7_Inflammation and Repair Flashcards
1
Q
inflammation:
define, cells involved, mechanism
A
- def: protective complex host response to injury
- cells involved:
- host cells, blood vessels, and proteins, and other mediators
- required to eliminate the initial cause of cell injury, necrotic cells and tissues resulting from the original insult
- mech:
- caused by diluting, destroying or neutralizing the harmful agent and injured tissue –>
- to permit injured tissue to permit healing/repair
2
Q
inflammation:
histo/clinical features, w/o inflammation, etc
A
- histo/clinical features: can vary considerably, depending upon extent of injury and nature and injurious agent
- w/o inflammation, infections would go unchecked and wounds would never heal
- pathological:
- inflammatory rxn and repair process can be harmful as also capable of injuring normal tissues
3
Q
what is the process of inflammation/damage/and repair
A
4
Q
acute and chronic inflammation
A
5
Q
what is the most important cell in:
- acute
- chronic
A
- acute phase: key/most important cell is the neutrophil
- chronic phase: key/most important cell is chronic inflammatory cell
6
Q
acute inflammation:
define
A
- the immediate response; neutrophil is most important cell
- rapid response (min to hours) to injurious agents/stimuli
- infxns,
- trauma (physical/chem agents),
- tissue necrosis,
- foreign bodies (splinters, dirt sutures, etc),
- immune reactions
7
Q
acute inflammatory response:
function, mech
A
- exudate carries plasma proteins, fluid, and cells from local blood vessels into the damaged area to mediate local defenses
- mech:
- infective or causative agent (e.g. bacteria) present in the damaged area
- can be destroyed or diluted and eliminated by components of the exudate
- the damaged tissue can be broken down and partially liquefied and the debris removed or digested from the site of damage
8
Q
what are the two major components in the acute inflammatory response?
A
- vascular changes: smooth muscle vasodilation, increased permeability of endothelium
- cellular events: emigration of neutrophils, their metabolic activation and chemotactice migration to site of injury, phagocytosis of microbes/damaged tissue
9
Q
when are there cells in the extracellular matrix?
A
there aren’t many cells in ECM unless you’re fighting infection
(normally they’re in the blood vessel)
10
Q
what are the 3 key effects on the inflammatory site during acute inflammation
A
- increased blood flow
- leakage of plasma proteins –> edema
- neutophil emigration
11
Q
what are the various stimuli for acute inflammation?
A
- microbial infections
- hypersensitivity reactions/ immune reactions –> excessive immune rxn
-
physical agents
- trauma, UV, ionizing radiation, burns, cooling
- irritant and corrosive chemicals
- tissue necrosis
12
Q
list some examples of acute inflammation
A
- laryngitis, pharyngitis, –itis
- skin rxn to burn/or scratch
- acute hepatitis, pericarditis
- pneumonia, inflammation of lung
- pleurisy, inflammation of the pleura
13
Q
which mechanisms do necrotic cells use to recognize microbes?
A
-
Pattern recognition receptors - recognize molecular patterns common to microbes
- e.g. phagocytes, dendritic cells, epithlial cells can detect molecular components from dead cells
-
Toll like receptors - recognize bacterial DNA, endotoxin, viral dsRNA;
- providing defense against all classes of infectious pathogens –> activates TFs causing synthesis of mediators of inflammation, interferons, that activate acute inflammation
- Inflammasomes - cytoplasmic complex that recognizes ingested products of dead cells, extracellular ATP, microbial products, cholesterol crystals and free fatty acids
14
Q
inflammasome:
mechanism, and effects
A
- mech:
- triggering inflammasome –> activates caspase-1 –> cleaves pro-IL-1b into biologically active IL-1b –> secreted and is an important cytokine recruiting leukocytes
- effects:
- cholesterol and fatty acids accumulate in atherosclerosis –> contributes to low-grade chronic inflammation of that disease
- cholesterol crystals are present in significant number of endodontic periapical lesions
15
Q
describe the vascular changes in inflammation
(and clinical symptoms)
A
- transient vasoCONSTRICTION (seconds)
- prolonged vasoDILATION of arterioles
- hyperemia: inc BF in capillary beds
- inc. intravascular hydrostatic pressure –> pushes fluid through vessel wall (transudate) –> excess extravascular fluid (edema)
- inc. vascular permeability
clinically: the area is warm (calor) and red (rubor/ erythema)
16
Q
difference between transudate and exudate?
A
-
Transudate: (less protein, few cells)
- fluid pushed through the capillary due to high pressure within the capillary;
- can occur w/ normal vessel permeability
-
Exudate (more protein, may have some RBCs/WBCs)
- is fluid that leaks around the cells of the capillaries caused by inflammation
17
Q
what is the hallmark of acute inflammation w/ regards to vasculature?
