INJURY TO CELL MEMBRANES
Let's begin with a quick review of the cell membrane...

Cell membranes are composed of a bimolecular layer of phospholipids and cholesterol, with hydrophilic and hydrophobic regions.

The water soluble polar heads of the phospholipids are exposed on both surfaces and the hydrophobic "tails" are buried in the interior 

Peripheral proteins move along the surfaces and integral proteins are embedded in the lipid bilayer. Some integral proteins extend through both layers (transmembrane proteins). Many of these are glycoproteins with surface carbohydrate units.

The cell membrane is the site of the sodium ion pump which maintains cell volume by pumping sodium out of the cell. The outer plasma membrane is permeable to ions, but not to larger molecules. It is also the site for hormone-receptor and cell signal interaction.

Membranes form the structural organization for RER, SER, and mitochondria. Oxidative phosphorylation takes place on the mitochondrial membrane and protein synthesis on the ribosomal membranes of the RER. Membranes are the "partitions" that separate subcellular organelles such as nucleus and mitochondria from each other and from the cytosol.

Injury to the cell membranes
Injury to the cell membrane has immediate and severe consequences. Even in anoxic injury, the common pathway to irreversible cell injury and necrosis involves damage to the cell membrane. In this unit, we will learn some of the important mechanisms of cell membrane damage and the consequences of membrane damage.
Consequences of membrane damage.
When cell membranes are exposed to noxious agents both outer plasma membrane and the membranes of organelles are at risk. What is the earliest sign of cell membrane damage?  
What are the three main mechanisms of cell membrane damage?
Damage to cell membranes results in abnormal ion fluxes and disfunction of organelles.
Now that we know a few of the important functions of cell membranes, what happens in the cell when membranes are damaged? 
Mechanisms of cell membrane damage
Cell membranes are highly susceptible to injury by free radicals. What are "free radicals" and where do they come from? 
This chart shows some endogenous sources of free radicals
Plasma membrane
Lipoxygenase activity
Prostaglandin synthetase
Lipid peroxidation 

Endoplasmic reticulum
Cytochrome P 450

Mitochondria
NADH dehydrogenase
Electron transport

Cytoplasm
Xanthine oxidase
Aldehyde oxidase
Divalent metals (Cu+, Fe++)

Peroxisomes
Oxidases

Free radicals can also be produced by ionizing radiation acting on water, or from enzymatic activity on exogenous drugs or chemicals.

Free radicals produced by endogenous metabolic reactions include superoxide anion (O2-), hydrogen peroxide (H2O2), and the hydroxyl radical (OH.).

Although all these reactions can take place concurrently in the body, convention has separated them into distinct reactions.
Chemical reactions leading to the endogenous production of free radicals
1) O2 O2·- superoxide anion
2) 2 O2·-   + 2 H+ H2O2 + O2  hydrogen peroxide
3) H2OH· +  OH- hydroxyl radical
FENTON REACTION
4) Fe++ + H2O2Fe+++  OH·  +  OH- hydroxyl radical 
HABER-WEISS REACTION

5) H2O2 + O2·OH· + OH- + O2 hydroxyl radical

An example of a free radical produced by enzymatic metabolism of an exogenous chemical is metabolism of the solvent carbon tetrachloride (CCl4) by mixed function oxidases in the liver to produce the free radical CCl3.
How do these free radicals damage membranes?
Unfortunately, once oxidation of fatty acids begins, further reactions form lipid radicals which combine with oxygen to form hydroperoxyl radicals that in turn form lipid peroxides. This reaction becomes self-propagating resulting in widespread membrane damage due to lipid peroxidation
Peroxidation of fatty acids by the CCl3 free radical
SMOOTH ENDOPLASMIC RETICULUM 
CCl4CCl3·
LIPIDHLIPID·
H
–C=C–C
–C=CC
O2
O
O

C=CC
LIPID PEROXIDE

By-products of fatty acid oxidation include aldehydes such as malondialdehyde which cause protein polymerization.  The membranes of subcellular organelles are particularly sensitive to lipid peroxidation because their membranes are high in unsaturated fatty acids.

As would be expected, the cell has defensive mechanisms against this kind of damage. Endogenous antioxidants such as vitamin E, ascorbate, ceruloplasmin, transferrin, and cysteine help protect membranes from oxidant injury.
Enzymes such as superoxide dismutase, glutathione peroxidase and catalase neutralize free radicals.
1) 2 H+ 2 O2·H2O2 + O2
2) 2 OH· + 2 GSH2 H2O + GSSG
3) 2 H2O2 O2 + 2 H2O
Any interference with these protective mechanisms can result in membrane damage by oxidants. Can you envision a mechanism by which vitamin E and selenium deficiency could result in cell injury? Click here for answer
What is the major component of the cell membrane?
Abnormalities in the cytoskeleton result in membrane damage.
The cytoskeleton composed of microfilaments, intermediate filaments and microtubules serves as a structural support system and transport system for the cell. Detachment of the cytoskeleton from the plasma membrane caused by cell swelling or drug intoxication (cytochalasin) results in membrane "blebs" and ultimately renders the cell membrane much more susceptible to lysis.
Damage to the cells energy supply and damage to the cell membrane are only 2 of many mechanisms of cell injury.
We have only covered two of the most important mechanisms of cell injury (disruption of the energy supply and membrane damage).  Direct damage to DNA or the protein synthesis machinery of the cell can also be lethal. We have not discussed all of the possible ways that membranes can be damaged, such as direct injury by viruses, complement, channel blockers and ionophores.
It should be apparent that damage to the cell's energy producing machinery and damage to the cell membrane are hopelessly intertwined. The unifying concept is that no matter what the initial cause of cell injury, somewhere in the progression from normal steady-state to cell death, membrane disfunction, disruption of the cell's energy supply, or both lead to cell death.
Injury to cells relates to the health of the animal.
Now that you have some understanding of injury at the cellular level, you must try to link the link these events at the cellular/molecular level with the health of the animal as a whole. How does cell injury result in a clinically ill or dying patient?  Once we understand which organ or organs are failing, and how cells are being injured or killed, we may be able to intervene medically to reverse the process and restore the animal to health.
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