INFLAMMATION

Crisfinah Canillo

Eula Anthonette Castillote

Kimberly Espino

Airon May Estremos

John Emmanuel Kintanar

Kaila Mari Gonzales

Jocelle Bert

Jake Nazareno

Mae Krizia Katrina Maramara

Rhea Charisma Serdan

Kristal Diane Soliva

Aileen Jane Yap

Clinical History:
An 18-year-old woman presented to the emergency department with a two-day
history of nausea, vomiting and periumbilical and lower abdominal pain. Earlier that day,
she experienced shaking chills and fever.  Physical exam showed local tenderness and
rigidity with rebound pain in the lower abdomen. Laboratory tests revealed a white blood
cell count of 21,900/ dL, C-reactive protein of 300 mg/L (normal <3.0 mg/dL) and an
erythrocyte sedimentation rate of 104 mm/h (normal 0-20 mm/h).  A peripheral smear
showed immature neutrophils (“band” cells). She underwent an exploratory laparotomy.

Objectives:

Goal 1: Mechanisms of Inflammation 

Objective 1: Acute Inflammatory Response

Objective 2: Phagocytosis

Objective 3: Mediators of Inflammation 

Objective 4: Systemic Changes in Inflammation 

Objective 5: Outcomes of Inflammation 

Objective 6: Morphologic Patterns of Inflammation

Objective 7: Acute, Chronic, and Granulomatous Inflammation 

Objective 8: Extravascular Fluids Associated With Injury 

Goal 2: Mechanisms of Tissue Regeneration, Renewal and Repair  

Wound Healing 
Goal 1: Mechanisms of Inflammation 

Objective 1: Acute Inflammatory Response

Has three major components:

 Dilatation of small vessels leading to an increase in blood flow

 Increased permeability of the microvasculature enabling plasma proteins an
leukocytes form the microcirculation, their accumulation in the focus of injury and
their activation to eliminate offending agent

Vascular Changes

Immediately following the injurious stimulus, there is a brief period of arteriolar

vasoconstriction for several seconds followed by a sustained vasodilation of local
arterioles allowing for substantially increased blood flow to the injured area.

Additionally, endothelial cells in local capillary beds contract and generating

spaces between the cells which substantially increase vascular permeability.

Increased local blood flow accounts for the clinically visible heat and redness
associated with acute inflammation while increased vascular permeability accounts for
the localized edema.

Immune Cell Extravasation

Following the initiation of vascular changes, a variety of leukocytes bind to

involved blood vessels and exit into the parenchyma.

However, the primary immune cell type to do so in the settings of acute

inflammation is the neutrophil. Binding and extravasation of leukocytes follows a series
of well- described stages.

 Margination: The vasodilation described generally slow the flow of blood at the
site of injury and causes immune cells to move toward the periphery of the
vessel, next to the vascular wall
  Rolling: Marginated immune cells initially display transient, low affinity
interactions with endothelial cells which result in their slowing down and literal
rolling along the vascular wall. These interactions are mediated by selectins.
 Adhesion: Rolling sufficiently slows the immune cells to allow for muh higher
affinity interactions between leukocyte integrins and endothelial ICAMs to take
place. These interactions strongly adhere the cells to the vascular wall, stopping
their further travel through blood stream.
 Extravastion: once bound to the vascular wall immune cells extravasate into the
parenchyma by squeezing between endothelial cells.

