INFLAMMATION AND TISSUE HEALING AND REPAIR Flashcards
1
Q
Inflammation is a protective response involving:
1
2
3
4
A
• host cells
• blood vessels
• proteins and
• other mediators
2
Q
to eliminate the initial cause of cell injury
• Its protective mission by:
1
2
3
4
A
INFLAMMATION
• Diluting
• destroying
• Neutralizing
• innate immunity
3
Q
Inflammation
Latin:
A
inflammare (to set on fire)
4
Q
- Roman writer 1st century AD listed the 4 signs of inflammation
- he said “___” meaning “____”
A
Celsus
“rubor et tumor cum calore et dolore” -> “redness and swelling with heat and pain”
5
Q
The 5th sign “___” ___ was added by ____ in 19th century
A
Functio laesa -> loss of function
Rudolf Virchow
6
Q
Scottish surgeon: Inflammation is not a dse but a response
A
John Hunter 1793
7
Q
a russian zoologist: discovered the process of phagocytosis
A
Elie Metchinkoff 1880s
8
Q
Etiology of Exogenous causes:
1
2
3
4
5
A
• Physical agents
trauma, electrical shock
• Mechanic agents:
fractures, foreign , sand
• Thermal agents:
burns, freezing
• Chemical agents:
toxic gases, acids, bases
• Biological agents:
bacteria, viruses, parasites
9
Q
Etiology of Endogenous causes:
1
2
3
A
• Circulation disorders:
thrombosis, infarction, hemorrhage
• Enzymes activation –
acute pancreatitis
• Metabolic products deposals –
uric acid, urea
10
Q
Changes in inflammation
1
2
3
4
A
• Tissue damage
• Cellular –vascular response
• Metabolic changes
• Tissue repair
11
Q
Feautures of Acute and chronic inflammation
ACUTE
Onset
Cellular Infiltrate
Tissue Injury, Fibrosis
Local and syatemic signs
CHRONIC
Onset
Cellular Infiltrate
Tissue Injury, Fibrosis
Local and syatemic signs
A
Feauture Acute
Onset
Fast: minutes or hours
Cellular Infiltrate
mainly neutrophils
Tissue Injury, Fibrosis
usually mild and self limited
Local and systemic signs
Prominent
Feauture Chronic
Onset
Slow: days
Cellular Infiltrate
Monocyte macrophage and lymphocyte
Tissue Injury, Fibrosis
often sever and progressive
Local and syatemic signs
less prominent, may be subtle
12
Q
• an immediate and early response to an injurious agent
• short duration, lasting for minutes, several hours or few days.
• It is characterized by :
1
2
A
ACUTE INFLAMMATION
• exudation of fluids and plasma proteins
• emigration of neutrophilic leukocytes to the site of injury.
13
Q
Cardinal signs of acute Inflammation
A
Redness rubor
Heat calor
Swelling tumor
Pain dolor
Loss of function functio laesa
14
Q
due to dilation of small blood vessels within damaged tissue . (____)
A
Redness (rubor)
cellulitis
15
Q
results from increased blood flow (____) due to regional vascular dilation
A
Heat (calor)
hyperemia
16
Q
due to accumulation of fluid in the extravascular space.
A
Swelling (tumor)
17
Q
results from the stretching & destruction of tissues due to inflammatory edema .
A
Pain (dolor)
18
Q
- inflamed area is inhibited by pain
- severe swelling may physically immobilize the tissue.
A
Loss of function
19
Q
Chemicals of acute inflammation
1
2
3
A
bradykinins
prostaglandins
serotonin
20
Q
Events of Acute inflammation
A
Vascular changes
cellular events
21
Q
- there will be an increase in blood flow
- bring cells and proteins to the site of injury
- by ___ and increase____ l
A
Vascular changes
- vasodilation
- vascular permeability
22
Q
recruitment of leukocytes
Activation of leukocytes leading to the process of destruction of invaders and production of mediators
A
cellular events
23
Q
Stages of Vascular response
1
2
3
A
(1) Vascular dilation and
increased blood flow
- causing erythema and warmth
(2) extravasation and deposition of plasma fluid and proteins (edema)
(3) leukocyte (mainly neutrophil) emigration and accumulation in the site of injury.
