Inflammation Flashcards
avascular tissue
cartilage or cornea
five cardinal signs of inflammation
redness, swelling, heat, pain/tenderness, loss of function
stresses that can cause inflammation
- Genetic mutations
- Hypoxia (lack of oxygen)
- Infection
- Physical agents (pressure and trauma)
- Immune reactions eg. hypersensitivities and autoimmunity
outcomes of mild transient injury
reversible, cell can recover and return to homeostasis as long as cell membranes remain intact eg. steatosis in liver
apoptosis general mechanism
- Membrane blebs (bubbles form)
- Chromatin condenses
- Blebs bud off to break cell up into apoptotic bodies
- Fragments digested by phagocyte
apoptosis energy dependant?
yes
Intrinsic (mitochondrial pathway) of apoptosis
removal of growth factors/hormones leads to cascade through mitochondrion, eventually producing caspases (protease enzymes) that disintegrate DNA and cytoskeleton to cause blebbing
Extrinsic (death receptor mediated) pathway of apoptosis
Fas death ligand binds to surface receptor to initiate protein cascade that produces caspases
when is apoptosis used?
in physiological development and homeostasis: if cells ordinarily divide, old ones may need to be destroyed
necrosis energy
passive process
general necrosis mechanism
Membrane blebs but then breaks down Cell bursts (lysis) and spills contents → mass inflammation Activated by toxins released/macrophages
types of necrosis
coagulative, liquefactive, caseous, gangrenous, fat
coagulative necrosis
nuclei stain darker and ‘jelly’ appearance as proteins denature eg. ischaemia in heart attack
Liquefactive necrosis
protein digested in lipid rich tissue so tissue structure lost; pus eg. stroke in brain
caseous necrosis
‘cheese’ appearance of granulomatous inflammation eg. tuberculosis
gangreous (dry) necrosis
coagulative necrosis in extremity due to slow vascular blockage eg. toe gangrene in diabetes. Wet gangrene= infection
fat necrosis
chalky deposits from degraded fat tissue eg. acute pancreatitis
types of inflammation
- Acute inflammation
- Chronic inflammation
- Subacute inflammation- inflammatory response that isn’t a rapid, immediate response to a new injury
- Acute on chronic inflammation- where a chronic condition rapidly worsen
- Fulminant inflammation- severe, acute inflammation with chronic damage that has become irremediable
what diseases can inflammation cause or worsen?
cancers, atherosclerosis, neurodegenerative disease
exudate
Delivered cells, proteins, fluid
types of danger signals
- Missing self-recognition- activation of NK cells and the complement system when certain signals usually present on host cells are absent
- Effector-triggered immunity (system surveillance)- detects disturbances in cellular processes (like ion fluctuations due to bacterial pore forming proteins)
- Structural pattern-triggered immunity- molecular patterns that indicate danger that are picked up by the immune system
DAMPs
damage associated, molecules that trigger the inflammatory response when cells are damaged- these include DNA, RNA and histones
PAMPs
pathogen associated, molecules on the surface of microbes trigger inflammation when infection occurs- can be foreign wall cell components (like lipopolysaccharide) or nucleic acid
how are danger signals recognised?
‘sentinel’ leukocytes that surveillance body- can be resident in tissues or circulaiting in tissue, have pattern recognition receptors (PRRs) which allow the release of cytokines that activated inflammatory response
examples of surface PPRs
C-type lectin receptors, TLRs (toll like receptors)
Examples of cytoplasmic PPRs:
endosomal TLRs and nod like receptors
effects of PPR activation
- Activation of pro-inflammatory cytokines eg. IL-1, IL-6, TNF-α
- Programmed lytic death
- Inflammatory mediators: histamine, prostaglandins, leukotrienes, bradykinin, cytokines and chemokines
cytokines
activate resident, endothelial or circulating immune cells to maintain vasodilation and cause lysis in infected cells so that the pathogen is exposed to the immune system
opsonins
mark out cells for phagocytosis, phagocytosis may be oxygen deprived or oxygen-independent
bradykinin
maintains vasodilation and activates pain receptors
vasodilation and oedema
increased blood flow with excess fluid in interstitial spaces, the blood flow will make the area red and hot while the fluid leakage will cause oedema which presents as swelling
how is the permeability of the arteriole increased?
Endothelial cells first swell and then contract to increase the space between them
Process is regulated by mediators, esp. histamine- (antihistamines can block histamine to prevent swelling)
(initial= histamine, rapid= bradykinin, delayed= cytokines)
types of exudates
- Pus: neutrophils, enzyme rich, bacteria and fibrin, often shows on micrograph, yellow-green peroxidase gives its colour
- Fibrinous: greyish, sticky fibrin strands, few cells
- Serous: mostly fluid, serum like, little fibrinogen/platelets (eg. Burn blister)
- Haemorrhagic: vascular destruction hence, leak of blood
when does passive leak occur?
site of endothelial injury until the endothelium regenerates (sunburn or leukocyte transmigration) or during angiogenesis (new capillaries are leaky)
main cells of inflammation
neutrophils
extravasation
• Process by which neutrophils migrate out of blood vessels and into the interstitial space (cells other than inflammatory cells can extravasate like RBCs)
process of extravasation
- Margination: neutrophils move to side of endothelium (wall of blood vessels)
Blood flow is slowed in arterioles due to fluid leakage and vasodilation; leukocytes naturally move to the side of blood vessels during haemostasis - Rolling (Diapedesis): neutrophils roll along the endothelium due selectins
Both rolling and adhesion are facilitated by the cell adhesion molecules (CAMs) on the surface of neutrophils and endothelial cells. - Adhesion: neutrophils bind to endothelium due to interaction between integrins and CAMs
- Emigration: Neutrophils leave blood vessels through junctions between endothelial cells
selectins
a CAM which bind neutrophil to endothelium loosely to allow for rolling eg. histamine.
