflammation and Repair
B. Arachidonic Acid (AA) Metabolite
• Increase in cytosolic Ca++ and activation of various kinases due
to mediators causes activation of phospholipase A2 to produce
eicosanoids:
o Prostaglandins
o Leukotrienes
• Cyclooxygenase enzyme produces prostaglandins.
• Lipoxygenase enzyme produces leukotrienes and lipoxins.
1. Prostaglandin
• Produced by mast cells, macrophages, endothelial
cells and many other cell types
• Generated by cyclooxygenases (COX-1 and COX-2)
• COX-1 is responsible for the production of
prostaglandins that are involved both in
inflammation and homeostatic functions.
• COX-2 is responsible only for inflammation.
• Prostaglandins involved in inflammation:
o PGE2, PGD2, PGF2: causes vasodilation and
increases permeability of post capillary
venules
o PGI2 (Prostacyclins): vasodilator and
inhibitor of platelet aggregation
o TXA2 (Thromboxane A2): vasoconstrictor
and platelet-aggregating agent
• PG’s are also involved in fever and pain
• PGE2 is hyperalgesic and makes the skin
hypersensitive to painful stimuli.
2. Leukotrienes
• Produced by leukocytes and mast cells by the action
of lipoxygenases.
• Involved in vascular and smooth muscle reactions
and leukocyte recruitment
3. Lipoxin
• Also generated by lipoxygenases but it is anti-
inflammatory
• 5-lipoxygenase in neutrophils convert arachidonic
acid to 5-hydroxyeicosatetraenoic acid, which is
chemotactic to neutrophils and a precursor of
leukotrienes
• LTB4 is a potent chemotactic agent and activator of
neutrophils
• LTC4, a cysteinyl-containing leukotriene, cause
intense vasoconstriction and bronchoconstriction,
and increase permeability of venules.
• It suppresses inflammation by inhibiting
recruitment of leukocytes.
• They inhibit neutrophil chemotaxis and adhesion to
endothelium
11
 Table 8. Principal mediators of inflammation

Mediator Source Action

Histamine Mast cells, basophils, platelets Vasodilation, increased vascular permeability,
endothelial activation
Prostaglandins Mast cells, leukocytes Vasodilation, pain and fever
Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis,
leukocytes adhesion and activation
Cytokines (TNF, IL-1, IL-6) Macrophages, endothelial cells, mast cells Local: endothelial activation (expression of
adhesion molecules)
Systemic: fever, metabolic abnormalities,
hypotension (shock)
Chemokines Leukocytes, mast cells Chemotaxis, leukocyte activation

Platelet-activating factor Leukocytes, activated macrophages Vasodilation, increased vascular permeability,

leukocyte adhesion, chemotaxis, degranulation,
oxidative burst
Complement Plasma (produced in liver) Leukocyte chemotaxis and activation, direct target
killing (membrane attack complex), vasodilation
(mast cell stimulation)
Kinins Plasma (produce in liver) Increased vascular permeability, smooth muscle
contraction, vasodilation, pain

