1
Q
Define inflammation
A
The reaction of vascularized living tissues to local injury whereby there are a series of changes in the terminal vascular bed, in blood, and in CT to eliminate the offending irritant and repair damaged tissue.
2
Q
What are the 3 general participants in the inflammatory process?
A
- Cellular/tissue participants
- Humoral participants
- Chemical participants (cytokines)
3
Q
What are the 3 functions of inflammation?
A
- Protecting the body
- Containing and isolating injurious agents
- Achieving healing and repair
4
Q
It is very common to have some degree of ____ in areas of inflammation and vice versa.
A
Necrosis
5
Q
Necrosis that is not initially the result of inflammation will invariably incite a _____________
A
Secondary inflammation response
6
Q
What are the 5 cardinal signs of inflammation?
A
- Pain
- Heat
- Swelling
- Redness
- Loss of function.
7
Q
Inflammation is a process involving _____ participants.
A
Multiple
8
Q
Inflammation occurs only in ____ tissue.
A
Living: need blood.
9
Q
Inflammation involves a series of events which overlap and form a ______.
A
Continuum
10
Q
Inflammation is a response to an ______ event.
A
Initiating
11
Q
How can inflammation be harmful?
A
- Can lead to necrosis
- Chronic cases can predispose to neoplasia (IBD -> lymphoma)
12
Q
Inflammation is primarily a _____ reaction.
A
Defensive
13
Q
The early stages of inflammation are relatively ____ across the board regardless of the _____.
A
stereotypical across the board regardless of the nature of the irritant.
14
Q
Many components of inflammation are found in the ____.
A
Blood stream
15
Q
What does it mean that inflammation is a ‘surface phenomenon’?
A
Cell membrane changes or signals are important.
16
Q
What is the overall goal of acute inflammation?
A
Get cells to the sources: WBC’s migrate from circulation, are activated, and leave the microvasculature through a process involving cytokines, selective adhesion, and migration between endothelial cells.
17
Q
What are the major cell types seen with acute inflammation?
A
- Mainly neutrophils: first at the site of injury
- Lymphocytes
- Macrophages in a small amount but they accumulate over time so are more prominent in chronic phase.
18
Q
In which phase of inflammation does vascular leakage occur?
A
In the acute phase: leads to fluid build up, heat, and redness (edema belongs to acute phase).
19
Q
Fibrin and exudate (pus) belong to which phase of inflammation?
A
Acute: amorphous pink material on histology due to proteins.
20
Q
What is the overall goal of chronic inflammation?
A
Repair (this is why there is so much fibrosis happening)
21
Q
What is the cell type distribution seen with chronic inflammation?
A
Macrophages, lymphocytes, and plasma cells
neutrophils can still be seen but in a much smaller amount than with acute phase.
22
Q
The presence of fibroblasts in chronic inflammation leads to what?
A
Fibrosis: scar formation.
23
Q
What species is prone to higher levels of granulation tissue production during chronic inflammation?
A
Horses.
24
Q
What are the differences seen in an otherwise stereotypical inflammatory reaction?
A
- Depends on the host and the initiating agent
- Differences seen in nature of exudate, distribution, time course, and severity of the reaction.
25
Why is it useful to classify inflammatory reactions?
Morphologic diagnosis helps point towards the etiology of the lesion --> different clinical approaches.
26
Why is it important for us as clinicians to understand how inflammatory processes are classified?
- Ability to formulate/understand a morphologic diagnosis makes communication between clinicians and pathologists easier and more productive
- Easier ability to interpret pathology reports you will receive.
27
What are the 2 terms used for inflammation of regular fat and SQ fat?
- Regular: steatitis
- SQ: panniculitis.
28
Inflammation can be classified according to what 5 factors?
- Anatomical location
- Type of exudate
- Distribution
- Duration
- Severity.
29
How are inflammatory processes classified according to the type of exudate produced?
- Predominant cell type
- Type of fluid/material that is present
(suppurative, fibrinosuppurative, etc.)
30
How does fibrinous exudate occur?
Increased vascular permeability due to injury to the endothelium and BM which allows for leakage of plasma proteins, including fibrinogen -->
fibrinogen polymerizes perivascularly to fibrin.
31
What is the time process of fibrinous exudate?
Acute: can form in minutes and can persist for days.
32
How does fibrinous exudate appear grossly?
Yellow-white or pale tan, stingy/elastic, shaggy meshwork that gives a rough irregular appearance to the tissue surface; can be easily broken apart and pulled from underlying tissue.
33
What is a diphtheric pseudomembrane?
Casts of friable material (fibrinous exudate) that forms on the lumen of tubular organs. (Mixture of dead cells and fibrin depositing in the organ)
34
How does fibrinous exudate appear histologically?
Thread-like meshwork or masses of solid, amorphous, VERY eosinophilic material.
35
What is the outcome of fibrinous exudate?
- Small amounts can be dissolved by enzymatic fibrinolysis (coag cascade) or phagocytosis by macrophages
- Large amounts provide support for eventual growth of fibroblasts, collagen, and new capillaries (granulation tissue).
36
What is the difference between fibrinous exudate and fibrosis?
- Fibrinous exudate: acute process
- Fibrosis: chronic process (scar formation).
37
Describe necrotizing inflammation.
- Characterized primarily by necrosis, with usually only a small amount of vascular and leukocyte contributions.
38
How does necrotizing inflammation appear histologically?
Severe necrosis (tissue destruction) with only scant evidence of vascular or leukocyte contributions.
39
Describe the etiology of necrotizing inflammation.
Often associated with ischemia or in association with toxin-producing bacterial infections: dry gangrene, blackleg, bacterial/viral hepatitis, etc.
40
Describe fibrinonecrotic inflammation:
- Necrosis of the surface epithelium and presence of fibrin
- Typically occurs on a **well-vascularized epithelial surface** (trachea, intestine, etc.).
41
Pseudomembranes/diphtheritic membranes are a form of what type of inflammatory exudate?
Fibrinonecrotic:
fibrin and necrotic surface epithelium forms a structure which resembles the luminal surface of the tissue (looks like affected tissue is covered by a membrane).
42
How does fibrinonecrotic inflammation appear in the gut?
A 'cast' of yellow-white material (fibrin and necrotic mucosa) that fills the lumen.
43
Describe suppurative (purulent) exudate:
Characterized by:
- pus
- large numbers of neutrophils
- dead tissue cells (cellular debris)
44
What is the difference between suppurative exudate in mammals vs. birds/reptiles/amphibians?
- Mammals: neutrophils have proteolytic enzymes, including myeloperoxidase, that causes tissue necrosis (pus)
- Birds/reptiles/amphibians: have heterophils which **lack myeloperoxidase**, so they form caseous exudates rather than purulent (liquefactive) ones.
45
Suppurative lesions are often ____ in origin.
Bacterial
46
What is the time process of suppurative inflammation?
Usually acute (within hours) but can be chronic (abscesses).
47
How does suppurative inflammation appear grossly?
Fluid or viscous material that may be within a cavity or within tissues.
48
What is an abscess?
Chronic localized form of suppurative inflammation that is walled off by a **CT capsule**.
49
What cell types make up granulomatous exudate?
- Macrophages (predominantly)
- +/- Lymphocytes
- Plasma cells
- Often multinucleated giant cells
50
How does granulomatous exudate appear grossly?
Single or multiple firm, pale nodules in tissue, usually along with caseous necrosis/exudate.
51
How does granulomatous exudate appear histologically?
Macrophages are clustered around the causative etiologic agent, or around a central necrotic area, or simply as organized nodules.
52
What is the time process of granulomatous exudate?
Always chronic: takes weeks or months to form.
53
What are the 3 etiologies of granulomatous inflammation?
- Non-digestible organism or particle that serves as a chronic inflammatory stimulus
- Infectious agents like Mycobacterium, A. bovis, B. dermatitidis, C. immitis
- Non-infectious agents: mineral oil, foreign bodies, vaccines, etc.
54
What is pyogranulomatous inflammation?
Clusters of neutrophils are admixed with the macrophages, usually seen with the neutrophils at the core of a cluster of macrophages.
