Inflammation

Question 1

Ποια είναι τα κύρια ερεθίσματα που επάγουν την οξεία φλεγμονή?

Answer 1

1) Μολύνσεις (bacterial, viral, fungal, parasitic) και μικροβιακές τοξίνες - Toll-like receptors (TLRs).
2) Ιστική νέκρωση. Ισχαιμία/ τραυματισμός κλπ.
Mediators : ουρικό/ ADP/ μεταβολίτες πουρινών.
Υποξία : HIF-1a + VEGF.
3) Ξένα σώματα (σκόνη κλπ).
4) Hypersensitivity reactions - Αυτοάνοσα.

Question 2

Ποια είναι η διαφορά μεταξύ exudate και transudate?

Answer 2

Το exudate έχει υψηλή συγκέντρωση πρωτεϊνών + κύτταρα, ενώ το transudate έχει χαμηλή - αποτελεί ένα υπερδιήθημα του πλάσματος.
Το οίδημα μπορεί να είναι οποιοδήποτε από τα 2.

Question 3

Τι είναι και τι περιέχει το πύον?

Answer 3

Είναι φλεγμονώδες exudate και περιέχει λευκοκύτταρα (κυρίως ουδετερόφιλα), τμήματα νεκρών κυττάρων + μικρόβια.

Question 4

Ποιες μεταβολές συντελούνται στην αιματική ροή και στη διάμετρο των αγγείων κατά τη φλεγμονή?

Answer 4

1) Αγγειοδιαστολή. Συχνά ακολουθεί μια παροδική συστολή των αρτηριολίων. Επάγεται από NO + histamine - Ερύθημα.
2) Ακολουθεί αυξημένη διαπερατότητα των τριχοειδών.
3) Ακολουθεί stasis - Συσσώρευση ερυθροκυττάρων στα μικρά αγγεία και βραδεία ροή.
4) Τα λευκοκύτταρα (κυρίως ουδετερόφιλα) προσκολλούνται κατά μήκος του ενδοθηλίου και μεταναστεύουν στον διάμεσο ιστό.

Question 5

Με ποιους μηχανισμούς αυξάνεται η διαπερατότητα των αγγείων ?

Answer 5

1) Συστολή των ενδοθηλιακών κυττάρων (περικύτταρα) με αποτέλεσμα την αύξηση των διάκενων μεταξύ τους - Στα φλεβίδια.
Mediators : Ισταμίνη/ Βραδυκινίνη/ Λευκοτριένια/ Ουσία Ρ.
Άμεση παροδική απόκριση (15-30min).
2) Ενδοθηλιακή βλάβη - Νέκρωση του ενδοθηλίου και αποκόλληση. (Συμβαίνει και από λευκοκύτταρα).
3) Αυξημένη transcytosis. (Venules)

Question 6

Ποια είναι η ακολουθία βημάτων κατά την πορεία των λευκοκυττάρων από τον αυλό του αγγείου στους ιστούς που έχουν υποστεί βλάβη ? (συνοπτικά).

Answer 6

1) Στον αυλό : margination, rolling, adhesion to endothelium.
2) Μετανάστευση διαμέσου του ενδοθηλίου και του αγγειακού τοιχώματος.
3) Μετανάστευση στους ιστούς μέσω χημειοτακτικών ερεθισμάτων.

Question 7

Ποιο αποτέλεσμα στην κατανομή των λευκοκυττάρων μέσα στον αυλό έχει το γεγονός της στάσης (stasis) ? (Slow blood flow).

Answer 7

Ακόμη περισσότερα λευκοκύτταρα υιοθετούν μια περιφερικότερη, προς το αγγειακό τοίχωμα, θέση. (Margination).

Question 8

Πού και με ποιον τρόπο συμβαίνει η transmigration των λευκοκυττάρων ?

Answer 8

Στα μετατριχοειδικά φλεβίδια μέσω διαπήδησης.

Question 9

Ποιοι είναι οι υποδοχείς των λευκοκυττάρων που αναγνωρίζουν εξωτερικά ερεθίσματα στη φλεγμονή?

Answer 9

1) Υποδοχείς για μικροβιακά προϊόντα - Toll-like receptors (TLRs) - Αναγνωρίζουν κυρίως lipopolysaccharide or endotoxins.
2) G-protein coupled receptors - αναγνωρίζουν Ν-φορμυλομεθειονυλο κατάλοιπα σε βακτήρια.
3) Υποδοχείς για οψονίνες.
4) Υποδοχείς για κυτοκίνες (Ιντερφερόνη Γ).