Figure 8. Production of arachidonic acid metabolites and their roles

PATHO – [03] Inflammation and Repair 12

 C. Pharmacologic Inhibitors of Prostaglandins and 3. Chemokines
Leukotrienes • A family of small (8-10kD) proteins that act primarily
1. Cyclooxygenase inhibitors as chemoattractant for specific types of leukocytes
• Aspirin and other NSAIDs (non-steroidal anti- • There are about 40 different chemokines classified
inflammatory drugs) into 4 major groups according to the arrangement
• Non-selective cyclooxygenase inhibitor inhibits both of cysteine residues:
COX-1 and COX-2 by irreversibly acetylating and • Function:
inactivating cyclooxygenases o Chemokines bind to G-protein coupled
• COX-2 selective inhibitor – does not inhibit COX-1 receptors
• COX-2 inhibitor – only inhibit inflammatory o In acute inflammation, inflammatory
processes but not the homeostatic processes of chemokines:
COX-1 ▪ Stimulate leukocyte attachment to the
endothelium
2. Lipoxygenase inhibitors ▪ Increase affinity of integrins
▪ Stimulate chemotactic migration
• Not affected by NSAID
▪ Maintenance of tissue architecture, by
• Zileuton inhibits 5-lipoxygenase, inhibiting homeostatic chemokines which
leukotriene production organize various cell types in different
anatomic regions
3. Corticosteroid
• Reduce transcription of genes encoding for COX-2, Table 9. Cytokines and chemokines.
Phospholipase A2, Pro-inflammatory cytokines, and Eicosanoid Action
iNOS C–X–C • One of amino acid residue separates the
Chemokines first 2 of the 4 conserved cysteine residue
4. Leukotriene receptor antagonist • Acts primarily on neutrophils
• Blocks leukotriene receptors and prevent its action • IL-8 is typical
o E.g. Montelukast – used for asthma; blocks C–C • First 2 conserved Cys group are adjusted
the leukotrienes to prevent the occurrence of Chemokines to each other
the symptoms of asthma • Attracts monocytes, eosinophils,
basophils, and lymphocytes
D. Cytokines and Chemokines
• Examples:
1. Cytokines o MCP-1 (monocyte chemoattractant
• These are proteins produced by many types of cells protein)
that mediate and regulate immune and o MIP-1α (macrophage inflammatory
inflammatory reactions (growth factors that act on protein)
epithelial and mesenchymal cells are not grouped o RANTES (Regulated on Activation
under cytokines). Normal T cell Expressed and
• Most common: 4 and 8 Secreted)
C • Lacks the 1st and 3rd of the 4 conserve Cys
2. TNF-1 and IL-1 Chemokines groups
• Serve critical roles in leukocyte recruitment by • Specific for lymphocytes
promoting adhesion of leukocyte to the CX3 • Contain 3 amino acids in between the 2
endothelium and their migration through vessels cysteines
• Mainly produced by activated macrophages and • Fractalkine is the only known member
dendritic cells • Two forms
• TNF can also be produced by T-lymphocytes and o Cell surface bound protein:
mast cells promotes strong adhesion of
• IL-1 can also be produced by some epithelial cells monocytes and T cells
• Actions of TNF and IL-1: o Soluble form is chemoattractant
o Endothelial activation – expression of P and
E selectin adhesion molecules E. Platelet-Activating Factor (PAF)
o Activation of leukocytes and other cells – • Phospholipid derived mediator
activates fibroblasts to synthesize collagen, o Platelet aggregation, vasoconstriction,
and stimulate proliferation of synovial and bronchoconstriction
mesenchymal cells o Secreted by platelets, basophils, mast cells, neutrophils,
o Systemic acute phase response – induce macrophages, endothelial cells
systemic responses such as fever. TNF o At low concentration – may induce vasodilation and
regulates energy balance to lipid and protein increased venular permeability
mobilization and suppresses the appetite
center.
 TNF antagonist have been remarkably effective in
the treatment of chronic inflammatory diseases,
e.g. rheumatoid arthritis, psoriasis

PATHO – [03] Inflammation and Repair 13

 Morphologic Patterns of Acute Inflammation
• The morphologic hallmarks of acute inflammatory reactions are
dilation of small blood vessels and accumulation of leukocytes
and fluid in the extravascular tissue.
• Recognizing the gross and microscopic provide valuable clues
about the underlying cause.
A. Serous Inflammation
• Marked by the exudation of cell-poor fluid into the spaces
created by cell injury.
• Fluids in serious exudation are not filled with destructive
organisms and do not contain leukocytes.
• It is usually derived from the plasma or the secretion of
mesothelial cells.
• Accumulation of fluid in the cavities is called an effusion.
Figure 9. Cross-section of skin blister showing the separation of epidermis
from the dermis by local serous effusion.
B. Fibrinous Inflammation
• Due to increased vascular permeability, large molecules such as
fibrinogen pass out the blood and forms fibrin deposits in the
extracellular space.
• Fibrin appears as an eosinophilic meshwork of threads
sometimes an amorphous coagulum.
• If fibrin is not removed, it stimulates the ingrowth of fibroblasts
and angiogenesis.
• A fibrinous exudate develops when the vascular leaks are large
or there is a local procoagulant stimulus
• Fibrinous exudate is characteristic of inflammation in the lining
of body cavities, such as the meninges, pericardium, and pleura.
Figure 10. (Left) Fibrous pericarditis, seen grossly are fibrin deposits in the
pericardium; (Right) Microscopically, a pink meshwork of fibrin exudates [F]
overlying the pericardium [P].
C. Purulent/Suppurative Inflammation
• Characterized by production of pus
o Pus is an exudate containing neutrophils, liquefied
debris of necrotic cell, and edema fluid.
PATHO – [03] Inflammation and Repair
• Most frequent cause is bacterial infection that causes
liquefactive necrosis, such as Staphylococci which is pyogenic
bacteria (pus-forming).
• Abscesses are localized collection of purulent inflammation
confined in a space with a central region that appears as a mass
of necrotic leukocytes and tissue cells.
Figure 11. (Left) Multiple bacterial abscesses in the lungs in a case of
bronchopneumonia; (Right) Abscess contains neutrophils and cellular debris.
Surrounded by congested blood vessels.
D. Ulcers
• It is a local defect or excavation produced by the sloughing of
inflamed necrotic tissue.
• It is most commonly encountered in the mucosa of the mouth,
stomach, intestines, GIT, skin, and subcutaneous tissue of
lower extremities.
o Best exemplified by peptic ulcer of the stomach or
duodenum.
• There is intense polymorphonuclear (PMN) infiltration with
vasodilation.
• Chronic ulcers develop fibroblastic proliferation, scarring, and
accumulation of lymphocytes, macrophages, and plasma cells.
Figure 12. (Left) Chronic duodenal ulcer; (Right) Cross-section of a duodenal
crater with acute inflammatory exudate in the base.
Outcomes of Acute Inflammation
• All acute inflammatory reactions typically have 1 of 3 outcomes
A. Complete Resolution
• Restoration of the site of acute inflammation to normal called
resolution
• Involves removal of cellular debris and microbes by
macrophages, and resorption of edema fluid by lymphatics
B. Healing by Connective Tissue Replacement (Scarring or
Fibrosis)
• Occurs when the inflammatory injury involves tissues that are
incapable of regeneration or when there is abundant fibrin
exudation in tissue or in serous cavities which was not cleared
o Connective tissue grows in area of damage or exudate.
o Converting it into a mass of fibrous tissue, a process also
called organization.
14
 Figure 13. Outcomes of acute inflammation

