Module 4 Flashcards

Inflammation

Movement of fluid and leukocytes from blood into affected tissue in response to injury or infection

May be chronic or acute

Cardinal signs of infection

redness

heat

swelling

pain

Heat/redness

caused by increased blood flow to tissue (called hyperaemia or erythema)

Swelling

increased fluid movement from blood into the tissue (called exudation)

Pain

increased sensitivity of pain receptors (called hyperalgesia)

Oedema

accumulation of fluid extra-vascularly in tissue

Exudate

oedema fluid with high protein content resulting from increased vascular permeability due to inflammation

Pus

inflammatory exudate containing viable and dead neutrophils, cell debris, viable and dead microorganisms, protein, lipids, DNA

Suppuration

the formation of pus

Steps of acute inflammation

1. Dilation of small vessels = increased blood flow

2. Increased vessel permeability = plasma protein and leukocytes can leave circulation

3. Emigration of leukocytes into extravascular tissue and focal area of injury

How exudate is formed in acute inflammation (Injury)

Injury → formation of vasoactive mediators → vasodilation (in arterioles) and endothelial contraction (in post-capillary venules) → hyperaemia and increased hydrostatic pressure (in aterioles) and increased vascular permeability to proteins (in post-capillary venules) → fluids, salts, antibodies, neutrophils move into affected tissue (= EXUDATE)

How exudate is formed in acute inflammation (Infection)

Infection → formation of chemotactic factors → upregulation of endothelium adhesion molecules (in post-capillary venules) and Neutrophil activation → Neutrophil margination and migration → fluids, salts, antibodies, neutrophils move into affected tissue (= EXUDATE)

Vasoactive Mediators

cause vasodilation in arterioles (hyperaemia and increase hydrostatic pressure follow)

causes endothelial contraction in post-capillary venules (increase permeability to protein follows)

Chemotactic factors

Increase adhesion molecules on endothelium of post-capillary venules

Increase neutrophil margination and migration

Exudate components

Fluid: for dilution of toxins and increase flow into lymphatic system to flush out infection

Plasma proteins: antibodies, complement system, and fibrin system components

Neutrophils: for destruction of foreign microorganisms

Changes in vascular flow

1. Vasodilation

   • earliest change - caused by histamines on vascular smooth muscle

   • affects arterioles, then capillary beds

   • causes heat + redness

2. Increased permeability

   • first transdudate forms (protein-low fluid)

   • second exudate enters tissue (protein-rich fluid)

3. Vascular congestion

   • increased viscosity of blood

   • slow moving blood allows for protein leakage

Process of leukocyte migration

1. Activation of leukocytes

2. Rolling of leukocytes along vessel cell membrane (with the help of selectins)

3. Firm adhesion of leukocytes on vessel cell membrane (with help of integrins)

4. Entering of leukocyte into tissue via diapedesis (with help of chemoattractants and integrins)

Polymononuclear cells (PMNs)

the first cells to reach site of injury/infection

• typically neutrophils

Mononuclear cells

the second cells to reach the site of injury/infection

• typically monocytes and macrophages

Neutrophils

produced in bone marrow and are rapidly recruited to site of injury

• function in rapid cytoskeletal rearrangement

• migrate through vessel endothelium into the tissue

Macrophages

are recruited more slowly but are more long-lived in the tissue

• involved in acute inflammation but are more important for chronic inflammation

Neutrophil function

• short-lived cells

  • 5 days in circulation

  • 2-6 hours in tissue

• phagocytose and kill bacteria by:

  • oxygen dependent killing mechanisms

  • enzymes

• death of neutrophils contributes to pus formation and spread of infection

  • needs to be drained

Systemic changes as a result of inflammation

• Leukocytosis - high white blood cell count

  • increase CSF and bone marrow leukocyte production

• Fever

  • caused by IL-1, TNF, hypothalamus prostaglandin, peripheral vasoconstriction)

• Elevated fluid protein

• Malaise (discomfort and weakness)

  • caused by IL-1, TNF, IL-6

Acute phase proteins

serum proteins that increase in concentration by >25% in response to inflammatory cytokines

• Fibrinogen (for coagulation)

• complement components, C-reactive protein (CRP), Serum amyloid A (SAA) [for anti-bacterial]