55
Vaccines can trigger inflammation, leading to neoplasia in cats. What kind of inflammation is this an example of?
Granulomatous inflammation
56
Describe hemorrhagic (sanguineous) inflammation.
Associated with inflammation of blood vessels; hemorrhage is the predominant feature that occurs due to blood vessel injury or marked diapedesis.
57
What is the time process of hemorrhagic inflammation?
Peracute to acute (minutes to hours).
58
What are 2 examples of situations where hemorrhagic inflammation occurs?
- Rabbit hemorrhagic disease (calicivirus)
- 'Hemorrhagic fevers' of primates (ebola).
59
Describe serous exudation.
- Accumulation of fluid relatively rich in protein on body surfaces with little cellular infiltrate (less cells)
- Can be a dominant pattern of exudation for a wide variety of mild injuries.
60
What is the time process of serous exudation?
Usually peracute (minutes) to acute (hours/days).
61
How does serous exudation appear grossly?
Pale yellow to transparent fluid that is somewhat viscous; i.e. traumatic blisters or a 'runny' nose because of cold/flu.
62
Describe mucoid exudate.
Consists of mucus as well as variable numbers of inflammatory cells. Mucopurulent exudate
chronic inflammation triggers a change in the epithelium that produces more goblet cells and maintains the mucus appearance.
63
How does mucoid exudate appear grossly?
'Snotty.'
64
What is mucopurulent exudate?
Exudate that contains abundant mucus and pus (turning more yellowish)
65
What is catarrhal inflammation?
Inflammation of a MM with marked increase flow of mucous and/or exudate (mucoid or mucopurulent exudate).
66
Describe eosinophilic inflammation.
Eosinophils are the primary cell type present; in some cases, it can be diagnosed grossly because the eosinophil granules give the affected tissue a **green tinge**.
67
What is the etiology of eosinophilic inflammation?
Parasites or hypersensitivity reactions i.e. eosinophilic dermatitis due to flea bites.
68
Describe non-suppurative inflammation.
Mononuclear cells predominate such as lymphocytes and plasma cells; used mostly for reactions to viral infections in the brain.
69
What is lymphocytic inflammation?
Inflammation where lymphocytes are the predominant inflammatory cell type; more chronic due to lack of neutrophils.
70
What is the purpose of classifying the distribution of an inflammatory process?
Indicates the location of the lesion within an organ and, indirectly, how much of it is affected; used both macro- and microscopically.
71
Define focal.
Single abnormality or inflamed area within a tissue.
72
Define multifocal.
Each focus of inflammation is separated from other inflamed foci by an intervening zone of relatively normal tissue.
73
Define locally (focally) extensive.
A significant portion of an organ (segmental often used for tubular organs).
74
Define diffuse.
The entire organ (usually a viral or toxic cause).
75
Classifying inflammation based on duration indicates:
Indicates how long the process has been underway
Can be very subjective: peracute, acute, subacute, and chronic.
76
The duration of inflammation may not correlate with what?
The onset of clinical signs: clinical signs can be acute but the condition can be chronic (acute manifestation of a chronic disease).
77
What are the characteristics of peracute inflammation?
- Very acute (0-4 hours)
- Only a few morphologic changes as there is insufficient time for immune system to respond to the insult
- Less common than acute.
78
Describe the vascular involvement of peracute inflammation.
- Hyperemia (area looks red due to active influx of blood), slight edema, and often hemorrhage
- Hyperemia causes heat.
79
How do lymphatics appear during peracute inflammation?
They may be filled with edema fluid and/or fibrin.
80
How do inflammatory cell populations appear with peracute inflammation?
Usually not numerous: barely had time to migrate to the site of injury.
81
What are the clinical signs associated with peracute inflammation?
If highly pathogenic agent can see shock/sudden death with few other signs.
82
What are examples of peracute inflammation?
Bee stings or highly pathogenic viruses.
83
What are the characteristics of acute inflammation?
- Short and often severe course
- Begins within 4-6 hours and can last 3-5 days.
84
Describe the vascular involvement seen with acute inflammation.
- Active hyperemia
- Edema: due to endothelial changes/damage of lymphatics and small blood vessels
- Occasional fibrin thrombi within vessels.
85
Describe the appearance of lymphatics seen with acute inflammation:
Often filled with exudate and edema (have important role in exudate removal).
86
Describe the inflammatory cell population seen with acute inflammation.
Neutrophils (suppurative exudate) usually predominate, but some mononuclear cells such as macrophages, lymphocytes, and plasma cells can be present as well.
87
What are the clinical signs associated with acute inflammation?
Most associated with classical signs of inflammation: heat, pain, swelling, redness, and loss of function.
88
What are the characteristics of subacute inflammation?
- Transition period separating acute and chronic inflammation: neutrophils have not decreased enough to be considered fully chronic
- Lasts from a few days to 1 week.
89
Describe the vascular involvement seen with subacute inflammation.
- Decline in magnitude of vascular changes compared to acute inflammation due to no more endothelial damage
- No evidence of repair yet (fibrosis/angiogenesis) that would be seen with chronic inflammation.
90
During subacute inflammation, there is ____ lymphatic drainage.
Increased lymphatic drainage.
91
Describe the inflammatory cell population seen with subacute inflammation.
Characterized by a 'mixed' or 'pleocellular' inflammatory infiltrate that is often predominately lymphocytes and plasma cells with variable numbers of macrophages and fewer neutrophils.
92
What are the characteristics of chronic inflammation?
- Inflammation which persists for weeks to months (variable time process of weeks to months to years).
- May follow acute response or develop as an insidious, low grade, subclinical process without history of a prior acute episode.
93
Describe the vascular involvement seen with chronic inflammation.
Proliferations of capillaries and small blood vessels (angiogenesis/neovascularization).
(New BVs are typically quite small and torturous on histo- very funky and thin, weird shape, bleed easily)
94
How do lymphatics appear with chronic inflammation?
Variable involvement, +/- proliferations and activation: lose the swelling that was seen previously.
95
Describe the inflammatory cell population seen with chronic inflammation.
- Primarily will see mononuclear inflammatory cells:
- macrophages used for phagocytosis and tissue debridement and can be in the form of epithelioid macrophages or giant cells.
- Evidence of repair, especially **fibrosis and angiogenesis** (granulation tissue/scar formation).
96
What are the clinical signs associated with chronic inflammation?
Variable dependent on the duration of illness and location/severity of the inflammatory lesions.
97
Many changes represented in chronic inflammation are also seen in areas of _______.
Repair.
98
What is chronic-active inflammation?
Tissues exhibit all the usual characteristics of chronicity, with superimposed features of acute inflammation; can be due to repeated overlapping episodes of inflammation usually due to the host failing to adequately contain the inciting agent.
99
What is the time process of chronic-active inflammation?
Chronic time frame (weeks to months) with exacerbations due to acute episodes.
100
Describe the vascular involvement seen with chronic-active inflammation.
Can have vascular changes of both acute and chronic.
101
How do the lymphatics appear in the case of chronic-active inflammation?
May be inflamed: lymphangitis.
102
How does chronic-active inflammation appear histologically?
- both neutrophils and cells of chronic inflammation
- fibrosis and angiogenesis are present
103
Describe how inflammatory processes are classified according to severity.
Very subjective description of the extent of the process that has occurred: mild, moderate, or severe; use moderate when you are not sure.
104
What are the 6 types of stimuli that can trigger inflammatory reactions?
- Infectious agents (viruses, fungi, bacteria, etc.)
- Trauma
- Physical/chemical agents
- Tissue necrosis (always acute)
- Foreign material
- Immune reactions/autoimmune disease
105
What are the 4 different mediators of acute inflammation?
- Exogenous/infectious: TLRs, PAMPs
- Endogenous: TLRs, DAMPs
- Necrosis (urate, purines, HMGB-1, DNA, ATP/AMP, Reduced Kcyto)
- Mannose binding lectin: collectins opsonize apoptotic cells for clearance
106
What is the main function of acute inflammation?
Move defense mechanisms from the vascular system out to the tissues, as a response to an injurious (inflammatory) stimulus, and to initiate repair.