C. Progression of the Response to Chronic Inflammation CHRONIC INFLAMMATION

• Occurs when the acute inflammatory response cannot be • Longer in duration
resolved • Associated with more tissue destruction
o A result of either the persistence of the injurious agent
• Presence of lymphocytes and macrophages
or some interference with the normal process of healing
• Proliferation of blood vessels
• Deposition of connective tissues
Summary of Acute Inflammation • More prominent in the reactions of the adaptive immunity
1. Host encounters injurious agent • A response of prolonged duration (weeks or months) in which
2. Phagocytes try to eliminate agents inflammation, tissue injury, and attempts at repair coexist, in
3. Phagocytes will react on host cells via presence of varying combinations
foreign substances (cytokines, mediators, etc.) • May follow acute inflammation
4. Mediators promotes recruitments of leukocytes • May begin insidiously, as a low-grade, smoldering response
5. Leukocytes try to remove offenders via phagocytosis without any manifestations of a preceding acute reaction
6. Agents eliminated
7. Anti-inflammatory mechanism activated Causes of Chronic Inflammation
8. Process subsides
A. Persistent Infection
9. Host cell return to normal state of health
• Microorganisms that are hard to eradicate
 Failure to remove agent quickly will lead to chronic • Tuberculosis and viral infections
inflammation. • Evokes an immune reaction called delayed-type
• The vascular and cellular reactions account for the signs and hypersensitivity
symptoms of the inflammatory response. • Takes a specific pattern of granulomatous reaction
• Increased blood flow to the injured area and increase vascular
permeability lead to the accumulation of extravascular fluid rich B. Hypersensitivity Diseases
in plasma proteins, known as edema. • Excessive and inappropriate activation of the immune system
• Redness (rubor), warmth (calor), and swelling (tumor) of acute o Autoimmune diseases
inflammation are caused by the increased blood flow and ▪ Immune reaction against self-antigens
edema. ▪ Auto-antigens evoke a self-perpetuating immune
• Circulating leukocytes, initially predominantly neutrophils reaction
• During the damage, and liberation of prostaglandins, ▪ Results in chronic tissue damage and inflammation
neuropeptides, and cytokines, one local symptom is pain ▪ E.g. rheumatoid arthritis and multiple sclerosis
(dolor). o Allergies
▪ Response against common environmental
substances
▪ E.g. bronchial asthma

PATHO – [03] Inflammation and Repair 15

 ▪ Reactions serve no useful purpose and only cause C. Major Pathways of Macrophage Activation
disease 1. Classic Activation
• Induced by:
C. Prolonged Exposure to Toxic Agents
o Microbial endotoxins: engage TLRs and other
• Silicosis: prolonged inhalation of silicon sensors
• Atherosclerosis: prolonged deposition in the arterial walls o T cell-derived signals
o Cytokine IFN-γ in immune responses
Morphologic Features o Foreign substances (crystals and particulate
• Infiltration with mononuclear cells matter)
o Includes macrophages, lymphocytes, and plasma cells o Classically activated (also called M1)
• Tissue destruction macrophages produce NO and ROS and
o Induced by persistent offending agent or the inflammatory upregulate lysosomal enzymes
cells • Enhance their ability to kill ingested organisms
• Attempts at healing • Secrete cytokines that stimulate inflammation
o Via connective tissue replacement of damaged tissue, • Important in host defense against microbes and in many
accomplished by angiogenesis and fibrosis inflammatory reactions
• Same activated cells are capable of injuring normal
tissue