Question 10

Ποια είναι τα τρία κύρια βήματα της φαγοκύττωσης?

Answer 10

1) Αναγνώριση και προσκόλληση του σωματιδίου που πρέπει να πεπτεί από το λευκοκύτταρο.
2) Εγκόλπωση με επακόλουθο σχηματισμό κυστιδίου.
3) Θάνατος - Αποδόμηση του σωματιδίου.

Question 11

Πώς επιτελείται χημικά ο θάνατος των μικροβίων στα φαγοκύτταρα?

Answer 11

1) Μέσω ROS (reactive oxygen species).

2) Μέσω nitrogen reactive species , from NO.

Question 12

Υπάρχουν άλλες χημικές ουσίες πέρα από τις ROS και nitrogen reactive species που έχουν αντιμικροβιακή δράση?

Answer 12

1) Elastase
2) Defensins
3) Cathelicidins
4) Lysozyme
5) Lactoferrin
6) Major basic protein (eosinophils)
7) Bactericidal/ Permeability increasing protein

Question 13

In which circumstances are the leukocytes a cause of injury to normal cells?

Answer 13

1) As part of a normal defense reaction - the healthy tissues suffer collateral damage.
2) In autoimmune diseases.
3) In allergic diseases.

Question 14

Mention 4 general categories of defects in leukocyte function.

Answer 14

1) Inherited defects in leukocyte adhesion (type 1 + type 2).
2) Inherited defects in phagolysosome function (Chediak-Higashi syndrome).
3) Inherited defects in microbicidal activity (chronic granulomatous disease).
4) Acquired deficiencies - bone marrow suppression (most common clinically).

Question 15

What happens in Chediak-Higashi syndrome?

Answer 15

1) Autosomal recessive.
2) Defective fusion of phagosomes and lysosomes in phagocytes.
3) Abnormalities in melanocytes (Causes albinism).
4) Cells of the nervous system (Nerve defects).
5) Platelets (bleeding disorders).
6) Neutropenia.
7) LYST protein involved in lysosome trafficking.

Question 16

What happens in chronic granulomatous disease?

Answer 16

1) Inherited defects in the genes encoding components of the phagocyte oxidase - defect in bacterial killing.
2) X-linked defect in membrane-bound component (gp91phox).
3) Autosomal recessive defects in cytoplasmic components (p47phox and p67phox).

Question 17

Which are the general principles of the mediators of inflammation?

Answer 17

1) They are either cell derived or plasma derived.
2) Active mediators are produced in response to various stimuli (microbial products, substances released from necrotic cells, kinins, complement).
3) One mediator can stimulate the release of another mediator (TNF stimulates IL-1).
4) Mediators vary in their range of cellular targets.
5) They are short-lived, once activated.

Question 18

Which are the two major vasoactive amines (cell derived mediators) of inflammation ?

Answer 18

Serotonin and histamine.

Histamine is released from mast cells (also from basophils and platelets).

Question 19

When and from which cells is serotonin secreted?

Answer 19

It is secreted from platelets.

After a contact with collagen, thrombin, ADP and antigen-antibody complexes. (Link between clotting and inflammation)

Question 20

Which are the most important prostaglandins in inflammation?

Answer 20

1) TxA2 (Platelets - thromboxane synthetase).
2) PGI2 - Vascular endothelium - prostacyclin synthetase.
3) PGD2 - mast cells along with PGE2.
4) PGE2 - Fever and pain.

Question 21

What is PAF ?

Answer 21

Platelet-activating factor - A variety of cells produces it.

Can elicit most of the vascular and cellular reactions of inflammation.

Question 22

Explain why release of ROS can be damaging to the host.

Answer 22

1) Endothelial cell damage with resultant increased vascular permeability.
2) Injury to other cell types (parenchymal cells, red blood cells).
3) Inactivation of anti-proteases, such as a-1 antitrypsin.

Question 23

Which are the local effects of the activation of TNF and IL-1?

Answer 23

1) Vascular endothelium : UP expression of leukocyte adhesion molecules + Production of IL-1/chemokines + UP proagulant activity.(Inflam.)
2) Leukocytes : Activation + production of cytokines.(Inflam.)
3) Fibroblasts : Proliferation + collagen synthesis (REPAIR)

Question 24

Which are the systemic effects of TNF/IL-1?