24
Q
Mechanism of Vascular response
• ___
• ___ of ___ and___
• Stasis of blood blood flow
• due to ___
• oozes protein-rich fluid into ___
• exudates clinically appear as ____
A
Mechanism of Vascular response
• Vasoconstriction
• Vasodilatation of arterioles and
venules
- due increased vascular permeability
•extravascular tissues.
• swelling (edema)
25
Mechanisms may contribute to increased vascular permeability in acute inflammatory reactions
1 Endothelial cell contraction leading to intercellular gaps in postcapillary venules
2 Endothelial injury
3 Increased transcytosis
26
occurs rapidly after binding of __, ___,___ (____)
induced by cytokines such ; ___
This reaction may take ___to develop after the initial trigger and persist for __ or more.
Endothelial cell contraction leading to intercellular gaps in postcapillary
venules
- histamine, bradykinin, leukotrienes (15 to 30 minutes)
- tumor necrosis factor (TNF) interleukin-1 (IL-1)
- 4 to 6 hours
- 24 hours
27
- results in vascular leakage by causing endothelial cell necrosis and detachment.
Endothelial injury
28
-of proteins by way of an ____
- occurs through channels formed by fusion of intracellular vesicles.
Increased transcytosis
- intracellular vesicular pathway vascular endothelial growth factor (VEGF)
29
• is a peripheral positioning of white cells along the endothelial
cells.
Margination
30
rows of leukocytes tumble slowly along the endothelium.
Rolling
31
- endothelium can be lined by white cells the binding of leukocytes with endothelial cells is facilitated by cell adhesion molecules
1
2
3
Pavementing
- selectins
- immunoglobulins
- integrins
32
• The movement of leukocytes by extending pseudopodia through the vascular wall.
Diapedesis
33
unidirectional attraction of leukocytes from vascular channels towards the site of inflammation within the tissue space guided by chemical gradients.
Chemotaxis
34
• The important chemotactic factors for neutrophils:
1 _
complement system, bacteria and mitochondrial products of arachidonic acid metabolism:
:
:
(C5a) –
complement system, bacteria and mitochondrial products of arachidonic acid metabolism:
leukotriene B4
cytokines (IL-8)
35
is the process of engulfment and internalization by specialized cells of particulate material.
Phagocytosis
36
Phagocytic cells:
1
2
3
polymorphonuclear leukocytes (neutrophiles)
monocytes
tissue macrophages.
37
Leukocyte recruitment is a multi-step process consisting of:
1
2
3
§ loose attachment to and rolling on endothelium (mediated by selectins);
§ firm attachment to endothelium (mediated by integrins)
§ migration through interendothelial spaces.
38
Steps of the inflammatory response (5Rs)
• Recognition of the injurious agent
> Cellular receptors (TLR's Toll like receptors)
• Recruitment of leukocytes
• Removal of the agent
• Regulation (control) of the response
• Resolution (repair)
39
• ___ can eliminate microbes and dead cells
• destruction in __.
• Caused by____ generated in activated leukocytes and lysosomal enzymes
Phagocytosis
- Leukocytes
- phagolysosomes
- free radicals
40
The outcome of acute inflammation
1
2
3
4
5
• Elimination of the noxious stimulus
• Decline of the reaction
• Repair of the damaged tissue,
• Persistent injury resulting in chronic inflammation
• resolution, healing by scarring (fibrosis), or chronic inflammation
41
Morphological Feature of AI
1
2
3
• Serous inflammation
• Fibrinous inflammation
• Suppurative (purulent) inflammation
42
43
• is characterized by the outpouring of a watery, relatively
protein-poor fluid that, depending on the site of injury
Serous inflammation
44
Fluid in a serous cavity is called an __.