(and resulting sxs)
A
INC. VASCULAR PERMEABILITY;
- inc in permeability –> leakage of fluid rich in protein/lrg molecules/ & eventually cells –> into surrounding tissue (exudate)
- inc extravascular proteins –> contribute to inflamm respose & draw fluid via osmosis
- inc hydrostatic pressure (pushing fluids out of vessel) + THE OSMOTIC PULL OF FLUIDS –> results in inc. in extravascular fluid (edema)
Sxs: swelling (tumor), and pain (dolor)
18
Q
what effect does the increased vascular permeability have on the blood flow? –> downstream effects?
A
- inc. vasc perm –> outpouring of protein-rich fluid into extravascular tissues –>
- RBCs in flowing blood becomes more concentrated –> inc viscosity –> stasis (slowing circulation) –> neutrophils marginate (accumulate) –> neutrophils adhere to endothelium –> emigrate into ECM
19
Q
what are the 7 key mechanisms of increased vascular permeability?
A
- endothelial cell CONTRACTION
- endothelial RETRACTION
- direct endothelial INJURY
- delayed prolonged LEAKAGE
- leukocyte-mediated endothelial injury
- increased TRANSCYTOSIS
- leakage from REGENERATING CAPILLARIES
20
Q
endothelial contraction:
mechanism of inc. permeability
A
- Aka “Immediate Transient Response”
- Most common mechanism
- Response is rapid, short-lived (15-30 mins) and reversible
- Leads to widened intercellular gaps in post-capillary venules
- Elicited by histamine, bradykinin, leukotrienes, etc binding to specific receptors on endothelium that lines post-capillary venules.
21
Q
endothelial retraction:
mechanism of inc. permeability
A
- Reversible; Slower and more prolonged retraction of endothelial cells –> leads to widened intercellular gaps in post-capillary venules
- Occurs via reorganization of cytoskeleton, which is a more complex change
- taking 4-6 hours to compete and lasting for 24+ hours.
- Induced by cytokines IL-1 and TNF.
22
Q
direct endothelial injury:
mechanism of inc. permeability
A
- Leakage is “immediate and sustained” until vessel thromboses or is repaired with new endothelium.
- Increased permeability due to endothelial cell necrosis and detachment (severe mechanical injuries, burns, bacterial lytic infections).
- Affects any or all levels of the microvasculature (arterioles, capillaries and/or venules) depending on type/extent of the injury.
23
Q
delayed prolonged leakage:
mechanism of inc. permeability
A
- Another type of direct injury that involves venules and capillaries only because the injury is less severe (bacterial toxins, sunburns, after X-irradiation).
- Leakage begins in 2-12 hours and lasts for hours or days.
- Mechanism unclear, but delayed cell damage occurs.
24
Q
leukocyte-mediated endothelial injury:
mechanism of inc. permeability
A
- Consequence of leukocytes accumulating in vessels at sites of injury, becoming “activated” and releasing toxic substances (enzymes, free radicals) that can damage adjacent endothelial cells.
- Largely restricted to sites where leukocytes adhere to the endothelium (venules at sites of inflammation, pulmonary capillaries).
25
**increased transcytosis:**
*mechanism of inc. permeability*
* There are **“channels” present in normal endothelium formed by a vesiculovacuolar** organelle system that extends across endothelial cells near cellular junctions.
* ^^ This transport system is increased in inflammation
* Induced by **VEGF**.
26
**leakage from regenerating capillaries:**
*mechanism of inc. permeability*
* **Newly forming capillaries** are an important part of angiogenesis and repair of tissues following injury.
* Regenerating capillaries are **patent but not tightly adherent** to each other, so leakage occurs.
* Tissues in early stages of repair are **still edematous**.
27
describe the process of **leukocyte extravasation** from the blood vessel
* stasis allows leukocytes to leave central column of blood --\> MARGINATE along BV wall --\> come in contact w/ ACTIVATED ENDOTHELIUM (\*site of injury)
1. ROLLING: *tumble over the endothelium, transiently sticking to cell surface adhesion molecules expressed by the “activated” endothelium.*
2. INTEGRIN ACTIVATION BY CHEMOKINES: *transient adhesions are mediated by selectins expressed on surface of endothelium (CD62E and CD62P) and leukocytes (CD62L). Selectins bind to sialylated oligosaccharides attached to mucin-like glycoproteins on the other cell.*
3. ADHESION: *slowed leukocytes --\> firm adhesion by inegrins (ICAM-1, VCAM-1) on "Activated" endothlial cells*
4. DIAPEDESIS: *Transmigration of leukocytes (diapedesis) occurs mainly at endothelial intercellular junctions in post-capillary venules.*
28
which integrins and chemokines and CDs are involved in leukocyte recruitment
* •Once leukocytes have sufficiently slowed, firm adhesion to endothelium is mediated by high affinity leukocyte **cell surface integrins binding to ligands (ICAM-1, VCAM-1)** on “activated” endothelial cells.
