Inflammation and Tissue
Healing - Big Ideas
Big Ideas
Inflammation
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Non-specific protection
Fever
o hypothalamus raises body temperature to make the organism
inhospitable to pathogens
o not always present especially in consideration of:
 age
 immunocompromise
Initial injury/infection
o Brief vasoconstriction
o Chemotaxis attracts neutrophils
 Marginization: Integrin receptors activate and stick to
integrins causing neutrophil to stop rolling and
accumulate along margins of endothelium
 Mast cell degranulation: release histamine
 Cause vasodilation (redness, heat)
 Endothelial cells contract, causing spaces between
cells
 Fluid and small particles escape from blood vessel
into tissue (edema)
 Neutrophils undergo diapedesis and move into
tissue, monocytes that move into tissue are
macrophages
 Bradykinin release causes pain (dolor)
 Interleukin-1 (of many) is the initial pro-inflammatory
chemokine initiating fever and signaling activation of
many systemic and cellular activities.
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Cellular response to injury
 Cell wall contains arachadonic acid which is released in
assault (whatever breaks up cell wall - trauma or chemo
receptor response)
 Arachadonic acid creates COX-1 and COX-2 as well as
lipoxygenase
 These stimulate creation of several immune modulating
substances, most noteably specific prostaglandins(by
COX) and leukotrienes (by lipoxygenase)
 Different prostglandins have different effects;
 Some are "constitutional" and considered protective.
 Some only involved in the inflammation process and are
"induced" by that process.
Pediatric and Elderly
 Immaturity of processes per physiologic developmental
norms must be considered for infants, children.
 Less efficient immune response, effects of aging on
collagen and chronic disease in either must be
considered.
3. CBC with differential
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WBC (total count) norm per LEWIS appendix C
Differential cell types purposes, possible interpretation of high and
low
Elevation in bands indicates infection of some type (shift to left)
4. Wound healing
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Factors that improve wound healing
o Consistent moisture
o Consistent temperature
o Consistent pH
o Proper nutrition
o Vasculature properly functioning - provide protection from
ischemia.
Factors to assess
o REEDA
 Redness
Edema
 Ecchymoses
 Drainage
 Approximation
Factors that decrease wound healing
o Infection
o Abscesses
o Hematoma
o Decreased blood flow (ischemia)
o Aging/children and developmental factors
Healthy wound bed: granulation tissue (beefy-red) with blurry edges,
no colored exudate or slough
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Review of immune physiology
COMPONENTS OF THE IMMUNE SYSTEM
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The primary lymphoid organs are the thymus and bone
marrow. T cells develop in the thymus, whereas B cells
develop in the bone marrow. Mature lymphocytes then migrate
to secondary lymphoid structures, including the spleen and
lymph nodes.
Blood cells are produced in the bone marrow in response to
specific hematopoietic growth factors. Granulocytes
(neutrophils, basophils, eosinophils) and monocytes
(macrophages) are phagocytic cells that provide innate
protection. Lymphocytes (B cells, T cells) are specific cells that
react only to particular antigens. NK cells are lymphocytes that
lack T-cell and B-cell markers and function in innate immune
responses. Other blood components produced by bone
marrow are erythrocytes and platelets.
Neutrophils are the most numerous WBCs in blood. A large
storage pool lies in the bone marrow and can be mobilized in
response to antigen. Neutrophils are the predominant WBC
type in early infection. They migrate to the area by following
chemotactic factors and perform phagocytic functions. During
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acute bacterial infection, larger numbers of immature
neutrophils (bands) are released into the blood, which is
termed a shift to the left. Chronic infections may produce a
shift to the right with more segmented neutrophils than normal.
Monocytes located in tissue are called macrophages.
Monocytes and macrophages are distributed in strategic
locations throughout the body, including the skin, lungs,
gastrointestinal tract, liver, spleen, and lymph. Macrophages
are powerful phagocytes and are predominant in late
inflammation.
T lymphocytes, the major effectors of cell-mediated immunity,
interact with specific antigens on cell surfaces. They are
important in immunity against foreign, infected, or mutant cells.
In addition, they secrete cytokines that boost the immune
response of B cells and other cell types. T cells are composed
of two main subtypes called CD4 (helper) and CD8 (cytotoxic).
B lymphocytes are the major effectors of antibody-mediated
immunity.
The complement system consists of about 20 plasma proteins
that interact in a cascade fashion to produce important
mediators of inflammation and immunity. The cascade can be
activated by microbial antigens (alternative pathway) or by
antigen-antibody complexes (classical pathway).
Cytokines are peptide factors released by immune cells. They
have many functions, including as inflammatory mediators,
chemotaxins, intercellular communication signals, growth
factors, and growth inhibitors. Macrophages and lymphocytes
are important sources of immune cytokines.
INNATE DEFENSES AND INFLAMMATION
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Previous exposure to foreign antigens is not required for the
activation of innate immune defenses. Inflammation is an
important aspect of innate immunity that involves localization
of harmful agents and the bringing of phagocytic cells to the
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area. Classic manifestations of inflammation are redness,
swelling, heat, pain, and loss of function.
Inflammatory chemicals such as histamine, prostaglandins,
and leukotrienes are released from injured tissues, mast cells,
macrophages, and neutrophils. These chemicals increase
vascular permeability, vasodilate, and attract immune cells to
the area (chemotaxis).
Phagocytes migrate to the inflamed area, collect at the side of
the vessel, and squeeze through into the tissue. Emigration of
neutrophils and macrophages is facilitated by selectins and
integrins present on the surface of endothelial cells and
leukocytes. Neutrophils arrive in large numbers in acute
bacterial infection and begin active phagocytosis. Neutrophils
and macrophages produce proteolytic enzymes and oxidizing
agents to destroy and digest antigens. With chronic
inflammation, macrophages and lymphocytes predominate.
