The Top 15 Things to Know About Cell Injury

1. How to study diseases: use four categoriesHow about we start with a few introductory statements about pathology? Seems a good way to get into the swing of things.

As Robbins says on page 1, Pathology is the study (logos) of disease (pathos). As you're studying diseases, a good way to organize the information is by breaking it down into four parts: etiology, pathogenesis, morphology, and clinical manifestations. Let's take a look at how this would work for a particular disease: lung cancer.

Etiology is the cause of a particular disease. For example, the etiology of most cases of lung cancer involves cigarette smoking. Most diseases have a bunch of different contributing factors (including genetic and environmental factors).

Pathogenesis is the actual mechanism of the disease - the way it develops in the body. Squamous cell carcinoma of the lung often progresses through stages of dysplasia before evolving into invasive carcinoma, each stage characterized by different and new genetic abnormalities within the cancer cells.

Morphology is the way a disease looks under the microscope. Squamous cell carcinoma cells are usually large, with abundant cytoplasm and intercellular bridges.

Clinical manifestations refer to the way the disease presents in the patient. Lung cancer often presents with a cough and weight loss.

There you go! I like this way of organizing information - it can be used for pretty much any disease you talk about in pathology.

For more on disease categories, see Robbins 9, page 32 (or 8, page 4).

2. Four types of cellular adaptationsWhen cells are injured, they respond by either adapting or by dying. In the area of adaptations, there are four words you should be able to define in your sleep:

1. Hyperplasia: an increase in the number of cells in a particular organ. For example, in pregnancy, the uterus gets a lot bigger, in part due to an increase in cell number (but also due to an increase in cell size).

2. Hypertrophy: an increase in cell size (not number) and functional activity. For example: when there is excess stress on the heart, the individual cells get bigger (cardiac muscle cells can't make more of themselves - so they just get bigger).

3. Atrophy: decrease in cell size and metabolic activity. For example, when muscles are not used, they atrophy; the individual muscle cells shrink in size. Tell me about it; I need to get to the gym.

4. Metaplasia: a change from one cell type to another. For example, sometimes the glandular cells in the cervix undergo squamous metaplasia in response to some irritant; presumably the squamous cells are hardier than glandular cells.

For more on cellular adaptations, see Robbins 9, page 34 (or 8, page 7).

3. What happens in necrosis at the cellular level?Irreversibly injured cells usually go down a pathway that leads to necrosis. In necrosis, intracellular proteins become denatured, and the whole cell is digested by enzymes (which may come from the dead cell itself or from incoming inflammatory cells).

Necrotic cells are usually red or pink ("red is dead"). Their nuclei show one of three characteristic patterns:

karyolyis (in which the chromatin fades) pyknosis (in which the nucleus shrinks and becomes dark) karyorrhexis (in which the nucleus fragments, like a cookie

crumbles into crumbs)

Apoptosis is a separate process; we'll discuss that later.

For more on necrosis, see Robbins 9, page 39 (or 8, page 14).

4. Six basic types of necrosisNecrosis comes in six basic flavors (well, four, if you’re a purist – but you’ll see fibrinoid and gangrenous necrosis tagging along for the ride in most lists):

1. Coagulative necrosis: cell outlines preserved but cells look ghostly; see this in infarcts.

2. Liquefactive necrosis: tons of neutrophils and cell debris; see this in infections and brain infarcts.

3. Caseous necrosis: fragmented cells and debris surrounded by lymphocytes and macrophages; see this in tuberculosis.

4. Fat necrosis: shadowy, bluish dead fat cells; see this in acute pancreatitis.

5. Fibrinoid necrosis: thick, pink-red vessel walls; see this in immune reactions in vessels.

6. Gangrenous necrosis: like coagulative necrosis, sometimes with superimposed liquefactive necrosis; see this when an entire limb loses blood supply.

For more on types of necrosis, see Robbins 9, page 43 (or 8, page 15).

5. Cell injury, super-short-attention-span versionCell injury is a long, complicated topic (see Robbins 9, pages 44-50, or Robbins 8, pages 11-23...it's a bear). Here’s a version for those of us with super short attentions spans (me).

Injury often starts with depletion of ATP. When that happens, cell membrane pumps don't work well, and calcium accumulates in the cell, doing all sorts of bad things. The four structures that are most vulnerable to cell injury are:

1. mitochondria2. cell membranes3. the protein synthesis apparatus 4. DNA

For more on how ATP damages these four structures, see Robbins 9, page 45 (or 8, page 17).