2. Alternative Activation
• Induced by:
o Cytokines other than IFN-γ (IL-4 and IL-13)
o T-lymphocytes and other cells
• Not actively microbicidal
• Cytokines may actually inhibit the classical activation
pathway
• Principal function: tissue repair
• Secrete growth factors
o Promote angiogenesis
o Activate fibroblast
o Stimulate collagen synthesis
Figure 14. Chronic inflammation in the lung, showing all three characteristic
histologic features: (1) collection of chronic inflammatory cells (asterisk), (2)
destruction of parenchyma (normal alveoli are replaced by spaces lined by
cuboidal epithelium) (arrowheads), and (3) replacement by connective tissue
(fibrosis) (arrows).

Cells and Mediators of Chronic Inflammation

A. Macrophages
• Dominant cells in chronic inflammation.
• Contribute by:
o Secreting cytokines and growth factors
o Destroying foreign invaders and tissues
o Activate other cells, notable T lymphocytes
• Originates from the bone marrow and in the fetal yolk sac and
Figure 15. Two pathways of activation of T lymphocytes.
liver during embryogenesis
• Found in specific locations:
o Von-Kupffer cells – liver D. Lymphocytes
o Alveolar macrophages – lungs • Amplify and propagate chronic inflammation
o Histiocytes – lymph nodes • Major function: mediators of adaptive immunity
o Microglia – CNS o Provides defense against infectious pathogens
• Collectively known as the Mononuclear Phagocyte System or • Dominant population in autoimmune and hypersensitivity
the Reticuloendothelial System (RES) diseases
• Antigen-stimulated (effector and memory) T and B
B. Function in Tissue Injury lymphocytes
• Blood monocytes last for about 1 day, but tissue macrophages o Use various adhesion molecule pairs (selectins,
can last up to days and weeks integrins, and their ligands) and chemokines to
• Ingest and eliminate microbes and dead tissue migrate into inflammatory sites
• Initiate the process of tissue repair • Cytokines from activated macrophages
• Also secrete mediators of inflammation o TNF, IL1, and chemokines
• Present antigens to T lymphocytes o Promote leukocyte recruitment, setting the stage for
persistence of the inflammatory response

PATHO – [03] Inflammation and Repair 16

 • Mobilized in both antibody-mediated and cell-mediated Granulomas Inflammation
immune reactions • Characterized by collections of activated macrophages, often
• Lymphocytes and macrophages interact in a bidirectional T lymphocytes and sometimes associated with central
way. Macrophages display antigens to T cells and produce necrosis
membrane molecules and cytokines that stimulate T cell • A cellular attempt to contain an offending agent that is
responses difficult to eradicate
• CD4 + T cells promote inflammation and influence the • Strong lymphocytes lead to macrophage activation and cause
nature of the inflammatory reaction, consists of 3 injury to normal tissues
subsets: • Epitheloid cells are activated macrophages that develop
o TH1 – produces IFN-γ, stimulates macrophages via abundant cytoplasm and begin to resemble epithelial cells
the classical pathway • Giant cells are fused, multinucleated activated macrophages
o TH2 – produces IL-4, IL-5, and IL-13 that activates
eosinophils and stimulates macrophages via the
Table 10. Granulomatous inflammation.
alternative pathway
Disease Cause Tissue Reaction
• TH17 – produces IL-17 and cytokines that induces the
release of chemokines to attract neutrophils and TB M. Acid-fast bacilli,
monocytes tuberculosis Caseating granuloma
Leprosy M. leprae Acid-fast bacilli,
Non-caseating granuloma
Syphilis T. pallidum Gumma
Cat Scratch Gram (-) Rounded or stellate
Disease bacillus granuloma
Sarcoidosis Unknown Non-caseating granuloma
with abundant activated
macrophages

