Introduction to Pathology and Inflammation Flashcards
What is Inflammation?
The immune system’s response to harmful stimuli such as pathogens, damaged cells, toxins or radiation.
It involves a series of complex changing responses to initiating the healing response
It is a defense mechanism that is vital to health
What is acute inflammation?
ACUTE inflammation is inflammation that happens in the short term
What is chronic inflammation?
CHRONIC inflammation is what happens if it persist and happens in the long term.
Why do we have acute inflammation?
It is the body’s response any time there is damage to vascularised tissue
The process of acute inflammation is to help deal with what has caused damage
and it helps “pave the path” for repair and healing
It is a normal immune response
it is part of the innate immune response (more on this in a few weeks time, lecture on Innate Vs Adaptive immunity)
What are the 4 main causes of inflammation?
Infective
Tissue Necrosis
Foreign body/chemical
Immune reactions/ Cell mediated
What is Atherosclerosis?
causes chronic inflammation causing plaque build up which leads to heart disease, strokes, type 2 diabetes etc. (More on this in chronic inflammation, ”foreign” body can be endogenous and exogenous)
What does IMMUNE REACTIONS / CELL MEDIATED mean regards to causes of inflammation?
Hypersensitivity disorders
Allergies
What is an example of foreign body/chemical with regards to inflammation?
A splinter or a rusty nail in your skin.
Embedded prosthesis or metal work, e.g. heart valve replacement causing endocarditis.
Atherosclerosis: causes chronic inflammation causing plaque build up which leads to heart disease, strokes, type 2 diabetes etc.
What are the infective forms of inflammation?
virus, bacteria, fungus, parasites
What are the classifications of inflammation?
Speed of onset and duration
Severity
Distribution
Predominant Cell type involved
What are the FIVE CARDINAL SIGNS OF ACUTE INFLAMMATION?
REDNESS (rubor)
HEAT (Calor)
SWELLING (Tumor)
PAIN (Dolor)
LOSS OF FUNCTION
What are the cellular processes linked to inflammation?
HYPERAEMIA
EXUDATION OF FLUID
EMIGRATION OF LEUCOCYTES
What is Hyperaemia?
Small blood vessels adjacent to the area of tissue damage become initially dilated with increased blood flow
What is Exudate composed of?
NEUTROPHIL POLYMORPHS
FLUID
FIBRIN
MACROPHAGES
LYMPHOCYTES
What is exudation of fluid?
The affected area is occupied by a transient material called the
acute inflammatory exudate.
The exudate carries proteins, fluid and cells from local blood vessels into the damaged area to mediate local defenses.
If an infective agent (eg. bacteria) is present in the damaged area, it can be destroyed & eliminated by components of the exudate.
The damaged tissue can be broken down & party liquefied & the debris removed from the side of damage.
How is exudate formed?
Following hyperemia, endothelial cells swell and partially retract so that they no longer form a completely intact internal lining
The vessels become leaky, permitting the passage of water, salts and some small proteins from the plasma into the damaged area (EXUDATION) .
One of the main proteins to leak out, is the small and soluble molecule fibrinogen.
What is fibrin?
Filamentous protein formed by the polymerization of numerous molecules of the smaller, more soluble precursor protein, fibrinogen.
The fibrinogen passes out from vessels with the fluid & salts polymerizing into insoluble fibrin threads once outside of the vessel lumen by activation of the blood coagulation cascade.
What is the emigration of Leucocytes?
irculating neutrophils polymorphs initially adhere to the swollen endothelial calls (MARGINATION)
They then actively migrate through the endothelial cell junctions by amoeboid movement through the venule wall into the tissue spaces (EMIGRATION) - passing into the area of tissue damage.
Later, small numbers of blood monocytes (macrophages) migrate in a similar way, as do lymphocytes.
What are the main effector cells in acute inflammation?
NEUTROPHILS
What are the three stages of Margination (of Neutrophils)?
Rolling
As blood slows, the WBC roll on the endothelial surface
- Adhesion
As they roll, they become increasingly adhesive to the endothelial cell surface.
