Acute and chronic inflammation Flashcards
(42 cards)
1
Q
Define acute inflammation
A
- A rapid response to deliver leukocytes and plasma proteins to sites of infection or tissue injury; short duration
- Examples are acute appendicitis, acute bronchitis, abscess
2
Q
Define chronic inflammation
A
- Inflammation of prolonged duration (weeks or months), in which inflammation, tissue injury and attempts at repair co-exist, in varying combinations
- Examples are tuberculosis, autoimmune diseases
3
Q
What is the purpose of inflammation broadly?
A
- Inflammation is a defensive reaction (innate immune response) of a macro-organism against injury caused by trauma, toxic chemical, or an invading pathogen
- Protective response, but can be harmful - components of inflammation capable of destroying microbes can also injure normal surrounding tissue
4
Q
What is the purpose of acute inflammation?
A
- Alert body and initiate appropriate immune response
- Limit spread of infection or injury
- Protect injured site from becoming infected
- Eliminate dead cells/tissue
- Create conditions required for healing
5
Q
What are the factors that cause acute inflammation?
A
- Infections
- Bacteria
- Viruses
- Parasites
- Fungi
- Toxins
- Tissue damage due to:
- Physical agents - frost bites, burns, radiation (ionising, UV)
- Chemical agents - chemical burns, irritants, bites
- Mechanical injury and ischemia - Trauma, tissue crush, reduced blood flow
- Foreign bodies
- Splinters
- Sutures
- Dirt
6
Q
What are the factors that cause chronic inflammation?
A
- Failure to close acute inflammatory reactions - Persistent infections (viruses, mycobacteria, parasites, fungi
- Misdirected inflammatory reaction - harmless environmental substances (allergies), self-antigens (autoimmune disease)
- Chronic inflammation underlyling many disorders - cancer, atherosclerosis, alzheimer, tpye 2 diabetes
7
Q
Describe the signs acute inflammation
A
- Heat - Increased blood flow and metabolic activity
- Redness - Increased blood flow (hyperaemia) to injured area
- Swelling - Fluid accumulation due to permeability of vessels
- Pain - Release of pain mediators; pressure on nerve ends
- Loss of function - Damage
8
Q
Describe the systemic changes that can occur as a result of acute inflammation
A
- Fever
- Endogenous pyrogens (IL-1, TNF- alpha)
- Exogenous pyrogens (microbial components)
Pyrogens are a group of substances that cause fever and shock. As seen, edogenous pyrogens (such as those listed cytokines) and exogenous pyorogens cause fever
- Neutrophilia
- GM-CSF (cytokine) stimulation of bone marrow to replenish dead neutrophils
- Acute phase reactants - These are molecules that are elevated as a result of acute inflammation
- C-reactive protein (CRP), fibrinogen, complement, serum amyloid A protein (SAP)
- Produced in the liver
- Induced by the cytokines IL-6, IL-1, TNF-alpha
- Increased fibrinogen means RBCs begin stacking = faster sedimentation rate (rate at which RBCs settle)
- Complications - In rare cases causing a severe systemic inflammatory reaction (sepsis) or inflammatory response syndrome (SIRS)
9
Q
Describe the stages of an acute inflammatory response
A
- Vascular - Acute changes in local vasculature. Vasodilation, plasma exudation, oedema
- Cellular - Infiltration of inflammatory cells. Cell recruitment, phagocytosis, NETosis (type of cell death)
- Humoral - Release of inflammatory mediators. Complement, plasma factors, clotting cascade, cytokines, chemokine
- Resolution - Inflammation is controlled and self-limiting. Healing, regeneration, repair of tissue
10
Q
Describe what happens during the vascular events of acute inflammation
What molecules induce these events to happen?