effusion
45
• manifested by the presence of large amounts of purulent exudate (pus)
• consisting of __,__,__ (eg__)
Suppurative (purulent) inflammation
- neutrophils, necrotic cells, and edema fluid. • (e.g., staphylococci)
46
• are focal collections of pus that may be caused by seeding of
pyogenic organisms into a tissue
• secondary infections of ___
Abscesses
- necrotic foci
47
a local defect, or excavation, of the surface of an organ or tissue that is produced by necrosis of cells and sloughing (shedding) of inflammatory necrotic tissue
ulcer
48
• is inflammation of prolonged duration • (weeks to months to years)
• in which active inflammation, tissue injury, and healing proceed simultaneously
Chronic inflammation
49
chronic inflammation is characterized by
1
2
3
4
5
6
Infiltration with mononuclear cells
macrophages,
lymphocytes,
plasma cells
Tissue destruction,
Repair, involving new vessel proliferation (angiogenesis) and fibrosis
50
Chronic Inflammatory Cells
1
2
3
4
macrophage
plasma cell
eosinophil
mast cell
51
• the dominant cells of chronic inflammation
Macrophages
• liver (Kupffercells),
• spleen and lymphnodes (sinus histiocytes),
• central nervous system(microglialcells),
• lungs (alveolar macrophages).
52
Classification of chronic inflammation
1
2
Nonspecific chronic inflammation
Specific inflammation (granulomatous inflammation)
53
• This involves a diffuse accumulation of __ and __ at site of injury that is usually productive with new fibrous tissue formations
Nonspecific chronic inflammation
- macrophages and lymphocytes
54
characterized by the presence of granuloma.
Specific inflammation (granulomatous inflammation)
1 granuloma
2 epithelioid
55
is a microscopic aggregate of epithelioid cells.
granuloma
56
cell is an activated macrophage, with a modified epithelial cell-like appearance.
can fuse with each other & form multinucleated giant cells.
Epithelioid
57
• is a distinctive pattern of chronic inflammation characterized by aggregates of activated macrophages that assume an epithelioid appearance.
Granulomatous inflammation
58
Two types of giant cells:
• . Foreign body-type giant cells
presence of indigestible materials. • . Langhans giant cells
59
• the nuclei are arranged peripherally in a horse –shoe pattern which is seen typically in __ and __
• . Langhans giant cells
- tuberculosis, and sarcoidosis
60
which have irregularly scattered nuclei in presence of indigestible materials.
• . Foreign body-type giant cells
presence of indigestible materials
61
Types of granulomas
Foreign body granuloma
Immune granulomas
62
granulomas are initiated by inert foreign
Foreign body granuloma
63
• Antigen presenting cells (___)
engulf a poorly soluble inciting agent.
• ___ helps to localize activated macrophages and epithelioid cells.
Immune granulomas
- macrophages
-Macrophage inhibitory factor
64
Major causes of granulomatious inflammation
1
2
3
4
5
1 Bacterial: Tuberculosis, Leprosy, Syphilis, Cat scratch disease, Yersiniosis
2 Fungal: Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Blastomycosis
3 Helminthic: Schistosomiasis
4 Protozoal: Leishmaniasis, Toxoplasmosis
5 Chlamydia: Lymphogranuloma venerum
65
SYSTEMIC EFFECTS OF INFLAMMATIONS
a
b
c
d
e
f
g
a. Fever
• b. Endocrine & metabolic responses •
c. Autonomic responses
• d. Behavioral responses
• e. Leukocytosis
• f. Leukopenia
• g. Weight loss
66
restoration of tissue architecture and function after an injury
• Occurs in two ways:
-
-
involves
-
-
Tissue repair
- Regeneration of injured tissue
– Replacement by connective tissue (scarring)
* Usually, tissue repair involves both processes
- cell proliferation
- interaction between cells and extracellular matrix
67
Ø Mechanisms regulating cell populations
Ø Cell numbers can be altered by:
-
-
Ø Changes in the rates of proliferation or differentiation.
