BGDA/Lectures/Chronic inflammation< BGDA
Inflammation of a prolonged duration (arbitrary >6 weeks) in which active inflammation, tissue injury and healing proceed simultaneously; characterised by:
- Infiltration with mononuclear cells – macrophages, lymphocytes, plasma cells
- Tissue destruction, largely induced by the products of the inflammatory cells
- Repair, involving angiogenesis and fibrosis
It may be due to an acute irritant which is not eliminated, for example persisting acute infections, or many autoimmune diseases. Alternatively, some forms of injury (such as foreign bodies, some viral infections) engender a response that involves chronic inflammation from the outset (i.e. low intensity irritant of long persistence).
Macrophages are the dominant cells of chronic inflammation; derived from circulating blood monocytes. In all tissues, macrophages act as filters and sentinels to alert lymphocytes. Macrophages may become activated by cytokines or microbial products (e.g. endotoxin), resulting in increased cell size, metabolism, content of lysosomal enzymes and ability to kill ingested organisms. They appear large and flat under microscopy, and so sometimes called epithelioid cells. They may also fuse into large multinucleated giant cells.
Granulomatous infection is a distinctive pattern of chronic inflammation, characterised by aggregates of activated macrophages. Granulomas wall off the offending agent, and therefore are a useful defence mechanism. However, they do not always lead to eradiation of the causal agent; granulomatous inflammation with subsequent fibrosis may even be a major cause of organ dysfunction in some diseases (e.g. tuberculosis). Granulomas contain epithelioid cells with pink, granular cytoplasm, and frequently giant cells. Aggregates of macrophages are surrounded by lymphocytes secreting the cytokines responsible for continuing macrophage activation. Older granulomas may have a rim of fibroblasts and CT. In granulomas associated with certain organisms, a combination of hypoxia and free-radical damage leads to a central zone of caseous necrosis (amorphous, structureless, granular debris)
Long term consequences of chronic inflammation
- Continuing effects of acute inflammation
- Destruction of tissue; scarring
- Systemic effects – activation of proinflammatory cytokines (especially TNFα and IL-1), released systemically causes the acute phase response
- Refer to the notes below in conjunction with the lecture slides
This lecture is related to the scenario, in the sense of a disease that we'll learn about soon that causes infertility. It is also a more general lecture - connected to previous lectures on acute inflammation
Definition is difficult - how long is long? Any time-based definition is completely arbitrary - nothing is likely to have happened to the cell between day 41 and day 42. Instead we look at tissue changes. Acute = neutrophils abundant (PMNs). Chronic = lymphocytes mainly (mostly cells with round nuclei - called mononuclear cells). But some acute inflammation has a lot of lymphocytes and few neutrophils - e.g. viral infections, allergic inflammation (that don't have chemoattractants for neutrophils.
The good definition is not as easy to identify, but it is accurate. It is where we have repair in parallel with inflammation (the battle goes on but nobody has won). Therefore there is ongoing tissue damage and tissue destruction. Chronic inflammatory processes have the potential to be much more destructive over a long period of time. It is usually true that we can recognise evidence of CI in the host immune response (which is often driving CI). Therefore, although AI and CI are distinct, there are lots of overlaps in terms of what you may see under a microscope.
There are at least 2 distinct steps to CI:
- 1) The acute irritant is not effectively disposed of
- persisting acute infections
- many autoimmune diseases: the irritant is you
- 2) Low intensity irritant of long persistence
- i.e. an irritant that never causes an acute response, because it is low intensity. But because it doesn't go away, it results in an immune response (CI)
- foreign bodies
- various chronic infections
Osteomyelitis in the tibia. Off-centre cut down the medullary cavity. There has been an infection in the bone. This involves bot the bone and the bone marrow (defined to be osteomyelitis). The inflammation that first develops is acute inflammation. However, bone is hard tissue, and there is nowhere for the exudate to go. This raises the pressure in the bone. This collapses the veins, so there is no venous outflow. Then there is no arterial inflow. Then the osteocytes die (the bones die), and all you have left is a crystalline matrix (a rock cave). The bacteria can then play hide-and-seek in the rock. The bacteria will obtain a foothold from which they cannot be dislodged.
Weird area = abscess, full of pus, due to suppuration trying to attack the bacteria (acute irritant - suppurative) that are chronically maintained. This drained through the area of weak resistance - through damaged cortical region. Drained to the outside
- Top = abscess cavity, above which is the sinus
- Bottom = abscess, in which we see vasodilated blood vessels, with lots of neutrophils. It is practically just acute inflammation.
- So layers are: above, acute inflammation. Below that, inflammation mixed with collagenous healing. Below that, primarily healing (bone being laid down)
- A little bit outside, we see something different: Still some dilated vessels, but not as noticeable.
- The main cell type has large cytoplasm with off-centre nuclei: mainly B plasma cells (antibody synthesis), but also macrophages.
- The filamentous background = a lot of collagen fibres being formed. This is because fibroblasts are being activated as part of the repair response. *This is granulation tissue, which surrounds the abscess. Because we have granulation tissue and inflammation, this is chronic. However, there is not only collagen in bone:
In bone, there is new bone laid down, a little further out
- In an abscess, it is easy to define the different layers in which inflammation and repair are occurring, in other cses it may be much more diffuse
- Changes in cellular composition
- Less marked vascular changes
- Granulation tissue and other responses of healing (e.g. laying down of bone -- which is actually regeneration)
- Mechanisms of chronic inflammation
- Everything in acute inflammation was driven by various chemical mediators (arachidonic acid-derived cytokines etc).
