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inflammation in pathology
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Lecture notes of 8 pages for the course Mechanisms of pathology at Aston (immunology notes)
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INFLAMMATION IN PATHOLOGY.INFLAMMATION
Defined by Cornelius celsus.
Original symptoms of inflammation: pain (dolor), redness (rubor), heat (calor),
swelling (tumor).
Many diseases have an inflammatory aetiology.
Inflammation is a key mechanism in tackling infection.
It can also lead to many diseases.
Many diseases have an inflammatory aetiology i.e. the mechanism of pathological
damage in the disease is inflammation.
This includes a wide variety of common diseases such as cancer, diabetes,
neurodegenerative diseases and ageing, cardiovascular diseases involving
atherosclerosis, respiratory adult distress syndrome (lung disorders), rheumatoid
arthritis and cataracts.
Inflammation- initiation and effects
Inflammation is a response to tissue injury, irritants or toxins and invasions by
pathogens.
The innate immune response is responsible for initiating inflammation in the early
stages.
Most types of cells in the body are able to detect damage and pathogens using
receptors that recognise “danger” e.g. toll-like receptors.
Toll like receptors are able to detect damage or pathogens, they detect pathogen
associated molecular patterns (PAMPS). Innate immune cells such as macrophages
and monocytes and neutrophils and dendritic cells have higher levels of Toll-like
receptors, but they are not the only cells that recognise this.
These receptors trigger pathways to produce signalling molecules such as cytokines
that recruit immune cells to the site of damage to tackle the problem.
This process of Inflammation enhances the innate and switches on the adaptive
immune systems in order to limit infection and repair damage.
However, uncontrolled or unresolved inflammation is also damaging to tissues and
causes pathology. This is where a chronic inflammation may occur and there is no
resolution of inflammation.
Inflammation- mechanisms of damage.
Mechanisms of damage that occur in inflammation:
The process starts with activated monocytes, macrophages and neutrophils, which
are the myeloid cells of the innate immune system.
All of these can produce a variety of factors that subsequently lead to tissue damage.
All 3 of these cell types have phagocyte oxidases that produce reactive oxygen
species. Monocytes, especially macrophages have nitric oxide synthases that
produce reactive nitrogen species.
The reactive oxygen and nitrogen species that are produced in this way go on to
cause oxidative stress which is an imbalance of reactive oxidance over the anti
oxidance systems that exist within the cells.
, These can cause damage to all macromolecules present in cells and extracellular
tissues and extracellular matrix such as lipids, proteins and DNA.
Ultimately this can lead to cell death via either apoptosis or necrosis or other forms
of cell death.
Macrophages, monocytes and neutrophils can also produce inflammatory cytokines
that lead to altered gene expression and signalling.
Oxidative stress can also alter gene expression and signalling.
Cell proliferation is altered, so cells may proliferate more and in some cases cells
may differentiate and start to do different things.
Many of these cells, especially neutrophils, are able to directly release proteolytic
enzymes, that are designed as anti-microbial enzymes.
They are reasonably good at killing microorganisms, they can also kill host cell and
cause host cell and tissue damage.
The altered gene expression and signalling can also lead to the activation of other
proteolytic enzymes called matrix metalloproteinases (MMP). These are very
important in inflammation, they are important in remodelling the tissue and leading
to repair. If over activated they can cause unwanted effects and damage.
All of these processes ultimately lead to disease.
Common pathways and factors that are considered as inflammatory signalling.
Nuclear factor kappa B (NF-KB)- this is one of the key signalling hubs that controls
the process of inflammation, receiving signals from TOLL-like receptors, and TNF
alpha receptors. It also switches on a lot of pro-inflammatory factors that lead to
downstream effects.
MAP kinase and SAP kinase (Stress activated protein kinase) family pathways-
The MAP kinases are mainly proliferative, whereas stress activated pathways switch
on responses to stress and upregulate things like heat shot proteins, but they can
also lead onto apoptosis and other responses.
They both (MAP and SAP) lead onto the activator protein-1 family pathway, this is a
family of transcription factors that regulate gene expression.
Then is the JAK/STAT pathway, these are factors that interact with receptors and
lead to signal transduction pathways that are very important in controlling T cell
responses and other inflammatory effects.
Then we have the Nrf-2 and KEAP1 partnership that together forms a protective
pathway that switches on antioxidant and stress responses by upregulating
antioxidant enzymes and their production. Therefore, this protects against oxidative
stress produced in inflammation.
NF-KB is a major TF regulating inflammation.
The NF-KB system is central in transducing signals from pathogens and tissue
damage to the expression of genes involved in inflammation.
NF-KB is activated by:
Various receptors and various ligands for example, TNF alpha, IL-1B (inflammatory
cytokines). These ligands binding to their receptors which is on the canonical
pathway.
PAMPs (pathogen-associated molecular patterns), such as bacterial products like
LPS, bind to TLRs and also switch on the canonical pathway.
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