Cell Injury

Hey everyone!

So for those of you who don't know where I've been, and are wondering why I haven't updated for so long, you are about to find out why! Basically, I'm currently on exchange in Canada. The units I'm taking are Pathophysiology, Immunology, Introduction to Teaching Music to Children, Beginning Language and Culture I (Inuktitut I) and Introduction to Statistics.

Because I'm busy with exchange and everything that comes with it (*cough*actuallyhavingtocookformyself*cough*) I probably won't update as much as I did back home. Also, not everything I say here will be relevant to the PATH and MICR units back home. Hopefully some of it will be though!

This first post is going to be about Pathophysiology, which I think is technically a third-year unit. One point I just wanted to mention is that over here, lectures are generally not recorded. Hence lots of people actually attend lectures. It's actually really weird to go to a pretty full lecture that's not a first-year lecture.

Anyway, time to move on to talking about the first topic!

Cell Functions Susceptible to Injury

The first topic is, as the title of this post suggests, cell injury. So let's look at the myriad of ways in which cells can be injured!

• Damage to the genetic apparatus (i.e. DNA). This can happen due to radiation etc. Nuclei can also break down- shrinkage of nuclei is called pyknosis whereas fragmentation is called karyorrhexis.
• Damage to the cell membrane. When cells are damaged, they release all of the stuff inside, like enzymes and so forth. These can be used as a diagnostic tool for finding out which areas of the body are damaged.
• Reduced capacity of the cell to produce ATP. One of the main effects of this is that the Na⁺/K⁺ pump no longer has enough energy to keep pumping out those ions. This causes more ions to hang around in the cell, which in turn causes more water to come in via osmosis, which eventually causes the cell to lyse (burst). One of the main causes of a cell losing its ATP-producing capacity is a lack of adequate blood flow.

Free Radicals

Free radicals are atoms that have an unpaired electron somewhere in this outer shell. This renders them highly reactive and liable to destroy stuff. Some common free radicals are hydroxyl radicals, which come from the breakdown of hydrogen peroxide (see, this is why you shouldn't drink bleach, kids), and superoxide (i.e. O₂ with an extra electron).

Free radicals can be formed by normal reactions in the body. For example, xanthine oxidase can break down hypoxanthine into uric acid and hydrogen peroxide, which in turn can break down into hydroxyl radicals. Exposure to radiation can also result in the formation of free radicals. Finally, Fe²⁺ can promote the formation of reactive oxygen-containing radicals.

Thankfully, we have several ways in which we can protect ourselves from free radicals. There are several enzymes tasked for this purpose, including but not limited to the following:

• Superoxide dismutase: converts superoxide and hydrogen ions into hydrogen peroxide and oxygen. Requires zinc to do so. And yup, I realise that the hydrogen peroxide is a problem, but it's not a problem for long due to the presence of...
• Catalase: Converts hydrogen peroxide into oxygen and water.
• Glutathione peroxidase: Converts hydrogen peroxide and glutathione into oxidised glutathione and water. Requires selenium.

Some molecules are also pretty good at "scavenging" for radicals and clearing them out of our system. These are known as antioxidants. Water-soluble vitamin C and lipid-soluble vitamin E are two examples of antioxidants.

Necrosis and Apoptosis

Necrosis is the death of a group of cells. There are several types of necrosis. Coagulative necrosis, which results from a lack of blood supply, causes proteins to denature but the cell outlines are still retained. Liquefactive necrosis is where cell contents are broken down by enzymes, but pockets of liquid remain. Finally, caseous necrosis, found in the lungs of tuberculosis-affected patients, is characterised by dead cells walled off by white cells (a.k.a. a granuloma).

While necrosis is the death of a group of cells due to injury, apoptosis is the controlled, programmed death of individual cells. In the process of apoptosis, internal proteases called caspases are activated. There is also a decrease in cytoskeleton formation, causing the cell surface to bleb. I've written about apoptosis on an earlier post, if you'd like a bit more detail.

Cell Adaptation

There are many ways in which cells adapt to changing environments. I'm only going to list off the really obvious, visible changes here.

• Atrophy- Decreased size of cells
• Hypertrophy- Increased size of cells
• Hyperplasia- Increased number of cells (but cells remain more or less the same size). This is in contrast to hypertrophy, which is the same number of cells but increased size.
• Metaplasia- Replacement of one cell type by another
• Dysplasia- Disordered arrangement, growth and nuclear shape. May be indicative of future cancer, and thus is one of the markers that they look for on Pap smears.
• Anaplasia- Undifferentiated cells. May be indicative of cancer.
• Neoplasia- Abnormal growth of new cells which are unresponsive to growth control. So basically just a fancy name for a tumour.