Clinical Consequences:

Acute inflammation is traditionally characterized by a number of gross, clinically

identifiable features:

Calor: Heat due to increased blood flow

Rubor: Redness due to dilatation of blod vessels

Tumor: Swelling, formally a localized edema due to increased permeability of vessles

and resultant extravasation of protein- rich fluid

Dolor: Pain due to chemical mediators such ad bradykinin

Functio laesa: Loss of function

Source: Robbins and Cotran Pathologic Basis of Disease, 9 th edition

 Objective 2: Phagocytosis

- cellular ingestion of offending agents

- ingestion of large particles such as bacteria, whole cells or degenerating tissues

- neutrophils: 1st line of defense in phagocytosis and a single neutrophil can

phagocytize 3-20 bacteria
- macrophages: end stage of monocytes much more powerful than neutrophils

3 selective procedure:

Rough surface increase phagocytosis

 Phagocytosis involves three sequential
steps:

(1) recognition and attachment of the particle

Most of dead tissues and foreign

to be ingested by the leukocyte

particles has no protein coats or (2) engulfment, with subsequent formation of

protective coats a phagocytic vacuole
(3) killing or degradation

Immune systems of the body

develops antibodies against
infections Objective 3: Mediators of Inflammation 

- These are substances that initiate and regulate

inflammatory reactions.

Principal Mediators of inflammation

Mediators Source Action

Histamine Mast cells, Basophils, Vasodilation, increased vascular permeability,

Platelets endothelial activation

Prostaglandins Mast cells, leukocytes Vasodilation, pain, fever

Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis,

leukocyte adhesion, and activation

Cytokine (TNF, IL- Macrophage, endothelial Local: Endothelial activation (Expression of adhesion
1, IL-6) cells, mast cells, molecules) Systemic: Fever, metabolic abnormalities,
hypotension (shock)

Chemokines Leukocytes, Activated Chemotaxis, leukocyte activation

 macrophages

Platelet-activating Leukocytes, mast cells Vasodilation, increased vascular permeability,

factors leukocyte adhesion, chemotaxis, degranulation,
oxidative burst

Complement Plasma Leukocyte chemotaxis and activation, direct target

killing (membrane attack complex), vasodilation

Kinins Plasma Increased vascular permeability, Smooth muscle

contraction, vasodilation, pain

Source: Robbins and Cotran Pathologic Basis of Disease, 9 th edition

Objective 4: Systemic Changes in Inflammation 

Acute Phase Response is a collective term of the systemic reactions associated with
inflammation. The following are the clinical and pathological changes:

 Fever is the most the most prominent manifestations of the acutephase response,
especially when inflammation is associated with infection. Pyrogens stimulate the
release of cytokines that increase the cyclooxygenase enzymes that reset the
temperature set point in the hypothalamus at higher level.

 Acute-phase proteins increase several hundredfold as part of the response to

inflammatory stimuli. Synthesis of these molecules in hepatocytes is stimulated by
cytokines, especially IL6 (for CRP and fibrinogen) and IL1 or TNF (for SAA). Three of the
bestknown of these proteins are Creactive protein (CRP), fibrinogen, and serum amyloid
A (SAA) protein. CRP and SAA binds to microbial cell walls and acts as fix complement
and opsonins, and may alsobind chromatin to aid necrotic ccell nuclei clearance.
Fibrinogen binds to red cells and causes rouleaux that sediments more than individual
red cells which will be the basis for erythrocyte sedimentation rate as a ssimple test for
an inflammatory response caused by any stimulus. Prolonged production of these
proteins, especially SAA, in states of chronic inflammation causes secondary
 amyloidosis, increased levels of CRP is a proposed marker for increased risk for
myocardial infarction.

 Leukocytosis is a common feature of inflammatory reactions, especially those induced

by bacterial infections. The leukocyte count usually climbs to 15,000 or 20,000 cells/mL,
but sometimes it may reach extraordinarily high levels of 40,000 to 100,000 cells/mL.
These extreme elevations are referred to as leukemoid reactions. Most bacterial
infections induce an increase in the blood neutrophil count, called neutrophilia. Viral
infections cause an absolute increase in the number of lymphocytes or lymphocytosis
and some certain infections is associated with a decreased number of circulating white
cells (leukopenia), while allergies and parasitic infestations, there is an increase in the
absolute number of eosinophils, creating an eosinophilia.

