Pathophysiology of inflammation
drsuryabrata@gmail.comWhat is inflammation?
Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants.
Inflammation is a process that removes or reduces harmful stimuli to help with the healing process.
Cardinal signs of inflammation:
There are 5 cardinal signs of inflammation. They are –
- Heat (calor)
- Redness (rubor)
- Pain (dolor)
- Swelling (tumor)
- Loss of function (functio laesa)
Loss of function mainly occurs due to pain and swelling. Consider septic arthritis of the knee and how pain and swelling may restrict movement.
What are the stimuli that can cause inflammation?
- Pathogens – any harmful bacteria, virus, parasite, or fungus that can initiate inflammation.
Remember, not all bacteria are harmful. Many bacteria live on our skin or mucous membrane, like inside our bowel, and are helpful to us. Our immune system does not develop an immune response to them as long as they are where they should be. However, if they enter a site that should normally be sterile, like our blood or inside the tissue, the immune system will remove them by mounting an inflammatory response.
- Trauma, heat, irritants, poison etc
- Autoimmune disease
Our cells or protein are recognised by our own (“self”) by our immune system. Hence it does not mount a response against it. However, in some diseases, this recognition of self is lost, and our own cell or cell components act as stimuli for inflammation. This is called autoimmune disease—for example – Rheumatoid arthritis.
Innate immunity and adaptive immunity
Inflammation and immunity are closely related. Inflammation is what we see when our immune system engages with a stimulus, for example, a pathogen.
So in this discussion, we will discuss the process of immunity – as we discuss inflammation.
Immunity can be divided into two parts – innate immunity and adaptive immunity.
Innate immunity is the more ancient of the two forms of immunity. It is involved in the regular day-to-day defence of our body. Always present, easily available.
It is non-specific and does not distinguish between different types of pathogens. It mounts an immune response as long as it recognises stimuli. It does not have memory – or in other words, does not remember a previous pathogen or type of insult. It knows only one way of dealing with threats and does it every time.
Adaptive immunity, on the other hand, is like a special force. It takes time to mobilise, but once done, it is much more specific. It also remembers a threat once encountered. Hence if that threat appears again, it mobilised much quicker.
| Innate immunity | Adaptive immunity |
| Evolutionary – recent. It takes time to initiate. Specific. Memory. | Evolutionary – recent. Takes time to initiate. Specific. Memory. |
Components of innate immunity
It is the first line of defence is skin and mucous membrane, which is a component of innate immunity. There are many other factors which, with skin and mucous membranes, protect us. They are – enzymes and acids (gastric acid, pancreatic enzyme), antibodies (IgA), mechanical factors (cilia on respiratory tract, flow of urine) and our own bacterial flora, which is called the microbiome. If a pathogen manages to evade these defences and enters our body, the 2nd line of innate immunity is activated.
These components are –
| Cellular component | Non-cellular component |
| Resident macrophages Mast cells Neutrophils Natural killer cells Vascular endothelium | Chemical mediators – Prostaglandin, Leukotriene, Histamine, TNF, IL Complements |
How does innate immunity recognise offending pathogens or stimuli?
Pattern recognition.
There are two types of patterns – pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP).
Components of pathogens like peptidoglycans or nucleic acids have areas that may appear the same over many pathogen types. These areas are called conserved areas. These are called PAMPs. A similar situation arises when there is a non-pathogenic stimulus that causes damage to our body, called DAMP.
The immune cell identifies these signals with pattern recognition receptors (PRP). One example of these PRPs is Toll-like receptors.
Innate immunity and inflammation
Our tissues have resident macrophages and mast cells, which initiate inflammation. They recognise the stimuli by PAMPs and DAMPs.
Once identified, the inflammatory cells release various chemical mediators to coordinate the inflammatory process. There are some mediators present in plasma as well.