6. Six ways our cells generate free radicalsFree radicals, those nasty chemical species with single unpaired electrons in their outer orbits, are a big cause of cell injury.

Our cells generate them in 6 settings: 1. Normal redox reactions during metabolism create small

amounts of partially reduced intermediates.2. Absorption of radiant energy can create free radicals (for

example, radiation can hydrolyze water into OH and H free radicals).

3. In inflammation, rapid bursts of reactive oxygen species are created in activated white cells.

4. Enzymatic metabolism of chemicals or drugs can generate free radicals.

5. Intracellular reactions involving transition metals (like iron and copper) can catalyze free radical formation (remember the Fenton reaction? Don't take iron if you don't need it!)

6. Nitric oxide can act as a free radical (it can also be converted into other reactive oxygen species).

For more on how we generate free radicals, see Robbins 9, page 47 (or 8, page 21).

7. Three ways to get rid of free radicalsFree radicals are nasty, no way around it. To survive, cells have to have ways to get rid of them. Here are the three main mechanisms:

1. Antioxidants (e.g., vitamins E and A). These guys either block the formation of free radicals or inactivate them (like little scavengers).

2. Iron and copper binding. Iron and copper can catalyze free radical formation. So it's a good idea to minimize the amount of free iron and copper around. A good way to do this is to bind it up and store it (using transferrin, ferritin, lactoferrin and ceruloplasmin).

3. Enzymes (e.g., catalase, superoxide dismutase, and glutathione). These guys are located near the places where free radicals are formed; they scavenge free radicals and break them down into harmless components.

For more on how we get rid of free radicals, see Robbins 9, page 48 (or 8, page 21).

8. Why are free radicals so bad, anyway?Free radicals attack three main structures within the cell:

1. Membranes. When oxygen is around, free radicals cause lipid peroxidation within plasma and organelle membranes. Free radicals attack the double bonds in unsaturated fatty acids, yielding peroxides (which are themselves unstable, and can cause the same type of membrane damage). A damaging chain reaction ensues.

2. Proteins. Free radicals oxidize amino acid side chains, forming protein-protein cross-links (disulfide bonds), and oxidizing the protein backbone. All sorts of proteins can be messed up this way: enzymes, structural proteins, you name it.

3. DNA. Free radicals do all kinds of nasty things to DNA: break it, cross-link it, and form adducts. DNA damage contributes to aging and sometimes to malignant transformation of cells.

For more on how free radicals attack our cells, see Robbins 9, page 49 (or 8, page 22).

9. Four ways membranes get damagedOne thing that's common to almost all forms of cell injury (except apoptosis) is cell membrane damage. There are four main ways that cell membranes can be damaged:

1. Lipid peroxidation. Free radicals can destroy the cell membrane.

2. Decreased phospholipid synthesis. If the mitochondria are not functioning properly, or there isn't enough oxygen around, then phospholipid synthesis will decrease.

3. Increased phospholipid breakdown. If there is excess calcium around, that can activate endogenous phospholipases, which break down phospholipids.

4. Cytoskeletal abnormalities. Calcium can also activate proteases, which damage elements of the cytoskeleton, allowing the cell membrane to detach and possibly rupture.

For more on cell membrane damage, see Robbins 9, page 49 (or 8, page 22)

10. ApoptosisApoptosis is a unique kind of cell death that happens in a pre-programmed fashion. The apoptotic cell is basically committing suicide according to the instructions it carries in its genes. It releases enzymes that degrade its own DNA and other proteins, and its cell structure becomes altered in such a way that phagocytes see the apoptotic cell as yummy.

Interesting: this phagocytosis happens before cellular contents leak out - so there's no stimulation of the host immune response. Necrotic cells, on the other hand, have massive membrane disruption and release their cellular contents, eliciting a host reaction.

For more on apoptosis, see Robbins 9, page 52 (or 8, page 25).

11. What's the difference between apoptosis and necrosis?Both apoptosis and necrosis are types of cell death. So what are the important differences?

First of all, and this may be the most important thing in this whole post: do NOT pronounce apoptosis like this: eh-pop-toh-sis. It does not start with a long "a" (like in "ailment"), and the second "p" is silent. It's pronounced like this: apuh-toh-sis (starting with "a" as in apple, and emphasis on the "toh" syllable). When I hear this word pronounced incorrectly, I feel a little sick, and it makes me question the credibility of everything else the person says. That might be harsh, but there you go.