Answer 24

1) Fever
2) Leukocytosis
3) Acute phase proteins
4) Loss of appetite
5) Sleep UP

Question 25

Describe the general classification of chemokines and their specific characteristics.

Answer 25

1) α-chemokines (C-X-C) : primarily on neutrophils. IL-8 is typical of this group.
Secreted by endothelial cells + activated macrophages + other types of cells.
2) β-chemokines : monocyte chemoattractant protein (MCP-1) / eotaxin / macrophage inflammatory protein 1α (MIP-1α) / RANTES. Attracts all but neutrophils.
3) γ-chemokines : primarily on lymphocytes.
4) CX3C : fractalkine.

Question 26

Which are the two main functions of chemokines?

Answer 26

1) Stimulation of leukocyte recruitment in inflammation.

2) Control of normal margination of cells through various tissues.

Question 27

How can occur the cleavage of C3 ?

Answer 27

1) Classic pathway : Fixation of C1 to an antibody (IgG or IgM) that has attached to an antigen.
2) Alternative pathway : Triggered by microbial surface molecules + other substances.
3) Lectin pathway : Plasma mannose lectin binds to carbohydrates on microbes and directly activates C1.

Question 28

What are the functions of the complement system?

Answer 28

1) Inflammation : C3a + C5a stimulate histamine release from mast cells. C5a is also a powerful chemotactic agent for neutrophils etc. + it also activates the Lipoxygenase pathway of AA metabolism in neutrophils and macrophages.
2) Phagocytosis : C3b + iC3b act as opsonins and promote phagocytosis.
3) Cell lysis : MAC makes cells permeable to water and ions.

Question 29

Which are the most important mediators activated by the complement, kinin, and clotting systems ?

Answer 29

1) Bradykinin
2) C3a, C5a (increased vascular permeability)
3) C5a (chemotaxis)
4) Thrombin (which has effects on endothelial cells and many other cell types)

Question 30

How can C3a and C5a be generated?

Answer 30

1) Classical pathway : Immunological reactions, involving antibodies and complement.
2) Alternative and Lectin pathway.
3) Agents not directly related to immune response, such as plasmin, kallikrein, some serine proteases.

Question 31

Which systems are initiated by the Hageman factor (factor 12) in inflammatory response?

Answer 31

1) The kinin system which produces vasoactive kinins.
2) The clotting system which induces formation of thrombin (inflammatory properties).
3) The fibrinolytic system - Produces plasmin and degrades fibrin - fibrinopeptides induce inflammation.
4) The complement system which produces anaphylatoxins and other mediators.

Question 32

Which mediators are responsible for the following events in inflammation : Vasodilation, increased vascular permeability, Chemotaxis - leukocyte recruitment and activation, fever, pain, tissue damage.

Answer 32

Vasodilation : Prostaglandins + NO + Histamine + PAF
Increased vascular permeability : Histamine - serotonin - C3a and C5a (indirectly) - bradykinin - LTC4 , D4, E4 - PAF - substance P.
Chemotaxis and Leukocyte recruitment and activation : TNF, IL-1 - chemokines - LTB4 - C3a and C5a.
Fever : IL-1 and TNF + Prostaglandins.
Tissue damage : Lysosomal enzymes of leukocytes - ROS - NO.

Question 33

Describe briefly the following types of inflammation : Serous, fibrinous, suppurative or purulent and ulcer.

Answer 33

Serous : outpouring of thin fluid that may be derived from plasma or from secretions (peritoneal, pericardial, pleural cavities - effusion).
Fibrinous : Greater increase in vascular permeability enables fibrinogen to pass and form fibrin to deposit in the extracellular space - eosinophilic meshwork.
Suppurative or purulent : Large amount of pus e.g. Acute appendicitis.
Ulcer : local defect, or extracavation, of the surface of an organ or tissue that is produced by the shedding of inflamed necrotic tissue.

Question 34

What is the definition of chronic inflammation?

Answer 34

Chronic inflammation is inflammation of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations.

Question 35

What are the major causes of chronic inflammation?

Answer 35

1) Persistent infections from microbes (they often evoke delayed-type hypersensitivity).
2) Immune mediated inflammatory diseases (autoimmune diseases).
3) Prolonged exposure to potentially toxic agents, either exogenous or endogenous (silicosis and atherosclerosis).

