بسم الله الرحمن الرحيم

قال تعالى:" و أن ليس لإلنسان إال ما سعى، و أن"سعيه سوف يرى

We already said in the last lecture that there are reversible and irreversible injuries, and here is the outline of this (figure on slide #5), you can see here that u have a normal cell, which is always under stress or injury. This cell can show no change, or it can adapt to the change , or shows some reversible changes of injury, or the injury is so bad that there is irreversible damage and death.

Causes of cell injury:

1- Hypoxia ( oxygen deficiency) and Ischemia (loss of blood supply in a tissue) .

Hypoxia is one of the most common causes of cell injury, it can be caused by many factors such as:

a-Low levels of oxygen in the air.

b- Poor or absent hemoglobin function, the hemoglobin itself may be abnormal, and cannot carry proper amount of oxygen.

c-Decreased erythropoiesis: production of red blood cells (the main cells carrying hemoglobin), so cells are not well oxygenated.

d- Reduction of oxygen capacity of the blood, as in respiratory disorders ( e.g. pneumonia) or cardiovascular disorders can also cause hypoxia.

Both of them - hypoxia & ischemia - induce mitochondrial damage, because the mitochondria are the main components that deal with the respiratory function in the cell.

When the mitochondria are defected , then we’ll have a decreased generation in energy (ATP), & this affects cell functions. If the defection is persistent and severe it leads to cell death.

As you see in this figure, once oxidative phosphorylation is reduced due to Ischemia, the Na pump and the anaerobic glycolysis are effected and so on.

In the case of hypoxia (oxygen deficiency) the cell resorts to anaerobic glycolysis (doesn’t use oxygen), so lactic acid will accumulate and this will generate acidosis.

Ischemia (the most common cause of hypoxia) injures the cell faster than pure hypoxia, why?

In the case of hypoxia, the cell resorts to anaerobic glycolysis. While in Ischemia, when blood that carries substrates (nutrients) needed for the cell to perform anaerobic glycolysis is blocked or reduced, anaerobic glycolysis cannot take place so the injury will be faster.

Now sometimes reperfusion (restoration of the flow of blood to a previously ischemic tissue or organ (as the heart or brain) - reperfusion following heart attack for example-) although it is helpful, in some cases it may lead to recovery or further damage through something called Ischemia/ reperfusion recovery. This can affect the cell and lead to progressive cell damage.

*examples where this occurs: frequently occurs in Myocardial and Cerebral Infarction in the heart, sometimes you see that the patient is first stable, and then he deteriorates after any of these infarctions.

Infarction: a localized area of tissue, as in the heart or kidney, that is dying or dead, having been deprived of its

blood supply because of an obstruction by embolism or thrombosis.

And this can be explained as the following:

Restoration of blood flow leads to generation of high levels of calcium, and we shall see later that when Ca enters the cell, it produces a rapid damage.

At the same time, reperfusion increases the recruitment of inflammatory cells. In every infarction, we see that inflammatory cells come to the area of infarction, these cells produce free radicals and free radical injuries.

Also, the damaged mitochondria –due to the ischemia- increase free radical production, and compromise antioxidant defence mechanisms; there is a defence mechanism against the generation of free radicals, some of it is in the mitochondria itself.

Mitochondrial damage Free radicals

Anti-free radical systems.

At the same time, the dead tissue itself, behaves foreign to the body, it becomes antigenic, it induces immune reaction in the body (antibody –antigen reaction), & activates the complement system . Now this complement also induces further cell damage!

All of these factors induce further cell damage when we have ischemia/reperfusion injury.

In some cases it is recommended that when we have ischemia in the heart or the brain, high oxygen therapy is not given to improve hypoxia because it generates oxygen derived free radicals.

Now, what is the free radical injury ?

Free radicals are chemical species , with a single unpaired electron in an outer orbit , they are chemically unstable, they are unstable electrons present in the cell , they react with other molecules resulting in further chemical damage .

And once the free radical are induced , they bind to various components of the cell and cause damage such as proteins , carbohydrates and lipids . In pathology free radicals can be produced by: (Source of free radicals in Pathology)

1. Chemical injuries .2. Physical injuries . 3. Inflammation ( inflammatory cells produce free

radicals).4. Oxygen toxicity ( when you have high level of oxygen in

ischemic tissue ) .5. Reperfusion injuries . 6. Malignant transformation ( malignant tumours generate

free radicals).7. Aging ( anyone who's old has more free radical than

anyone who's young ) .

Now free radicals in the body can be produced by one of two ways, either endogenous (in the body), or exogenous.

