Pathology - Inflammation & Tissue Repair Flashcards
What are the main characteristics of acute inflammation
1) changes in vascular flow = transient vasoconstriction followed by vasodilation
2) increased vascular permeability
3) leukocytes recruitment = margination, transmigration, migration (neutrophils 6-24 hours, monocytes 24-48 hours)
4) phagocytosis
5) termination of acute inflammatory response
Describe the vascular changes in acute inflammation
- initial transient contraction of arteries lasting for a few seconds (serotonin)
- vasodilation mediated by histamine, nitric oxide and prostaglandin leading to increased blood flow
- increased vascular permeability mostly induced by contraction of venule endothelium to form intracellular gaps
- stasis due to increased viscosity
What are the mechanisms responsible for increased vascular permeability in inflammation
- contraction of venule endothelium to form intracellular gaps by histamine, serotonin, bradykinin and substance p
- direct injury to endothelium
- leukocyte mediated leakage
- increased transcytosis induced by VEGF
How are leukocytes delivered to the site of injury
-multistep process mediated and controlled by adhesion molecules and chemokines
1) margination = when leukocytes adopt a peripheral position along the epithelium (rolling, activation, adhesion)
2) transmigration = movement across the endothelium
3) migration = movement into interstitial tissues towards chemotactic stimuli
What is chemotaxis of leukocytes and describe the mediators involved
-chemotaxis: movement of white cells along a chemical gradient
-mediators:
exogenous = bacterial products
endogenous = cytokines (IL-8), complement (C5a), arachidonic acid metabolites (LTB4)
What stimuli cause the production of inflammatory mediators
substances released from necrotic cells, microbial products, cell injury, mechanical irritation
What are some chemical mediators of acute inflammation and their actions
-histamine: vasodilation, increased vascular permeability, chemotactic, pain
-serotonin: vasoconstriction, increased vascular permeability, platelet aggregation
-prostaglandin:
PGD2 = vasodilation and increased vascular permeability
PGE2 = pain and fever
PGI2 = vasodilation and inhibits platelet aggregation
-leukotrienes: recruit leukocytes (chemotaxis, adhesion, activation)
-cytokines: induce endothelial adhesion molecules, acute phase response
-nitric oxide:
iNOS = cytotoxic metabolite to kill bacteria
eNOS = vasodilation and smooth muscle relaxation
-PAF: degranulation, vasodilation, increased vascular permeability, chemotaxis, adhesion
-kinins: increase vascular permeability, vasodilation, smooth muscle contraction, pain
-complement: leukocyte chemotaxis and activation
What mediators of inflammation are derived from cells
- preformed: histamine, serotonin
- newly synthesised: arachidonic acid metabolites, ROS, PAF, NO, cytokines
What cells release histamine
mast cells
basophils
platelets
What chemical mediators are responsible for pain, fever and tissue damage
IL1, TNF, prostaglandins (PGE2), bradykinin, oxygen metabolites, lysosomal enzymes
What is the complement system and how does activation occur
-plasma protein system involved in immunity against microbes
-20 proteins in plasma in inactive form, activation by proteolysis, activated protein fragments serve as proteases
-3 pathways: all result in cleavage and activation of C3
classical = triggered by antigen-antibody reaction
alternate = triggered by bacterial endotoxin
lectin = triggered by microbe carbohydrates interacting with mannose-binding lectin
How do activated complement products mediate acute inflammation
- C3a, C5a mediate histamine release from mast cells, causing increased vascular permeability and vasodilation
- C5a enhances leukocyte adhesion, chemotaxis and activation
- C3b acts as an opsonin on microbe to lead to phagocytosis
- C5b forms the MAC causing cell lysis
Why do neutrophils predominate in the first 6-24 hours
more numerous in the blood
respond more rapidly to chemokines
attach more firmly to adhesion molecules
What is the role of leukocytes in acute inflammation
recognition/attachment of opsonins
kill microbes by phagocytosis
amplify inflammation by releasing products
What are the different types of acute inflammation
serous = transudates with low protein content (burns, effusions)
fibrinous = exudates with large amounts of fibrinogen (inflammation in body cavities)
purulent = exudates with neutrophils, necrotic cells and edema (appendicitis)
ulcer = localised erosions of epithelial surfaces
What are the outcomes of acute inflammation
complete resolution
fibrosis (healing by connective tissue replacement)
progression to chronic inflammation
What are the characteristics of chronic inflammation
- inflammation for a prolonged period, characterised by macrophages, lymphocytes and plasma cells