107
Inflammation is designed to do what?
Kill microbes/pathogens in tissue by letting WBCs out of blood vessels via endothelial cells.
108
What are the 2 major components of acute and chronic inflammation?
- **Vascular changes** allow circulating blood cells to slow down and make their way into adjacent tissues.
- **Cellular events** result from activation of inflammatory cells and repair tissue.
109
Describe the process of WBC's moving out of tissues for acute inflammation.
- Diapedesis and rolling adhesion required in order to have migration of WBC out of blood vessels.
- Mediated via cytokines which are secreted by other inflammatory cells such as macrophages.
110
What are the 5 basic series of events seen with inflammation?
1. Vasodilation (increased blood flow): heat and redness.
2. Increase permeability of microvasculature: swelling.
3. Blood flow slows and RBCs concentrated in capillaries and veins due to fluid loss: redness.
4. Cellular events: swelling and pain.
5. Tissue damage/repair (chronic): loss of function.
111
What are the 3 characteristics of vasodilation (step 1 of acute inflammation)?
- Arteriolar dilation and opening of new capillaries (sometimes after vasoconstriction for a few seconds).
- Increase in amount of blood to tissue.
- Result of histamine and NO acting on vascular smooth muscle.
112
What are the characteristics of increased permeability of microvasculature (step 2 of acute inflammation)?
Swelling due to outpouring of fluids into the extravascular tissues, especially postcapillary venules.
113
What are the 5 cellular events that occur during step 4 of inflammation?
- Margination/rolling/adhesion of WBCs in capillaries and venules.
- Emigration of WBCs to tissue.
- Accumulation of WBC at site of injury: swelling.
- Activation of inflammatory cells and production of chemical mediators (cytokines): pain.
- Removal of stimulus.
114
What are the 4 steps taken by leukocytes to leave blood vessels during inflammation?
- Margination.
- Rolling.
- Pavementing (sticking).
- Migration.
115
What is the hallmark of acute inflammation?
Increased vascular permeability which leads to the escape of protein-rich exudate.
116
What are the 5 mechanisms of increased vascular permeability with acute inflammation?
1. Retraction of endothelial cells.
2. Direct endothelial injury.
3. Leukocyte-dependent endothelial injury.
4. Increased transcytosis.
5. Leakage from new capillaries as they regenerate during neovascularization.
117
Describe endothelial cell contraction.
- Rapid, transitory (15-30 mins), and reversible; occurs mainly in venules.
- Inflammatory stimuli cause release of inflammatory mediators such as histamines.
- Mediator binds to receptor which contracts epithelial cells and widens gap junctions.
118
Describe delayed prolonged leakage.
Mechanism of permeability of endothelial cells for acute inflammation that is thought to be due to endothelial cell contraction or mild endothelial degeneration; occurs in some forms of mild injury after a delay of 2-12 hours but lasts several hours to days.
119
Describe direct endothelial injury as a mechanism of increased vascular permeability during acute inflammation.
- Affects arterioles, venules, and capillaries.
- Occurs when severe injurious stimuli cause endothelial necrosis and detachment.
- Induces an immediate and sustained response that lasts several hours to days until vascular structures are repaired.
120
What is leukocyte-dependent endothelial injury?
Mechanism of increased vascular permeability whereby neutrophils that adhere to the endothelium during inflammation injure the endothelium and amplify the reaction; associated with later stages of inflammation.
121
How does increased transcytosis work as a mechanism of increased vascular permeability?
Certain factors such as vascular endothelial growth factor (VEGF) or histamine can increase the number and/or size of normally occurring endothelial cell channels in venules.
122
How does leakage from new capillaries work as a mechanism of increased vascular permeability?
During the repair process, proliferating endothelial cells are ______.
Leaky; mediated by VEGF (vascular endothelial growth factor).
123
Paracellular transport is due to what 2 factors?
- Retraction of endothelial processes which occurs in venules
- Histamine and NO (Mediated right as soon as stimulus)
124
Where does transcytosis occur?
Venules.
125
Transcytosis is upregulated by ____.
VEGF.
126
Transcytosis is important for what location?
Crossing of the blood brain barrier: may involve receptor-mediated endocytosis or caveolae.
127
What is the major difference between exudate and transudate?
- Exudate is inflammatory in origin; fluids with more protein and more WBCs that escape to the extravascular space when gap junctions are opened or endothelial cells are damaged.
- Transudate is non-inflammatory in origin and is the result of increased hydrostatic pressure or decreased colloid osmotic pressure in vasculature in which fluid has low protein and cellular content (edema in interstitium).
128
What is modified transudate?
An in-between fluid such as in FIP where the fluid is protein rich but cell poor.
129
What are the cellular events of acute inflammation required for?
To deliver leukocytes to the site of inflammation (contributing to exudate) so they can internalize pathogens through phagocytosis and kill or digest them by releasing proteolytic enzymes, chemical mediators, and reactive oxygen species.
130
What are the main inflammatory cells?
- Polymorphonuclear leukocytes: neutrophils/heterophils, eosinophils, basophils.
- Mast cells.
- Mononuclear cells: monocytes/macrophages, lymphocytes, plasma cells.
- Platelets.
131
Which inflammatory cells are not normal inhabitants of circulating blood?
Plasma cells, macrophages, and mast cells.
132
What can be used as an inflammatory diagnostic tool?
Total WBC count in peripheral blood and the relative proportions of different WBCs: can be greatly modified in response to inflammation.
133
The neutrophil of which species looks more eosinophilic than the others?
Bovine.
134
Which type of cell does this describe:
- Rapid ameboid movement.
- Respond to a wide variety of chemotaxic compounds.
- Have good phagocytic and bactericidal activities for killing microorganisms, tumor cells, and eliminating foreign material.
- End cell: don't divide.
- Average time in circulation is likely just a few days (short).
- Once out of circulation they don't return and may live for 1-2 days in tissue: once they release their granules they die.
Neutrophils (polymorphs, polys, PMN’s, neuts)
135
Which WBC is the major cellular defense system against bacteria and a major part of the innate immune system?
Neutrophils.
136
What are the 2 distinct pools of neutrophils in the blood?
- Marginating pool: composed of neutrophils within blood vessels but lying out of the flow; can be mobilized very quickly.
- Circulating pool: all the other neutrophils that are in laminar flow of circulation and take longer to get to the site of injury.
137
What other area of the body has a storage pool of neutrophils that can be released when needed?
Bone marrow.
138
What are the 3 types of granules contained in neutrophils?
- Azurophil granules (primary): myeloperoxidase, lysozyme, elastase, etc.
- Specific granules (secondary): WBC adhesion molecules, histaminase, etc.
- Tertiary granules (gelatinase).
139
What are the functions of neutrophils?
- Phagocytosis.
- Mediate tissue injury via release of oxygen free radicals and lysosomal enzymes into tissue.
- Regulates inflammatory response via releasing mediators such as leukotrienes or platelet activating factors.
140
What is phagocytosis?
Ingesting material that is opsonized by C3b and immunoglobulins, neutralizing them, and destroying them via either the production of O2 free radicals, hydrogen peroxide, or lysosomal enzymes.
141
What are heterophils?
Equivalent of neutrophils in some species that do not contain myeloperoxidase in their granules; have eosinophilic granules that resemble eosinophils.
142
When are eosinophils seen?
Numerous at inflammatory sites which result from parasites and allergic/immune-mediated disease but may be present in any exudate or in tissues that contact the environment such as intestine, skin, lung, and mucous membranes.
143
_______ causes a reduction in the release of eosinophils from bone marrow.
Corticosteroids.
144
What is the most important cytokine for the production and recruitment of eosinophils?
IL-5.
145
Why do we often see lots of mast cells and eosinophils together?
Granules of mast cells contain histamine which is very eotactic.
146
Describe the appearance of eosinophil granules.
Vary in size depending on the species but all stain with acid dye eosin.
147
What are the 3 components of eosinophilic granules?
- Major basic protein: pro-inflammatory.
- Eosinophil cationic protein: pro-inflammatory.
- Histaminase: anti-inflammatory.
148
What is the function of major basic protein?
