Transcript Cellular Biology

INNATE IMMUNITY: INFLAMMATION
AND WOUND HEALING
Paula Ruedebusch, ARNP, DNP
IMMUNITY

First line of defense


Second line of defense


Innate (natural) (native) immunity
Inflammation
Third line of defense

Adaptive (acquired) immunity
2
LINES OF DEFENSE
3
FIRST LINE OF DEFENSE

Physical barriers:
Skin
 Linings of the gastrointestinal, genitourinary, and
respiratory tracts

Sloughing off of cells
 Coughing and sneezing
 Flushing
 Vomiting
 Mucus and cilia

4
BARRIERS
5
FIRST LINE OF DEFENSE (CONT’D)

Epithelial cell-derived chemical barriers:
Synthesized and secreted saliva, tears, ear wax,
sweat, and mucus
 Antimicrobial peptides
 Normal bacterial flora

6
NORMAL FLORA
Colon mostly sterile at birth
 1st year = colonization with bacteria
 Microorganisms help digest fatty acids, large
polysaccharides and other substances
 Help absorb calcium, iron and magnesium
 Compete with pathogens for nutrients and block
attachment to epithelium
 Produce chemicals (toxic proteins) that inhibit
colonization by pathogenic microorganisms

7
8
9
NORMAL FLORA, CONT.

Broad-spectrum antibiotics:
Amoxicillin
 Carbapenems


Imipenem, Meropenem, Ertapenem
Piperacillin
 Levofloxacin, Gatofloxacin, Moxifloxacin, Ciprofloxacin
 Streptomycin
 Tetracycline

10
NORMAL FLORA, CONT.
Some normal flora are opportunistic
 Normally controlled by innate and acquired immune
system
 Pseudomonas aeruginosa = normal flora of skin
 Produces toxin to prevent staph infection
 Burns compromise integrity of skin
 Risk for life-threatening systemic pseudomonal
infections

11
12
13
SECOND LINE OF DEFENSE

Inflammatory response (first immune response to injury)

Caused by a variety of materials


Infection, mechanical damage, ischemia, nutrient deprivation,
temperature extremes, radiation, etc.
Local manifestations

Redness, heat, swelling, pain, loss of function
14
SECOND LINE OF DEFENSE (CONT’D)

Inflammatory response

Vascular responses:
Blood vessel dilation
 Increased vascular permeability and leakage
 White blood cell adherence to the inner walls of the vessels
and migration through the vessels

15
INFLAMMATION

Goals:
Limit and control the inflammatory process
 Prevent and limit infection and further damage
 Initiate adaptive immune response
 Initiate healing

16
PLASMA PROTEIN SYSTEMS

Protein systems:
Complement system
 Coagulation system
 Kinin system

17
PLASMA PROTEIN SYSTEMS (CONT’D)

Complement system
Can destroy pathogens directly
 Activates or collaborates with every other component
of the inflammatory response
 Pathways:

Classical
 Lectin
 Alternative

18
CLASSICAL PATHWAY

Antibodies


Proteins acquired in the immune system
Antigens

Proteins or carbohydrates from bacteria or other agents
19
ALTERNATIVE PATHWAY




Surface of infectious
organisms
Unique proteins activate C3.
C3 leads to C5 activation and
convergence with classical
pathway
No antibody needs to be
present
20
LECTIN PATHWAY
Similar to classical pathway
 Activated by proteins

21
COMPLEMENT CASCADE, CONT.

3 different means
Classical
 Alternative
 Lectin


4 functions
Opsonization – pathogen marked for destruction by
phagocyte
 Anaphylatoxic activity resulting in mast cell
degranulation – C3 and C5 (release histamine,
vasodilation and increased capillary permeability)
 Leukocyte chemotaxis – movement of WBCs to the
area
 Cell lysis – pores in cell membrane allow water to enter,
cell bursts

22
PLASMA PROTEIN SYSTEMS (CONT’D)

Coagulation (clotting) system

Forms a fibrinous meshwork at an injured or inflamed
site
Prevents the spread of infection
 Keeps microorganisms and foreign bodies at the site of
greatest inflammatory cell activity
 Forms a clot that stops bleeding
 Provides a framework for repair and healing


Main substance is an insoluble protein called fibrin
23
PLASMA PROTEIN SYSTEMS (CONT’D)

Kinin system
Functions to activate and assist inflammatory cells
 Primary kinin is bradykinin
 Causes dilation of blood vessels, pain, smooth muscle
contraction, vascular permeability, and leukocyte
chemotaxis