* Endothelial cells express **CD31 at cell junctions and neutrophil CD31 binds to it** forming a dimer, signaling where to transmigrate.
*
29
Function of collagenase and chemokines during **leukocyte recruitment?**
* **Collagenase** aids in piercing the vascular basement membrane
* **Chemokines** aid in **firm adhesion** and induce leukocytes to transmigrate.
30
when/where do **neutrophils** accumulate, and when do **monocytes** become involved?
* **Neutrophils** accumulate at sites of acute inflammation first:
* more numerous in the blood,
* they **respond more rapidly to chemotactic factors**, and
* attach more firmly to adhesion molecules initially expressed by endothelium.
* Transmigration of **monocytes** become more numerous 24-48 hrs later. T
* They become macrophages and live longer.
* Very important phagocytic cell in inflammation that removes necrotic tissue, dead neutrophils, etc.
31
which curve corresponds with:
* monocytes
* edema
* neutrophils
and why?
* **edema** - is extravascular fluid; and leakage
* **neutrophils** are more numerous and respond to chemotactic factors
* **monocytes** become macrophages and live longer; but take longer to transmigrate
32
in a patient w/ fever/cough and yellowish sputum x 2 days --\>
which type of inflammatory cell would be most likely present in GREATLY INCREASED NUMBERS in the sputum?
NEUTROPHILS;
accumulate; found in sputum
33
what are the key steps of leukocyte transmigration?
34
(slide 35)
35
how is **leukocyte activation** process induced?
A number of **chemical factors (chemical mediators, products of necrotic tissue, bacterial components) bind cell surface receptors (e.g. TLRs)** and induce this process
36
what metabolic changes are involved in **leukocyte activation?**
* **Enhanced phagocytosis** and intracellular destruction of microbes
* **Increased secretion of lysosomal enzymes,** free radicals to destroy extracellular microbes, breakdown necrotic tissue.
* Increased **production of mediators** that recruit more cells, expand the inflammatory response.
37
when can **leukocyte activation** be harmful?
•can be potentially harmful **if occurs away from site of injury** (e.g. in the blood vessel causing endothelial damage).
38
**leukocyte phagocytsis:**
*definition, and mechanism*
* def: Engulfment of cell debris, microbes, foreign material. Principal phagocytes are **neutrophils, monocyte/macrophages**
* mech:
* **1) recognition and attachment** occurs via opsonins
* **2) engulfment** - binding of opsonized particles to leukocyte cell surface tiggers engulfment
* **3) killing/degradation** - phagosome and lysosome fuse --\> lysosomal contents spill into phagolysosome --\> resulting in enzymic degradation adn degranulation of the granulocyte
39
what are the mechanisms of **microbial killing and degradation?**
* Bacterial killing occurs via **_reactive oxygen species_** formed in phagolysosome.
* Phagocytosis leads to a **burst in O2 consumption**:
* as **NADPH oxidase oxidises NADPH**( reduced nicotinamide adenine dinucleotide phosphate) and in the process converts O2 to **superoxide free radical.**
* Superoxide then converted to **H2O2**
* Lysosomal myeloperoxidase then uses Cl- + H2O2 to create HOCl free radical. Most efficient bacteriocidal system, **killing bacteria by halogenation or protein/lipid peroxidation.**
* •Dead bacteria are then further degraded by **lysosomal acid hydrolases.**
40
how do the following affect microbial killing and degradation?
1. **inherited deficiency in MPO,** or an
2. **inherited deficiency in NADPH reductase**
1. inherited deficiency in myeloperoxidase (MPO)--\> can still kill microbes via **superoxide, hydroxyl free radical, OONO radical.**
2. Inherited deficiency in NADPH oxidase --\> results in **chronic granulomatous disease, recurrent infections.**
41
what are the **non-oxygen dependent** mechanisms in *microbial killing and degradation?*
"BLAM!" are non-oxygen dependent
* **Bacterial permeability-increasing protein** *(activates phospholipase and membrane phospholipid degradation)*
* **Lysozyme** degrades bacterial coat oligosaccharides
* **Arginine-rich cationic peptides** (defensins) that kill microbes by creating holes in membranes
* **Major basic protein** produced by eosinophils that is cytotoxic to parasites.
42
**function of granule components** secreted by leukocytes? (re:microbial killing/degradation)
mechanisms of secretion?