 Other manifestations include increased pulse and blood pressure; decreased

sweating, mainly because of redirection of blood flow from cutaneous to deep vascular
beds, to minimize heat loss through the skin; rigors (shivering), chills (search for
warmth), anorexia, somnolence, and malaise, probably because of the actions of
cytokines on brain cells.

 In severe bacterial infections or sepsis, the large amounts of bacteria and their products
in the blood stimulate the production of enormous quantities of several cytokines,
notably TNF and IL1. This clinical triad is known as septic shock.
Objective 5: Outcomes of Inflammation 

The entire purpose of the inflammation process is the elimation of the offending
agent within the body, once this has been achieved the inflammation process begins to
terminate. When this takes place the reaction mediators are broken down and dissipate
and anti-inflammatory mechanisms are activated, serving to control the response and
prevent it from causing excessive damage to the host. Finally the process of tissue
repair is set in motion.

Acute inflammation

All acute inflammatory reactions have one of three outcomes

 Complete resolution – offending agent is eliminated and restoration of the site

of acute inflammation back to normal takes place. Resolution involves
regeneration of damaged parenchymal cell , removal of cellular debris and
resorption of edema fluid by lymphatics.
 Healing by connective tissue replacement ( scarring and fibrosis) – there is
substantial tissue destruction and the tissues involved are incapable of
regeneration or when there is abundant fibrin exudation in tissue or in serous
cavities that cannot be adequately cleared. In all these situations connective
 tissue grows into the area of damage, and converts it into a mass of fibrous
tissue--- process called organization
 Progress to chronic inflammation- the acute inflammatory response cannot be
resolved, leading to a persistence of the injurious agent or interference with
normal process of healing.

Source: Robbin’s Pathology 10th Ed

Objective 6: Morphologic Patterns of Inflammation

Different inflammatory processes vary in morphology depending on the

underlying cause. according to the offending agent:

o vasodilation (histamine, PAF)

o increase in vascular permeability (PGE2, PGI2,
LTC4, LTD4, LTE4

These variations, depending on the intensity of the pro-inflammatory stimulus,

are often responsible for the different morphologic patterns followed by acute
inflammation.

Serous Inflammation
 The hallmark of serous inflammation is the accumulation of a thin, protein-free
fluid derived either from the blood plasma (i.e. exudate) or from mesothelial cells
(termed effusion). Blisters, for example, are formed because of the accumulation of this
thin fluid between epidermal layers. Serous inflammation is typical of burning and viral
infections (Herpes).

Fibrinous Inflammation

In fibrinous inflammation the increase in vascular permeability is greater than in

serous inflammation. In fact, we have a protein rich exudate which contains among
others fibrin. Fibrinous inflammation is always accompanied by a pro-coagulative
stimulus and is characteristic of the lining of body cavities, especially serous
membranes.

Suppurative inflammation

Characterized by the formation of pus, a cell-rich exudate, suppurative

inflammation is typical of bacterial infections (e.g.: Streptococci). The induced
vasodilation is strong enough to allow the passage of cellular fragments into the
extracellular space. If the bacterium penetrates deep into the organ parenchyma an
abscess is often formed. Abscesses have a central part rich in cells that have
undergone liquefactive necrosis surrounded by neutrophils and congested blood
vessels.

Ulcer
 Ulcers are damages or excavations of organ surfaces due to the shedding of
superficial necrotic tissues. They are common in the mucosas of hollow organs (e.g.
mouth, intestine, genitourinary tract.) and in the lower limbs of older patients suffering
from circulatory diseases or diabetes.