Kills parasites (helminths) and induces histamine release from mast cells.
149
What is the function of eosinophil cationic protein?
Parasite killing (helminths) and shortens coagulation time/alters fibrinolysis.
150
What is the function of histaminase?
Inactivates histamine.
151
What are the functions of eosinophils?
- Kill/damage helminths and other pathogens by Ab-dependent cell-mediated cytotoxicity.
- Cause and assist in type 1 hypersensitivity reactions.
- Regulate inflammation, particularly to mast cell products.
- Phagocytosis, but to a much smaller degree than neutrophils.
152
Describe how/when basophils and mast cells are seen.
Basophils are rare circulating granulocytes while mast cells are relatively numerous and are found in perivascular sites, particularly in areas of contact with the environment.
153
Where do basophils and mast cells originate?
Both are derived from bone marrow and have similar functions, but they come from separate stem cell lineages.
154
Describe the granules of basophils and mast cells.
Both have abundant cytoplasmic metachromatic granules that stain magenta with toluidine blue and are rich in histamine, proteases, and potent inflammatory mediators; they don't die after releasing their granules like neutrophils do.
155
Describe the membrane receptors of basophils and mast cells.
Bind the Fc portion of IgE antibody which mediates type 1 hypersensitivity.
156
What do basophils and mast cells produce?
Both produce cytokines and arachidonic acid metabolites.
157
Mast cells are the major source of _______ in acute inflammation.
Histamine.
158
What are the functions of mast cells?
Intimately involved in acute inflammation with hypersensitivity reactions. Cross-linking of IgE membrane receptors on mast cells triggers release of histamine which causes smooth muscle dilation in arterioles and increased permeability in venules. Recruitment of eosinophils via IL-5, leukotriene C4.
159
How are mast cells activated?
By IgE-bound Ag's as well as substance P from nerves and macrophages (has role in pain due to substance P).
160
Which leukocytes are known for being 'the most dynamic and gifted of the leukocytes'?
Monocytes/macrophages.
161
Where do macrophages originate from?
Derived from circulating blood monocytes of bone marrow origin or can also originate from division of resident macrophages.
162
Macrophages are relatively ____-lived in tissues.
Long.
163
What are the characteristics of monocytes?
Not a very large reserve pool in bone marrow. Motile: take 8-12 hours to get to sites of inflammation (sluggish compared to PMNs).
164
What are the functions of macrophages?
Phagocytic and antimicrobial. Recruit other WBCs via chemokines and cytokines. Stimulate/modulate other cell activity (vascular effects). Clean up debris, especially after neutrophil destruction. Source of epithelioid macrophages and giant cells.
165
Lymphocytes and plasma cells are the main cells of ______ reactions.
Immune.
166
What are the functions of lymphocytes and plasma cells?
Ab response: B lymphocytes and plasma cells activated by CD4 T cells. Delayed cellular hypersensitivity responses (CD4/TH1 and CD8 T cells). Down regulation of immune system (regulatory/suppressor T cells).
167
Lymphocytes and plasma cells are ____ motile than neutrophils and monocytes.
Less: seen more in chronic inflammation.
168
What are examples of other, non-leukocytic cells that are also involved in inflammation?
Platelets, endothelial cells, and fibroblasts.
169
How do platelets act as inflammatory cells?
Contain cytoplasmic granules and release their products through secretory degranulation.
170
What are the 2 most important products of platelets that act in inflammation?
P-selectins (itching during healing) and histamine.
171
What are the functions of platelets in the inflammatory response?
Release histamine to increase vascular permeability and provide local amplification. Produce adhesion molecules such as p-selectin to facilitate WBC migration from blood to tissues. Release cationic inflammatory mediators that directly activate C5 (complement) which is chemotactic for WBCs.
172
What pro-inflammatory substances are endothelial cells responsible for in acute inflammation?
Prostacyclin, prostaglandins, PAF, IL-1, IL-8, and NO.
173
What are expressed by endothelial cells during acute inflammation that allow for WBC adhesion and migration to occur?
Adhesion molecules.
174
Endothelial cells down-regulate the inflammatory response how?
Through the production of TGF-beta.
175
How do fibroblasts function in the acute inflammatory process?
Produce IL-6 which stimulates B and T cell proliferation. Produce TGF-beta which functions in anti-inflammation and repair (ends inflammation).
176
What is the most important feature of the inflammatory reaction?
Accumulation of WBCs.
177
What is the leukocyte adhesion cascade?
Regulation of the migration of WBCs from vasculature to tissue by binding of complementary adhesion molecules, some found on WBC membrane, and the others on the surface of the endothelial cell.
178
Most endothelial leakage occurs where?
Venules.
179
Step by step, give the sequence of leukocyte events in acute inflammation.
1. Leukocyte adhesion cascade: margination --> rolling adhesion --> emigration. 2. Chemotaxis to tissues. 3. Phagocytosis and intracellular killing/degradation. 4. Extracellular release of WBC products (granules). 5. Synthesis of chemical mediators of inflammation.
180
Describe the margination step of the leukocyte adhesion cascade.
Flow slows and stagnates due to increased vascular permeability and makes WBC fall out of central column and tumble to periphery of vascular lumen until they come into contact with surface of endothelial cells of capillaries and post-capillary venules.
181
Describe leukocyte rolling and adhesion.
Marginated WBCs line the endothelium and become adhered to surface of endothelial cells through various adhesion molecules. Adhesion is loose at first which causes rolling on the lumen of the vessel. When adhesion becomes firm, WBC becomes stationary and can then begin to migrate through endothelium and into site of inflammation.
182
What are the 4 main groups of adhesion molecules?
1. Selectins: P-selectin and E-selectin on endothelium and L-selectin on WBC. 2. Mucin-like ligands: Sialyl-Lewis X, etc. on WBC. 3. Integrins: CD11/CD18 on WBC. 4. Ig-superfamily adhesion molecules: IgSAM's on endothelium and PECAM on endothelium and WBC.
183
P-selectin and E-selectin on endothelial cell binds to what on the WBC for what effect?
Mucin-like ligands (Sialyl-Lewis X) on WBC for rolling.
184
IgSAM's (MadCAM, etc.) on the endothelial cell binds to what on the WBC for what effect?
L-selectin on WBC for arrest and adhesion.
185
IgSAM's (ICAM, VCAM) on the endothelial cell binds to what on the WBC for what effect?
Integrins (CD11/CD18) on WBC for firm adhesion.
186
IgSAM's (PECAM) on the endothelial cell binds to what on the WBC for what effect?
IgSAM's (PECAM) on WBC for emigration.
187
What occurs during the rolling phase of the leukocyte adhesion cascade?
P-selectin is activated first due to release of histamine, thrombin, and PAF. E-selectin follows in 1-2 hours, stimulated by secretion of TNF-alpha and IL-1 by macrophages, mast cells, and/or damaged endothelial cells. P and E-selectins bind Mucin-like ligands on leukocytes.
188
What occurs during the arrest and adhesion phase of the leukocyte adhesion cascade?
L-selectin on WBC binds to Mad CAM on endothelial cell.
189
What occurs during the firm adhesion phase of the leukocyte adhesion cascade?
WBC becomes activated and expresses integrins (CD11/CD18) which bind to endothelial IgSAM's such as ICAM and VCAM.
190
What is bovine leukocyte adhesion deficiency (BLAD)?
An autosomal recessive disease of Holsteins, characterized by an increased susceptibility to infectious agents; affected cattle are homozygous for a single point mutation in part of the CD18 gene which results in inadequate passage of these cells into the perivascular tissue and overlying epithelium.
191
What is the result of cattle affected by BLAD?
Usually 2 weeks to 8 months old. Inadequate mucosal immunity resulting in chronic, recurrent respiratory and GI infections without pus formation. Persistent neutrophilia.
192
What is leukocyte adhesion deficiency in Irish setter dogs (CLAD)?
Also known as 'canine granulocytopathy syndrome': known to be due to CD11/CD18 deficiency which is characterized by delayed umbilical cord separation at birth, impaired wound healing, and recurrent bacterial infections.
193
What is emigration?