Crohn’s Disease Immune Non-caseating

reaction granulomas in the
intestine with dense
chronic inflammation

Figure 16. Macrophage-lymphocyte interactions in chronic inflammation.
Activated T cells produce cytokines that recruit macrophages (THF, IL-17,
chemokines) and others that activate macrophages, in turn stimulate T cells
by presenting antigens and via cytokines such as IL-12.
E. Plasma Cells
• Activated B lymphocytes that produce antibodies
• In some chronic inflammations, lymphocytes, antigen-
presenting cells, and plasma cells cluster together to
form a lymphoid tissue called Tertiary Lymphoid Organ
F. Eosinophils
• Immune reaction mediated by IgE and in parasitic
infections
• Contains major basic protein which highly cationic and
toxic to parasites, and also causes lysis of mammalian
epithelial tissues
G. Mast Cells
• Widely distributed in connective tissues
• Participate in both acute and chronic inflammatory
reactions
• Bind to Fc portion of IgE antibodies
• Secrete plethora of cytokines
H. Neutrophils
• Though these are more abundant in acute inflammation,
they can be seen in large numbers in some forms of
chronic inflammation (e.g. prolonged bacterial infection)
TYPES OF GRANULOMAS
A. Foreign Body Granuloma
• Incited by inert foreign bodies
• Does not elicit an immune reaction
• These granulomas form around talc, sutures, or other
fibers that are large enough to preclude phagocytosis by
macrophages
• Epitheloid and giant cells are apposed to the surface
B. Immune Granuloma
• Caused by variety of agents capable of eliciting an
immune reaction
• This happens when the inciting agent is difficult to
eradicate
• In such instances, macrophage activates T cells to
produce cytokines (e.g. IL-2) that activates other T cells
• IFN-γ from T cells activates macrophages
SYSTEMIC EFFECTS OF INFLAMMATION
• Even if localized, is associated with cytokine induced
systemic reactions that are collectively called the acute-
phase response.
• It is mediated by TNF, IL-1, IL-6 and Type 1 interferons.
ACUTE PHASE RESPONSE
• Defective inflammation is responsible for increased
susceptibility to infections.
• Commonly caused by leukocyte deficiency
A. Fever
• 1° to 4°C increase of body temperature

PATHO – [03] Inflammation and Repair 17

 • When inflammation is associated with infection
• Caused by pyrogenic molecules
o Pyrogens are substances that induce fever
• Increase in body temperature is caused by prostaglandins D.
that are produced in the vascular and perivascular cells of
the hypothalamus
• May induce heat shock proteins that enhance lymphocyte
responses to microbial antigens
B. Acute-phase proteins
• Plasma proteins synthesized in the liver
• Increases hundred-fold as a part of response to
inflammation E.
• Three major proteins:
▪ C-Reactive Protein (CRP)
- Synthesis is stimulated by IL-6
▪ Fibrinogen
- Synthesis is stimulated by IL-6
▪ Serum Amyloid A (SAA)
- Synthesis is stimulated by IL-1 or TNF
• CRP and SAA
o Bind to microbial cell walls → act as opsonins
→fix complement
o Bind chromatin → aid in clearing necrotic cell
nuclei
• Fibrinogen F.
o Binds to red cells → form stacks (rouleaux)
o Have beneficial effects during acute
inflammation
G.
o Prolonged production of these proteins
(especially SAA) in states of chronic
inflammation causes secondary amyloidosis
• Iron regulating peptide hepcidin
o Production is increased
C. Leukocytosis
• Usually climbs to 15,000-20,000 cells per mL
• Leukemoid reactions – if it reaches high levels (40-
100,000)
• Increased pulse, blood pressure, and decreased sweating
– due to the redirection of blood flow from cutaneous to
deep vascular beds
• Occurs initially because of accelerated release of cells
from the bone marrow postmitotic reserve pool A.
• Left shift – rise in the number of more immature
neutrophils in the blood
• Prolonged infection
o Induces proliferation of precursors in the bone
marrow
o Caused by increased production of colony-
stimulating factors
o Bone marrow output of leukocytes is increased
→compensate for the loss of these cells
• Microbial infections
o Neutrophilia: increase in the blood neutrophil B.
count
• Viral infections
o Lymphocytosis: absolute increase in the
number of lymphocytes
• Parasitic infections and allergies
o Eosinophilia: absolute number of eosinophils
• Certain infections: typhoid fever and infections caused by
some viruses, rickettsiae, and certain protozoa
o Leukopenia: decreased number of circulating
white cells
Other Manifestations
• Increased pulse and blood pressure
• Decreased sweating
• Rigors (shivering)
• Chills (search for warmth)
• Anorexia
• Somnolence
• Malaise
Sepsis
• Severe bacterial infections
• Large amounts of bacteria and their products in the blood
stimulate the production of enormous quantities of
several cytokines
• High blood levels of cytokines in various widespread
clinical manifestations
o Disseminated intravascular coagulation
o Hypotensive shock
o Metabolic disturbances (insulin resistance and
hyperglycemia)
 This clinical triad is known as septic shock
Excessive inflammation
• Underlying cause of many human diseases
Defective inflammation
• Responsible for increased susceptibility to infections
• Commonly caused by leukocyte deficiency
TISSUE REPAIR
• Also called healing
• Refers to the restoration of tissue architecture and function
after an injury
• Depends on the type of wound, inflammatory process, matrix
damage, and the organ’s capability to divide
• Consists of a combination of regeneration and scar formation
by collagen deposition
Overview of Tissue Repair
Regeneration
• Occurs by proliferation of cells and tissues
• Replace the structures and function
• Some tissues can replace the damaged component and
return to normal
o In the rapidly dividing epithelia of the skin and
intestines
o In some parenchymal organs, notably the liver
• Check figure 17
Connective Tissue Deposition (Scar Formation)
• Occurs in injured tissues incapable of complete restitution
• Also occur if the supporting structures of the tissue are
severely damaged
• Fibrosis – extensive deposition of collagen that occurs in
the lungs, liver, kidney, and other organs as a
consequence of chronic inflammation, or in the
myocardium after extensive ischemic necrosis
(infarction)

