Inflammation and Cell Injury/Death Flashcards
Explain the three major components of acute inflammation.
- Dilation of small vessels; leads to increased blood flow to affected
area. - Increased permeability of microvasculature; leads to movement of
fluid and plasma proteins from circulation into tissue (exudation). - Emigration of leukocytes (white blood cells) from microcirculation,
with their accumulation at site of injury and activation to eliminate
offending agent.
a. Circulating cells - Neutrophils, monocytes, eosinophils,
lymphocytes, basophils and platelets
b. Cells in tissue – Mast cells, macrophages and lymphocytes
Describe four common types of stimuli that trigger acute inflammation
- Infections and microbial toxins
- Tissue necrosis – May be due to ischemia, trauma, or
physical/chemical agents (i.e. burns, frostbite, irradiation) - Foreign bodies
- Immune reactions – Autoimmune diseases, hypersensitivity
reactions
Understand the two major results of the vascular response in acute
inflammation to be vasodilation and increased vascular permeability, and
describe the forces favoring fluid movement out of vessels.
Vasodilation
Early event in acute inflammation, which primarily affects arterioles
1. Mechanism – Actions of chemical mediators (i.e. histamine and
nitric oxide) on vascular smooth muscle
2. Result – Opens capillary beds increased blood flow
Increased vascular permeability
1. Primarily involves post-capillary venules
2. Forces favor fluid movement out of vessels into extravascular
tissue:
a. Increased intravascular hydrostatic pressure due to
increased blood flow
b. Decreased intravascular oncotic pressure due to loss of
protein
3. Lack of endothelial integrity – Fluid and proteins must breach the
endothelium to gain access to extravascular space. Some
mechanisms to explain how this occurs:
a. Formation of endothelial gaps (contraction of endothelium
leads to increased space between endothelial cells)
i. Immediate, transient response – Due to actions of
histamine (primarily), although other chemical
mediators (bradykinin, leukotrienes) play a part
ii. Delayed prolonged leakage – Due to thermal injury,
radiation
b. Direct endothelial injury – Due to burns, microbes
i. Leads to endothelial necrosis and detachment
c. Leukocyte mediated vascular injury – Due to actions of
inflammatory cells and their mediators
d. Increased transcytosis – Direct movement of fluid and
proteins through specialized channels within endothelial
cell cytoplasm
e. Leakage from new blood vessels (angiogenesis) - New
vessels are leaky until endothelial cells mature and form
intercellular junctions
Name the chemical mediator responsible for the primary, transient
vascular permeability response and identify the type of blood vessel in
which increased permeability primarily occurs.
histamine
post capillary venules
Know the sequence of events in leukocyte extravasation, and explain how
adhesion molecules are involved at various steps
- Margination – Leukocyte slow down and accumulate to the periphery
of the vessel near the endothelium
a. Due to changes in blood flow (stasis) that occurs secondary to
vascular dilation and loss of intravascular fluid - Rolling – Slow “tumbling” of cells with transient interactions to the
endothelium (adherence, detachment and re-adherence).
a. Adhesion molecules: Selectins – Low affinity binding - Adhesion to endothelium – Leukocytes come to rest and adhere
firmly.
a. Adhesion molecules: Integrins – High affinity binding - Transmigration (diapidesis) – Leukocytes squeeze through
intracellular junctions, then across the basement membrane
a. Adhesion molecules: Immunoglobulin superfamily
b. Occurs primarily in post-capillary venules
The type of inflammatory cell involved depends on time course and type
of injurious agent. Generally in acute inflammation, neutrophils
predominate in first 6-24 hours while monocytes start to replace
neutrophils after 24-48 hours. Neutrophils are short lived in tissue and
disappear after 48 hours. Note that neutrophils may continue to be
recruited if the injury is repeated or with certain types of stimuli.
Explain the three main steps of phagocytosis, and describe four
processes that are important in the third step (killing and degradation of
microbes).
Once activated, inflammatory cells phagocytose and kill/degrade the
microbial agent or foreign invader in three main steps:
1. Recognition and attachment – Special receptors on the surface of
leukocytes bind directly to the microbe
a. Examples: Mannose receptors, scavenger receptors,
integrins, receptors for opsonins
2. Engulfment – Extensions of cell cytoplasm (pseudopods) flow around
the microbe and enclose it within a space (phagosome) created within
the cell cytoplasm. The phagosome then fuses with the cell lysosome (containing enzymatic granules) to create a hybrid organelle
“phagolysosome”.
3. Killing and degradation – Occurs within phagolysosome. This step is
highly oxygen dependent (“respiratory burst”) with several main
mechanisms:
a. Oxidation of NADPH to generate reactive oxygen species
(ROS) such as hydrogen peroxide (H2O2)
b. Action of myeloperoxidase (MPO) – Enzyme within
neutrophil lysosomal granules. MPO converts hydrogen
peroxide (H2O2) to a potent antimicrobial agent called
hypochlorite (active ingredient in bleach) in the presence of
chloride.
c. Nitric Oxide – Soluble gas derived predominantly from
endothelium. Combines with superoxide anion to generate
free radical molecule which contributes to microbial killing.
d. Lysosomal enzymes – Various enzymes such as
proteases degrade proteins and extracellular matrix
components.