Process by which leukocytes escape from the blood to the perivascular tissue and move to the site of inflammation.
194
What occurs after firm adhesion in the emigration step of leukocyte migration?
WBCs insert large cytoplasmic extensions (pseudopodia) into the endothelial gaps that have been created by actions of histamine and other chemical mediators as well as by the WBC itself.
195
Which adhesion molecule is most directly responsible for the insertion of pseudopodia into the gaps in the endothelial cells?
PECAM which is expressed on both endothelial and WBC surfaces.
196
What must the leukocyte do to pass through the basement membrane of the vessel?
Secrete collagenases (produces gaps of less than 1 micron in diameter).
197
What does the WBC do as it leaves the vessel?
Expresses beta-1 integrins that help it bind to the extracellular matrix proteins in the perivascular tissue.
198
Where does emigration occur and why?
Occurs in the postcapillary venule because it is there that adequate numbers of inter-endothelial gaps and receptors (histamine receptors) are found.
199
In what order do WBCs emigrate?
Neutrophils are usually the first: predominate for the first 6-24 hours, peaking at 4-6 hours. Monocytes usually follow neutrophils and are longer lived (last longer than 24-48 hours). In viral infections, lymphocytes are the first to arrive. In some hypersensitivity reactions, eosinophils arrive first.
200
Define chemotaxis.
Directional migration in response to a chemical gradient of chemoattractant (aka chemotaxin).
201
What kind of process is chemotaxis?
Receptor-mediated: what WBCs do after they reach the perivascular space in order to reach the injurious agent/inflammatory site.
202
_____ leukocytes respond to chemotactic stimuli.
All: neutrophils are fastest, then monocytes, then lymphocytes.
203
What are the different classifications of chemoattractants?
Exogenous: LPS in the wall of gram negative bacteria or foreign material. Endogenous: found in plasma or produced by inflammatory and/or necrotic tissue cells.
204
What kinds of leukocytes does LPS attract?
Neutrophils, eosinophils, monocytes/macrophages.
205
What are the different kinds of endogenous chemoattractants and what do they attract?
Histamine: eosinophils. Complement (C5a): neutrophils, eosinophils, monocytes, basophils. Fibrin-degradation products: neutrophils. Leukotrienes from arachidonic acid metabolism: neutrophils and eosinophils. Chemokines (IL-8): neutrophils, macrophages, and eosinophils.
206
What are chemokines?
A type of cytokine whose main function is to attract leukocytes and make them migrate across capillaries and post-capillary venules.
207
What are the functions of chemokines?
Stimulate locomotion. Activate WBCs to produce inflammatory mediators, engage in phagocytosis, and initiate oxidative burst.
208
What allows a cell to orient towards a chemotactic gradient?
Microtubules.
209
What is the function of microfilaments (actin and myosin) in chemotaxis?
Responsible for the movement, which is achieved by the formation of a pseudopod that pulls the remainder of the cell in its direction.
210
Describe phagocytosis.
Engulfing, killing, and degrading foreign material, most commonly bacteria via cellular mechanisms that are like those of chemotaxis but aimed at engulfing an injurious agent.
211
What are the steps of phagocytosis?
1. Recognition and attachment of agent: mannose on bacterial wall is recognized by WBC mannose receptor or bacteria are opsonized and then recognized. 2. Engulfment: WBC pseudopods flow around the attached particle until it is engulfed and pinch together, fuse, and form a phagosome. 3. Phagolysosome formation: fusion of lysosomal granules with phagosome and bacterial killing in phagolysosome.
212
What are the 2 categories of bactericidal mechanisms that are recognized in the phagolysosome?
Oxygen-dependent mechanisms and oxygen-independent mechanisms.
213
Oxygen-dependent mechanisms for intracellular killing and degradation are based on what?
Production of reactive oxygen species such as superoxide anion, hydrogen peroxide, and hydroxyl radical in the 'respiratory burst' part of phagocytosis.
214
Hydrogen peroxide + chloride ion?
Bleach via myeloperoxidase.
215
What is the name of the reaction that uses iron to produce hydroxyl radicals?
Haber-Weiss Reaction.
216
What are oxygen-independent mechanisms for intracellular killing and degradation based on?
Substances within WBC granules.
217
What happens after a microorganism is phagocytized by the phagolysosome?
The pH in the phagolysosome drops to 4-5, which is optimal for the action of degradative enzymes within lysosomes.
218
What are 3 strategies developed by some microorganisms to survive and avoid killing after phagocytosis?
1. Escape phagolysosome and grow in cytoplasm.
2. Block lysosome-phagosome fusion.
3. Survival within phagolysosome.
219
What is an example of how defects in phagocytic cells can interfere with the destruction of microorganisms?
Chronic granulomatous disease of children where they have neutrophils with defective oxidases incapable of producing superoxide anion, leading to recurrent infections.
220
What is the purpose of leukocytes releasing their products (granules) extracellularly?
To release toxic metabolites/enzymes into phagolysosomes and the site of inflammation, which helps kill microorganisms and enhances the inflammatory reaction; can also cause necrosis of the tissue.
221
What are the 4 mechanisms whereby phagocytic cells release their products?
1. Lysosomal suicide (cytotoxic release).
2. Regurgitation during feeding.
3. Reverse endocytosis (frustrated phagocytosis).
4. Neutrophil extracellular traps (NETs).
222
What is a chemical mediator?
Any messenger that acts on blood vessels, inflammatory cells, or other cells to contribute to an inflammatory response.
223
Where do the chemical mediators of inflammation originate from?
1. Plasma: they are in an inactive state and must be activated.
2. Cell: they are often within granules and need to be secreted or are synthesized in response to a stimulus.
224
What triggers the production of active mediators of inflammation?
Microbial products or host proteins (cytokines).
225
What are the characteristics of chemical mediators of inflammation?
1. Some have direct activity, while others require binding to receptors.
2. One mediator may have different effects on different cells.
3. Most are short-lived and have potential to be harmful, e.g., sepsis.
226
Describe amplification as it relates to chemical mediators of inflammation.
One mediator can stimulate the release of other mediators by target cells.
227
What does it mean that chemical mediators are interactive and redundant?
They guarantee amplification and preservation of the response even if one or more components of the response are deficient.
228
Which chemical mediators of inflammation lead to vasodilation?
Histamine, NO, and prostaglandins I2, E2, and D2.
229
Which chemical mediators of inflammation lead to increased vascular permeability?
Histamine, C3a/C5a (anaphylotoxins), bradykinin, oxygen metabolites, leukotrienes, and PAF.
230
Which chemical mediators of inflammation lead to chemotaxis?
C5a, leukotrienes, chemokines, and bacterial products such as LPS.
231
Which chemical mediators of inflammation lead to fever?
IL-1, IL-6, TNF, and prostaglandins.
232
Which chemical mediators of inflammation lead to pain?
Bradykinin, substance P, and PGF2.
233
Which chemical mediators of inflammation lead to tissue damage?
Oxygen metabolites (ROS), NO, and lysosomal enzymes.
234
What are the primary mediators of the immediate active phase of increased permeability?
Histamine and serotonin.
235
What is caused by vasoactive amines and how does it happen?
They cause vasodilation and increased vascular permeability by causing endothelial cells to round up, increasing cellular gaps, and increasing vesiculovacuolar transfer of fluids.
236
Vasoactive amines are stored within cells for _________ release.
Immediate.
237
Where is histamine found?
Extensively distributed in tissues, with the main source being mast cells (in granules with heparin) that are commonly present in the perivascular CT; also present in granules of basophils and in platelets.
238
What functions is histamine important for?
1. Early inflammatory responses and type 1 hypersensitivity reactions.
2. Immediate active phase of increased vascular permeability.
3. Allergic reactions: promotes contraction of extravascular smooth muscles in the bronchi and stimulates stromal cells to synthesize and release eotaxins.
239
Describe serotonin as a vasoactive mediator.
Present in platelets and in some mast cells, it acts primarily on venules during the early phase of acute inflammation.
240
How is the release of histamine and serotonin from platelets (platelet release reaction) stimulated?