- Chronic inflammation are all driven by chemical signals, mainly from newly-produced cytokines (unlike in acute inflammation, where the cytokines are ready-to-go under a cascade when tissue damage occurs). There are chemoattractants that promote macrophage recruitment, immobilisation (not wander away), activation (to release cytokines and to actually do things) and to proliferate locally (although they also proliferate away from here).
- Cytokines may be released to recruit particular clones of CD4+ and CD8+ T cells, and B cells
- Lymphocyte recruitment, activation and differentiation
- May be granulocyte recruitment (e.g. neutrophils for example). But if there is low-intensity
- Endothelial cell and fibroblast ..
- Foreign bodies are a common cause of chronic inflammation without recruitment of granulocytes -- low intensity irritants.
- Here we have an accumulation of crystals of monosodium irate (due to gout)
- causes chronic inflammation in the tissues
- (also causes acute inflammation in the joint, but that is for another day).
- This is similar to the case of a nail, splinter etc
- The cells surrounding the crystal are macrophages (long-lived cells, unlike neutrophils, and have the potential to phagocytose relatively large particles). We have an aggregation of macrophages all the way around the border of the foreign body
Inflammatory giant cell (top right) = macrophages fusing together to form a large, multinucleate that is trying to phagocytose Granuloma = localised collection of macrophages an their derivatives -- a characteristic of foreign bodies. In most granulomas, the low-intensity irritant can also trigger an immune response, and immune cells are also recruited (lymphocytes AND macrophages). However, we have the simplest form of a granuloma, that just has macrophages and some derivatives
Granuloma formed by injecting silicate crystals into tissue. Can see silicate particles inside the giant cell, indicating their increased phagocytes
Parasitic infection of ova. Giant cell going to gobble up the ovum
Sarcoidoisis - don't know the aetiology Here we have a more complex granuloma with both macrophages and lymphocytes. These macrophages are much bigger, loose cytoplasm, can't tell where one ends and the other starts - they APPEAR syncitial. In the middle - we have a very prominent giant cell. All around the edge we have lymphocytes that are driving the whole process. In immunologically-driven granulomas, the macrophages The name of this type of macrophages is called epithelioid cells. Activated for cytokine secretion rather than phagocytosis. Note that granuloma (aggregate of mostly-macrophage-derived cells) ≠ granulation tissue (gives rise to fibrous tissue)
We have bands of connective tissue surrounding many granulomas. Very often, there is granulation tissue surrounding the granuloma, because it's a chronic inflammatory response.
Long term consequences of chronic inflammation Clinical manifestations can be caused by 1) continuing effects of acute inflammation 2) destruction of tissue 3) scarring 4) systemic effects. The systemic effects of acute inflammation, if they continue, switch the body to catabolism, and can cause wasting: these people may demonstrate the symptoms of being malnourished.
Asthma Peptic ulcers Rheumatoid arthritis Ulcerative colitis/Crohn's disease Most forms of chronic renal disease Tuberculosis Another in the practical class
Asthma - a chronic inflammatory disease. We have background chronic inflammation and changes in the airways resulting in the production of lots of mucus. The acute inflammatory episodes, that are recurrent, are what cause the clinical manifestations.
Peptic ulcer of the stomach. Ulcer has gone all the way through the posterior wall of the stomach. The base of the ulcer is the pancreas. The trigger for this is helicobacter pylori. This is a chronic process with acute inflammation on top
Top = lumen of stomach Below that, there is acute inflammation Below that is granulation tissue forming new collagenous CT (scarring). Part of clinical presentation is because of acute inflammation, but part is because of scarring, which reduces the size of the lumen of the stomach. Since many ulcers are in the pylorus, they can block the communication to the duodenum --> peptic stenosis.
Rheumatoid disease (not just arthritis -- systemic) At the top = joint lumen The lining surface is not nice and flat. Instead it's thrown into folds, full of inflammatory cells (look like villi)
Villi are full of plasma cells, lymphocytes and macrophages. This is accompanied by a huge granulation tissue response (scarring), resulting in cartilage destruction. The acute inflammation, causing inflammatory cells to go into the synovial fluid and synovial membrane. The swelling reduces joint movement. They also have the clinical manifestations of chronic inflammation (wasting etc)
Ulcerative colitis We have the lining of the colon, with a piece of paper showing the fragments of remaining mucosa with everything surrounding it ulcerating (pseudopolyps).
We have lots of lymphocytes, macrophages and plasma cells. Lots of neutrophils inside the intestinal crypts (acute - on - chronic component). There is a variable amount of systemic disease as well
Glomerular nephritis (originates in the glomerulus). Chronic kidney disease, of which there are many types. Scarring of the glomeruli results in loss of bloodflow to the rest of the nephron, and you end up losing whole nephrons. We see loss of kidney structures (only collecting ducts visible), and a lot of lymphocytes/macrophages/plasma cells. This corresponds to loss of kidney function None of the clinical manifestations result from the inflammation, but instead from the tissue destruction. This results in
Tuberculosis - low-level persistent irritant. It is a tough irritant that won't go away and is hard to kill. It proliferates quite slowly, but is not killed easily. Inflammatory cells try to kill the cause, but they "die trying" and kill surrounding lung tissue --> caseous necrosis.
Can see granulomas of TB. Microscopically, we have an unstructured necrosis (missing nuclei and you can see no cellular outlines either - so it is caseous necrosis). Lots of lymphocytes, macrophages, and the granulation tissue surrounding the granuloma. The tissue destruction produces weight loss etc. Haemorrhaging may result. Acute manifestations result in the person feeling quite ill.