Cellular Proliferation
- increased or decreased rates
of stem cell input
- cell death due to apoptosis
68
69
Processes in the proliferation of cells
1
2
1. DNAreplication
2. Mitosis
70
Cellular Proliferation
• divided into three groups:
1 Continuously dividing (labile) tissues
2 Stable tissues
3 Permanent tissues
71
Cells are continuously proliferating
Can easily regenerate after injury
Contain a pool of stem cells
• • Examples:
• _,_,_
Continuously dividing (labile) tissues
- bone marrow, skin, epithelium
72
• Cells have limited ability to proliferate
• Limited ability to regenerate
• Can proliferate if injured
• Examples: __,__,__
Stable tissues
- liver, kidney, pancreas
73
• Cells can’t proliferate
• Can’t regenerate
• injury always leads to scar
• Examples: __,___
Permanent tissue
- neurons, cardiac muscle
74
Three phases in granulation - tissue
1. Phase of inflammation
2. Phase of demolition
3. Ingrowth of granulation tissue
75
inflammatory exudate, platelet aggregation and fibrin deposition.
Phase of inflammation
76
The dead cells liberate their autolytic enzymes.
There is an associated macrophage infiltration.
Phase of demolition
77
proliferation of fibroblasts and an in growth of newblood vessels into the area of injury, with a variable number of inflammatory cells.
Ingrowth of granulation tissue
78
is a mechanical reduction in the size of the defect.
Wound contraction
79
- results in much faster healing,
• If prevented, healing is slow and a large scar is formed.
Contraction
80
Molecular control of healing process
___ - have the capacity to stimulate cell division and proliferation
• promote cell survival
Growth factors
81
82
• Sources of Growth Factors:
1
2
3
4
5
• 1. Platelets, activated (TGF)
• 2. Damaged epithelial cells, (EGF)
• 3. Circulating serum growth factors,
• 4. Macrophages, (angiogenic factor)
• 5. Lymphocytes recruited to the area of injury
83
The main phases of cutaneous wound healing:
•
•
•
• Inflammation
• Formation of granulation tissue
• ECM remodeling
84
is the network that surrounds cells
• Two forms:
Extracellular Matrix
- interstitial matrix
-basement membrane
85
The Functions of ECM
• It provides mechanical support to tissues
• It acts as a substrate for cell growth and the formation of tissue microenvironments.
• It regulates cell proliferation and differentiation
• An intact ECM is required for tissue regeneration
86
It provides mechanical support to tissues
> this is the role of __ and __
collagens and elastin
87
• proteoglycans bind growth factors and display them at high concentration, and fibronectin and laminin stimulate cells through cellular integrin receptors.
It regulates cell proliferation and differentiation
88
Healing of a wound demonstrates both
1
2
epithelial
• regeneration (healing of the epidermis)
• repair by scarring (healing of the dermis).
89
Two patterns of wound healing
1. Healing by first intention
(Primary union)
2. Healing by second intention
90
• Occurs in small wounds that close easily
• ___ predominates over fibrosis
• Healing is fast, with minimal
scarring/
Examples:
__
Healing by first intention (primary union)
- Epithelial regeneration
- Well-approximated surgical incisions
91
By 24 hours
• clot forms
• neutrophils come in
• epithelium begins to regenerate
92
• By 3-5 days
• macrophages come in
• granulation tissue is formed
newbloodvessels
fibroblasts
• collagen begins to bridge incision
• epithelium increases in thickness
93
• Weeks later
• Weeks later
• granulation tissue gone
• collagen is remodeled
• epidermis full, mature
• eventually, scar forms
94
• larger wounds that have gaps between wound margins
• __ predominates over epithelial regeneration
• Healing is slower, with more inflammation and
• granulation tissue formation, and more scarring
• Examples:
1
2
Healing by second intention (secondary union)
- Fibrosis
• – Infarction
• – Large burns and ulcers
95
Factors that influence wound healing
• Local Factors
> Type, size, and location of the wound
> Vascular supply
> Infection
> Movement
> Ionizing radiation
96
Systemic Factors;
1
2
3
4
• Circulatory status
Cardiovascular status
• Infection
Systemic infections delay wound healing.