A
Vasodilation:
- Increase in vascular diameter
- Induced by histamine and serotonin released by injured cells, mast cells, macrophages
- Results in hyperaemia (increase BV to area, leads to redness, heat)
Increased vascular permeability (micro vessels):
- Leads to leakage of fluids into tissues (swelling)
- As exudate accumulates, pressure increases, nerve endings stimulated by excess fluid and inflammatory mediators (pain)
- Endothelial cell activation increasing their expression of adhesion molecules
Leucocytes + plasma proteins exit vessels, enter inflammation site to deal with infection
Endothelial cells constriction- gaps occur due to contraction (e.g myosin and shortening of individual endothelial cells)
- Loss of proteins (especially albumin and fibrinogen) from place into the tissue, increases osmotic pressure, leads to fluid leakage to area, causes oedema
- Cell transmigration - chemotaxis
Inflammatory exudate (due to increased vessel permeability)
- Water. salts, small plasma proteins (fibrinogen), inflammatory cells, red blood cells -> these get out of vessels and enter tissues or serous cavities
Transudate = fluid leaks due to altered osmotic/hydrostatic pressure; vessel permeability normal
11
Q
Describe the types of inflammatory exudate
A
- Serous:
- A few cells, no/few microbes
- Fluid derived from plasma, secreted by mesothelial cells
- Serous cavities (pleura, peritoneum, pericardium)
- Skin blisters (burns, viral infections)
- Purulent (fibrino-purulent):
- Pus - many leucocytes (neutrophils), dead cells, microbes
- Pus-producing bacteria (pyogenic) e.g staphylococci, acute appendicitis, abscess (localised collection of purulent inflammation)
- Fibrinous:
- Fibrin deposition (derived from fibrinogen in plasma)
- Large vascular leaks (fibrinogen exits blood and enters tissue)
- Serous cavities (meninges, pleura, pericardium)
- Can lead to scarring if not cleared (fibroblasts → collagen)
- Haemorrhagic:
- Red blood cells predominate
- Blood vessel ruptures, trauma
12
Q
What cells are mediators of inflammation?
A
- Macrophages
- Neutrophils
- Mast cells
- Platelets
13
Q
What are the humoral factors that mediate inflammation?
A
- Complement
- Plasma factors
- Clotting cascade
- Cytokines
- Chemokines
14
Q
Describe the role of tissue resident macrophages in inflammation
A
- Generally first tissue resident cell to recognise an invading pathogen through pattern recognition receptors on their cell surface
- Macrophage becomes activated, engulfs bacterium and then immediately produces mediators of inflammation for example, prostaglandins, leukotrienes and platelet activating factor (PAF)
- Macrophage then secretes inflammatory cytokines and chemokines
15
Q
Describe the actions of the proinflammatory cytokines
A
- Activated tissue resident macrophages secrete the inflammatory cytokines:
- IL-1 - Activates vascular endothelium, activates lymphocytes, local tissue destruction, increases access of effector cells, causes a fever and production of IL-6
- IL-6 - Lymphocyte activation, increased antibody production, causes fever, induces acute-phase protein production
- CXCL-8 (IL-8) - Chemotactic factor recruits neutrophils, basophils, and T-cells to site of infection
- IL-12 - Activates NK cells, induces the differentiation of CD4 cells into TH 1 cells
- TNF- alpha - Activates vascular endothelium and increases vascular permeability, which leads to increased entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes. Causes fever, mobilisation of metabolites, shock
- These cytokines act locally + play key role in forming inflammatory response
16
Q
Describe the role of mast cells in inflammation
A
- Secrete histamine
- Chemical signals released by activated macrophages + ,mast cells at injury site cause endothelial activation, vasodilation, increased vascular permeability
17
Q
Describe the role of the complement system in inflammation
A
Activated very soon after initial infection producing various complement fragments
Complement is a system of plasma proteins that interacts with pathogens to mark them for destruction by phagocytes, helps amplify the immune response. These proteins are produced in the liver. Complement proteins can release anaphylotoxins (C3a and C5a) which are pro-inflammatory so attract more immune cells to site of infection.