The leukocyte endothelial adhesion is achieved by the expression on the surface of activated endothelial cells (known as selectins).
On stimulation of endothelial cells by proinflammatory cytokines such as TNF or interleukin -1 there is transcriptional activation of the genes encoding in these proteins – this can last 4-6 hours, but can be sustained for hours or days. - Aggregation
Adjacent neutrophils adhere to each other and undergo shape changes.
Activation of Endothelium is a key process in Acute Inflammation. True or false
True
What are the main factors excreted by the endothelium?
Nitric Oxide & Prostacyclin
Which induce vascular relation and inhibit platelet aggregation
Endothelin, thromboxane A2 and angiotensin 2
Vascular constriction
Growth Factors, PDGF
Which promote inhibitors
Chemokines
What do Neutrophil Phagocytosis help to do?
they are involved in clearing the infectious agent e.g. bacteria.
What are Neutrophil Phagocytosis work?
Neutrophils do not phagocyte material to which they do not bind – they have membrane receptors.
Micro-organisms must be coated by opsonis (immunoglobulins, complement and carbohydrate molecules)
Neutrophils bind to the abnormal particle by its specific receptors
The cell pushes psuedodopia out to surround the particle.
The pseudopodia fuse to enclose the abnormal particle completely, forming and endocytic vesicle
Now called a phagosome, it fuses with neutrophil granules which discharge their contents .
What are Macrophages?
Play a small part in the acute inflammatory exudate.
Macrophages are derived from monocytes in the circulating blood which migrate to the damaged area after later than neutrophils.
The increase in numbers over time to facilitate elimination of dead material.
Actively phagocytic
Can survive for longer due to their capacity for oxidative metabolism.
They also produce growth factor, cytokines which mediate some of the events in the inflammatory response.
Macrophages have more important roles in chronic inflammation
What are the ways that exudate can vary in composition?
Purulent –
Neutrophils dominated and the material is liquefied to form pus
Fibrinous
Fibrin in abundance, seen in relation to serosal surfaces
Serous
when fluid is the major component
What conditions that cause exudate can be harmful?
Acute Epiglottitis
Acute Meningitis
What are inflammatory cellular mediators?
Stored
- Histamine
Active Synthesis
Prostaglandins
Leukotriens
Platelet Activating Factor
Cytokines
Nitric Oxide
Chemokines
What are inflammatory Plasma- Derived Mediators?
Kinin System
Bradykinin
Clotting Pathway
Activated Hageman Factor
Thrombolytic System
Plasmin
Complementary Pathway
- C3a, C3b, C5a
What is Histamine?
Main pre formed mediator of inflammation
Released from mast cells, basophils and platelets
Causes transient dilation of arterioles, increases permeability in venules
What are Prostaglandins & Leukotrines (cellular mediators) ?
Derived from local synthesis from arachidonic acid.
(long chain fatty acid which are liberated from cell membranes by activation of the enzyme phospholipase Az.
What are Platelet Activating Factor (cellular mediator)?
Synthesis by mast cells / basophils
Stimulated by IgE- Mediated release
Also synthesized by platelets, neutrophils, monoctes and endothelium
& specialized phospholipid compound which causes vasoconstriction, increased permeability and platelent aggregation
- It’s a thousand times more potent than histamine!
What are Cytokines (cellular mediator)?
A large group of polypeptide proteins of activated lymphocytes and monocytes
Main ones in acute inflammation:
Interleukin-1
Interleukin – 8
Tumour Necrosis Factor Alpha (TNFa)
Which are responsible for:
Induction of cell adhesion on endothelium
Induction of prostacyclin synthesis
Indution of PAF synthesis
Fever, Anorexia and stimulation of acute phase protein synthesis by the liver
Stimulation of fibroblast proliferation and secretory activity
Attraction of neutrophils into the damaged area.
What are Chemokines (cellular mediator)?
Secreted and leukocytes & endothelial cells in response to tissue damage
During neutrophil rolling, chemokine receptors are activated and this signals the activation of leukocyte integrins, mediating adhesion and emigration.