PATHO – [03] Inflammation and Repair 18

 • Organization – when fibrosis develops in a tissue space o Endothelial cells
occupied by inflammatory exudates o Fibroblasts
o Smooth muscle cells
 However, they have the limited capacity to regenerate
after an injury, except for the liver.

C. Permanent Tissues
• Tissues that are terminally differentiated and non-
proliferative
• Examples:
o Neurons and cardiac muscles are permanent
tissues
o Tissues in the G0 phase of the cell cycle
 In permanent tissues, repair is typically dominated by scar
formation
 Cell proliferation is driven by signals provided by growth
factors and from the extracellular matrix. The most
important sources of these growth factors are
macrophages that are activated by the tissue injury, but
epithelial and stromal cells also produce some of these
factors. In the process of regeneration, proliferation of
residual cells is supplemented by development of mature
cells from stem cells.

Organ Regeneration
• Mammals cannot regenerate a whole organ, or a whole tissue
because mammals:
o Do not form blastema
o Rapid fibroproliferative response after injury
o Wnt / β-cathetin is highly conservative

Figure 17. Liver regeneration and repair

Cell and Tissue Regeneration

• Ability of tissues to repair themselves is determined, in part,
by their intrinsic proliferative capacity
• Body tissues can be divided in to 3 depending on their
proliferative activity:
A. Labile Tissues
• Continuously dividing tissues consistently lost and
replaced
• Proliferates all throughout life
• These tissues can readily regenerate after injury as long
as the pool of stem cells is preserved Figure 18. Organ regeneration of liver
• Examples:
o Hematopoietic cells (bone marrow) • Restoration of liver mass is achieved without the
o Stratified squamous epithelia – oral cavity, regrowth of the lobes that were resected
vagina, cervix • Involves 2 major mechanisms:
o Cuboidal epithelia – ducts of exocrine organs o Proliferation of remaining hepatocytes
o Columnar epithelia – lining of the GIT, uterus, o Repopulation from progenitor cells
fallopian tube • Compensatory growth (restitution of functional mass
o Transitional epithelia – lining of the urinary rather than form)
bladder • Almost all hepatocytes replicate during liver regeneration
B. Stable Tissues • Triggered by combined actions of cytokines and
• Quiescent tissues in the G0 phase of the cell cycle polypeptide growth factors
• Only minimal proliferative activity in their normal state
• Capable of dividing in response to injury or loss of tissue Repair by Connective Tissue Deposition
mass  If repair cannot be accomplished by regeneration alone, it
• Examples: occurs by replacement of the injured cells with connective
o Parenchyma of solid organs – liver, kidney,
pancreas

