Week 10 - Infection and inflammation Flashcards
What are the 5 cardinal symptoms associated with tissue damage?
- Redness
- Pain
- Heat
- Loss of function
- Swelling
What substances are involved in vascular resistance / arteriolar tone?
Noradrenaline + sensory nerves = constrictor / dilator factors
Endocrine and pancreatic hormones
pO2 + pCO2
What happens during the acute imflammatory state?
Inflammatory vasodilators override arteriolar tone influencers (from tissue fluid, tissue cells, nerve endings, leukocytes)
Histamine (skin mast cells –> vasodilation)-REDNESS
Bradykinin (vasodilation and endothelial prostaglandin release + stimulation of nociceptors)-PAIN
Vasodilator peptides in sensory nerves (substance P, VIP, CGRP)
Each = + blood flow and temperature
What happens during microcirculation in acute extravasation?
All cells = contractile elements
Arteriolar endothelium = even protein distribution
Venular endothelium = selective distribution around pores
Venular site = low hydrostatic pressure and large SA
Oedema from plasma protein and fluid leakage into extracellular space -SWELLING
Endothelial damage
Postcapillary venule pore modulation
What happens during microcirculation in intermediate extravasation?
Acute inflammation = =2 hours
Tumour necrosis factor released
Complement 5 activation, attracting neutrophils to site of injury
Cytokines activate vascular endothelium and interleukin-8 release
What happens during acute modulation of venular permeability when it is + and -?
+ venular permeability = Ca2+ elevated, contracting pore proteins
Histamine, Bradykinin, Leukotriene C4 / D4, Platelet activating factor
- venular permeability = pore proteins relax by cyclic AMP
‘B’2-adrenoceptor agonists, PGI2
What happens during the triple response?
Flush – histamine release from mast cells and vasodilation
Flare - + vasodilation and redness, sensory nerve orthodromic activation (pain + itching), antidromic activation of branches –> P, CGRP, VIP release
Wheal – oedema in damaged area, protein extravasation
What happens during neutrophil-dependent extravasation?
Release of IL-8 from activated endothelium
Stimulate neutrophil G protein coupled chemokine receptor
Permits interaction between integrin and endothelial Ig CAM
Promotes adhesion of neutrophil to endothelium (2 hours after injury)
Neutrophils cross endothelium (diapedasis) and migrate towards chemoattractant at site of injury
What happens when there are + neutrophils?
+ phospholipase A2 regulation and cyclooxygenase–2 induction
+ blood flow
IL-1 and TNF release, activating endothelial receptors
Endothelial-leukocyte adhesion molecule production for monocytes –> conversion into macrophages
Induction of Nitric Oxide Synthase II
What happens during the late phase?
Cytokines from activated neutrophils and macrophages = degradation of damaged tissue + site of injury preparation for healing
Breakdown of tissue for repair = lead by leukocyte production of proteolytic enzymes and oxygen radicals
What is the role of cytokines in injury response?
Act centrally to pyrogenic response –> receptors in hypothalamus (fever)
Elevate corticosteroids as ‘stress response’, promoting inflammation in short-term
+ hepatic protein
Bone marrow stimulation
What happens during the proliferative / granulation phase?
Growth factors produced by macrophages and platelets
Granulation of tissue caused by proliferation of + cells
Macrophages, fibroblasts + neovascularisation = in loose collagen matrix
Failure to stop phase = rheumatoid arthritis, scleroderma –> calcification and ossification of cartilage
Fibroblasts = produce collagen for structure
Blood vessel proliferation = for oxygen and nutrient supply
Cell movement in site of injury stimulated by metalloproteinases
Angiogenesis = inhibited by methotrexate
Affected by sex hormones
What happens during the maturation phase?
Remodelling of tissue
Macrophages involved
Reduced vascularisation = - nutrient demand and – tissue metabolic activity
Collagen remodelling and reinnervation by nerves = + tissue strength and sensation
Scar tissue = caused by lack of elastin
How do NSAIDS work?