• Metabolic status
Poorly controlled diabetes mellitus
• Nutritional deficiencies
97
Complications of Wound Healing
• Infection
• Deficient Scar Formation
Wound Dehiscence
Ulceration
• Excessive Scar Formation
Keloid Formation Hypertrophic Scar
98
Selectins and Selectin Ligands
P-selectin
E- selectin
Glycam-I, CD 34
99
P-selectin
- Sialyl-Lewis X-modified proteins
- Rolling
100
E-selectin
- Sialyl-Lewis X-modified proteins
-Rolling and adhension
101
GlyCam-1, CD34
- L selectin
- Rolling (neutrophils, monocytes)
102
Integrins and Integrin Ligands
l
ICAM-1 (immunoglobulin family)
VCAM-1 (immunoglobulin family)
103
VCAM-1 (immunoglobulin family)
- VLA-4 integrin
- Adhesion
104
- CD11/CD18 integrins (LFA-1, Mac-1)
- Firm adhesion, arrest, transmigration
ICAM-1 (immunoglobulin family)
105
CD31
- CD31 (homotypic interaction)
- Transmigration of leukocytes through endothelium
106
Acquired
Bone marrow suppression:
tumors (including leukemias).
radiation, and chemotherapy
Diabetes, malignancy, sepsis, chronic dialysis
Anemia, sepsis, diabetes, malnutrition
107
Defects
- Production of leukocytes
Bone marrow suppression:
tumors (including leukemias).
radiation, and chemotherapy
108
Defects
- Adhesion and chemotaxis
Diabetes, malignancy, sepsis, chronic dialysis
109
defects
- Phagocytosis and microbicidal activity
Anemia, sepsis, diabetes, malnutrition
110
Genetic
Leukocyte adhesion
deficiency 1
Leukocyte adhesion
deficiency 2
Chronic granulomatous disease
X-linked
Autosomal recessive
Myeloperoxidase deficiency
Chediak- Higashi syndrome
111
- Defective leukocyte adhesion because of mutations in B chairs of CD11/CD18 integrins
Leukocyte adhesion
deficiency 1
112
- Defective leukocyte adhesion because of mutations in fucosyl transferase required for synthesis of sialylated oligosaccharide (receptor for selectins)
Leukocyte adhesion
deficiency 2
113
defect
- Decreased oxidative burst
Chronic granulomatous disease
114
defect
- Phagocyte oxidase (membrane component)
X-linked
115
defect
- Phagocyte oxidase (cytoplasmic components)
Autosomal recessive
116
defect
- Decreased microbial killing because of defective MPO—H2 O2 system
Myeloperoxidase deficiency
117
defect
- Decreased leukocyte functions because of mutations affecting protein involved in lysosomal membrane traffic
Chediak- Higashi syndrome
118
Three steps in Phagocytosis
(1) recognition and attachment of the particle to the ingesting leukocyte
(2) engulfment, with subsequent formation of a phagocytic vacuole
(3) killing and degradation of the ingested material
119
119
- resulting in greater vascular permeability allows large molecules (such as fibrinogen) to pass the endothelial barrier.
- A fibrinous exudate is characteristic of inflammation in the lining of body cavities,
- such as the _,_,_
Fibrinous inflammation
- meninges, pericardium, and pleura
120
cell derived mediator
Histamine
Secrotonin
Prostaglandins
Leukotrienes
Platelet-activating factor
Reactive oxygen species
Nitric oxide
Cytokines (TNF,IL-I,IL-6)
Chemokines
121
- Mast cells, basophils, platelets
- Vasodilation, increased vascular permeability, endothelial activation
Histamine
122
- Platelets
- Vasoconstriction
Secrotonin
123
124
- Mast cells, leukocytes
- Vasodilation, pain, fever
Prostaglandins
125
- Mast cells, leukocytes
- Increased vascular permeability, chemotaxis, leukocytes adhesion and activation
Leukotrienes
126
- Leukocytes, mast cells
- Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
Platelet-activating factor
127
- Leukocytes
- Killing of microbes, tissue damage
Reactive oxygen species
128
- Endothelium, macrophages
- Vascular smooth muscle relaxation: killing of microbes
Nitric oxide
129
- Macrophages, endothelial cells, mast cells
- Local: endothelial activation (expression of adhesion molecules).