18
Q
Describe the role of chemokines in inflammation
A
- Released by inflammatory cells, attract more phagocytic cells from blood to injury site
19
Q
Describe the role of neutrophils in inflammation
A
Recruited to kill pathogens + remove cell debris at the site
20
Q
Describe the role of monocytes in inflammation
A
- Differentiate into macrophages which enhances clearance by phagocytosis
21
Q
How is regulation and tissue repair promoted in inflammation?
A
- By the release of immunoregulatory factors (TGF-Beta)
22
Q
What are the steps involved in neutrophil recruitment?
A
- Margination and rolling
- Integrin activation by chemokines
- Firm adhesion to endothelium
- Transmigration through endothelium into tissue
- Chemotaxis (attraction and movement) to inflamed site
23
Q
What are the processes involved in neutrophil recruitment?
A
- Rolling- mediated by selectins
- Activation - by chemoattractant stimulus
- Arrest and adhesion- mediated by integrins and cell adhesion molecules
- Transendothelial migration
24
Q
What are the molecules involved in neutrophil recruitment?
A
Adhesion molecules
- Selectins - Initial tethering and rolling of neutrophils on endothelium
- Integrins - Vital for neutrophils to bind to endothelium of blood vessels, arrest them (stop their flow). Once arrested, integrins help neutrophils move out of bloodstream and into tissues.
- Immunoglobulin superfamily cell ashesion molecules (CAMs) - Once adhered, neutrophils use CAMs to “squeeze” or “diapedese” through the endothelial layer and into the surrounding tissue, allowing them to reach the site of infection or inflammation. Adhesion of neutrophils also activates them
25
Describe the role of selectins
- Mediate rolling of neutrophils - As cells flowing, low affinity interaction is disrupted by flowing → repetitive binding and detaching → rolling; slow down
- Expressed by activated endothelium:
- P-selectin - pre-formed granules
- E selectin - induced by IL-1 and TNF- alpha (cytokines produced by macrophages, mast cells, endothelial cells at site of inglammation)
- Leucocytes (neutrophils, monocytes, lymphocytes) express L-selectin; ligands on endothelium
- Endothelial selectins bind to ligands on neutrophils, this is a low affinity interaction, it requires repetitive contact before they bind
- E and P selectins on endothelium interact with L-selectins on neutrophils, mediates rolling mechanism
26
Describe integrin activation by chemokines
- Neutrophils rolling slows them down by increasing contact to endothelium, activates endothelial cells
- Neutrophils express integrins (LFA-1)
- Integrins in low affinity configuration; no binding to ligands
- Activated endothelial cells produce chemokines
- Chemokines bind to receptors on neutrophils
- Integrins are activated to change to high affinity configuration
- Integrins bind to ligands on endothelium:
- Integrin ligands - ICAM-1, VCAM-1
- Integrin ligands induced by IL-1, and TNF-alpha (cytokines produced by macrophages, mast cells, endothelial cells at sit of inflammation)
- Results in firm adhesion of neutrophils to endothelium
27
Describe neutrophil transmigration
- Neutrophils migrate through interendothelial spaces
- Neutrophils pass through vessel wall and enter tissue
- Migrate (chemotaxis) through tissue towards inflamed site
- Gradient of chemoattractants guides migration in tissues
28
Describe neutrophil chemotaxis
- Movement of cells through tissue towards inflamed sites
- Guided by chemoattractants:
- Produced at site of infection/damge
- Diffuse into adjacent tissue and form a gradient
- Bacterial components (peptides containing N-formyl-methionine-leucine-phenylalanine; lipids
- Chemokines (IL-8)
- Complement components (C5a)
- Leukotriene B4 (LTB4)
Cells sense the gradient by comparing the activation of receptors on different sides of the cell.
If there's a higher concentration of chemoattractant on one side, more receptors will be activated there, creating a directional bias.
This bias is then translated into cellular movement towards the higher concentration.
29
What are the mechanisms involved in pathogen destruction mechanisms?