Objective 7: Acute, Chronic, and Granulomatous Inflammation  

Acute inflammation - it typically develops within minutes or hours and is of short

duration, lasting for several
hours or a few days. When acute inflammation achieves its desired goal of
eliminatingthe offenders, the reaction subsides, but if the response fails to clear the
stimulus, the reaction can progress to a protracted phase that is called chronic
inflammation.
  has three major components:
(1) dilation of small vessels leading to an increase in bloodflow,
(2) increased permeability of the microvasculature enabling plasma proteins and
leukocytes to leave thecirculation,
(3) emigration of the leukocytes from the microcirculation, their accumulation in
the focus ofinjury, and their activation to eliminate the offending agent

- the vascular reactions of acute inflammation consist of changes in the

flow of blood and the permeability of vessels, both designed to maximize the
movement of plasma proteins and leukocytes out of the circulation and into the
site of infection or injury.

Chronic inflammation - is of longer duration and is associated with more tissue

destruction, the presence of lymphocytes and macrophages, the proliferation of blood
vessels, and the deposition of connective tissue.
 arises in the following settings:
(1) Persistent infections by microorganisms that are difficultto eradicate
(2) Hypersensitivity diseases
(3) Prolonged exposure to potentially toxic agents, either exogenous or
endogenous.

(4) Neurodegenerative diseases

 characterized by:
(1) Infiltration with mononuclear cells, which include macrophages, lymphocytes,
and plasma cells
(2) Tissue destruction, induced by the persistent offending agent or by the
inflammatory cells
(3) Attempts at healing by connective tissue replacement of damaged tissue,
 accomplished by angiogenesis (proliferation of small blood vessels) and, in
particular, fibrosis

Source: Robbins and Cotran Pathologic Basis of Disease, 9 th edition

Objective 8: Extravascular Fluids Associated With Injury  

Increased vascular permeability

The walls of small blood vessels act as a microfilter, allowing the passage of
water and solutes but blocking that of large molecules and cells. Oxygen, carbon
dioxide and some nutrients transfer across the wall by diffusion, but the main transfer of
fluid and solutes is by ultrafiltration, as described by Starling. The high colloid osmotic
pressure inside the vessel, due to plasma proteins, favors fluid return to the vascular
compartment.

Under normal circumstances, high hydrostatic pressure at the arteriolar end of

capillaries forces fluid out into the extravascular space, but this fluid returns into the
capillaries and lymphatics at their venous end, where hydrostatic pressure is low.

In acute inflammation, however, not only is capillary hydrostatic pressure

increased, but there are spaces between endothelial cells allowing escape of plasma
proteins into the extravascular space, increasing the colloid osmotic pressure there.
Consequently, much more fluid leaves the vessels than is returned to them. The net
escape of protein-rich fluid is called exudation; hence, the fluid is called the fluid
exudate.

Factors involved in vascular permeability in acute inflammation

How does increased permeability happen

 Toxins and physical agents may cause necrosis of vascular endothelium, leading
to abnormal leakage (non-mediated vascular leakage).

 Chemical mediators of acute inflammation may cause retraction of endothelial

cells, leaving intercellular gaps (mediated vascular leakage).

Experimental work has demonstrated three patterns of increased leakage of fluid

from vessels, which occur at different times following injury.

 A transient immediate response that lasts for 30-6O minutes, and is mediated by
histamine acting on endothelium.
  A delayed response that starts 2-3 hours after injury and lasts for up to 8 hours.
This is mediated by factors synthesized by local cells, e.g., prostaglandins and
platelet activating factor or plasma proteins bradykinin and complement.
 A prolonged immediate response that occurs over 24 hours is seen if there has
been direct necrosis of endothelium, e.g., in a burn or by a chemical toxin.
 In natural diseases it is likely that all three responses are activated. There would
be overlap of these three processes if active inflammation is sustained.

Goal 2: Mechanisms of Tissue Regeneration, Renewal and Repair 

Wound Healing 
 process that involves both epithelial regeneration and the formation of connective
tissue scar
 the healing of skin wounds is said to occur by first or second intention.