When platelets aggregate after contact with collagen, thrombin, ADP, and Ag-Ab complexes.
241
Describe substance P as a vasoactive amine.
A neuropeptide produced in some sensory nerve fibers and WBC that has similar effects to those of bradykinin.
242
Describe plasma proteases as chemical mediators of inflammation.
Three interrelated systems that are important in the inflammatory response and are found within plasma, all capable of being activated by Hageman's factor (factor XIIa of the coagulation cascade).
243
What are the 3 systems that relate as plasma proteases?
Complement, kinin, and clotting.
244
What is the complement system?
A set of plasma proteins that act together to attack extracellular forms of microbial pathogens.
245
How is the complement system activated?
Can be activated directly by certain pathogens or by antibodies binding to a pathogen.
246
What happens once pathogens are coated with complement proteins?
1. Their removal by WBCs is facilitated (opsonized).
2. Directly killed by membrane attack complex (MAC).
247
What functions does the complement system have other than facilitated killing of microorganisms (C3b)?
1. Vascular permeability via histamine release from mast cells (C3a and C5a).
2. Chemotaxis: C5a attracts neutrophils, monocytes, eosinophils, and basophils.
248
What is the role of the kinin system as a chemical mediator of inflammation?
Generates vasoactive peptides from plasma proteins called kininogens by the action of specific proteases called kallikreins, ultimately leading to activation of bradykinin.
249
What are the functions of bradykinin once activated by the kinin system?
1. Vasodilation and stimulation of histamine release by mast cells for increased vascular permeability.
2. Contraction of non-vascular smooth muscle (bronchi).
3. Produces pain.
4. Activation of arachidonic acid cascade.
250
What is the intrinsic clotting system?
A sequence of plasma proteins that can be activated by Hageman factor (XII), which is produced in the liver and circulated in its inactive form.
251
What is the final phase of the clotting cascade?
Conversion of fibrinogen to fibrin via thrombin.
252
What are the functions of thrombin other than to convert fibrinogen to fibrin?
1. Mobilize P-selectin to cell membrane to express adhesion molecules for integrins.
2. Produce chemokines, PAF, and NO.
3. Induce cyclooxygenase-2 for the production of prostaglandins.
4. Alter endothelial shape.
253
Thrombin binds to receptors in what locations to enact its functions?
Platelets, endothelium, and smooth muscle cells.
254
Describe the amplification that occurs between Hageman's factor and the plasma proteases.
Factor XIIa initiates the clotting, kinin, and complement systems, but the products of the initiation of these systems can also activate Hageman's factor, resulting in significant amplification of the effects.
255
What are oxygenated arachidonic acid derivatives?
Active lipid mediators generated by the remodeling of damaged cell lipid membranes, acting in a variety of processes, including inflammation.
256
Where does arachidonic acid originate from?
Directly from the diet or by conversion from linoleic acid.
257
How does arachidonic acid exist in the cell?
Esterified in membrane phospholipids; must be activated by cellular phospholipases, particularly phospholipase A2.
258
By what 2 pathways are metabolites of arachidonic acid able to be biosynthesized after activation?
Cyclooxygenase pathway or lipoxygenase pathway.
259
What 2 enzymes are responsible for producing the products of the cyclooxygenase pathway?
1. COX-1: normally present and necessary for everyday activities as well as in inflammation.
2. COX-2: transcriptionally regulated and only present in certain circumstances such as inflammation.
260
What are the 3 main products of the cyclooxygenase pathway?
1. Thromboxane A2: found in platelets and other cells, a potent platelet aggregator and vasoconstrictor.
2. Prostacyclin: found predominantly in endothelial cells, a potent inhibitor of platelet aggregation and vasodilator.
3. Prostaglandins: vasodilation, increased vascular permeability, and pain.
261
How do drugs such as corticosteroids, aspirin, and indomethacin act as anti-inflammatories?
They inhibit specific steps of arachidonic acid metabolism.
262
Describe the lipoxygenase pathway.
Enzymes involved are found in only a few cells and result in the production of leukotrienes and lipoxins, which have opposing effects.
263
What is the purpose of leukotrienes in the lipoxygenase pathway?
Exacerbate the acute inflammatory response by acting as potent mediators of increased vascular permeability, chemotactic for WBCs, vasoconstrictors, and causing bronchospasms.
264
What is the significance of leukotriene B4?
One of the most potent chemotactic agents for neutrophils and macrophages.
265
Describe lipoxins in the lipoxygenase pathway.
Secreted by platelets and act as a negative regulator of inflammation by counteracting leukotrienes.
266
How do lipoxins counteract leukotrienes?
Inhibit neutrophil chemotaxis and adhesion to endothelium but promote macrophage adhesion, which is important for the resolution phase of inflammation.
267
What is the significance of Lipoxin A4?
Causes vasodilation and counteracts leukotriene-induced vasoconstriction.
268
Describe lysosomal constituents as inflammatory mediators.
Found mainly in neutrophils, macrophages, cytotoxic lymphocytes, eosinophils, and mast cells; granzyme and perforin in T cells and NK cells.
269
What is the role of granzyme and perforin?
1. Perforin: punches holes in the membrane of a target cell, allowing granzyme to enter the cytoplasm.
2. Granzyme: activates caspase cascade that results in apoptosis.
270
What is the role of oxygen free radicals once they are released into tissues?
1. Endothelial cell damage with resultant increased vascular permeability.
2. Inactivation of antiproteases, allowing unopposed protease activity and increased destruction of ECM.
3. Injury to a variety of cell types (tumor cells, RBC, parenchymal cells).
271
What are the inflammatory effects of platelet activating factor (PAF)?
1. Platelet aggregation and release.
2. Bronchoconstriction and vasoconstriction at high concentrations.
3. Vasodilation and increased vascular permeability at low concentrations; much more potent than histamine.
4. WBC adhesion to endothelium, chemotaxis, degranulation, and oxidative burst.
272
What are cytokines?
Polypeptides produced by many cells (mainly macrophages and lymphocytes) that function to modulate the function of other cell types; essential transmitters of cell-to-cell communication in many physiological and pathophysiological processes.
273
What are the main cytokine mediators of inflammation?
1. IL-1 and TNF-alpha.
2. IL-5.
3. IL-6.
4. IL-8.
5. IFN-gamma.
6. PDGF.
274
What are the master cytokines produced by monocyte-macrophages?
IL-1 and TNF-a.
275
What are the biological activities of IL-1 and TNF-a?
1. Increase WBC adhesion on endothelial cells, stimulate synthesis of PGI2 and PAF, and increase pro-coagulant activity.
2. Induce systematic acute phase responses such as fever, neutrophilia, and hemodynamic effects (shock).
3. On fibroblasts, they induce proliferation, increased collagen formation, and increased collagenase and protease synthesis.
276
How does IL-5 function in inflammation?
Produced by helper T cells and mast cells, it influences proliferation, chemotaxis, and activation of eosinophils (parasites, allergy, etc.).
277
How does IL-6 function in inflammation?
Produced by T lymphocytes and macrophages for B and T cell proliferation; sometimes considered a 'master cytokine' with IL-1 and TNF-a.
278
How does IL-8 function in inflammation?
Produced by WBCs and endothelial cells as a powerful chemoattractant and activator of neutrophils and to a lesser extent monocytes and eosinophils (more of a chemokine).
279
How does IFN-gamma function in inflammation?
Produced by T cells and NK cells to activate macrophages and T cells against viral infections.
280
How does PDGF function in inflammation?
Produced by WBCs, endothelial cells, and fibroblasts, most importantly for chronic inflammation but present from the beginning; chemoattractant for WBCs and mesenchymal cells (stimulates proliferation of fibroblasts).
281
How does NO function in inflammation?
Produced mainly in endothelial cells and neurons as well as macrophages in inflammation to relax smooth muscles in vessels.
282
How is NO formed in cells?
Via enzyme nitric oxide synthase: when NOS is upregulated in macrophages during sepsis, there is massive vasodilation and shock.
283
What does superoxide anion do to NO?
Converts it to its own free radical (peroxynitrite), which is bactericidal.
284
How does acute inflammation end?