Cyclooxygenase inhibitors:
- Reduces inflammation by supressing PG synthesis
- Reduce vasodilation and hyperaemia
- Reduce hydrostatic pressure in venules
- Reduce protein leakage into extracellular space
- Reduce pain
How do glucocorticoids work?
- Inhibit inflammation with long-term treatment
- Reduced cell adhesion molecule expression
- Reduced chemotaxis of neutrophils
- Reduced cytokine production
How do selective COX-2 inhibitors work?
- prostanoid and thromboxane A2 levels
What are the functions of skin?
External damage protection (UV)
Barrier (waterproof)
Sensation
Metabolic (subcutaneous fat energy store)
Thermoregulation (insulation)
What are the 3 layers of the skin and how are they structured?
Epidermis (epithelium) –> stratified squamous keratinised
Dermis (connective tissue) –> dense, irregular connective tissue (fibroblasts, collagen I, elastin, blood, nerves, receptors), divided into papillary and reticular dermis
Hypodermis / subcutis (fascia) –> adipose tissue and main blood supply
What are the 5 epidermis keratinocyte layers?
What are the epidermis barriers?
Tight junctions (prevent paracellular diffusion)
Desmosomes and hemidesmosomes (mechanical and sheer)
Keratin (microorganisms)
Phospholipid (waterproof)
How do the 5 epithelial keratin layers form?
Basal layers divide
Differentiate as they rise through layers
Intermediate layers produce keratin and lose organelles and nucleus, becomming stratum corneum flattened cells
Hemidesmosomes tether basal layer to dermis
Intermediate layers have + desmosomes
What are the types and properties of keratinocyte cancers?
Basal cell carcinoma (approx. 80%) from basal layer
Squamous cell carcinoma (approx. 20%) from upper epidermal layers
Both are curable
Linked to total cumulative sun exposure
Common on head, neck and hands
In people of all skin colours
What are the properties of keratinocytes and melanocytes?
Keratinocytes: 95% of cells
Stratified squamous keratinising epithelial cells
Produce keratin
Melanocytes:
pigment synthesising cells responsible for skin and hair colour
Neural crest derived cells lying in the stratum basale
Melanosomes in cytoplasm contain melanin and are passed to keratinocytes – scattering of UV light
What are the properties of langerhans cells and merkel cells?
Langerhans cells:
All layers and upper dermis-prominent in spinosum. Bone marrow derived. Dendritic, antigen presenting cells-migrate to regional lymph nodes and communicate with the immune system.
Merkel cells:
Clear cells in stratum basale. Plentiful in touch areas. Connected to keratinocytes and afferent nerves. Neuroendocrine function
What are the 4 skin cell types?
Keratinocytes
Melanocytes
Langerhans cells
Merkel cells
What are examples of skin pigmentation disorders?
Lentigo maligna
Albinism: Lack of melanin due to lack of enzyme required to make melanin: tyrosinase
Vitiligo: macules of de-pigmented skin enlarging over time. Cause unknown
What are the properties of a melanoma?
Asymmetry
Border
Colour
Diameter
How does the skin stay on?
+ surface area from interdigitation between epidermis and dermis
Epidermis and dermis adhered by hemidesmosomes
Basement membrane between epidermis and dermis
What are the properties of the dermis?
Dense connective tissue:
collagen 70%
Papillary: conical papillae (rete ridges), richly vascularised (capillaries), lymph and nerve
Reticular: Horizontal collagen and elastin fibres
Contains hair and gland structures
How is skin varied?
Thin skin:
- Most locations
- eccrine glands and thin keratin layer
- Less well defined rete ridges
Thick skin:
- Fingertips + soles of feet
- Thick epidermis and keratin layer and well developed rete ridges
- eccrine glands, no hair
Hairy skin:
- Thin epidermis and lots of hair follicles and sebaceous glands
What are the skin specialisations?
What is the main virus structure?