PATHO – [03] Inflammation and Repair 19

 tissue, leading to the formation of a scar, or by a combination
of regeneration of some residual cells and scar formation.
A. STEPS IN SCAR FORMATION
Figure 19. Steps in scar formation.
1. Inflammation
 Breakdown products of complement activation,
chemokines released from activated platelets, and other
mediators produced at the site of injury function as
chemotactic agents to recruit neutrophils and then
monocytes over the next 6 to 48 hours.
 These inflammatory cells eliminate the offending agents,
such as microbes that may have entered through the
wound, and clear the debris. As the injurious agents and
necrotic cells are cleared, the inflammation resolves.
2. Angiogenesis
• Formation of new blood vessels, which supply nutrients
and oxygen needed to support the repair process
• Newly formed vessels are leaky because of incomplete
inter-endothelial junctions and because VEGF, the growth
factor that drives angiogenesis, increases vascular
permeability
3. Migration and proliferation of fibroblast
• Include deposition of loose connective tissue, together
with the vessels and interspersed leukocytes, form
granulation tissue
4. Connective tissue remodeling
• Maturation and reorganization of the connective tissue
(remodeling) produce the stable fibrous scar
5. Scar formation
 Macrophages play a central role in repair by clearing
offending agents and dead tissue, providing growth
factors for the proliferation of various cells, and secreting
cytokines that stimulate fibroblast proliferation and
connective tissue synthesis and deposition. The
macrophages that are involved in repair are mostly of the
alternatively activated (M2) type. Repair begins within 24
hours of injury by the emigration of fibroblasts and the
PATHO – [03] Inflammation and Repair
induction of fibroblast and endothelial cell proliferation.
By 3 to 5 days, the specialized granulation tissue that is
characteristic of healing is apparent.
B. ANGIOGENESIS
• Angiogenesis can be via:
o Proliferation from endothelial precursor cells
(EPC)
o Formation from pre-existing vessels
• Growth Factors Involved in Angiogenesis
o VEGF (vascular endothelial growth factor)
stimulates both migration and proliferation of
endothelial cells
o FGF-2 (fibroblast growth factor) stimulates
proliferation of endothelial cells and migration
of macrophage and fibroblasts in the damaged
area
o Angiopoietins 1 and 2 plays a role in
angiogenesis and structural maturation of new
vessels. Newly formed vessels need to be
stabilized via recruitment of pericytes and
smooth muscles, and deposition of ECM
proteins.
Figure 20. Angiogenesis In tissue repair, angiogenesis occurs mainly by sprouting of
new vessels. The steps in the process and the major signals involved are illustrated.
The newly formed vessel joins up with other vessels (not shown) to form the new
vascular bed. ECM, Extracellular matrix; MMPs, matrix metalloproteinases; VEGF,
vascular endothelial growth factor.
• ECM Regulates Angiogenesis
o Integrins for the formation and maintenance of
newly formed blood vessels
o Matrix cellular proteins – destabilize cell matrix
interactions and therefore promote
angiogenesis
o Proteinases, e.g. plasminogen activators –
cleaves extracellular proteins, releasing matrix
bound growth factors
20
 C. DEPOSITION OF CONNECTIVE TISSUE
• Laying Down of Connective Tissue Occurs in 2 Steps:
1. Migration and proliferation of fibroblasts into the site of
injury
2. Deposition of ECM proteins produced by these cells
 Transforming growth factor-β (TGF-β) is the most important
cytokine for the synthesis and deposition of connective tissue
proteins.
 As healing progresses, the number of proliferating fibroblasts
and new vessels decreases; however, the fibroblasts
progressively assume a more synthetic phenotype, and
hence, there is increased deposition of ECM. Collagen
synthesis, in particular, is critical to the development of
strength in a healing wound site.
D. REMODELING OF CONNECTIVE TISSUE
• The outcome of the repair process is influenced by a balance
between synthesis and degradation of ECM proteins.
• The degradation of collagens and other ECM components is
accomplished by a family of matrix metalloproteinases (MMPs),
so called because they are dependent on metal ions (e.g., zinc)
for their activity.
• ADAMs (a disintegrin and metalloproteinase) are anchored to
the plasma membrane and cleave and release extracellular
domains of cell-associated cytokines and growth factors, such
as TNF, TGF-β, and members of the EGF family.
Factors That Influence Tissue Repair
A. Nutritional status
• Protein deficiency and vitamin C deficiency inhibits
collagen synthesis and retards healing
B. Metabolic status
• Diabetes: one of the most important systemic cause of
abnormal wound healing
C. Circulatory status
• Poor perfusion due either to arteriosclerosis and diabetes
or to obstructed venous drainage– impairs healing
D. Hormones
• Glucocorticoids (steroids): have anti-inflammatory
effects that can either produce:
o Undesirable effect: its administration may
result in weakness of the scar due to inhibition
of TGF-β production and diminished fibrosis
o Desirable effect: prescribed in corneal
infections to reduce the likelihood of opacity
that
E. Infection
• Clinically one of the most important causes of delay in
healing
• Prolongs inflammation and potentially increases the local
tissue injury
F. Mechanical factors
• Increased local pressure or torsion
• May cause wounds to pull apart, or dehisce
PATHO – [03] Inflammation and Repair
G. Foreign bodies (e.g. fragments of steel, glass, bone)