Healing is mediated by growth factors released from platelets
and immune cells that stimulate fibroblasts to divide and
manufacture extracellular matrix proteins. Endothelial cells
respond to angiogenic growth factors by forming capillary
networks. Inflammatory exudate functions to transport immune
cells, antibodies, and nutrients to the tissue and dilute the
offending substances. Serous exudate is watery and low in
protein; fibrinous exudate is thick, sticky, and high in protein;
purulent exudate contains infective organisms, leukocytes, and
cellular debris; and hemorrhagic exudate contains red blood
cells.
Systemic manifestations of inflammation include fever,
neutrophilia, lethargy, muscle catabolism, increased acute
phase proteins (CRP), and increased ESR. These responses
are attributable to the IL-1, IL-6, and TNF-α released from
macrophages and inflamed tissues.
SPECIFIC ADAPTIVE IMMUNITY
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Specific immunity refers to functions of B and T lymphocytes.
Each lymphocyte recognizes and reacts to only one particular
antigen. On initial exposure to an antigen, lymphocytes
undergo clonal expansion so that many lymphocytes are
distributed throughout the body that can recognize and react to
that particular antigen. These cells are called memory cells.
Subsequent exposure results in a much faster and larger
lymphocyte response.
T lymphocytes are able to bind antigens only when they are
displayed on the surface of cells. Cytotoxic T cells (CD8+)
react to cells that have foreign MHC class I proteins on their
surface. T helper cells (CD4+) bind to cells that have MHC
class II proteins on their surface. MHC class II proteins are
found on antigen-presenting cells (B cells, dendritic cells, and
macrophages). These cells engulf foreign antigens and
combine the antigens with MHC class II proteins on their cell
surface.
T cells, which mature in the thymus, have two major
subgroups: T helper cells and cytotoxic T cells. T helper cells
perform a central role in specific immunity. Activation of T
helper cells results in secretion of the cytokines necessary for
clonal expansion of T and B lymphocytes. Cytotoxic T cells
locate and lyse abnormal cells through the actions of perforins.
B- and T-cell functions are interdependent. T cells cannot
respond to soluble antigens. B cells can process free antigen
and present it to T cells. On first exposure, B cells are
minimally activated by antigen unless they are stimulated by
cytokines and coreceptors from T cells.
B lymphocytes mature in bone marrow and lymph tissue. B
cells have receptors on their surfaces that can bind antigens.
Each B cell binds only one particular antigen. With appropriate
T helper cell help, antigen binding causes the B cell to divide
(clonal expansion). Some of the daughter cells become
plasma cells, which actively produce and secrete antibodies.
Other daughter cells (memory cells) resemble the original cell
and are distributed in lymph throughout the body. On
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subsequent exposure to the antigen, antibody production is
rapid.
Antibodies are proteins that specifically bind a particular
antigen. Antibodies have several functions, including
precipitation, agglutination, neutralization, opsonization, and
complement activation.
The five major antibody classes are IgG, IgM, IgA, IgD, and
IgE. Antibody class is determined by the structure of the Fc
portion. IgG is the most prevalent antibody class (75%). IgM is
the first kind to be produced on antigen exposure. IgA is found
primarily in body secretions. IgD is present on the B-cell
membrane and functions in signal transduction. IgE binds to
basophil and mast cell membranes and mediates inflammation
and allergy.
Administration of preformed antibodies confers passive
immunity. Passive immunity provides immediate but temporary
protection. Active immunity occurs when individuals are
exposed to antigen that stimulates their own lymphocytes to
produce memory cells. Active immunity confers long-term
protection but may take several weeks to develop.
INTEGRATED FUNCTION AND REGULATION OF THE
IMMUNE SYSTEM
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Specific and innate immune cells work together to protect the
body from foreign antigens. Macrophages and dendritic cells
play a central role because they are commonly the first
immune cells to encounter the antigen. Macrophages secrete
cytokines that stimulate WBC production and help WBCs
locate the area. Tissue reactions activate the clotting cascade
and kinin system, which help to localize the antigen and
promote movement of fluid and immune cells into the tissue.
Macrophages and dendritic cells are antigen-presenting cells
that engulf and display antigen on their cell surface in
association with MHC class II proteins. T helper cells are
specifically activated by these antigen-presenting cells. T
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helper cells secrete cytokines that stimulate the production of
WBCs in the marrow, initiate proliferation of mature B and T
cells, and stimulate the phagocytic potential of macrophages
and neutrophils.
B-cell proliferation and antibody secretion usually require T-cell
help. B cells internalize and present antigen to T cells, which
then stimulate B-cell proliferation. B cells secrete antibodies
that help phagocytic cells localize and destroy antigens.
The immune response to primary exposure is slow and often
insufficient to prevent illness. Memory cells that develop during
primary exposure can mount a more effective response on
subsequent exposure and usually prevent manifestations of
illness.
T and B lymphocytes must be tolerant to self. T lymphocytes
capable of reacting with self tissue are thought to be destroyed
or permanently inactivated during development in the thymus.
One theory suggests that lymphocytes must come in contact
with all self antigens during development, and those that do
not specifically bind self antigens are allowed to survive.
B cells are subject to careful regulation by T helper cells and
by negative feedback from high concentrations of circulating
antigen-antibody complexes.
Mechanisms to inhibit and control the immune response
include regulatory T-cell cytokines, complement inhibitors,
degradation of inflammatory mediators, circulating
antiproteases, and antioxidants.