Inflammation And Repair Pathology Flashcards
Acute vs chronic inflammation
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)
Causes of inflammation
Infections, Tissue necrosis, Immune reactions, Foreign bodies
Recognition of microbes
Cellular receptors - TLR’s —> mediators —> adhesion molecules on endothelial cells
Fc of antibodies receptors —> opsonisation
Sensors of cell damage - cytosolic
Complement system
Features of inflammation
Recognition Recruitment Removal Regulation Resolution
Acute inflammation
Dilation, increased permeability, emigration of leucocytes
Complement
Vascular permeability, chemotaxis, opsonisation
Culminates in formation of MAC
3 main functions - inflammation, opsonisation/phagocytosis, cell lysis (MAC) - particularly important in thin walled cells
Phagocytosis
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
Termination of inflammation
AA metabolite switch
liberation of anti-inflammatory cytokines - IL10 and TGF beta
Patterns
Purple to, Serous (cell poor fluid), fibrinous (inflammation in lining of body cavitiies)
Outcomes
Complete resolution
Healing by connective tissue placement
Chronic inflammation
Classical and alternative macrophage activation
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
Scar formation
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
Skin wounds
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
Lipoxins
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.
Granules of neutrophils
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).
Neutrophils
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.
Complement
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.
Cheddar Higashi
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.
Endothelial cell activation
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.
Phagocytosis
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.
Hageman factor
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.