Tumours and Cancer

As mentioned above, a tumour, or neoplasia, is the abnormal growth of new cells which are unresponsive to growth control. There are two main types of tumours: benign and malignant. Benign tumours grow more slowly, have differentiated cells, and normally stay put. These are denoted by the suffix -oma. Malignant tumours, on the other hand, are undifferentiated, fast growing cells, which can spread to other areas of the body (metastasise). These are denoted by the suffixes -carcinoma and -sarcoma, and are generally what we refer to when we talk about cancer.

Cancer is a disease resulting from the accumulation of many DNA mutations acquired over time. Some of the most prominent genes involved include tumour suppression genes such as the retinoblastoma gene (it's not only involved in retinoblastomas, it's just that that's the first place where they found it) and oncogenes. Factors predisposing someone to cancer include poor DNA repair mechanisms and age (i.e. more time to acquire more mutations). Factors that can lead to cancer, including environmental factors like smoking, inherited factors like gene mutations and viruses like HPV, are known as initiators. Other factors that do not cause cancer but instead might help cancer cells grow, like oestrogen in breast cancer and testosterone in prostate cancer, are known as promoters.

Aside from the characteristics of malignant cancer cells discussed above, malignant cells are also able to avoid apoptosis by using telomerase to keep their telomeres long, VEGF (vascular endothelial growth factor) to grow new blood vessels for themselves, and lose their contact inhibition due to defective cadherin and catenin molecules (which normally make cells stop dividing once they're squished by other cells). Pretty cheeky I reckon.

Coagulation

Right, now onto the fun times of talking about that long coagulation pathway which you've probably seen somewhere before! Don't worry, you don't need to know about every single clotting factor. Just a few of them.

There are two main pathways that lead to coagulation: the intrinsic and the extrinsic pathways. The extrinsic pathway is thought to be more important than the intrinsic pathway when it comes to coagulation. The only thing you need to keep in mind for now is that part of the intrinsic pathway involves the use of Factor VIII and vWF (von Willebrand Factor) to create a platelet plug. Actually no, that's not the only thing. The other thing you need to keep in mind is that the two pathways meet at the step where Factor X is converted into Factor Xa, a step that requires calcium. Drink yo' milk, kids. (Huh, that's the second time I've said "kids" in this post. I must really like calling you a kid.)

What does Factor Xa do, you might ask? Well, it converts prothrombin into thrombin. Prothrombin is a substance that can only be created if you have vitamin K, but if you take warfarin (a blood thinner) then the synthesis of prothrombin is inhibited. Also, another substance called heparin can prevent prothrombin from becoming thrombin. That sounds like a bad thing, but y'know, having a disorder where your blood clots at inopportune times would suck too.

Anyway, we still have the rest of the pathway to look at! Thrombin catalyses the conversion of fibrinogen into fibrin (remember, if something ends with "-ogen," it's likely to be an inactive precursor of some other molecule). Fibrin, with the help of Factor XIII, can then form a clot. Yay!

But what if you don't want clots to form? Well then it's plasmin to the rescue! Plasmin is formed from plasminogen, with the help of tPA, or tissue plasminogen activator.

Coagulation time can be measured with a few tests. PT (prothrombin time) and INR (International Normalised Ratio) are used to measure the extrinsic pathway. PT is highly variable, so INR is used instead (INR is essentially just comparing your PT to that of a control sample). PTT, or partial thromboplastin time, is used to measure the intrinsic pathway. (Just remember- when measuring intrinsic, put an extra T "into" the acronym.)

Such diagnostic tests are important, as they can help diagnose coagulation disorders. Haemophilia A is one such disorder, in which Factor VIII is defective. Another common disorder is von Willebrand Disease (which as you might guess is a deficiency of von Willebrand Factor), which is treated with desmopressin, an analogue of vasopressin.

Wound Healing

Healing of wounds requires several steps- yup, above and beyond the coagulation pathway that I outlined above. Firstly, vasospasm, or contraction of blood vessels, occurs in order to prevent further blood loss. The coagulation cascade takes place, causing platelet plugs and clots to form. Neutrophils and macrophages come in and remove damaged cells.

Meanwhile, regeneration starts to take place. Nearby cells undergo mitosis, forming granulation tissue (essentially just the new stuff). Growth factors such as VEGF and FGF (fibroblast growth factor) promote angiogenesis. Finally, fibroblasts, if they have enough vitamin C, produce collagen fibres, which can shorten to produce a scar. This seals up the wound, but unfortunately collagen isn't quite an adequate substitute for the hair follicles, glands, nerves or whatever else was in that spot before the scar was formed.

And that's the end of my first post from Canada! Yay!