Question 36

What are the major morphologic features of chronic inflammation?

Answer 36

1) Infiltration with mononuclear cells (macrophages, lymphocytes and plasma cells).
2) Tissue destruction.
3) Fibrosis and small angiogenesis.

Question 37

What is the role of macrophages in chronic inflammation?

Answer 37

Inflammation and tissue injury : ROS and nitrogen species + proteases + cytokines, including chemokines + coagulation factors + AA metabolites.
Repair : PDGF, FGF, TGF-β + fibrogenic cytokines + angiogenic factors (FGF).

Question 38

What is granulomatous inflammation?

Answer 38

A distinctive pattern of chronic inflammation.

Question 39

What is a granuloma ?

Answer 39

A granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are transformed into epithelium-like cells, surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells.

Question 40

Mention 7 granulomatous diseases.

Answer 40

1) Tuberculosis (prototype)
2) Sarcoidosis
3) Cat-scratch disease
4) Lymphogranuloma inguinale
5) Leprosy
6) Syphilis
7) Brucellosis

Question 41

Which are the systemic effects of acute inflammation?

Answer 41

1) Fever (exogenous and endogenous pyrogens).
2) Acute phase proteins (C-reactive protein CRP, fibrinogen, serum amyloid A (SAA) ).
3) Leukocytosis (usually 15.000-20.000/μl).
4) Increased pulse + blood pressure.
5) Decreased sweeting.
6) Rigors and chills.
7) Sepsis.

Question 42

What can persistent infections evoke?

Answer 42

Because they are difficult to eradicate, they can evoke delayed-type hypersensitivity.
The inflammatory response sometimes takes a specific pattern : granulomatous reaction.

Question 43

How is extravasation of monocytes mediated?

Answer 43

The same way, as the extravasation of neutrophils.

Question 44

What stimuli can activate the macrophages?

Answer 44

1. Microbial products that engage TLRs and other cellular receptors.
2. Cytokines : IFN-γ secreted by sensitized T lymphocytes, by NK cells and other chemical mediators.

Question 45

What do the products of activated macrophages serve?

Answer 45

Serve to eliminate injurious agents such as microbes and to initiate the process of repair, and are responsible for much of the tissue injury in chronic inflammation.

Question 46

Why do inappropriately activated macrophages cause tissue destruction?

Answer 46

Because of their great weaponry! Also, the ongoing tissue destruction can ITSELF activate, the inflammatory cascade, so features of both ACUTE + CHRONIC inflammation may coexist in certain circumstances.

Question 47

What cells have TLRs ?

Answer 47

1. Macrophages
2. Kupffer cells
3. Histiocytes
4. Mast cells (!! They are not APCs)
5. Alveolar macrophages
6. Dendritic cells

Question 48

Besides macrophages, what other cell types are involved in chronic inflammation?

Answer 48

1. Lymphocytes
2. Plasma cells
3. Eosinophils
4. Mast cells

Question 49

What is immune inflammation?

Answer 49

The involvement of the immune component (B and T cells) in an inflammatory reaction (chronic, severe).

Question 50

What are the tertiary lymphoid organs?

Answer 50

In SEVERE chronic inflammatory reactions :
The accumulation of lymphocytes, APCs, and plasma cells may ASSUME the morphology of lymphoid organs (particularly lymph nodes) - even containing well-formed germinal centers. These are called tertiary lymphoid organs.

Question 51

Why eosinophils contribute to tissue damage in allergies?

Answer 51

Because of basic major protein : highly cationic protein that is toxic to parasites but also causes lysis of mammalian EPITHELIAL cells.

Question 52

Can neutrophils be seen in chronic inflammation?

Answer 52

Yep - chronic bacterial infection of bone (osteomyelitis), neutrophilic exudate may persists for months.
Also important in the chronic damage induced in the lungs by smoking.

Question 53

Why is growth of blood vessels and lymphatic vessels often prominent in chronic inflammation?

Answer 53

Because of the VEGF secreted by macrophages and endothelial cells.

Question 54

What is briefly a granuloma?

Answer 54

A cellular attempt to contain an offending agent that is difficult to eradicate.

Question 55

Why is recognition of the granulomatous pattern in a biopsy specimen particularly important?

Answer 55

For diagnostic purposes : the possible conditions that cause it are limited.