Apoptosis is programmed cell death. The cell decides to kill itself, and that's that. The mechanisms for doing so are already programmed into the cell's DNA; it just needs the right signal. It's usually a tightly-regulated and controlled process. It can occur in pathologic processes, like tumors, but it is also a part of certain physiologic processes, like embryogenesis (the hand starts out as a little paddle, then parts of the tissue undergo apoptosis, and what remains becomes the baby's fingers).

Necrosis, on the other hand, is always pathologic and never physiologic. It is the result of irreversible injury to a cell. It's not tightly controlled - the cell just dies because it's been injured by lack of blood supply, free radical damage, infection, toxins, or other nasty things.

For more on apoptosis, see Robbins 9, page 52 (or 8, page 25).

12. AutophagyIn times of starvation, cells can eat their own contents and recycle the digested materials. This is called "autophagy." Organelles and cytoplasm are sequestered in an autophagic vacuole, which fuses with a lysosome to form an autophagolysosome. The whole process is regulated by a set of genes called, not surprisingly, "autophagy genes." Autophagy has been proposed as a form of cell death in different diseases such as neurodegenerative diseases and degenerative diseases of muscle.

For more on autophagy, see Robbins 9, page 60 (or 8, page 32).

13. What does “hyaline” mean?Here's a term that's thrown around a lot in pathology as if everyone knows what it means: "hyaline." Usually, the word hyaline is used descriptively, to refer to an accumulation of pink, glassy material.

Many processes can lead to hyaline change, including: Protein accumulation (Russell bodies and alcoholic hyaline are

pink and glassy) Scarring (fibrous tissue in old scars can look pink and glassy) Vascular changes in hypertension and diabetes (extravasated

plasma proteins and deposition of basement membrane material can give the vessel walls a pink, glassy appearance)

For more on hyaline change, see Robbins 9, page 63 (or 8, page 36).

Mallory body (or Mallory hyaline) at the center of the ballooning hepatocyte in the

center of the photo.

Hyaline change in renal arteries.

14. Five main tissue pigmentsPigments (colored substances) are sometimes seen in histologic sections. They can be normal or abnormal, and they may be from the outside (exogenous) or made inside the body (endogenous). There are five main pigments seen within tissues.

1. Carbon (coal dust)This is the most common exogenous pigment. It's seen in urban dwellers, coal miners and smokers. The official name for the blackening of the lungs seen in these patients is anthracosis.

2. Tattoo pigmentTattoo pigments are often composed of metal salts (like iron oxide), but vegetable dyes and plastic-based dyes may be used too. The pigment is phagocytosed by dermal macrophages which retain the pigment for the person's lifetime.

3. LipofuscinThis pigment, known as the wear-and-tear pigment, is composed of a bunch of lipids and proteins and has a yellow-brown appearance The name is derived, in part, from the Latin word fuscus, which means dingy, brown, or dark. That's probably why "obfuscate" means "to make unclear or obscure." This is the weird kind of thing that makes me happy. I have no idea why finding the Latin connection between two seemingly unrelated words should make me happy in such disproportionate measure - or happy at all - but it does. Happiness aside, lipofuscin accumulates with age, and is of no clinical significance. 

4. MelaninMelanin comes from the Greek word for black (melas). This doesn’t make me as happy as fuscus. I don’t know why. It is a deep brown-black pigment that is seen, not surprisingly, in melanocytes.

5. HemosiderinThis yellow-brown pigment is one of the major storage forms of iron.

Lipofuscin

It is normally seen in macrophages in the bone marrow, spleen and liver (which are actively breaking down red cells). It is also seen when there is a local excess of iron (as in a bruise) or systemic excess of iron (for example, in patients with repeatedblood transfusions).

For more on tissue pigments, see Robbins 9, page 64 (or 8, page 37).

15. Adult progeria

Werner syndrome, often called "adult progeria," is a rare autosomal recessive disorder in which patients undergo premature, accelerated aging. The incidence in Japan is 1 in 100,000, but outside Japan, the incidence is more like one in a million to one in 10 million people.

The defective gene product in this syndrome is a DNA helicase (a protein that participates in DNA replication and repair). When this enzyme is defective, chromosomal damage (mimicking that which normally occurs during aging) accumulates.

Patients usually present in their early teens with a lack of the normal teenage growth spurt. Patients age rapidly following puberty; by age 40, they often appear several decades older, with gray hair, a hoarse voice, and any of a number of "older people" diseases like cataracts, hypogonadism, atherosclerosis, cancer, and diabetes.

Note: this is different than "regular" progeria, which is a disease also characterized by accelerated aging but begins much earlier in life.

For more on Werner syndrome and aging, see Robbins 9, page 66 (or 8, page 41).