Inflammation
Okay, you probably already have a vague idea of what inflammation is. When you have an inflamed insect bite or whatever, your skin becomes red, warm, swollen and sore. These are the main signs of inflammation.
So why does this actually happen? Well, the gist of it is that when an areas is inflamed, the vessels dilate and become more "leaky," allowing fluid and leukocytes (i.e. white blood cells) to leak out. The fluid and protein exudate can be serous (watery, like in burns), fibrinous (high fibrin, leaving scars) or purulent (containing pus, which is essentially just dead cells). The exudate leads to the swelling, the vasodilation and increased blood flow leads to redness and warmth, and if the swelling presses against nerves, pain can result.
Sometimes inflammation can also lead to systemic signs. These systemic signs include fever, a higher erythrocyte sedimentation rate (due to the agglutination of red blood cells), increased levels of C-reactive protein (CRP) (an opsonin involved in the acute phase of inflammation- don't worry, I'll explain opsonins in a bit) and leukocytosis. Leukocytosis is an increase in the number of WBCs, and the type of WBC that increases depends on the type of inflammation. In acute inflammation, the number of immature neutrophils increases; in chronic inflammation, the number of lymphocytes increases. (Don't worry, I'm going to explain the different types of leukocytes soon.) A differential count, which looks at the ratio between immature neutrophils and lymphocytes, can help in diagnosis. Allergies and parasitic infections may increase the number of eosinophils. In contrast, viral infections may lead to leukopenia (decreased number of WBCs), as some viruses destroy white blood cells.
Leukocytes
Let's backtrack a bit to talk about the main leukocytes involved in inflammation. Some important cells to know are mast cells, neutrophils, eosinophils, monocytes, macrophages and lymphocytes.
Neutrophils, the most common type of WBC, are the first cells to arrive at the scene. They are drawn to the site via chemotaxis, a process in which they move towards areas with a higher concentration of signalling molecules (which in this case includes bacterial peptides, complement, prostaglandins and so on). Once they get to the site in question, they attach to proteins called selectins that line the vascular wall in a process called margination, before eventually moving across the vessel membrane in a process called diapedesis.
Neutrophils have relatively short lives (24-48 hours), during which they engulf and digest pathogens (om nom nom!). Before they do this, though, they need to recognise their antigens so they know what to eat and what not to. One way in which they recognise antigens is by binding to opsonins, which are molecules that can be used to coat antigens. For example, when antibodies bind to antigens, the antibodies are opsonins. Antibodies are specific opsonins (that is, antibodies will only bind to specific molecules), but there are other non-specific opsonins as well, such as complement.
After neutrophils eat their prey, they digest it. This digestion occurs in phagosomes, where superoxide radicals help to eat things up. It does this by being converted into hydrogen peroxide and then into hypochlorite radicals, courtesy of the enzyme myeloperoxidase (which catalyses the latter step). Superoxide is originally created by the reaction of oxygen with NADPH in a process called an "oxidative burst."
Okay, enough about neutrophils! The next important cells to talk about are monocytes and macrophages, which are the next to arrive after the neutrophils. Monocytes circulate in the blood, but once they get into the tissue, they differentiate into macrophages. Macrophages, from macro (big) and phage (to eat) are big eaters! They are the main phagocytic cells of the immune system.
Finally, a few other cells! They're important too, but not so much for now.
Eosinophils are cells that mainly attack parasites, but unfortunately they attack allergens too. Rude.
Mast cells can secrete histamine-containing granules. Histamine is an important mediator of inflammation, as we'll see later.
Lymphocytes come in several types. The most important types to know for now are B-lymphocytes, which make antibodies, cytotoxic T-lymphocytes, that kill stuff directly, and helper T-lymphocytes, that release mediators and signalling molecules to help coordinate everything.
Chemical Mediators of Inflammation
Time to overwhelm you with names! I'm so sorry...
Histamine is released by mast cells and basophils in response to trauma, IgE binding to mast cells, complement and/or interleukin. It causes bronchoconstriction, vasodilation and increased vascular permeability. This is good in that it helps white blood cells get out into the tissue, but can be bad if it happens to excess. In excess, blood pressure can drop, causing anaphylaxis.
Complement is a collection of proteins made in the liver. The proteins have many different functions, and may help to increase vascular permeability, act as opsonins and so on. Some complement molecules can get together and assemble into a MAC, or Membrane Attack Complex. This is basically a pore that forms in the bacterial membrane, causing fluid to enter the bacteria, which in turn causes swelling and lysis.
Arachidonic acid, stored in membranes and released by phospholipase A2 (which is activated by complement, which I guess highlights how important complement is), has a lot of important metabolites. Arachidonic acid can be broken down by lipoxygenase into the leukotrienes, or by cyclooxygenase into prostacyclins, prostaglandins or thromboxanes.
Leukotrienes are formed by the breakdown of arachidonic acid by lipoxygenase. They cause bronchospasm (bronchiolar constriction), vasodilation and increase vascular permeability, sorta like histamine. They also promote chemotaxis. Leukotrienes, unlike other arachidonic acid metabolites, are not affected by NSAIDs (non-steroidal anti-inflammatory drugs, like ibuprofen).
Prostaglandins, just like histamine and leukotrienes, promote vasodilation and oedema development. They also mediate fever and pain. Prostaglandins also have a few other functions in other areas of the body, but we don't have to go into those now.
Thromboxanes, like TXA2, are formed in platelets. These are a bit different to the other molecules we've discussed so far, as they actually promote vasoconstriction, as well as platelet aggregation.
Prostacyclins, like PGI2, are the opposite of thromboxanes. They are formed in endothelial cells and inhibit platelet aggregation while promoting vasodilation. This ensures that a clot somewhere in your body won't randomly spread somewhere else. Prostacyclins are less sensitive to NSAIDs than thromboxanes, which is useful: taking a small amount of an NSAID, like aspirin, can prevent clotting via thromboxanes, without affecting the prostacyclin pathway.
Cytokines are signalling molecules in the immune system which mediate interactions between WBCs and promote chemotaxis. They are produced by activated lymphocytes and macrophages. There are three main types that you need to know:
- Interleukins activate T-lymphocytes and increase vascular permeability. They are pyrogenic- that is, they induce fever.
- Tumour necrosis factor (TNF) causes release of proteolytic enzymes.
- Interferon interferes with viral replication and gets uninfected cells ready for viral attack.
And that's two out of three topics down before the topic test on Thursday! Yay!
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