1. Mediators are produced in short bursts while the stimulus is present and degrade soon after release.
2. Switch to anti-inflammatory lipoxins and production of anti-inflammatory cytokines (TGF-b).
3. Inhibition of TNF production in macrophages.
4. If the stimulus remains, chronic inflammation follows.
285
What are the possible outcomes of the acute inflammatory response?
1. Resolution (ideal outcome).
2. Abscess formation: seen with pyogenic organisms or foreign bodies.
3. Fibrosis: repair by CT replacement.
4. Chronic inflammation: persistent stimuli.
286
What are the characteristics of resolution of acute inflammation?
Destruction, dilution, or inactivation of inciting stimulus; mediators are neutralized or decay; return to normal vascular permeability; cessation of WBC infiltration and death of neutrophils already in tissue; removal of excess fluid (foamy macrophages), WBCs, foreign material, and necrotic debris.
287
Complete resolution of acute inflammation is more likely in what scenario?
If the area of inflammation, exudate, and numbers of inflammatory cells are small.
288
Fibrosis as a result of acute inflammation is associated with what?
Substantial tissue destruction: occurs when affected tissue cannot regenerate and fibrin exudation is abundant and cannot be cleared.
289
What is the primary purpose of chronic inflammation if acute inflammation cannot clear the stimulus?
To contain and degrade pathologic agents that are difficult to eliminate.
290
Define chronic inflammation.
Inflammation of prolonged duration in which inflammation, tissue injury, and attempts at repair occur at the same time.
291
What are the most numerous WBCs in chronic inflammation?
Mononuclear inflammatory cells.
292
What are the characteristic occurrences of chronic inflammation?
Tissue destruction is present and often prominent; repair is underway through proliferation of fibroblasts and endothelial cells (fibrosis and angiogenesis).
293
What are examples of specific injurious agents which typically cause chronic inflammation?
Some viral infections such as caprine arthritis encephalitis virus or porcine circovirus type 2; persistent bacterial infections such as Mycobacterium spp and fungi; prolonged exposure to some toxic agents such as asbestos; some autoimmune diseases such as lupus.
294
How does chronic inflammation appear grossly?
Shrunken, firm to hard tissue, uneven surface that may be discolored (white due to CT replacement).
295
How does chronic inflammation appear histologically?
Numerous macrophages, lymphocytes, and plasma cells along with tissue degradation.
296
Attempts at healing through chronic inflammation are via what two processes?
Granulation tissue (fibrosis) and angiogenesis (neovascularization).
297
When is the term 'chronic-active' used?
Only if there are large numbers of neutrophils or fibrin in a chronic lesion; seen with hardware disease.
298
What are the functions of macrophages in chronic inflammation?
Phagocytosis of particulate matter, microbes, and senescent cells; recruitment of B and T cells; most numerous WBC as they begin emigrating early in acute inflammation.
299
What are classically activated macrophages (M1)?
Activated by microbial products and then incited by either ROS/NO/lysosomal enzymes for phagocytosis and killing or by IL-1/IL-12/IL-23/chemokines for inflammation.
300
What are alternatively activated macrophages (M2)?
Activated by IL-23/IL-4 and then incited by either growth factors/TGF-b for tissue repair and fibrosis or by IL-10/TGF-b for anti-inflammatory effects.
301
What are epithelioid macrophages?
Specialized macrophages with more abundant eosinophilic cytoplasm and eccentrically located, round to oval nucleus, thus resembling epithelial cells; have numerous lysosomes and vacuolated cytoplasm and specialize in secretion of cytokines.
302
What are multinucleated giant cells?
Large cells formed by fusion of macrophages under the influence of IL-4 and IFN-gamma.
303
Continued recruitment of macrophages due to a persistent stimulus is the result of what?
Steady expression of chemotactic factors such as C5a, IL-8, PDGF, and TGF-b; can also proliferate locally.
304
What happens when macrophages become activated?
They become immobilized and long-lived at the sites of chronic inflammation and can cause tissue destruction.
305
What is one of the hallmarks of chronic inflammation?
Tissue destruction.
306
What are the main actions of activated macrophages?
Inflammation/tissue injury due to release of ROS, proteases, cytokines/chemokines, coag factors, and arachidonic acid metabolites; repair/fibrosis due to growth factors, fibrogenic cytokines, angiogenesis factors, and collagenases.
307
What is the role of T cells in chronic inflammation?
Macrophages present processed Ag fragments on their cell surface and interact with T cell to activate it and then activated T cell produces mediators that activate additional macrophages; cycle persists until triggering Ag is removed or reaction is modulated.
308
What is the role of B cells in chronic inflammation?
Stimulated by macrophages and helper T cells to become plasma cells and produce Ag-specific Ab's.
309
Define granulomatous inflammation.
A chronic inflammatory reaction which is histologically dominated by macrophages (epithelioid or giant cells).
310
Granulomatous inflammation is a mechanism for what?
Dealing with indigestible substances and certain microorganisms that are difficult to kill.
311
What process can accelerate development and intensity of granulomatous inflammation?
Cell-mediated hypersensitivities.
312
How does granulomatous inflammation appear grossly?
Type of inflammation that is often firm and may or may not be well demarcated; diffuse thickening of a tissue such as with Johne's disease; nodular/multinodular lesions often with central area of caseous necrosis or suppuration (pyogranuloma).
313
Define granuloma.
Focal type of granulomatous inflammation consisting of a central aggregate of macrophages which is surrounded by variable numbers of primarily lymphocytes and plasma cells and often circumferential fibrous CT capsule.
314
How does a simple granuloma appear histologically?
Organized accumulation of macrophages and epithelioid cells, often rimmed by lymphocytes and a capsule.
315
How does a complex granuloma appear histologically?
Central area of necrosis which may show dystrophic calcification/mineralization; necrosis may be due to a release of free radicals, lysosomal enzymes, or ischemia.
316
How does a pyogranuloma appear histologically?
Core is rich in neutrophils which have often undergone degeneration.
317
How does a foreign body granuloma appear histologically?
Characterized by abundance of foreign body giant cells; due to inert particles, lipids resistant to metabolism, plant material, suture material, hair, keratin, sperm, etc.
318
By what mechanisms are granulomas formed?
Certain pathogens stimulate macrophages or DC's to activate T lymphocytes by IL-12; T cells secrete IFN-y which promotes transformation of macrophages to epithelioid macrophages/giant cells; if pathogen persists macrophages organize into granuloma.
319
What are the characteristics of repair after inflammation?
Process by which lost or necrotic cells are replaced by vital cells either via regeneration or fibrosis; events that contain damage and prepare for surviving cells to replicate are set in motion even as cells/tissues are still being injured; recruited inflammatory cells not only clean up necrotic debris but also elaborate mediators that drive synthesis of new extracellular matrix.
320
What are the 2 ways in which repair is achieved?
Regeneration: replacement of cells by those of identical type; begins early in inflammatory process via mediators that are both pro-inflammatory and pro-repair; fibrosis: replacement by fibrous CT called granulation tissue which has a particular arrangement of fibroblasts, collagen, and neovascularization (new BV's).
321
What has to be true of a tissue for regeneration to occur?
Must have the capacity for parenchymal regeneration and the maintenance of the architectural framework: cannot happen in the heart.
322
Return to normal at the end of a repair process depends on what factors?
Ability of host to eliminate inciting agent; how much necrosis/tissue damage occurs particularly to CT framework; how much exudate is removed/resolved; ability of injured tissue cells to regenerate.
323
Because there are so many requirements for the return of a tissue to normality after inflammation, what is the most common occurrence?
Some degree of scarring is more common rather than complete resolution.
324
What are the different classifications of tissue proliferative capability?
Labile (continually dividing) cells: cells which continue to multiply throughout life to replenish cells lost due to normal turnover; stable (quiescent) cells: long life spans and are capable of rapid division following damage; permanent (nondividing) cells: no regenerative ability; can only regenerate portions of the cell.
325
What are examples of tissues with labile cells?
Epithelium of skin and MM, lymphoid cells, hematopoietic cells in bone marrow.
326
What are examples of tissues with stable cells?