Sytemic fever, metabolic abnormalities, hypotension (shock)
Cytokines (TNF,IL-I,IL-6)
130
- Leukocytes, activated macrophages
- Chemotaxis, leukocyte activation
Chemokines
131
Plasma Protein-Derived
Complement
Kinins
Proteases activated during coagulation
132
- Plasma (produced in liver)
- Leukocyte chemotaxis and activation, direct target killing (MAC). vasodilation (mast cell stimulation)
Complement
133
- Plasma (produced in liver)
- Increased vascular permeability, smooth muscle contraction, vasodilation, pain
Kinins
134
- Plasma (produced in liver)
- Endothelial activations, leukocyte recruitment
Proteases activated during coagulation
135
136
A typical granuloma resulting from infection with __ showing central caseous necrosis, activated epithelioid, macrophages, many giant cells, and a peripheral accumulation of lymphocytes
Mycobacterium tuberculosis
137
develop from activated B lymphocytes produce ab
Plasma cells
138
are charac found in inflammatory sites around parasitic infections or as part of immune reactions mediated IgE, typically ass with allergies
Eosinophils
139
distributed in connective tissues throughout the body and they can participate in both acute and chronic inflammatory responses
mast cells
140
Vasodilation
Mediators:
- Prostaglandins
- Nitric oxide
- Histamine
141
Increased vascular permeability
Mediators:
- Histamine and serotonin
C3a and C5a (by liberating vasoactive amines from mast cells, other cells)
- Bradykinin
- Leukotrienes C4, D4, E4
- PAF
- Substance P
142
Chemotaxis, leukocyte recruitment and activation
Mediators
- TNF, IL-I
- Chemokines
- C3a, C5a
- Leukotriene B4
- Bacterial products (e.g.. N-formyl methyl peptides)
143
Fever
Med
- IL-I. TN
- Prostaglandins
144
Pain
med
- Prostaglandins
- Bradykinin
145
Tissue damage
med
- Lysosomal enzymes of leukocytes
- Reactive oxygen species
- Nitric Oxide
146
Epidermal growth factor (EGF)
Sources
- Activated macrophages, salivary glands, keratinocytes, and many others cells
Function
- Mitogenic for keratinocytes and fibroblasts: stimulates keratinocyte migration: stimulates formation of granulation tissue
147
Transforming growth factor-a (TGF-a)
Sources
- Activated macrophages, keratinocytes, many other cell types
Func
- Stimulates proliferation of hepatocytes and many other epithelial cells
148
Hepatocyte growth factor (HGF) (scatter factor)
Sources
- Fibroblasts, stromal cells in the liver, endothelial cells
Function
- Enhances proliferation of hepatocytes and other epithelial cells: increases cell motility
149
Vascular endothelial growth factor (VEGF)
Sources
- Mesenchymal cells
Function
- Stimulates proliferation of endothelial cells: increases vascular permeability
150
Platelet-derived growth factor (PDGF)
Sources
- Platelets, macrophages, endothelial cells, smooth muscle cells, keratinocytes
Function
- Chemotactic for neutrophils, macrophages, fibroblasts, and smooth muscle cells: activates and stimulates proliferation of fibroblasts, endothelial, and other cells; stimulates ECM protein synthesis
151
Fibroblasts growth factors (FGFs), including acidic (FGF-I) and basic (FGF-2)
Sources
- Macrophages, must cells, endothelial cells, many other cell types
Function
- Chemotactic and mitogenic for fibroblasts; stimulates angiogenesis and ECM protein synthesis
152
Transforming growth factor-B (TGF-B)
sources
- Platelets, T lymphocytes, macrophages, endothelial cells, keratinocytes, smooth muscle cells, fibroblasts
function
- Chemotactic for leukocytes and fibroblasts; stimulates ECM protein synthesis; suppresses acute inflammation
153
Keratinocytes growth factor (KGF) (i.e., FGF-7)
sources
Fibroblasts
func
- Stimulates keratinocytes micgration, proliferation, and differentiation
155
156
157