haemostasis
stopping of a flow of blood
chemotaxis
attract neutrophils to the site of injury eg. chemokines
protein that forms a scaffold for neutrophils to move along
fibrin
pyogenic molecules
Molecules responsible for neutrophil chemotaxis because when neutrophils die they become key components of pus
in parasitic infections what molecule dominates the first stage of inflammation
eosinophils
macrophages
monocytes in tissue rather than blood, arrive later on to phagocytose and produce cytokines
last resort stimulated by PRRs- NETs
neutrophil extracellular traps
If a pathogen cannot be phagocytosed, an enzyme moves into the neutrophil nucleus, releasing its contents (granular proteins and sugar phosphate backbone of DNA), which act as a net to prevent spread
resistance of Strep and S. aureus
Step will have fibrin-degrading enzymes and S.aureus hides within fibrin layers
systemic effects of acute inflammation
- Acute phase response mediators- IL-1, IL-6, TNF-α
- Prostaglandin production → body thermostat changes via hypothalamus → shivering, fever (aspirin can block this)
- Raised WBC count (due to cytokine IL-8 moving to bone marrow and stimulating production of more neutrophils)
- Release of acute phase proteins made in liver eg. CRP
lymphatic system
network of fine vessels draining excess fluid from tissue. Exudate can flow through this into nodes, where lymphocytes process foreign molecules and instigate an immune response
types of lesions
- Sinus: cavity lines with granulation
- Abscess: pus in newly formed cavity, surrounded by granulation
- Fistula: abnormal tract linking epithelia that should not be linked
- Erosion: loss of some epithelial layer but basement membrane left to guide healing
- Ulcer: loss of epithelial and basement membrane layers (eg. Exposing muscle to inflammation), may fissure
- Granuloma
granulomas
organised cluster of large macrophages with ruffled membranes, form in response to a stimulus that cannot be removed, low turnover versions form around foreign bodies and have long- lived macrophages, high turnover ones are immune related and contain T-cell and short-lived macrophages
consolidation
light patches on micrograph due to exudate congestion in a tissue
outcomes of acute inflammation
- Resolution: if the trigger subsides, pro-resolving agents (immunoresolvants clearing mediators, cells, debris and pathogens) or anti-inflammatory influences terminate inflammation and the tissue is restored to its healthy condition. After resolution, changes to gene expression may change tissue response to injury
- Organisation: tissues are replaced by granulation tissue (pre-scar tissue) which is stickier and may be problematic, scarring is protective but if it is widespread its destructive to tissue eg. In cirrhosis
- Chronic inflammation
- Death
where do monocytes mature and what do they mature into?
tissues early in inflammation where they mature into macrophages
characteristic features of chronic inflammation
Macrophages and granulation tissue
cell types that can be involved in chronic inflammation
lymphocytes, eosinophils (in case of allergy/parasite infection) and mast cells
Amyloidosis
aggregation of mutated (misfolded) proteins, causing atrophy (wasting) in chronic inflammation or dementia
Cystitis
bladder inflammation, can be caused by urinary catheters, UTIs can leads to urinary incontinence and confusion
Fibrosis
occurs with constant inflammation that the body is unable to heal properly
Labile cells
always proliferating so regenerating- epithelia such as skin, GI tract
Stable cells:
do not normally proliferate but can do so after injury- liver, kidney
Permanent
cannot regenerate so much scar- neurones, heart muscle
high risk responses in blood can lead to
septic shock (low blood pressure and inflammatory tissue damage), immunity and coagulation are suppressed and patients have susceptibility to 2° infection
what can regeneration be stimulated by?
- soluble growth factors which bind to receptors to initiate a downstream cascade of reactions, cumulating in the release of transcription factors that binds to DNA and alter gene transcription
- physical cell-cell and cell-matrix interactions via the ECM and cell junctions, mediated by integrin proteins to produce a cascade of signals
scarring order
Bleeding → Clotting cascade → Acute inflammation (neutrophils) becomes chronic inflammation (macrophages and granulation) → Fibroblasts migrate to lay down new ECM → Angiogenesis and collagen → Scar maturation
fibrotic tissue compared to health tissue
weaker and less elastic than healthy tissue
fibroblasts
connective tissue stem cells and growth factors cause them to migrate and proliferate and they secrete ECM components, collagen and elastin
tissue remodelling
matrix metalloproteinases (MMPs) are enzymes that each break down ECM components, they mediate long-term scar maturation and degradation which is why lesions can look better over time, actions of MMPs is regulated by TIMPs which inhibit their action
what can destruction of blood vessel walls cause?
blood to leak into airways, can be coughed up with sputum
what can consolidation of exudate in airways cause?
blockage of airways and patients may have breathing difficulties leading to hypoxia
pus on a micrograph
looks like fibrin and many nuclei of neutrophils
inflammatory response releases
cytokines, leading to fever, shivers and tachycardia (raised heart rate)
treatment of inflammatory bowel diseases
corticosteroids or immunosuppressant drugs
inflammatory bowel disease examples
Ulcerative colitis and Crohn’s disease
What is responsible for the production of the new extracellular matrix after angiogenesis?
fibroblasts- synthesises the extracellular matrix and collagen