What is Nitric Oxide (cellular mediator)?
A small molecule that is locally synthesied by the endothelium and macrophages through the activity of the enzyme, Nitric Oxide Synthase.
A powerful cause of:
vascular dilation & permeability
Can also mediate cell and bacterial killing
What is the The Complement System (plasma derived mediator)?
Is compromised of a set of plasma proteins with important roles in immunity and inflammation.
There is a cascade of activation which produces a number of intermediately activated peptides
What are The Kinins?
Small peptides. Derived from plasma precursors
Increase vascular permeability
Cause pain and activates the compliment system
What is the The Clotting Pathway?
Responsible for coagulation of blood by the formation of fibrin from fibrinogen thus forming fibrinopeptides
Stimulates deposition of fibrin, activates the Kinins & thrombolytic pathway
Causes vascular permeability
What is the The Thrombolytic Pathway?
The enzyme plasmin is a proteolytic enzyme with several roles in inflammation
Activates the complement system
Activates Hageman Factor
Lyses fibrin to form fibrin degradation products which increase permeability of vessels.
There are 2 mechanisms for increased permeability of small vessels following tissue damage: what are they?
1) Toxins & Physical Agents
May cause necrosis of vascular endothelium leading to abnormal leakage (non- mediated vascular leakage)
2) Chemical mediators of acute inflammation
cause retraction of endothelial cells, leaving intracellular gaps (mediated vascular leakage)
What is the Summary of Vascular Permeability?
Immediate Response
transient, lasts for 30-60mins
Mediated by Histamine acting on the Endothelium
Delayed Response
Starts 2-3 hours after injury, lasts up to 8 hours
Mediated by factors synthesized by local cells, e.g. bradykinin, factors derived from complement & from dead neutrophils in the exudate.
Immediate Response that is prolonged for over 24 hours
Seen if there has been direct necrosis of endothelium e.g. a burn or chemical toxin
What is RESOLUTION – the complete restoration of normal conditions after acute inflammation?
1 - Minimal cell death & tissue damage
2 - Rapid elimination of the causal agent e.g. bacteria
3 - Local conditions which favor the removal of fluid & debris
What is Lobar Pneumonia?
Lobar Pneumonia is a type of acute inflammation of the lung
Caused by bacteria excreting toxins into the alveolar sacs, thus causing epithelial cell death (type 1 & type 2 pneumocytes).
The body’s response is the produce an acute inflammatory exudate (components which are fluids, salt, fibrin / fibrinogen, proteins, neutrophils & macrophages).
As the infection develops, the air in a large area of the alveoli is replaced by exudate.
This tends to spread rapidly through alveolar sacs within a particular lobe of the lung.
Patient’s gas exchange capacity is lost.
Importantly,
Although cells lining the alveoli die, the support stroma & vascular structure of the ling remain intact.
Under favorable conditions, especially if the patient is treated with antibiotics, the neutrophils in the exudate phagocytose & destroy all the causative bacteria
And thus the resolution process can begin.
Enzymes released by neutrophils break up structural proteins (e.g. the Fibrin) & remnants of dead cells, rendering the exudate highly liquid.
Some of it is coughed up in sputum
But most of it is re-absorbed into the alveolar capillary network or into the pulmonary lymphatic system.
Macrophages phagocytose any residual undigested debris, pass into the lymphatic system & are transmitted into regional lymph nodes.
At the same time, remnant epithelial stem cells divide to re-line the alveolar air spaces, differentiating into new Type1 & Type 2 alveolar lining cells.
What is SUPPURATION?
Is the formation of PUS
Where pus accumulates, an ABCESS will form.
What is the purpose of acute inflammation?
It is the initial protective response to tissue injury / infection with the aim to replace the damaged area by organized tissue, which is identical in structure and function to that originally present (termed restitution).
Restitution is the ideal outcome.
It can only be achieved if:
the damaging agent is removed
Cell debris is cleared from the site
The specialized cells have the capacity to regrow / regenerate