* fxn: to destroy extracellular microbes (*enzymes like elastase, antimicrobial peptides)*
* mech:
* **phagolysosome remains transiently open** as it forms, releasing enzymes into surrounding tissue *(regurgitation during feeding)*
* **Inability to phagocytose** particles *(microbes, immune complexes)* on a surface leads to activation of leukocyte and secretion of enzymes (frustrated phagocytosis)
* **Leukocyte death** may release active or ruptured phagolysosomes
43
**neutrophil extracellular traps (NETs):**
*define, structure*
* def: **Extracellular fibrillar networks** produced by neutrophils **in response** to microbial pathogens, inflammatory mediators
* structure:
* framework of nuclear chromatin with embedded granule proteins *(antimicrobial peptides, enzymes).*
* high conc of antimicrobial substances at sites of infection & traps the microbes preventing their spread
* chromatin is supplied by the neutrophils, resulting in cell death.
44
what is postulated to be the **source of nuclear antigens** in systemic autoimmune diseases (e.g. lupus)?
exposed nuclear chromatin (includes histones, DNA, etc) of NETs
## Footnote
*(NETs contain a framework of nuclear chromatin with embedded granule proteins (antimicrobial peptides, enzymes)*
45
describe the processed by which **leukocytes can induce tissue injury?**
1. The products produced and potentially released from leukocytes can contribute to tissue injury.
2. **Bystander tissues can be damaged** --\>**Certain infections difficult to eradicate** (TB, some viral diseases) the host response contributes more to the pathologic process than does the microbe.
3. **Autoimmune response** -- normal tissues can be damaged inappropriately
4. Excessive reaction to **non-toxic environmental substances** (asthma, pneumoconioses)
5. **Prolonged inflammation --\>** inflammatory reaction can be responsible for much of the tissue injury. *(Immune-mediated vasculitis, arthritis, atherosclerosis, glomerulonephritis, septic shock, etc)*
46
what are the possible consequences of **leukocyte dysfunction?**
* **increased susceptibility to infection**
* can causes of **defective inflammation**
* bone marrow suppression caused by tumors or tx (chemo, radiation)
* metabolic disease such as diabetes (causes abnormal leukocyte fxn)
*
47
list some examples of **inherited disorders of leykocyte dysfunction**
* **Leukocyte adhesion deficiency type-1:** defective leukocyte integrins
* **LAD-2:** absence of sialylated glycoprotein on leukocytes for E-selectin
* **Chronic granulomatous disease-**defect in microbicidal activity
* **Chediak-Higashi syndrome:** A.R. impaired fusion of lysosomes and phagosomes, impaired secretion of lytic granules by cytotoxic T cells.
48
draw out the process map of ACUTE vs CHRONIC inflammation
49
**serous inflammation:**
*define, location*
when exudate is **protein-poor** resulting --\> in **watery fluid** that accumulates:
* in area of injury (e.g. a skin blister) or
* in body cavities by mesothelial secretion (effusion).
50
when considering histological slides, what are we evaluating for?
* nature of the injurious agent
* severity of the tissue injury
* type of tissue injured --\> all influence the histological picture (morphology)
51
**fibrinous inflammation:**
*define, mech, pathology*
* def: **consequence of severe injuries, resulting in greater vascular permeability that allows fibrin to pass the endothelial barrier, greater outflow of protein into extravascular spaces.**
* mech:
* Fibrinogen into the body cavities --\> clotting/sticky fibrin mass that coats surfaces of the cavity, fills the space causing organs to adhere to body wall.
* (e.g. Pleural, pericardial, peritoneal cavities lined by mesothelium
* With fibrinolysis and phagocytosis of debris, body cavity structure and function restored (resolution).
* PATHOLOGICAL: if fibrinolysis is not timely, fibroblasts and new blood vessels migrate into the fibrin mesh forming granulation tissue (organization) leading ultimately to fibrosis/scarring --\> Results in **permanent fibrous adhesions of organ, restricting movement.**
52
**suppurative (purulent) inflammation**:
## Footnote
*define, cause, clinical*
* def: dominated by **large numbers of neutrophils, edema and necrotic debris (pus).**
* cause: Typically **due to pyogenic bacterial infections** such as Staphylococci, actinomyces.
* clinical signs:
* **Abscesses**: localized foci of suppurative inflammation in a tissue, organ, or confined space.
* May persist for months, walled off by fibrous tissue.
* Due to central tissue destruction, usual outcome is **fibrous scar.**
53
**ulcers:**
*define, location, cause*
* define: **Local defect in surface of organ or tissue produced by sloughing of inflamed, necrotic tissue**
* location: most common in the GI tract, mouth and on skin of lower extremities in elderly with poor circulation. Involves focal loss of epithelium.
* cause:
* Underlying acute and chronic inflammation;
* ulcers from chronic inflammation can become extensive when healing is slow or there is repeated insult *(peptic ulcer, large aphthous ulcers).*