Simple
Nucleic acids
Proteins
Lipids
No organelles
What are the properties of virus metabolism?
Metabolically inert
Rely on host cell
Are obligate intracellular parasites
What are the properties of virus replication?
Independent component part synthesis
Can be in separate parts of cell
Under separate control
Assembly into new particles
What are the properties of virus nucleic acids?
DNA –> double / single stranded, circular / linear, 3kb-200kb
RNA –> ds / ss, ss = +ve / -ve polarity, linear / segmented, 5kb-10kb
What are the functions of proteins in viruses?
Capsid formation –> symmetry (icosahedral / helical)
Attachment –> specific cellular receptor and viral ligand interaction, determines viral tropism (preference to infect certain cell types)
Enzymes –> macromolecular synthesis enzymes
Interference with cell function –> i.e. stop apoptosis, avoid immune recognition
What are the functions of the lipid envelope of viruses?
From host cell membranes
Needs to contain external attachment proteins
Loss of infectivity if envelope stripped
Virus more fragile if enveloped
What is virus clasification based on?
Nature of genetic material
Nature of capsid
Enveloped
Size / shape
Families, genera, strains
What are the stages of viral replication?
Attachment (cellular receptor / viral ligand)
Entry (endocytosis, fusion)
Uncoating
Macromolecular synthesis (multiple viral genome and viral protein copies (requiring +ve ss RNA))
Assembly
Release (budding (yielding enveloped virus), cell lysis)
What is a virion?
What is positive / negative polarity of RNA?
What is a viral tropism?
Virion = mature virus particle –> nucleic acid, protein coat (capsid), lipid envelope
-ve polarity = can be translated at a ribosome
Viral tropism = specificity of a virus to a specific host cell
What are the anti-viral effects of antibodies?
Antibodies = block entry and binding to cells, activate intra-cellular degradation via TRIM21
Antibodies + complement = damage enveloped viruses, opsonisation for phagocytosis
Antibody bound to infected cells = antibody-dependent cellular cytotoxicity
What is antigenetic shift?
Recombination between 2 different viruses, forming a totally new one
What are the functions of interferons?
Type 1 = enhance HLA class 1 protein expression and activate natural killer cells
Interferons produced by infected cells bind to receptors on uninfected cells
Uninfected cell is resistant to viral cell replication
Protein synthesis is inhibited in cell and viral mRNA is degraded
How do cytotoxic T cell work?
Have CD8 receptors on surface
Viral cell proteins degraded by protease, forming peptides
Peptides are expressed on infected cell surface HLA class 1 proteins
Cytotoxic T cells bind to the HLA class 1 protein and kill infected cell
How do natural killer cells work?
Have kill activating receptor molecules
Have kill inhibition receptor molecules too
Binding to normal cell = don’t kill as stronger inhibition signal
Abnormal cells = kill signal is dominant
How is an enveloped RNA virus formed?
What are the criteria for screening a population?
- The condition sought should be an important health problem
- There should be an accepted treatment for patients with recognized disease, and treatment should be better at an earlier stage
- Facilities for diagnosis and treatment should be available
- There should be a recognizable latent or early symptomatic stage
- There should be a suitable test or examination
- The test should be acceptable to the population
- The natural history of the condition, including development from latent to declared disease, should be adequately understood
- There should be an agreed-upon policy on whom to treat as patients
- The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole
- Case-finding should be a continuing process and not a “once and for all” project.
What are the benefits of screening programmes?
- Screening may produce earlier diagnoses
- Earlier diagnosis may improve prognosis for those who develop disease
- In some cases disease may be prevented
- If treating early is cheaper than treating late, then screening may sometimes save money
What are the disadvantages of screening programmes?
- Screening programmes cost money
- Screening may induce anxiety in the well
- Tests my cause harm directly
- No screening test will detect all disease
- A screen negative patient may delay presenting symptomatic disease if falsely reassured
- There will be false positives
- There will be over diagnosis
What is lead time bias?