Endogenous Free Radicals:

physiologically are produced by Redox (reduction-oxidation reaction) reactions in the mitochondria.

Also metals in the body , which usually are carried by various components in the blood, when they are free like copper & iron, they catalyse the formation of free radicals unstable molecules, by donating or accepting free electrons.

In iron, we get what we call Fenton reaction where ferrous Iron(II) is oxidized by hydrogen peroxide to ferric iron(III), a hydroxyl radical and a hydroxyl anion.

Exogenous Free Radicals:

1-Ionizing radiation

2-Certain drugs can be very active and induce free radical formation.

Please refer to slide # 18 and read free radicals examples.

Now, how do free radicals injure the cell?? (Mechanism of injury by free radicals)

1 . It produces what is called Lipid Peroxidation ( oxidative degradation of lipids ) and here there will be destruction of

unsaturated fatty acids by binding to methylene groups (CH2) that posses reactive hydrogen molecules usually in the membranes . 2. It also produces Protein Destruction , By cross linking proteins forming disulfide bonds (S-S) → inactivate various enzyme systems in the cell , & degradation of various polypeptides.

3- Also these free radicals go to the nucleus, and there they induce DNA alteration producing single strand breaks in DNA, this Induces mutation that interfere with cell growth.

Inactivation of free radicals:

In Any physiological system in the body, we have activators and a deactivators. For example in blood clotting, we have factors that induce blood clotting, and others that prevent it, & this is always balanced.

So free radicals are deactivated either by spontaneous decay, or we have enzymes, these enzymes include:

Superoxide dismutase,

glutathione peroxidase, and catalase

These are present in various components in the cell, some are in the mitochondria, and they destroy these free radicals. In many cases these reactions end up by production of water.

Or we have what we call antioxidants, that actually block the synthesis of free radicals, or inactivate them. These include: vitamin E, vitamin C, albumin, transferrin (a blood plasma protein for iron delivery), & ceruloplasmin (the major copper-carrying protein in the blood, Ceruloplasmin carries about 70% of the total copper in human plasma while albumin carries about 15%. )

Eat vegetables and fruits rich with vitamins because they are antioxidants; they prevent free radicals formation.

Any questions so far?

Ra3ed asks his question 3 times, until finally he gets to set in the first row to ask:

How is Nitric oxide related to inflammation?? (I couldn’t hear the question clearly as well :P).

The doctor answers: Nitric oxide doesn’t produce inflammation, it is an agent present in blood vessels, it causes dilatation of blood vessels, this (dilatation) is one of the changes that occur in acute inflammation. So nitric oxide NO is one of the factors produced in the case of inflammation, and it can change to nitrite, which is toxic.

Ya3ni some components in our body can act as free radicals, many factors are induced during the inflammatory response in the body, and these generate free radicals, but we have specialized techniques that compensate this generation as the one we mentioned above.

CHEMICAL AGENTS : It can act in many ways : 1- Act directly on the cell , they go to a certain part in

the cell and they cause damage in that part . (Direct contact of the chemical with molecular components of the cell) .

2- Act indirectly on the cell , they go to the liver and in the liver they change to something active and this produces the injury .

3- Responsible for the formation of free radicals, or lipid peroxidation.

Examples of chemical injuries :

Cyanide => disrupts cytochrome oxidase which presents in mitochondria .

Mercuric chloride => binds to cell membrane in cell resulting in increased permeability.

Chemotherapeutic agents & antibiotics which means the drugs used in the treatment of cancer , they generate free radicals and so cause chemical injury .

Carbon monoxide ( CO ) => it causes chemical injury through binding to hemoglobin instead of

oxygen ( hemoglobin has higher affinity to CO than to O2 ).

Ethanol (alcohol) produces toxics.

Lead .

Action of Carbon Monoxide (CO): Carbon Monoxide has a very high affinity to hemoglobin producing carboxyhemoglobin (COHb) , and this will cause death , because hemoglobin then cannot bind to oxygen. In some cases when it is not severe smaller quantities of COHb leads to tiredness, dizziness & unconsciousness.

Action Of Ethanol : the conversion of ethanol to acetaldehyde leads to the formation of free radicals, and this will initiate changes in the liver :

Fatty change

Liver enlargement

Liver cell necrosis.

The liver becomes very big because it contains a lot of fat, such case can be found with alcoholic patients .

Action Of Lead :

This mimics the action of other metals such as ( Iron , Zinc, and Calcium ) and acts as cofactors in many catalyzing enzymatic reactions (they stop the enzyme from working ) .It acts on the CNS by interfering with neurotransmitters and

blocking glutamate receptors . It also affects hemoglobin synthesis . Chronic lead poising which used to occur many years ago from using lead pipes for transporting water , which causes water contamination (but now they are all changed ) .