- Release of granule content
- Phagocytosis
- Generation of reactive oxygen/nitrogen species
- Formation of Neutrophil Extracellular Traps (NETS) (netosis)
30
Describe NETs
- Mesh of nuclear content (chromatin)
- Mesh traps microbes
- Contains anti-microbial molecules
31
Describe the small and large granules in neutrophils
Specific granules (small) :
- Lysozyme
- Collagenase
- Gelatinase
- Lactoferrin
- Alkaline phosphatase
Azurophil granules (large)
- Myeloperoxidase
- Lysozyme
- Defensins
- Acid hydrolases
- Proteases (elastase, cathepsin G, collagneases, proteinase 3)
Granule content can cause tissue damage
32
Describe how monocytes are recruited to the site of inflammation
- Monocyte binds adhesion molecules on vascular endothelium near site of infection, receives chemokine signal
- Monocyte migrates into surrounding tissue
- Monocyte differentiates into a macrophage and migrate to the site of infection
33
Describe the timescale for the different cells present at the inflammation site over time
- Neutrophils - (6-24 hr) short lived, die in tissues (24/48 hr)
- Monocytes (24hr-48hr) survive longer, proliferate
- Eosinophils + lymphocytes can be involved in inflammatory response
34
What are the characteristics of chronic inflammation?
- Lasts weeks to months (leans towards adaptive immune response)
- Main cells : Macrophage, lymphocytes, plasma cells
- Co-exists with tissue damage and repair attempts
- More tissue destruction: Cellular infiltrates; blood vessel proliferation and connective tissue deposition
35
What are the mediators of chronic inflammation?
- TNF- alpha
- INF- gamma (produced by T-cells and NK cells, activates macrophages, increases microbicidal activity)
- Chemokines IL-17, IL-12
36
What is non-specific chronic inflammation?
- Develops when acute inflammation fails to eliminate causative agent
- Gastritis, gastric ulcer caused by Helicobacter pylori or non-steroidal anti-inflammatory drugs (NSAIDs)
- Inflammatory cells: lymphocytes, plasma cells
- Ulceration: Loss of surface cells or tissue necrosis - oral mucosa, stomach, intestine GU tract
37
What is autoimmune inflammation?
- Immune response to self-antigens
- Crohn's disease, rheumatoid arthritis
- Inflammatory cells: macrophages, lymphocytes
- Mechanisms complex, not completely understood - insidious start, progressive, persistent chronic inflammation, tissue damage
38
How does chronic inflammation occur in rheumatoid arthritis?
- Chronic inflammation in synovium (lining of joints) - Swelling: expansion of synovium by inflammatory cell infiltrate
- Pannus formation: fibrin deposition
- Massive bone damage and joint destruction
39
What is chronic suppurative inflammation?
- Persistent suppurative (pus forming) inflammation
- Pilonidal disease abscess, empyema, osteomyelitis
- Inflammatory cells: mainly neutrophils, eosinophils (if parasite)
- Starts as acute suppurative inflammation - local pus accumulation cannot be clear spontaneously (access) - needs surgical procedure (incision and drainage)
40
What is chronic granulomatous inflammation?
- Causative agent cannot be eradicated - granuloma formation to isolate and prevent spread of agent
- Inflammatory cells: epitheloid cells, giant cells, lymphocytes
Granulomas consist of:
- Macrophages
- Lymphocytes
- Fibroblast, collagen
- Necrotic tissue (may or may not be present)
Immune granulomas associated with persistent T cell activation (infections - difficult to eradicate infectious agents (TB, leprosy, syphilis, Schistosomiasis (parasite))
Also caused by autoimmune disease- response against self antigens
41
Describe the outcomes of acute inflammation
- Clearance of injurious stimuli
- Clearance of mediators and acute inflammatory cells
- Replacement of injured cells
- Normal function
- Pus formation (abscess)
- Progression into chronic inflammation, Loss of function (fibrosis) - occurs when causative agent not removed
42
Describe the outcomes of chronic inflammation
Loss of function (fibrosis)
