Inflammation And Repair Pathology

Question 1

Acute vs chronic inflammation

Answer 1

Acute - oedema and emigration of leukocytes (predominantly neutrophils) - INNATE

Chronic - If acute fails to clear stimulus, presence of lymphocytes and macrophages - usually adaptive immunity (more severe and progressive tissue injury - less systemic signs)

Question 2

Causes of inflammation

Answer 2

Infections, Tissue necrosis, Immune reactions, Foreign bodies

Question 3

Recognition of microbes

Answer 3

Cellular receptors - TLR’s —> mediators —> adhesion molecules on endothelial cells
Fc of antibodies receptors —> opsonisation
Sensors of cell damage - cytosolic
Complement system

Question 4

Features of inflammation

Answer 4

Recognition
Recruitment
Removal
Regulation
Resolution

Question 5

Acute inflammation

Answer 5

Dilation, increased permeability, emigration of leucocytes

Question 6

Complement

Answer 6

Vascular permeability, chemotaxis, opsonisation

Culminates in formation of MAC

3 main functions - inflammation, opsonisation/phagocytosis, cell lysis (MAC) - particularly important in thin walled cells

Question 7

Phagocytosis

Answer 7

Recognition, engulfment, killing

Mannose receptors/scavenger receptors for opsonins

Phhagosome —> phagolysosome —> killing

Opsonins not essential for phagocytosis but improve efficiency - IgG C3b and plasma lectins

Question 8

Termination of inflammation

Answer 8

AA metabolite switch

liberation of anti-inflammatory cytokines - IL10 and TGF beta

Question 9

Patterns

Answer 9

Purple to, Serous (cell poor fluid), fibrinous (inflammation in lining of body cavitiies)

Question 10

Outcomes

Answer 10

Complete resolution
Healing by connective tissue placement
Chronic inflammation

Question 11

Classical and alternative macrophage activation

Answer 11

Classical - pro inflammatory IFN gamma - IL1, 12, 23

Alternative - anti-inflammatory - M2 - tissue repair - IL-4 and 13 NO GAMMA —> activate fibroblasts

Activated classical macrophages work bidrectionally propagating and sustaining chronic inflammation by activated Th1 and Th17

Question 12

Scar formation

Answer 12

M2 macrophages

Angiogenesis
Repair begins within 24 hjopurs though
Formulation of granulation tissue (day 3-5)
Remodelling of connective tissue

Connective tissue lasting down —> migration and proliferation of fibroblasts and deposition of ECM proteins produced by fibroblasts

TGF beta is so important for deposition
MMP important for remodelling

Question 13

Skin wounds

Answer 13

First intention - neutrophils 24 hours, macrophages and granulation tissue day 3, neovascularisation by day 5, continued collagen and fibroblast in 2cond week (end of first month all inflammatory cells gone)
(EPITHELIAL cell proliferation after 24-48 hours)

-70% wound strength max
After they are removed 10% of normal skin —> increases rapidly over 4 week
3 months 70-80% of normal

Complications : Hypertrophic scars, dehiscence, ulceration, excessive granulation, wound contracture

Second intention - More extensive tissue loss - more granulation tissue, wound contraction by myofibroblasts

Question 14

Lipoxins

Answer 14

Lipoxins are endogenous anti-inflammatory molecules produced from arachidonic acid derivatives. Production of lipoxins requires both leukocytes and platelets. Lipoxins play a vital role in reducing excessive tissue injury and chronic inflammation. The mechanisms of action of lipoxins at the site of inflammation include inhibition of neutrophil chemotaxis and adhesion, and modulation of levels of various inflammatory transcription factors such as nuclear factor κB, activator protein-1, and peroxisome proliferator-activated receptor γ.

Question 15

Granules of neutrophils

Answer 15

There are two types of granules contained within neutrophils. Primary - azurophil granules contain MPO, bactericidal factors (such as defensins), acid hydrolases, and a variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase 3). Smaller secondary - specific granules, contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase. Both types of granules play integral roles in the degradation of microbes and dead tissues and may contribute to tissue damage if left unchecked.

Neutrophils contain granules that can bind to their cell membranes and release their contents to destroy enemy cells. Contents of these granules include enzymes, defensins, lactoferrin, major basic protein and free radicals. Selectins are cell surface proteins involved in the initial rolling and adhesion of leukocytes to vascular endothelium. They bind their ligands with low affinity, allowing for the “rolling” process of leukocyte adhesion.