Healing by First Intention (Primary Union)

 principal mechanism of repair is epithelial regeneration when the injury involves
only the epithelial layer,
 example: healing of a clean, uninfected surgical incision approximated by
surgical sutures
 The repair consists of three connected processes:
1. inflammation
2. proliferation of epithelial and other cells
3. maturation of the connective tissue scar.

 Wound  rapid activation of coagulation pathways  formation of a blood clot

on the wound surface

Clot: contains entrapped red cells, fibrin, fibronectin, and complement

proteins.
 serves to stop bleeding and acts as a scaffold for migrating cells
Release of VEGF  increased vessel permeability and edema.
As dehydration occurs at the external surface of the clot, a scab covering
the wound is formed

 Within 24 hours, neutrophils are seen at the incision margin, migrating toward
the fibrin clot.
o Neutrophil  release release proteolytic enzymes  begin to clear the
debris
 Within 24 to 48 hours, epithelial cells from both edges have begun to migrate
and proliferate along the dermis,  depositing basement membrane components
 cells meet in the midline beneath the surface scab yielding a thin but
continuous epithelial layer that closes the wound
 By day 3, macrophages replaces the neutrophils and granulation tissue
progressively invades the incision space
o Collagen fibers are now evident at the incision margins.
 o Epithelial cell proliferation continues, forming a covering approaching the
normal thickness of the epidermis.
 By day 5, neovascularization reaches its peak as granulation tissue fills the
incisional space
o New vessels are leaky  allowing the passage of plasma proteins and
fluid into the extravascular space
o Fibroblasts migration & proliferation. They become more abundant and
begin to bridge the incision.
o epidermis recovers its normal thickness as differentiation of surface cells
yields a mature epidermal architecture with surface keratinization.
 During the 2nd week, continued collagen accumulation and fibroblast
proliferation.
o Leukocyte infiltrate, edema, and increased vascularity are substantially
diminished.
o “blanching” begins with increasing collagen deposition within the incisional
scar and the regression of vascular channels.
 By the end of the first month, comprises a cellular connective tissue largely
devoid of inflammatory cells and covered by an essentially normal epidermis.

Healing by Second Intention (Healin by secondary union)

 When cell or tissue loss is more extensive, the repair process involves a
combination of regeneration and scarring.
 There is development of abundant granulation tissue, accumulation of ECM and
formation of a large scar, and wound contraction by the action of myofibroblasts.

Secondary healing differs from primary healing in several respects:

  In wounds causing large tissue deficits, the fibrin clot is larger, and there is more
exudate and necrotic debris in the wounded area. Inflammation is more intense.
Large defects have a greater potential for secondary, inflammation-mediated,
injury.
 Much larger amounts of granulation tissue are formed. A greater volume of
granulation tissue generally results in a greater mass of scar tissue
 At 2 weeks, provisional matrix is replaced by a matrix composed primarily of
type I collagen.
o the original granulation tissue scaffold is converted into a pale, avascular
scar, composed of spindle-shaped fibroblasts, dense collagen, fragments
of elastic tissue, and other ECM components.
 By the end of the first month, the scar is made up of acellular connective tissue
devoid of inflammatory infiltrate, covered by intact epidermis
 Wound contraction generally in large surface wounds, it helps to close the wound
by decreasing the gap between its dermal edges and by reducing the wound
surface area
o Initial steps of wound contraction involve the formation, at the edge of the
wound, of a network of myofibroblasts,
 Within 6 weeks, large skin defects may be reduced to 5% to 10% of their
original size, largely by contraction.

Wound Strength
 Carefully sutured wounds have approximately 70% of the strength of normal skin
 When sutures are removed, usually at 1 week, wound strength is approximately
10% of that of unwounded skin, but this increases rapidly over the next 4 weeks.
 The recovery of tensile strength results from the excess of collagen synthesis
over collagen degradation during the first 2 months of healing, and, at later times,
from structural 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.
Source: Robbins and Cotran Pathologic Basis of Disease 9 th edition