- tissue destruction is not a primary component and is initiated by inflammatory cells
- attempts at healing by connective tissue replacement by angiogenesis and fibrosis
What type of cells are present in chronic inflammation
macrophages (mainly), lymphocytes, eosinophils, mast cells
What processes mediate the persistent accumulation of macrophages in chronic inflammation
- continued recruitment of monocytes due to continued expression of chemotactic factors
- local mobilisation and proliferation of macrophages
What products are released by activated macrophages in chronic inflammation
- products associated with injury: proteases, chemotactic factors, aa metabolites, nitric oxide, ROS, complement
- products associated with fibrosis: growth factors, angiogenesis factors, collagenases
What clinical conditions cause chronic inflammation
- persistent infection by intracellular microbes = tuberculosis, syphilis, empyema, abscess
- hypersensitivity diseases = autoimmune (RA, MS, IBD, SLE), allergic
- prolonged exposure to toxic substances = exogenous (foreign body, trauma, silica), endogenous (lipids)
- other diseases not considered as inflammatory = metabolic syndrome
What is the arthus reaction
localised T3HR
usually antigen injected under the skin (vaccine)
excess of antibody
large immune complexes
What is angiogenesis, what are the steps and give examples
-the formation of new bloods vessels, occurs by 2 methods:
branching and extension of existing vessels
recruitment of endothelial progenitor cells
steps:
1) vasodilation, increased permeability
2) degradation of parent vessel basement membrane allows for formation of capillary sprout and cell migration
3) mobilisation of endothelial precursor cells (EPC) from the BM and from pre-existing vessels
4) migration of endothelial precursor cells to area of injury by angiogenic stimuli
5) maturation and differentiation of endothelial precursor cells with remodelling into capillary tubules
6) recruitment of periendothelial cells for support structure formation
factors involved: VEGF, PDGF, TGFB
examples: wound healing, chronic inflammation, tumours
Describe the pathogenesis of fibrosis and what cells are activated
-the excessive deposition of collagen and other extracellular matrix components in tissue in chronic disease
steps:
1) chronic inflammation leads to a persistent stimulus that triggers release of growth factors (PDGF, TGF, FGF)
2) growth factors stimulate the proliferation of fibroblasts
cells: macrophages, mast cells, eosinophils
examples: cirrhosis, chronic pancreatitis, pulmonary fibrosis, glomerulonephritis
What are the local triggers of fibroblast migration and proliferation and what are the sources of triggers
triggers: growth factors (TGF-beta, PDGF, EGF, FGF) and cytokines (IL-1, TNF)
sources: platelets, macrophages and endothelium
What are the stages of scar formation
-occurs by replacement of injured cells with connective tissue and forms a scar
1) angiogenesis = pre-existing vessels send out capillary buds/sprouts
2) formation of granulation tissue = fibroblast migration and proliferation and extracellular matrix deposition
3) tissue remodelling to produce a stable fibrous scar
Stages of wound healing (inflammation, proliferation and maturation)
1) wound activates coagulation pathways
2) neutrophils arrive at incision margin and release enzymes to clear debris (24 hours)
3) epithelial cells from margins proliferate across the dermis
4) neutrophils are replaced by macrophages and granulation tissue invades the incisional space (day 3)
5) neurovascularization occurs
6) fibroblasts produce type III collagen (day 5)
7) type III collagen is replaced by type I collagen (week 2)
8) wound contraction occurs by myofibroblasts in healing by secondary intention
9) connective tissue remodelling with recovery of tensile strength and scar well formed (week 4)
What is wound contraction
- process that occurs in healing by secondary intention with large and deep wounds, occurs by myofibroblasts
- helps to close the wound by decreasing the gap between edges, can contract wound to 5-10% of original size
What influences scar formation (describe systemic and local factors)
- systemic: nutrition (protein/vitamin c deficiency), metabolic (diabetes), poor circulation, hormones (steroids inhibit)
- local: infection, mobility, foreign body, size of wound, location of wound, skin type
How do wounds recover tensile strength and what is the time frame
-increased production of type I collagen and structural modification of collagen with cross linking
time frame: sutured wounds 70%, one week post suture removal 10%, by 3 months 70-80%
What are the effects of PDGF on wound healing
monocyte chemotaxis
fibroblast migration/proliferation
collagen synthesis
collagenase secretion