Question 56

In a granuloma, how are giant cells produced?

Answer 56

By fusion of epithelioid cells.

Question 57

What are the two main morphologic types of giant cells?

Answer 57

1. Langhans-type giant cell : nuclei arranged peripherally.

2. Foreign body-type giant cell : nuclei arranged haphazardly.

Question 58

What are the two types of granulomas?

Answer 58

1. Foreign body granulomas

2. Immune granulomas : caused by a variety of agents that are capable of inducing a cell-mediated immune response.

Question 59

In immune granulomas, what cytokine is secreted by T cells to activate other T cells?

Answer 59

IL-2

Question 60

What cytokine that is secreted by T cells, is important in activating macrophages and transforming them into epithelioid cells and multinucleate giant cells?

Answer 60

IFN-γ

Question 61

What are the main characteristic of tubercle?

Answer 61

It is often characterized by the presence of CENTRAL caseous necrosis. Caseous necrosis is rare in other granulomatous diseases.

Question 62

What happens in lymphangitis and lymphadenitis?

Answer 62

Lymphangitis : during acute inflammation the lymphatics may become secondarily inflamed.
Lymphadenitis : the same but for lymph nodes.

Question 63

How do the leukocytes pierce the basement membrane, after transversing the endothelium?

Answer 63

Probably by secreting collagenases.

Question 64

Where do the chemotactic agents of leukocytes bind?

Answer 64

To specific 7 transmembrane G protein coupled receptors on the surface of leukocytes - activation of small GTPases (Rac/Rho/cdc42)

Question 65

What is the time frame of neutrophil and monocyte appearance in most forms of acute inflammation?

Answer 65

6-24h : neutrophils

24-48h : monocytes

Question 66

What are the reasons for the early appearance of neutrophils?

Answer 66

1. They are more numerous in the blood
2. They respond more rapidly to chemokines
3. They may attach more firmly to the adhesion molecules that are induced on endothelial cells (P and E Selectins).

Question 67

How many TLRs have been identified?

Answer 67

10 mammalian TLRs - each one seems to be required for responses to different classes of infectious pathogens.

Question 68

Where are TLRs present?

Answer 68

On the cell surface and in the endosomal vesicles of leukocytes (and many other cell types), so they are able to sense products of extracellular and ingested microbes.

Question 69

What are the major receptors that function to bind and ingest microbes?

Answer 69

1. Mannose receptors : Lectin that binds terminal mannose and fucose residues of glycoproteins and glycolipids.
2. Scavenger receptors
3. Opsonin receptors

Question 70

What cytokines are invlolved in the repair/fibrosis by “alternatively activated” macrophages ?

Answer 70

IL-4 and IL-13 : products of Th2 cells.

Question 71

What are the two major “resident cells” in tissues?

Answer 71

1. Mast cells

2. Macrophages

Question 72

How does acute inflammation stop?

Answer 72

1. In part, simply declines because of rapid mediators bursts + short half lives.
2. Also the process actively terminate the reaction : switch to anti inflammatory lipoxins instead of pro inflammatory LTs.
3. Also anti inflammatory TGF-β, IL-10 from macrophages and other cells.
4. Anti inflammatory lipid mediators : resolvins and protectins.
5. Neural impulses that inhibit the TNF production.

Question 73

What are the principal inflammatory actions of AA metabolites?

Answer 73

1. Vasodilation : PGI2, PGE1, PGE2, PGD2
2. Vasoconstriction : TxA2, LTC4, LTD4, LTE4
3. Increased permeability : LTC4, D4, E4
4. Chemotaxis and adhesion : LTB4, HETE

Question 74

What is the principal action of lipoxins?

Answer 74

To inhibit leukocyte recruitment and the cellular components of inflammation.

Question 75

Ποιες είναι οι κύριες μεταβολές που συντελούνται κατά την οξεία φλεγμονή?

Answer 75

1) Αύξηση της διαμέτρου των αγγείων που οδηγεί σε αύξηση της αιματικής ροής.
2) Δομικές μεταβολές στα τριχοειδή που επιτρέπουν στις πρωτεΐνες του πλάσματος και στα λευκοκύτταρα να διαφεύγουν από την κυκλοφορία.
3) Συσσώρευση και ενεργοποίηση των λευκοκυττάρων στο σημείο του τραύματος και εξόντωση του επιτιθέμενου παράγοντα.