Time between when a disease can be detected through screening and when it can be clinicaly detected
What is length bias?
What are the 4 outcomes of virus infection?
Cell death –> cytolytic or cytocidal infection (Rhinovirus)
Chronic infection –> continuous viral replication in cell, cell survives (Hep B)
Latency –> No replication of virus, no viral protein production, always infected once infected, reactivation of virus replication can occur, primary and secondary infections (herpes)
Transformation –> cell immortalisation (Epstein-Barr virus)
How are viruses spread to hosts?
Skin
Mucosal surfaces
Respiratory tract
Gastrointestinal tract
Placenta
How are viruses spread within hosts?
Skin – vesicles
Respiratory tract – droplets
Gastrointestinal tract – saliva, faeces
Urogenital tract – urine, semen, female genital tract secretions
Blood – BBV incl HBV, HCV, HIV
Breast milk
What is cytolytic infection?
What is cytopathic effect?
Where a cell is destroyed
Change in host cell structure caused by viral infection
What happens during hypertrophy?
Increase in the size of cells
Can be physiologic/pathologic
No new cells-just bigger
Cells that don’t divide e.g. Cardiac and skeletal muscle
Examples: exercise, hypertension
What happens during hyperplasia?
Increase in the number of cells
Breast development at puberty/liver regeneration after resection/wound healing
Eg psoriasis leads to thickened skin
What do hypertrophy and hyperplasia both result in and when do they occur at the same time?
Both adaptations individually result in enlargement of tissue
Example of both together:
Uterine enlargement (hypertrophy) during pregnancy is a consequence of smooth muscle hypertrophy and hyperplasia
What is atrophy?
Shrinkage in cell size due to loss of cell substance
Functionally diminished but alive
Eg immobilised or aging limb muscle
What is involution?
Reduction in number of functioning cells
Due to reduction in functional demand (myometrium of uterus post partum)
Usually by programmed cell death (apoptosis)
What is metaplasia?
Change in type of cell - reprogramming of stem cells
Survival mechanism in response to injury e.g. Smoking
Specialised function is lost
Can predispose to neoplasia
Reversible
+ cancer risk
What is the purpose of acute inflammation?
A protective mechanism that functions to:
Eradicate cause of injury
Remove damaged cellular material
Initiate repair process
What are the 3 steps of acute inflammation?
1. Vasodilation
Slowing the local blood flow to the area
(allowing time for plasma containing mediators to leave and for neutrophils to come into contact with the vessel wall)
Enabling cells to contact the capillary endothelium
Generating heat and redness
2. Increased vascular permeability
Allowing plasma carrying mediators out
Causing swelling (oedema/tumor/turgor)
3. Cellular activation and migration
Neutrophils are activated to migrate from the vessels. They have a great capacity for phagocytosis
Short lived so need to be replaced
What are the outcomes of acute inflammation?
Resolution –> minimal damage, normal tissue restored
Repair –> damage too severe (scar forms)
Chronic inflammation –> persistent stimulus
Abscess forms
What are the 3 types of cells?
Labile – replicate throughout life –> i.e. skin (resolve)
Stable – Non-dividing in normal circumstances but capable of regeneration –> i.e. liver and kidney (resolve or scar)
Permanent – non-dividing cells –> i.e. neurons and heart (always scarring)
What happens during fibrosis?
Granulation tissue –> macrophages + fibroblasts + new blood vessels
Fibrosis + scar formation –> matrix laid down by fibroblasts, + collagen laid down forming scar to strengthen tissue
Remodelling –> reduction in number of vessels so pale scar remains
What is the process of wound healing?
Inflammatory phase –> macrophages producing growth factors for next phase
Proliferative phase –> granulation tissue, fibroblasts secrete matrix components + growth factors for angiogenesis, regrowth of epithelial cells over wound
Remodelling –> - vascularity, wound contraction
What are the functions of growth factors?
- Mediators of repair
- Stimulate cell proiliferation, differentiation and maturation