Name two diseases that occur due to defects in leukocyte function.
These generally manifest as increased vulnerability of patient to infection.
Defects can occur at all phases of leukocyte activity.
1. Specific types:
a. Defects in leukocyte adhesion – Recurrent infections,
impaired wound healing
b. Defects in phagolysosome function - Recurrent bacterial
and fungal infections
Example: Chediak-Higashi syndrome
c. Defects in formation of reactive oxygen species –
Recurrent bacterial and fungal infections
Example: Chronic granulomatous disease
d. Bone marrow suppression – Multiple causes, leads to
generalized immune suppression due to reduced
production of leukocytes
Know the two main types of vasoactive amines, their source and explain
their main effects.
Vasoactive = effects on blood vessels
1. Histamine
a. Principal mediator of the primary, transient vascular
response of inflammation
b. Source: Mast cells (predominantly), also derived from
basophils and platelets
c. Effects: Dilation of arterioles, increased permeability of
post-capillary venules by inducing endothelial gaps
2. Serotonin
a. Source: Mostly platelets
b. Effects: Neurotransmitter in GI tract, also vasoconstriction.
Importance in inflammatory response still unclear.
Know the two main pathways of the arachidonic acid cascade and
describe where anti-inflammatory medications act in the cascade to inhibit
the production of prostaglandins and leukotrienes.
Arachadonic acid (AA) is a fatty acid present in the cell membrane that is
activated by an enzyme (phospholipase A) as a result of various stimuli. Activation of AA leads to an enzyme cascade resulting in formation of
multiple lipid metabolites which affect inflammation. Many common antiinflammatory medications work by inhibiting various aspects of the AA
cascade. The cascade has two main pathways:
1. Cyclooxygenase pathway
a. Generates prostaglandins – Effects on vascular tone and
permeability, platelet aggregation, pain and fever
b. Enzymes: COX-1 and COX-2
2. Lipoxygenase pathway
a. Generates leukotrienes and lipoxins
i. Leukotrienes – Promotes leukocyte
chemotaxis/activation, vasoconstriction, vascular
permeability, and bronchospasm (important in
asthma)
ii. Lipoxins – Regulatory function to inhibit leukocyte
recruitment (suppress inflammation)
3. Anti-inflammatory medications
a. Aspirin, non-steroidal anti-inflammatory drugs (NSAIDS) – Inhibit
prostaglandin pathway (COX-1, COX-2 enzymes)
b. Zileuton, Montelukast – Inhibits lipoxygenase and leukotriene
pathways, used in treatment of asthma
c. Corticosteroids – Broad spectrum inhibition of both pathways
(inhibit phospholipase A2 as well as COX-2), reduce production of
pro-inflammatory cytokines
. Explain how nitric oxide acts as an endogenous regulator of inflammation.
As described in section IIID above, nitric oxide is a soluble gas produced
by endothelial cells and macrophages, which can combine with
superoxide to form reactive nitrogen species and contribute to killing of
microbes. In addition to this antimicrobial effect, nitric oxide also serves a
regulatory function to reduce some of the effects of inflammation. To this
end, NO is a potent vasodilator, reduces platelet aggregation, inhibits
mast cells and regulates leukocyte recruitment.
Know two main cytokines involved in inflammation and describe their
major effects.
Cytokines are proteins produced by many cell types which mediate and
regulate various aspects of inflammation.
1. Tumor necrosis factor-alpha (TNFα) and interleukin-1 (IL-1) are
important cytokines which trigger local and systemic acute phase
responses to acute inflammation:
a. Systemic: Fever, loss of appetite, slow wave sleep, leukocyte
recruitment
b. Local: Trigger endothelial and leukocyte activation, promote
leukocyte adhesion to endothelium and migration into tissue
2. TNFα and IL1 mediate many of the effects of septic shock (a systemic
response that occurs when bacteria gain access to the blood stream)
Recognize the complement, kinin and clotting systems as enzyme
cascades that can act to modify the inflammatory response.
Several important enzyme cascades can be triggered within cells during
inflammatory rections, resulting in the creation of various proteins which
futher mediate the effects of inflammation. The activation of these
cascades are tightly regulated.