24
CELLULAR MEDIATORS OF INFLAMMATION

Cellular components:

Granulocytes

Basophils, eosinophils and neutrophils
Platelets
 Monocytes
 Lymphocytes

25
CYTOKINES
Proteins – cell signaling
 Proinflammation or anti-inflammation
 Short distances = affect target cell
 Long distances = induction of fever
 More than 100 types
 Majority are interleukins or interferons

26
CYTOKINES

Interleukins (IL)
Produced primarily by macrophages and lymphocytes
in response to a pathogen or stimulation by other
products of inflammation
 Many types

27
CYTOKINES (CONT’D)

Interferon (IFN)
Protects against viral infections
 Produced and released by virally infected host cells in
response to viral double-stranded RNA

28
CYTOKINES (CONT’D)

Tumor necrosis factor-alpha

Secreted by macrophages
Induces fever by acting as an endogenous pyrogen
 Increases synthesis of inflammatory serum proteins
 Causes muscle wasting (cachexia) and intravascular
thrombosis

29
CYTOKINES (CONT’D)

Chemokines
Attract leukocytes to site of inflammation
 Synthesized by many cells (macrophages, fibroblasts,
endothelial cells)

30
MAST CELLS

Cellular bags of granules located in the loose
connective tissues close to blood vessels


Skin, digestive lining, and respiratory tract
Contain histamine and chemotaxic factors
31
MAST CELLS (CONT’D)

Activation
Physical injury, chemical agents, immunologic
processes, and toll-like receptors
 Chemical release in two ways

1. Degranulation
 https://www.youtube.com/watch?v=eVBqMXMIFnM
 2. Synthesis of lipid-derived chemical mediators

32
MAST CELL DEGRANULATION

Histamine
Vasoactive amine that causes temporary, rapid
constriction of the large blood vessels and the dilation
of the postcapillary venules
 Increased capillary permeability
 Retraction of endothelial cells lining the capillaries
 Receptors:

H1 receptor (proinflammatory)
 H2 receptor (anti-inflammatory)

33
HISTAMINE

Receptors:

H1 receptor


Present in smooth muscle cells of the bronchi
H2 receptor

Present on parietal cells of the stomach mucosa
 Induces the secretion of gastric acid
34
MAST CELL DEGRANULATION (CONT’D)
35
ANTI-HISTAMINE
36
H1 BLOCKERS
VS.
H2 BLOCKERS
37
MAST CELL SYNTHESIS OF MEDIATORS

Leukotrienes



Product of arachidonic acid from mast cell membranes
Similar effects to histamine in later stages
Prostaglandins


Similar effects to leukotrienes; they also induce pain
Aspirin and some other nonsteroidal anti-inflammatory drugs
(NSAIDs) block the synthesis of prostaglandins, thereby
inhibiting inflammation
38
ENDOTHELIUM

Endothelial cells adhere to underlying connective
tissue matrix



Interact with circulating cells, platelets, plasma proteins
Regulate circulating inflammatory components
Damage to these initiates platelet adherence
39
PLATELETS
Activated by tissue destruction and inflammation
 Activation leads to interaction with coagulation
cascade


Degranulation with serotonin release (acts like histamine)
40
PHAGOCYTES

Neutrophils
Also referred to as polymorphonuclear neutrophils (PMNs)
 Predominate in early inflammatory responses
 Ingest bacteria, dead cells, and cellular debris
 Cells are short lived and become a component of the
purulent exudate

41
PHAGOCYTES (CONT’D)

Monocytes and macrophages
Immature form of WBCs in the blood
 Monocytes are produced in the bone marrow, enter the
circulation, and migrate to the inflammatory site, where
they develop into macrophages
 Macrophages typically arrive at the inflammatory site
24 hours or later after neutrophils

42
PHAGOCYTES (CONT’D)

Eosinophils
Mildly phagocytic
 Defense against parasites and regulation of vascular
mediators
 “Worms, wheezes and weird diseases”

43
PHAGOCYTES (CONT’D)

Dendritic cells
In peripheral organs and skin
 Migrate through lymph vessels to lymph tissue and interact
with T lymphocytes to generate an acquired immune
response


T lymphocytes

Active during wound healing
44
PHAGOCYTOSIS
Process by which a cell ingests and disposes of
foreign material
 Production of adhesion molecules
 Margination



Adherence of leukocytes to endothelial cells
Diapedesis

Emigration of cells through the endothelial junctions
45
PHAGOCYTOSIS (CONT’D)
46
PHAGOCYTOSIS (CONT’D)

Steps:





Adherence
Engulfment
Phagosome formation
Fusion with lysosomal granules
Destruction of the target
http://vimeo.com/70326148
47
ACUTE AND CHRONIC INFLAMMATION

Acute
Self limiting
 Local manifestations-result from vascular changes and
corresponding leakage of circulating components into the
tissue

Heat, swelling, redness, pain
 Exudative fluids

48
EXUDATIVE FLUIDS

Serous exudate


Fibrinous exudate


Thick, clotted exudate: indicates more advanced
inflammation
Purulent exudate (supperative)


Watery exudate: indicates early inflammation
Pus
Hemorrhagic exudate

Exudate contains blood: indicates bleeding
49
EXUDATES
50
SYSTEMIC MANIFESTATIONS OF ACUTE
INFLAMMATION

Fever



Caused by exogenous and endogenous pyrogens
Act directly on the hypothalamus
Leukocytosis

Increased numbers of circulating leukocytes
51
LEFT SHIFT
52
CHRONIC INFLAMMATION
Inflammation lasting 2
weeks or longer
 Often related to an
unsuccessful acute
inflammatory response

53
CHRONIC INFLAMMATION (CONT’D)

Characteristics:
Dense infiltration of lymphocytes and macrophages
 Granuloma formation
 Epithelioid cell formation
 Giant cell formation

54
RESOLUTION AND REPAIR
Regeneration
 Resolution



Returning injured tissue to the original structure and
function
Repair


Replacement of destroyed tissue with scar tissue
Scar tissue

Composed primarily of collagen to restore the tensile
strength of the tissue
55
RESOLUTION AND REPAIR (CONT’D)

Debridement


Cleaning up the dissolved clots, microorganisms,
erythrocytes, and dead tissue cells
Healing
Filling in the wound
 Sealing the wound (epithelialization)
 Shrinking the wound (contraction)

56
WOUND HEALING

Primary intention


Wounds that heal under conditions of minimal tissue loss
Secondary intention

Wounds that require a great deal more tissue replacement

Open wound
57
WOUND HEALING (CONT’D)

Phases:
I. Coagulation & Inflammatory
 II. Proliferation
 III. Remodeling & Maturation

58
WOUND HEALING (CONT’D)
Proliferative phase
 Granulation
 Epithelialization
 Requires fibroblast proliferation, collagen formation,
wound contraction

59
WOUND HEALING (CONT’D)

Remodeling and
maturation phase
Continuation of
cellular differentiation
 Scar tissue formation
 Scar remodeling

60
HEALING
61
DYSFUNCTIONAL WOUND HEALING

Dysfunction during inflammatory response





Hemorrhage
Fibrous adhesion
Decreased blood volume (hypovolemia)
Lack of nutrients (proteins, glucose oxygen)
Infection
62
DYSFUNCTIONAL WOUND HEALING (CONT’D)

Dysfunction during reconstructive phase

Impaired collagen matrix assembly
Keloid scar – raised, extends beyond original boundaries of
wound
 Hypertrophic scar – raised, remains within original
boundaries or wound

Keloid Scar
Hypertrophic scar
63
DYSFUNCTIONAL WOUND HEALING, CONT.

Impaired epithelialization


Wound disruption


Anti-inflammatory steroids, hypoxemia, and nutritional
deficiencies
Dehiscence (increases risk of infection)
Impaired contraction

Contracture
 Positioning, ROM exercises and surgery can release.
64
PEDIATRICS
Neonates have transiently depressed
inflammatory and immune function
 Neutrophils are not capable of efficient chemotaxis
– cutaneous abscesses caused by staph, and
cutaneous candidiasis
 Deficient oxidative and bacterial responses
 Develop overwhelming sepsis


And meningitis when infected by a bacteria which no
maternal antibodies are present.
65
66
OLDER ADULTS
Impaired function of innate immune cells
(phagocytes)
 Impaired inflammation is likely a result of chronic
illness


Diabetes, cardiovascular disease, etc.
Chronic medication intake decreases the
inflammatory response
 Healing response is diminished because of skin’s
loss of regenerative ability
 Infections and chronic inflammation are more
common in older adults

67
TEST YOURSELF!
1. An injury to a vascularized tissue has occurred
and activated an acute inflammatory response.
Which of the following is TRUE regarding this
response? It:
A.
B.
C.
D.
Is nonspecific
Is activated slowly
Is the third line of defense
Relies on cellular components only
68
TEST YOURSELF!
2. The mature white blood cell is called a:
A.
B.
C.
D.
Platelet
Monocyte
Neutrophil
T lymphocyte
69