Epithelium of liver, kidney and lungs, endocrine organs, muscle cells, fibroblasts, and endothelium.
327
What are examples of tissues with permanent cells?
Neurons, cardiac muscle cells, and lens epithelium.
328
Fibrosis repair begins when?
Within 24 hours of the occurrence of injury/start of inflammatory reaction.
329
What are the first events of fibrosis?
Fibroblasts migrate to site of injury; induction of fibroblast and endothelial cell proliferation (angiogenesis); within 3-5 days granulation tissue forms; over weeks to months there is a gradual increase in collagen and regression of vessels (scar).
330
What are the 4 components of repair by fibrosis?
Angiogenesis; migration and proliferation of fibroblasts; deposition of ECM; maturation and reorganization of fibrous tissue.
331
Describe angiogenesis.
Proteolytic degradation of parent vessel BM to allow formation of capillary sprouts; migration of endothelial cells to angiogenic stimulus via integrins binding to fibrin and fibronectin; proliferation of endothelial cells especially VEGF; maturation into capillary tubes with recruitment/proliferation of supporting pericytes and smooth muscle.
332
Newly formed blood vessels via angiogenesis are described as?
Leaky.
333
Migration and proliferation of fibroblasts is due to what?
Growth factors produced by activated endothelial cells and activated WBCs: platelet derived growth factor (PDGF), TGF-b, and fibroblast growth factor (FGF).
334
How does the deposition of ECM occur during fibrosis?
Fibroblasts synthesize ECM starting from 3-5 days and continuing onward mainly via TGF-b and PDGF.
335
What are fibrocytes?
Plump fibroblasts that are indicative of the healing stage of inflammation.
336
Maturation and reorganization of fibrous tissue is responsible for what?
Appearance of granulation tissue and subsequent scar tissue formation.
337
Describe the appearance of well-organized granulation tissue.
Fibroblasts and collagen fibers run in bundles perpendicular to long thin blood vessels of neovascularization.
338
What are the general steps of wound healing regardless of etiology?
Induction of acute inflammation via initial injury; parenchymal cells regenerate; migration/proliferation of both parenchymal and CT cells; synthesis of ECM proteins; remodeling of parenchymal elements to restore function; remodeling of CT to achieve wound strength.
339
Wound healing results in restoration of tissue continuity how?
With or without function.
340
What are the factors that can impair wound healing?
Infections, nutritional factors, glucocorticoids, mechanical factors, poor perfusion, foreign bodies, etc.; type/volume of tissue injured; location of injury.
341
What are the 2 main ways in which a cutaneous wound will be resolved?
First intention: close apposition in a wound i.e. scalpel cut; primary union where epithelial regeneration predominates over fibrosis; second intention: poor apposition i.e. ragged cut from large mass removal in which there is a more complex regenerative process.
342
What are the characteristics of second intention healing?
More extensive inflammatory component (fibrin and WBCs); wound contraction occurs due to myofibroblasts; more granulation tissue: bleeding and fragile; results in irregular scar.
343
What are the characteristics of wound strength?
About 10% at week 1 and then 70-80% by 3 months; if sutured, immediately 70%.
344
Define granulation tissue.
CT that forms within a healing wound that appears granular and is located on the surface of wounds; very pink and bleeds easily.
345
How does granulation tissue appear histologically?
Proliferation of new, small blood vessels and fibroblasts.
346
What are the different zones of granulation tissue?
Zone of necrotic debris and fibrin: superficial area of variable thickness; zone of macrophages and in-growing capillaries; zone of proliferating capillaries and fibroblasts that grow perpendicular to the defect; zone of mature fibrous CT: oldest portion of healing process.
347
Describe exuberant granulation tissue.
Occurs often in horses as an abnormal way of injury repair involving excessive granulation tissue; occurs when there is severe/prolonged tissue injury, loss of tissue framework (BM), or large amounts of exudate.
348
What are the consequences of granulation/fibrosis?
Loss of functional parenchymal tissue; alteration of physical properties of tissue: skin with scar is more prone to tearing or pulmonary fibrosis that decreases compliance and increases workload for respiration.
349
Healing in the liver has a specific capacity of?
Regeneration.
350
Describe healing in the liver.
Varies from complete parenchymal regeneration to extensive scar formation; outcome dependent on insult, location, extent, and chronicity.
351
Describe liver cirrhosis.
Multinodular appearance and firm texture of liver due to presence of hepatocyte regeneration and fibrosis of ECM framework occurring simultaneously after severe hepatic injury; will often see double-nucleated hepatocytes.
352
Describe the regenerative capacity of the kidney.
Maximal in renal cortical tubule; minimal in medullary tubule; none in glomeruli.
353
What is essential for regeneration to occur?
Intact basement membrane.
354
Describe what occurs when there is damage to cortical tubules of kidney with damage of BM.
As the basement membrane is disrupted, epithelial cells have no platform to proliferate on, so macrophages and fibroblasts infiltrate and proliferate; fibrous connective tissue replaces the affected tubules and surrounds, sometimes suffocating, the surviving ones, atrophying them.
355
Describe what occurs when there is damage to cortical tubules of kidney without damage of BM.
The surviving tubular cells in the vicinity of the wound flatten and migrate into the necrotic area along the BM; frequent mitosis and occasional clusters of epithelial cells projecting into lumen; within a week, the flattened cells are more cuboidal and differentiated cytoplasmic elements appear; tubular morphology and function are normal by 3-4 weeks.
356
Describe an alveolar injury in the lung with intact BM.
Regeneration if the alveolar exudate is cleared by neutrophils & macrophages; if the inflammatory cells fail to lyse the alveolar exudate, the exudate is organized by granulation tissue and intra-alveolar fibrosis results.
357
What are the cells responsible for regeneration in the lung?
Type 2 pneumocytes: migrate to denuded areas and undergo mitosis to generate cells with features intermediate between type 1 and type 2 pneumocytes; as they establish contact with other epithelial cells mitosis stops and they differentiate to type 1 pneumocytes.
358
Describe alveolar injury in the lung with BM damage.
Results in fibrosis/scarring; mesenchymal cells from the alveolar septa proliferate and differentiate into fibroblasts and myofibroblasts.
359
Describe repair in the heart specifically.
Healing occurs by granulation tissue and scarring; myocardial cells have limited ability to proliferate.
360
Describe healing in the brain.
Neurons are permanent cells with limited proliferative capabilities; glial cells and perivascular/meningeal fibroblasts are capable of robust proliferation.
361
What happens when neuropil of the brain is punctured by a sterile instrument?
Lesion heals by astrocytic gliosis and fibrosis; lesion fills with fibrous core derived from mening.
362
What do fibroblasts and myofibroblasts do?
They proliferate and differentiate.
363
How does healing occur in the heart?
Healing occurs by granulation tissue and scarring; myocardial cells have limited ability to proliferate.
364
How does healing occur in the brain?
Neurons are permanent cells with limited proliferative capabilities; glial cells and perivascular/meningeal fibroblasts are capable of robust proliferation.
365
What happens when the neuropil of the brain is punctured?
The lesion heals by astrocytic gliosis and fibrosis; it fills with a fibrous core derived from meninges and perivascular adventitia.
366
What is the significance of astrocytes in brain tissue healing?
Astrocytes are stimulated by edema and ischemia and are less vulnerable to injury than nerve cells; if they are not destroyed during injury, they form a branching network around the wounded neuropil to replace tissue.
367
What is the function of microglial cells in brain healing?
They are migratory, actively phagocytic cells of neuropil that clean up debris.
368
What are the steps of bone healing?
1-2 days: extensive blood clot forms; inflammatory phase: neovascularization and organization of blood clot; reparative phase: formation of callus of cartilage and woven bone; remodeling phase: cortex revitalized and new bone organized along stress lines.
369
What is a soft callus?
The organizing, predominantly uncalcified connective tissue that provides some anchorage between ends of fractured bones but offers no structural rigidity for weight bearing.
370
What is a hard callus?
Hard bony tissue that develops around the ends of fractured bone during healing; as it mineralizes, the stiffness and strength of the callus increases until weight-bearing is tolerated.
Veterinary Pathology 1
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