• Alpha 2 macroglobulin (for proteinase inhibition)

• metal metabolism

Sources of pain

Pain receptors are sensitized by:

• prostaglandins (PGE2 and PGI2)

Inflammatory mediators act on pain receptors

• histamine and bradykinin

Local changes due to inflammation

• erythema

• swelling

• gingival fluid

• tooth extrusion

• serous crusting

• abscess formation

• fluid drainage

Outcomes of acute inflammation

• Recovery

  • dilution of toxins by exudate

  • phagocytosis and destruction of foreign bodies

  • Treatment

• Ulceration (with or without pus formation)

• Abscess (necrosis)

• Progression to chronic inflammation

Acute pain (nociceptive pain)

Noxious stimuli that bind to nociceptors (pain sensory organs) and threaten or cause tissue damage

Types of nociceptors

1. Mechanical

2. Thermal

3. Polymodal

4. Silent

Mechanical nociceptor

Located superficially

activated by strong stimuli such as pressure or puncturing of the skin

stimuli transmitted via A-delta fibers

Thermal nociceptors

Located superficially

activated by extreme heat (above 45 C) or extreme cold (below 5 C)

sensation of pain transmitted by A-delta fibers

Polymodal nociceptors

Located throughout the body

activated by noxious mechanical, heat, cold, or irritant (chemical) stimuli

slow, dull pain that persists long after stimulus is removed

transmitted via C fibers

Silent nociceptors

Located in muscle, joints, and viscera

activated by noxious stimuli in muscles, joint, viscera

transmitted via c-fibers

A-delta fibers vs. C-fibers

A-delta fibers: first pain sensations - fast acting - lightly myelinated

C-fibers: second pain response - slow acting - unmyelinated

Difference between nociception and pain

Nociception = transmission of electrical signals from peripheral nociceptors to the CNS

Pain = the perception of unpleasant stimuli by the brain’s nociceptive input. It is a homeostatic mechanism to protect oneself from harm

Pain and nociception are often coupled, but can be experienced independently

Ascending pathway that transmits noxious stimuli

Primary afferent synapses on dorsal horn of second order neurons within spinal cord → ascends to brain for processing

Where do pain and temperature stimuli synapse for the upper limbs

in the cervical spinal cord

Where do pain and temperature stimuli synapse for the lower limbs

in the lumbar spinal cord

Where do pain and temperature stimuli synapse for the orofacial region

Stimuli enter via trigeminal nerve → trigeminal cell bodies in the pons → descend and synapse in spinal trigeminal nucleus in the medulla and upper spinal cord

Spinomesencephalic tract

Neurons start in dorsal horn and ascend to midbrain → crosses on contralateral side to the periaqueductal grey (PAG) which surrounds the cerebral aqueduct

• PAG mediates fight or flight

• response and modulates pain stimuli

Spinoreticular tract

from dorsal horn of spinal cord to reticular formation of brainstem

senses temperature, pressure, and visual/auditory information

Spinothalmic tract

from dorsal horn of spinal cord to the thalamus and the to various parts of cerebral cortex

provides sensory and emotional information that are integrated in the prefrontal cortex, insular cortex, cingular gyrus (not as important in survival instinct)

Pain modulating pathway

Numbs the brain to pain in response to overwhelming noxious stimuli via endogenous analgesia

• endogenous analgesia begins in PAG of midbrain → medulla → spinal cord → trigeminal nucleus

Opioids act in same way

Lewis triple response

Characterizes physiological pain

• retrograde activation of C-fibers releases Substance P which sensitizes nociceptors

• Substance P triggers mast cell degradation and histamine release = swelling

• Tissue damage = local release of bradykinin, prostaglandins, K+ which bind to nociceptors

Primary hyperalgesia/allodynia

sensitization of nociceptors leading to increased pain response to mechanical stimuli

Allodynia = previous innocuous (non-painful) stimuli becomes painful

Hyperalgesia = noxious stimuli perceived as more noxious

Central sensitization (normal acute pain)

CNS becomes more sensitive to pain as a result of glutamate (rapid depolarization of second order neurons) and substance P (delayed, long-lasting depolarization) signals