Myeloperoxidases are found in the larger azurophil primary granules of neutrophils. Secondary granules contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase. Primary granules contain myeloperoxidase, lysozyme, defensins, acid hydrolases, and neutral proteases (elastases, collagenases, cathepsin G, proteinase 3).

Question 16

Neutrophils

Answer 16

Neutrophils and macrophages have many methods of killing foreign microbes. The most common methods are destruction by reactive oxygen and nitrogen species. Reactive oxygen species are created in the lysozymes of neutrophils by a process called the “respiratory burst”. This generates superoxide anions, which are then converted mainly to hydrogen peroxide (H2O2). The myeloperoxidase (MPO) enzyme then converts hydrogen peroxide into hypochlorite ions by combining it with chloride ions. The H2O2-MPO-halide system is the most potent method of bacterial killing available to neutrophils. Other powerful free radicals include hydroxyl radicals (OH.) and peroxynitrite (ONOO.).

Other methods of bacterial killing include enzymes such as granzyme or lysozyme, toxic proteins like defensins, major basic protein and lactoferrin, and bactericidal/permeability increasing factor. The latter works by binding bacterial endotoxin (not exotoxin). Thus, it is effective against gram-negative bacteria, which release endotoxins (lipopolysaccharides, a component of gram-negative cell walls) when they are broken down.

Question 17

Complement

Answer 17

The complement system is formed by a large number of distinct plasma proteins. C3 is the most abundant component, and its plasma levels serve as biomarkers of systemic lupus erythematosus (SLE) flare. C5a is an important chemotactic for neutrophils and macrophages. There are three distinct pathways through which complement is activated: classical, alternative, and lectin pathways. The complement can opsonize bacteria and stimulate the lipoxygenase pathway of arachidonic acid.

Question 18

Cheddar Higashi

Answer 18

Chediak–Higashi syndrome is a rare autosomal recessive immunodeficiency state causing impaired phagocytosis, leading to recurrent pyogenic infections. It also features peripheral neuropathies and albinism (not hyperpigmentation). Neutropaenia is common.

Question 19

Endothelial cell activation

Answer 19

Endothelial activation during the inflammatory process is mediated by tumor necrosis factor (TNF) and interleukin-1 (IL-1). They act by enhancing the expression of E-selectin and P-selectin on the endothelial surface. They also increase the procoagulant activity of the endothelial cells. Interleukin-12 causes increased production of interferon-gamma which further activates the macrophages. Interleukin-17 recruits neutrophils and monocytes to the site of inflammation. Interleukin-6 generates the systemic acute-phase response.

Question 20

Phagocytosis

Answer 20

Phagocytosis occurs in three steps. The first step is the recognition and attachment of microbe to leucocyte. The second step is engulfment and formation of the phagolysosome. The third step is the killing and degradation of the ingested particle. Phagocytosis is enhanced by the opsonization of the particle by complement C3b. Particles to be phagocytosed are recognized by and attach to the receptors present on the leucocyte membrane. A phagosome is a cytosolic vesicle that contains the ingested particle. A phagosome combines with a lysosome to form a phagolysosome.

Question 21

Hageman factor

Answer 21

Hageman factor (factor XII) is a coagulation plasma protein produced and secreted by the liver. Factor XII initiates the formation of bradykinin by cleavage of prekallikrein to kallikrein. It can convert C5 to C5a to promote chemotaxis, and stimulates the production of thrombin through the clotting cascade. Factor XII circulates as an inactive precursor (zymogen) that is “activated” (factor XIIa) as clotting commences. Plasma antiplasminogen activator inhibits fibrinolysis by preventing the conversion of plasminogen to plasmin.

The coagulation cascade has been divided into extrinsic and intrinsic pathways. Tissue factor is the major initiator of coagulation in the extrinsic pathway, whereas Hageman factor and the prekallikrein complex initiate the intrinsic pathway.

The factors involved in the extrinsic pathway are factors III (tissue factor and VII. The factors involved in the intrinsic pathway are factors XII, XI, IX, and VIII. The common pathway factors are X, II (thrombin), I (fibrin) and XIII (fibrin stabilising factor).

Remember that tissue factor is number 3, and 3+7 = 10, so the extrinsic pathway is factors 3 and 7, which then catalyse conversion of 10 to 10a.

Whereas the intrinsic pathway is all the factors 12 - 8 EXCEPT 10 - which is part of the COMMON pathway. So the intrinsic pathway is factors 12, 11, 9 and 8.