Some of these chemicals are
| Mediators | Source | Action |
| Histamine, serotonin | Mast cell, Platelets | Vasodilation, Increase in vascular permeability |
| Prostaglandins, Leukotrienes | Leucocytes, Mast cells | Vasodilation, pain, fever |
| TNF, IL1 | Mast cells, macrophages, endothelial cells | Margination of leucocytes, pain, fever |
| Complement | Plasma | Bacterial killing – directly by opsonisation and pore formation |
These leads to –
Vasodilation and increased blood flow – resulting in redness, increase in temperature
Extravasation of fluid and cells from the leaky capillaries – oedema/swelling
Stimulation of the afferent nerve fibres – pain
It also brings more inflammatory cells to the affected sites – neutrophils, natural killer cells, monocytes etc.
Phagocytosis
Macrophages are the primary phagocytic cells in the tissue at the site of inflammation. Neutrophils are present in the blood, and monocytes are in the blood, spleen and lung, ready to be mobilised to the site of inflammation when needed.
Many types of cells are capable of phagocytosis, but some of these are specialised professional phagocytes.
These are – macrophages, monocytes, neutrophils, dendritic cells etc.
Phagocytosis helps to clear the pathogen and damaged tissue and activates the next phase of immunity, adaptive immunity, if needed.
Dendritic cells are primarily involved in activating adaptive immunity.
Example of phagocytosis
Complement system
Complements are plasma protein that helps the immune system in multiple ways. It can coat the pathogen so that it becomes a more attractive target for the phagocytic cells – it is called opsonisation. It is also known to form pores on the pathogen, directly killing them.
What if the pathogen is intracellular?
This poses a particular problem as the immune system may not damage our cells.
In this case, the cell with the pathogen inside secretes interferon, which activates natural killer cells (NK cells).
The infected cells also downregulate MHC class 1 molecule on it. As a result, the immune system does not recognise these cells as our own anymore. This is called loss of self.
NK cells then initiate apoptosis (which is the death of a cell in a controlled manner) of the infected cell.
Next stage of inflammation
The inflammation starts resolving if innate immunity removes the cause of offending stimuli. However, if it doesn’t, then our adaptive immunity start its activity.
Acute inflammation typically last days.
If adaptive immunity is successful, the inflammatory process stops. If not, the inflammatory process continues – which is known as chronic inflammation.
Adaptive immunity
Adaptive immunity – takes time to activate but is specific. It is medicated by – T and B lymphocytes.
T lymphocytes are responsible for cell-mediated immunity (CMI). B lymphocytes are responsible for antibody-mediated immunity (humoral immunity).
This process starts with dendritic cells or macrophages presenting portions of pathogens to immature T lymphocytes. They present these antigens with the help of the Major Histocompatibility Complex (MHC). You may find these MHCs by another name – Human Leukocyte Antigen (HLA).
When the antigen is presented to immature T lymphocytes, they mature into Cytotoxic T cells or helper T cells. It depends upon what types of receptors the immature T cells have. CD4 receptor cells mature into helper cells, which are vital coordinators of the immune reaction.
Cytotoxic T cells develop from T cells with CD8 receptors; they are effector cells. These effector cells can destroy pathogens, but they must be controlled to prevent damage to other tissues and organs. They are controlled by the helper T cells.
Helper T cells control other types of immune cells like macrophages, eosinophils and B lymphocytes.
Once the activity of helper T cells is finished, they retire, forming memory cells. Memory cells reactivate and start the immune system if our body encounters a similar threat again.
Humoral immunity
B lymphocytes help our immune system by producing antibodies. However, to do that B cells must transform into plasma cells with the help of helper T cells.
Plasma cells form antibodies that coat antigens to help in phagocytosis, agglutinate and neutralise the toxin and activate the complement system. Plasma cells also form memory cells after their function is completed.
Resolution
Once the offending stimuli have been removed, the resolution process starts. It is a healing process that tries to bring the body back to homeostasis. If the damage is extensive, the healing may occur by scar formation.
If the healing process is impaired, a chronic inflammatory process may start.
This is an active process that involves –
Platelets and fibrous tissue take an active part in resolution.
Use cases
How steroids and NSAIDs work
You may remember the chemical mediators of inflammation from our discussion. Let’s look at it closely.
During the inflammation process phospholipid component of the cell membrane undergoes a metabolic pathway to form leukotrienes, prostaglandins and thromboxanes. These mediators are responsible for pain, inflammation and fever.
Steroids can inhibit both pathways, as described below, while NSAIDs prevent the cyclooxygenase pathway.
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