Glutamate binds to AMPA

Substance P binds to neurokinin1

Persistent pain response

Persistent pain in spinal trigeminal neurons open the NMDA receptor (normally blocked by Mg) → causes Ca and Mg release that increase pain response → secondary hyperalgesia develops to increase and prolong pain

Pain may be modulated via Opioids, adrenergic agents, GABA, 5HT receptors

Nitric oxide

product of the opening of the NMDA receptor → releases Ca

prolonged activity of spinal trigeminal neuron triggers death of spinal trigeminal cells → intracellular Ca → production of nitric oxide synthase

Nitric oxide is toxic to pain inhibitory neurons (GABA) and contributes to increase pain experience

Types of cells in the nervous system

1. Neurons (usually multipolar)

2. Glia

Classifications of Glia

CNS

• Astrocytes

• Microglia

• Oligodendrocytes

• Ependymal

PNS

• Schwann cells

Astrocytes

neuron support, BBB maintenance, injury response

Microglia

immune cells, inflammation, injury response, synaptic pruning

Oligodendrocyte

myelination

Ependymal

CSF secretion

Schwann Cells

myelination, neuro-regeneration

Multipolar cells

one axon extends from cell body with multiple dendrites, facilitating communication with other neurons

Bipolar Cells

single dendrite and one axon on other side

Unipolar/Pseudounipolar cells

Cell body in the middle of two axons - one axon innervates dendrites and the other travels to CNS

Myelinated vs Unmyelinated cells

Myelinated

• fast impulse transmission via saltatory conduction

• contains Nodes of Ranvier

Unmyelinated

• slower impulse transmission with continuous conduction

• responsible for dull aches and burning sensations

Hydropic change

cellular injury characterized by a larger than normal vacuole in the cell

Fatty change

cellular injury characterized by increase lipid vacuoles in the cell

Hypertrophy, Hypotrophy, Atrophy

Hypertrophy = increase in size

Hypotrophy = decrease in size

Atrophy = death of tissue

Describe the injury in this image (A, B, C)

Kidney Tubules Hydropic Degeneration

A) Normal

B) Early reversible ischaemic injury - increased eosinophilia of cytoplasm - protein denatured - swelling

C) Necrotic irreversible injury - loss of nucleus and cell fragmentation

Cardiac muscle Hypertrophy

• causes myocytes to become bigger

• continue growth will injure myocytes → cell death

  • contribute to acute myocardial infarction

Sialosis

cellular injury characterized by enlargement (hypertrophy) or reduction (atrophy) of acinar cells of the major salivary glands

Lipofuscin

• a yellow-brown pigment made of lipid-phospholipid-protein polymers

• contributes to oxidative stress of organelle membranes

• Commonly known as “wear and tear pigment”

Hyaline change

Left: Russel bodies

• found in plasma cells

• excessive immunoglobulin synthesis

Right: Rushton’s bodies

• specific to odontogenic cysts

• found in the epithelium of cysts

Hyperplasia and example

Excessive cell proliferation

Ex. Traumatic Keratosis - epithelial cells proliferating to form increase cells on surface

Metaplasia and example

change in cell differentiation from one form to another

Ex. Smoker’s lung epithelium will shift to become squamous to protect airways

Dysplasia and example

disordered growth that alters size, shape, and organization of cells in tissue

• reversible

• may be cancerous

Ex. cancer of skin epithelium, bronchus, cervix

Anaplasia

loss of differentiation only in presence of malignant neoplasia (cells that become cancerous)

Cell Death (Coagulation)

Death of nucleus while cell remains intact

Types:

• pyknosis - nuclear shrinkage

• karyorrhexis - nuclear fragmentation

• karyolysis - nuclear degradation

Cell Death (Liquefaction)

Associated with microbial infection

Cell becomes soft, liquefied and filled with pus

Cell death (Caseous)

Cheese like appearance under a microscope

Symptoms of coagulation and liquefaction

Caused by tuberculosis

Cell death (Fat necrosis)

Occurs in fat cells

Enzymes break down fats leaving free fatty acids in cell

Fatty acids react with calcium to form deposits

Often occurs in pancreas and breasts

Common structures that arise from apoptosis

fusion of palate, gland lumen formation, involution of breast tissue

Pathological apoptosis

death of healing cells, atherosclerosis, autoimmune disease

Caused by:

• radiation, toxins, free radical → DNA damage

• withdrawal of growth factors/hormones

• receptor-ligand mediated apoptosis

• Cytotoxic T cells triggering apoptosis

Necrosis vs. Apoptosis

Processes that cause Cell Death

1. ATP depletion

   • loss of energy-dependent cell functions = cell death

2. Loss of membrane integrity

   • Mitochondria membrane disruption = loss of ATP and cell death

   • Lysosomes can degrade cell membrane = death

   • Plasma membrane degradation = loss of cell contents and death

3. Increase intracellular Ca

   • Protein breakdown and DNA damage = cell death

4. Reactive oxidative stress

   • Protein breakdown and DNA damage = cell death

Dental Pulp

Soft connective tissue core of tooth

Contains:

• cells

• water

• collagen

• blood vessels

• lymphatics

• nerves

Functions of dental pulp

1. nourish the dentine of the tooth via blood vessels

2. provide sensation (temp, pressure, pain)

3. protection (immune tissue through lymphatic system and production of tertiary dentine)

The pulp chamber

• Coronal Pulp = pulp closest to the crown

• Radicular Pulp = pulp in the root canals

• Pulp chamber surrounded by periodontium

• Pulp chamber may have accessory canals

• canals can be potential avenue for bacterial passage

Dentine-pulp complex

• odontoblasts present at dentine-pulp junction on pulpal side

  • produce and secrete dentine

  • have processes that extend into dentine via dentinal tubules

• Stimulus/injury of either causes response from other

Histological zones of pulp

1. Odontoblastic zone

2. Cell-free zone of Weil

3. Cell-rich zone

4. Pulp core

Odontoblastic zone

• consists of the cell bodies of the odontoblasts

• dentinal tubules linked together laterally via tight junctions and adherens junctions

  • serum protein can pass between these junctions

• lifespan of odontoblasts in this zone linked to lifespan of tooth

Cell-free Zone of Weil

• region with very few cell bodies and nuclei

• evident in coronal pulp

• not present during development

• contains capillaries, nerves

  • called Subodontoblastic plexus of Raschkow

Cell-rich Zone

• region of high cell-density

• most evident in coronal pulp

• many fibroblasts and stem cells (become odontoblasts)

Pulp core

• majority of pulp volume

• contains major vessels, nerves, and connective tissue matrix

  • CT matrix = fibroblasts, immune cells, undifferentiated mesenchymal cells, odontoclasts

Innervation of pulp

• nerves (sensory and sympathetic) enter pulp via apical foramen

• nerve bundles run along blood vessels and branch out toward periphery of the pulp

  • these nerves contribute to nerves in cell-free zone (subodontoblastic plexus of Raschkow)

Drug definition

substance that exerts biological effect when administered to the body

• may be natural or synthetic

Medicine definition

preparation of substances to be administered for therapeutic use

Process of medicine approval

Pre-clinical testing → clinical trial → licensing approval → patient access

Pharmacology

the study of drugs used in therapeutics

Pharmacotherapeutics

application of pharmacological knowledge to use on drugs to manage a condition

Pharmacokinetics

what the body does to the drug (absorption, distribution, metabolism, excretion)

Pharmacodynamics

what the drug does to the body

Clinical pharmacology

right medicine + patient + dose + dose form + route + time + documentation = right response

Regulatory bodies of medicines in Australia

• Therapeutic Good Administration (TGA)

• Quality us of Medicines (QUM)

• National Medicines Policy

Common medicines in Australia for cardiac conditions

• rovuvastatin

• atorvastatin

• pantoprazole

Resilient Arteries Protected (RAP)

Nurofen

Drug Class:

• NSAID, analgesic, antipyretic

Mechanism of Action:

• inhibits cyclooxygenase 1 and 2, decrease prostaglandins

Indications (what it treats):

• pain, inflammation, arthritis, fever

Precautions:

• dehydration, asthma, coagulation disorders, renal impairment, cardiovas disease, GI issues, elderly, pregnany

Contraindications:

• active peptic ulcer or GI bleeding

Adverse Effects:

• nausea, salt/fluid retention, hypertension, diarrhea, stroke, heart attack, rash

Dose:

• 200-400mg (1-2 tabs), 3-4 times daily