Indirect injury of some chemicals :

Other chemicals are not intrinsically biologically active, but must be first converted to reactive toxic metabolites, which then acts on target cells, this is what we call an indirect injury.

This modification is usually accomplished by the P-450 mixed function oxidases in the SER of the liver.

Now when CCl4 is converted to the toxic free radical CCl3, this causes membrane phospholipid peroxidation with rapid break down of the ER.

This will induce fatty liver, because it destroys proteins and lipids, and since liver needs apoprotiens for transport, when we don't have proteins to transport, this will induce fatty liver.

Mitochondrial injury follows ® ↓ATP ® Failure of cell function ® increased cytosolic Ca+ ® cell death.

Acetaminophen(paracitamol) – is a widely used analgesic (pain reliever) and antipyretic (fever reducer) – when given in large doses can act similarly.

Physical agents:

This can be caused by:

1. Mechanical Injury , resulting in tearing, or crushing of tissues.

e.g. : blunt injuries , car accidents , falling of a roof …etc .

2. Ionizing Radiation , it ionizes the water inside the cell and generates free radicals , and by this also the DNA might be hit producing mutations(!).

3. Extreme Temperatures, hypothermia (very low temperature) & hyperthermia; prolonged exposure to elevated temperatures can result in heat cramps, heat exhaustion, and heat stroke.

4- Changes in the atmospheric pressure, is produced by blast injuries, you may be not injured externally but it causes ruptures of internal organs. Pressure in water can decrease or increase rapidly, this causes air embolism which we’ll discuss later.

Infectious injuries:

Bacteria produces toxins; endotoxin and exotoxin.

Bacterial exotoxins are secreted proteins that directly cause cellular injury and frequently underlie disease manifestations.

Viruses can produce damage by many ways, they decrease the ability of producing proteins. Some viruses enter the cell and bind to the nucleus and change the host’s genetic properties.

5-Immunological reactions

Usually injures the cell membrane by contact with immune components such as lymphocytes, macrophages,…etc. exposure to these agents cause changes in membrane permeability.

6. Genetic diseases

Play a substantial role in cellular structure and function. For example , sickle cell anemia , in which the RBC’s have a sickle shape and has sharp ends instead of being round , and this can block the capillaries producing obstruction. Or for example, this genetic defect may affect an enzyme system in the body causing destruction and inability to metabolize a certain substance in the body.

7. Nutritional imbalance

Adequate amounts of proteins, lipids, carbohydrates are required. However, Low levels or high levels may affect the cell.Low levels of plasma proteins, like albumin, encourages movement of water into the tissues, thereby causing edema (swelling of the cells ) .

Blood sugar; Hyperglycemia, hypoglycemia is what happens in all cases of diabetes. ketone bodies are produced which are very toxic.

Vitamin deficiencies are important sources of injury (vitamins E, D, K, A, and folic acid), just like too little food, too much food and obesity is also a type of cell injury. Because these patients develop many diseases including cardiovascular diseases and diabetes, so obesity is classified as a nutritional imbalance.

Mechanism of cell injury & sites of damage

Generally, when any cell is damaged, what happens is that the function is lost before morphological changes occur. The first thing that happens in the cell is that it has disturbed function. We don’t see it by any microscope. After that we have the electron microscope changes. Then we’ll have the microscopic changes, and later on, we’ll have the naked eye (gross) changes.

So it is a step-by- step change in the morphology and function of the cell.

Check slide # 37 to see the figure !

الحمد لله الذي بنعمته تتم الصالحات

Sorry if it took you a long time to read my lecture, I really made my best to give the best. Some of the information are copied from the internet and the book since the doctor’s explaining wasn’t that clear. Excuse me for any mistakes !

Special thanks to my dearest friend and sister Samah Abu Omar for her HUGE support and help, I really can’t thank you enough! Ibrahim Miqdadi, thank you very much for your help always Thank you all llll my friends, I will write a special dedication for you all in my next lecture ;).

Good luck folks!

ل اإلمام ابن القيم: "إذ استغنى الناس بالدنيااق بالدنيا فافرح فاستغن أنت بالله، وإذا فرح الناس

أنت بالله، وإذا أنس الناس بأحبائهم فأنس أنتإلى ملوكهم وكبرائهم بالله، وإذا ذهب الناس

يسألونهم الرزق ويتوددون إليهم فتودد أنت إلى"الله