• Impede healing
H. Type and extent of tissue injury
• Injury to tissues with stable and labile cells
o Complete restoration can occur
o In extensive injury, incomplete tissue regeneration
and at least partial loss of function can occur
• Injury to tissues with permanent cells
o Must inevitably result in scarring with attempts at
functional compensation by the remaining viable
elements (e.g. myocardial infarct)
I. Location of the Injury
• Inflammation in tissue spaces (e.g. pleural, peritoneal,
synovial cavities)
o Develops extensive exudates
o Repair is through resolution (digestion of the
exudate, initiated by the proteolytic enzymes of
leukocytes and resorption of the liquefied exudate)
o In the absence of cellular necrosis, normal tissue
architecture is generally restored
o In the setting of larger accumulations, the exudate
undergoes organization: granulation tissue grows
into the exudate, and a fibrous scar ultimately
forms.
Examples of Tissue Repair and Fibrosis
TYPES OF REPAIR
A. CUTANEOUS (SKIN) WOUND HEALING
• Involves epithelial regeneration and formation of
connective tissue scar
o Based on the nature and size of the wound, the
healing of skin wounds is said to occur by first
or second intention
Figure 21. Steps in cutaneous wound healing
1. First Intention or Primary Union Healing
• Principal mechanism for the injury, which involves only
the epithelial layer, is epithelial regeneration
• Examples:
o Surgical sutures
o Re-epithelialization
o Thin scar
• Repair consist of 3 connected processes:
o inflammation,
21
 o proliferation of epithelial and other cells
o maturation of the connective tissue
2. Healing by Second Intention or Secondary Union
• Repair process involves a combination of regeneration
and scarring when tissue loss is more extensive (e.g. in
large wounds, abscesses, ulceration, and ischemic
necrosis or infarction in parenchymal organs)
• The inflammatory reaction is more intense
• There is development of abundant granulation tissue,
accumulation of ECM and formation of a large scar, and
wound contraction by the action of myofibroblasts.
• Substantial scar formation
• Thinning of the epidermis
Figure 22. Steps in wound healing by first intention (left) and second intention (right).
In the latter, note the large amount of granulation tissue and wound contraction.
 Excisional wound → intense inflammatory reaction →
greater tissue granulation → wound contraction (initially
by actin-containing fibroblast; permanently by
myofibroblast → substantial scar formation thinning of
the epidermis
Wound Strength
• Carefully sutured wounds have approximately 70% of the
strength of normal skin, largely because of the placement
of sutures.
• After 1 week of suture removal, wound strength is
approximately 10% of that of unwounded skin, but this
increases rapidly over the next 4 weeks
• Recovery of tensile strength due to excess of collagen
synthesis over collagen degradation during the first 2
months of healing and from modifications of collagen
fibers after collagen synthesis ceases
• Wound strength reaches approximately 70% to 80% of
normal by 3 months but usually does not substantially
improve beyond that point.
B. FIBROSIS IN INJURED PARENCHYMAL ORGANS
• Excessive deposition of collagen and other ECM
components in a tissue
• Most often refers to the abnormal deposition of collagen
that occurs in internal organs in chronic diseases
PATHO – [03] Inflammation and Repair
• Pathologic process induced by persistent injurious stimuli
such as chronic infections and immunologic reactions,
and is typically associated with loss of tissue
• Responsible for substantial organ dysfunction and even
organ failure
• TGFβ - Major cytokine involved in fibrosis
o Triggers for activation include cell death by
necrosis or apoptosis and production of ROS
• Fibrotic disorders include diverse chronic and debilitating
diseases such:
o Liver cirrhosis
o Systemic sclerosis (scleroderma)
o Fibrosing diseases of the lung (idiopathic
pulmonary fibrosis
o Pneumoconioses, and drug-radiation induced
pulmonary fibrosis)
o End-stage kidney disease
o Constrictive pericarditis
Figure23. Mechanisms of fibrosis. Persistent tissue injury leads to chronic
inflammation and loss of tissue architecture. Cytokines produced by
macrophages and other leukocytes stimulate the migration and proliferation
of fibroblasts and myofibroblasts and the deposition of collagen and other
extracellular matrix proteins. The net result is replacement of normal tissue
by fibrosis.
Abnormalities in Tissue Repair
• Complications of Cutaneous Wound Healing
• can arise from abnormalities in any of the basic
components of the process
• Deficient scar formation
o Inadequate formation of granulation tissue
o Wound dehiscence and ulceration
o Dehiscence due to increased abdominal
pressure
o Ulceration due to inadequate vascularization
during healing
22
 • Excessive formation of repair components
o Excessive collagen
o Hypertrophic scar and keloids
o Scar tissue grows beyond the boundaries
of the original wound and does not regress.
o Exuberant granulation formation of
excessive amounts of granulation tissue,
which protrudes above the level of the
surrounding skin and blocks re-
epithelialization.
o Proud flesh, desmoids, aggressive
fibromatoses
• Formation of contractures
o Particularly prone to develop on the palms,
soles, and anterior aspect of the thorax

REFERENCES
• Doc Racelis’ powerpoint presentation
• Kumar, V., Abbas, A.K., & Aster, J.C. (2021). Robbins and
Cotran Pathologic Basis of Disease (10th ed.). Elsevier
Inc.
• Naregta Trans

PATHO – [03] Inflammation and Repair 23