As I have already suggested, chemicals released in the inflammatory response can cause damage to cells and the response can also lead to the formation of oedemas. Of course, the response can also be initiated by tissue damage in the first place. Ideally, when any pathogens or foreign bodies - and/or dead or damaged cells - have been removed in the way I described earlier, the healing process will begin. Some cells, such as epithelial cells, are easily capable of regenerating. Some structures, such as the skin, are easy to reconstruct. Some cells, however, such as liver cells, do not generally regenerate - but can be made to - and some do not regenerate at all. Again, some structures, such as glands, are not easy to reconstruct. In the case of cells which can easily regenerate, they will do so and, where simple structures need to be reconstructed, they are rebuilt quite happily.
Where, however, there is substantial damage, or the damaged area is difficult to heal, a repair process will take place. In this case, scar tissue is built which "patches up" the damage. It is often imperfect. New blood vessels are constructed first from endothelial cells and fibroblasts form loose connective tissue. What results is granulation tissue. The new blood vessels establish blood flow to the growing tissue and collagen is formed from the fibroblasts. Ultimately, one is left with a scar, primarily formed of this collagen. It functions much like a patch on clothes and, much like a patch on clothes, it is not usually a perfect substitute. Improper repair can cause organ dysfunction, as in cirrhosis of the liver.
A second non-optimal result is suppuration, which is the formation of pus - which consists largely of dead and otherwise spent neutrophils and bacteria, fluid (from the blood vessels) and debris (from the cells). It occurs as a result of a pathogen or foreign body which is hard to remove and, hence, the neutrophils, bacteria, etc. remain and collect as pus. This pus will accumulate and an abscess will eventually develop, which is simply the accumulated pus enclosed by a membrane. Difficult to treat, due to the membrane, they may need to be surgically removed. Some, however, such as boils, will simply burst. Which is nice. At least, it's nice after a manner of speaking. When the abscess does burst, or when it's removed, the surrounding tissue is repaired as normal.
With this - and the brief foray into chemotaxis - concluded we have a good overview of what inflammation is and what it does. The question we must answer is how all of this is achieved. Those cells which initiate the inflammatory response are macrophages, dendritic cells, histiocytes, Kupffer cells and mastocytes. These cells possess cell surface receptors called pattern recognition receptors (PRRs). These are proteins, such as TLR 1 (toll-like receptor 1):
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| Figure 1.2: A rendering of toll-like receptor 1 (TLR 1). (Image courtesy of "Yookji," via Wikipedia) |
Which bind specifically with pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). PAMPs are molecules which are conserved in many different pathogens, but are peculiar to pathogens. That is to say that PAMPs are generic pathogen molecules - most pathogens will have them and they can be recognised by the PRRs. Remember that inflammation is non-specific, it is a response to pathogens in general and this is the how and the why. Generic pathogen molecules can be recognised and the response is always the same. DAMPs, meanwhile, are molecules which are released when cells are damaged. The principle is, again, the same. A cell such as a macrophage, which possesses PRRs, will recognise a DAMP as coming from a damaged cell and will respond to it. The response is generic.
I will take macrophages as an example. Macrophages have TLR 1 as one of their PRRs and so do neutrophils. Not all of the cells involved in the immune response will have TLR 1 and TLR 1 is only one PRR among many. Nevertheless, I will use it as an example. TLR 1, in combination with TLR 2, can recognise the polymer peptidoglycan, which forms the cell wall of many bacteria. Peptidoglycan is found in large numbers of pathogens, but not natively in the body. As such, the ability to recognise peptidoglycan is very useful. It is peculiar to pathogens and so its presence is always indicative of pathogens. It is also common and so a good number of pathogens can be recognised simply by the presence of peptidoglycan. As such, natural selection has furnished us with cells with receptors on them that are good at recognising peptidoglycan (and other such PAMPs).
Suppose, then, that peptidoglycan binds with TLR 1. (From this example we can understand the general principle which underlies all such processes. It will not be necessary to consider every cell, every receptor, every PAMP, etc. but it is necessary to appreciate that each receptor will be different and work in its own way.) TLR 1 actually functions either as a homodimer1 - which is to say that two TLR 1 molecules together recognise a PAMP - or as a heterodimer2 with TLR 2. The shape and chemical composition of TLR 1 (and TLR 2) is crucial and it is this which allows it to "recognise" PAMPs; this is why particular receptors only bind to certain, specific molecules and bind to them well. Thus each receptor is specific in what it recognises, meaning that the right cells recognise the right molecules (and, therefore, pathogens) and the right response is elicited. In our case, the result of peptidoglycan binding to TLR 1 - either in combination with another TLR 1 receptor, or with TLR 2 - is a conformational change of the receptors, which activates a signalling pathway.
Cell signalling is an extremely important and fundamental process which allows collections of individual cells to function as part of a larger whole - such as a muscle, or an organ - and, ultimately, as part of a complex organism. It is a means of communication and coordination, and it is the means by which our cells are made to do what is required of them. Cells communicate with each other either by cell-to-cell contact (juxtacrine signalling); or by releasing signalling molecules,3 which may be used for communication with nearby cells (paracrine signalling), or with many cells around the body and/or cells which are far away (endocrine signalling). This signalling is achieved by ligands binding to cell surface receptors. Again, when the ligand binds to the receptor, it brings about a change in the conformation of the receptor. In some cases this, in itself, brings about the required response of the cell. In other cases, signal transduction takes place. The conformational change in a receptor will initiate a series of chemical reactions inside the cell which, ultimately, brings about the required response.
In our case, when peptidoglycan binds with TLR 1, signal transduction also takes place. Here, however, the signal is not from the body, but from a pathogen. In the case of PRRs, signalling pathways are employed to elicit an immune response to a pathogen, rather than to coordinate some bodily function, such as stimulating the ovaries to release an egg, or stimulating blood vessels to dilate. In our case, the response elicited is the release of cytokines.
Once again I will now briefly pause my discussion of inflammation for a slight tangent, where cell signalling will be discussed more deeply. Once again, feel free to skip straight on to the rest of the discussion.
1A dimer is a large macromolecule formed from two macromolecules joined together. In the case of homodimers, these two component molecules are the same
2Naturally, in the case of heterodimers, the two component molecules are different
3The three primary types of signalling molecules are hormones, neurotransmitters and cytokines
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