1. Complement system
a. System of plasma proteins and membrane receptors crucial to
the defense against microbial agents, also active in pathologic
inflammatory reactions
b. Two pathways: Classical (triggered by antibodies) and
Alternative (triggered by microbial surfaces or other
substances, in the absence of antibody)
c. Effects: Lysis of microbial cells, histamine release (vascular
dilation, increased permeability), leukocyte adhesion,
chemotaxis, more effective phagocystosis
2. Kinin system
a. Enzyme cascade that closely interacts with the clotting system
b. Results in the release of bradykinin – Potent vasoactive
peptide that increases vascular permeability, causes
contraction of smooth muscle, dilation of blood vessels, and
causes pain (when injected)
3. Clotting system
a. Cascade of proteins that culminates in the formation of a fibrin
clot in response to injury (coagulation)
b. Coagulation and inflammation are tightly linked
i. Acute inflammation can trigger activation of clotting
cascade
ii. Components of coagulation cascade can bind to
receptors on various cells to induce inflammation
Explain the four common morphologic patterns of acute inflammation in
tissues, and be able to give an example of each pattern
A) Serous inflammation
Outpouring of thin (cell-poor) fluid into the extracellular space or within
body cavities lined by peritoneum, pleura or pericardium (Examples: skin
blister, pleural effusion).
B) Fibrinous inflammation
Fluid plus fibrinogen collects within the extracellular space and forms an
exudate containing fibrin.
1. Seen with more severe injury – Greater vascular permeability
allows for leakage of larger molecules like fibrinogen
2. Can also occur in areas lining body cavities (Example: fibrinous
pericarditis)
3. Fibrin appears pink and amorphous in histologic sections
C) Purulent (suppurative) inflammation
Production of large amounts of purulent exudate (containing numerous
neutrophils, necrotic debris and edema fluid) (Examples: acute
appendicitis, bronchopneumonia)
1. Most frequent cause is bacterial infection - certain bacteria are
“pyogenic” (pus-producing) and characteristically produce this
response
2. Abscess – Localized collection of purulent inflammation, buried
deep within a tissue, organ or confined space
D) Ulcer
Local defect of the surface of a tissue or organ due to shedding of
inflamed and/or necrotic tissue
1. Occur most commonly in GI tract, genitourinary tract and skin
(Example: gastric ulcer)
Describe the three main outcomes of acute inflammation and explain
factors favoring each outcome. Explain why some types of ongoing or
repeated injury responses may display a mixed (both acute and chronic)
inflammatory picture.
A) Complete resolution
Resolution can occur when the injury is limited or short-lived, with minimal
tissue destruction and/or there is ability of the cells to regenerate. It
involves the neutralization of chemical mediators, return of normal
vascular permeability, cessation of leukocyte infiltration, apoptosis of
neutrophils, and removal of fluid, protein and cell debris.
B) Healing by connective tissue replacement (i.e fibrosis, scarring)
Fibrosis is a common outcome to acute inflammation that follows
significant tissue destruction, when tissues are unable to regenerate, or
when there is abundant fibrinous exudate that cannot be quickly removed.
Connective tissue grows into area of injury, creating a mass of fibrous
tissue or scar. This process is also called organization.
C) Progression to chronic inflammation
A transformation from acute to chronic inflammation occurs when the
body cannot resolve the acute inflammation, due to persistent
injury/stimulus or interference with the normal healing process.
In some cases of ongoing infection or repeated injury, there may be a
mixed inflammatory picture, with a base of chronic inflammation that is
continuously present, and phases of superimposed acute inflammation
during times of severe or active injury.
Describe the various types of extracellular fluid collections, including
exudate, transudate, edema and pus
- Exudate – Fluid with a high protein concentration, containing
cellular debris, and specific gravity >1.020 - Transudate – Fluid with a low protein content (mostly albumin),
minimal cells, and specific gravity <1.020 - Edema – General term for excess fluid in the interstitial space or
serous cavities (can be exudate or transudate) - Pus (i.e purulent exudate) – Inflammatory exudate containing
numerous leukocytes (especially neutrophils), cellular debris with
dead cells, and often, microbes
LO #1: Define chronic inflammation.
Chronic inflammation is inflammation of prolonged duration (often weeks
to months), in which active inflammation, tissue destruction and repair are
occurring simultaneously.
LO #2: Describe three major causes of chronic inflammation, and be able to
give an example of each.
- Persistent infections – Examples include persistent bacterial
infections, as well as viruses, fungi, parasites, and mycobacteria
(a special class of microorganisms, of which one species causes
tuberculosis) - Autoimmune diseases and hypersensitivity responses –
Pathologic immune reactions due to excessive or inappropriate
activation of the immune system. In autoimmune disease, the
patient develops an inflammatory reaction against their own
tissues (Examples: rheumatoid arthritis, systemic lupus
erythematosus) - Prolonged exposure to toxic agents (Examples: exposure to
asbestos or coal causing pulmonary inflammation and fibrosis;
alcohol abuse causing liver cirrhosis)
LO #3:Describe the morphologic features of chronic inflammation, including
the predominant cell types.
- Infiltration with mononuclear inflammatory cells (macrophages,
lymphocytes and plasma cells)
In cases of sufficient duration, organized lymphoid tissue with
germinal centers may form. - Tissue destruction, due to the persistence of the injury process
- Healing by connective tissue replacement (scar formation or
fibrosis), with proliferation of blood vessels (angiogenesis)
