Cellular Pathology - Mechanism of Diseases (MOD) Lecture 1: Adaptation PDF

07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi Cellular pathology – Mechanism of diseases (MOD) – PROFESSOR Bonecchi Lecture 1: Adaptation Pathology, the Study of Disease: What is pathology? - General pathology = general mechanism through which disease is developed Wha...

07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi Cellular pathology – Mechanism of diseases (MOD) – PROFESSOR Bonecchi Lecture 1: Adaptation Pathology, the Study of Disease: What is pathology? - General pathology = general mechanism through which disease is developed What are the subjects of study of pathology? - Etiology = the cause of the disease (ex. infection, genetic, etc.), often multifactorial - Pathogenesis = the progression of the disease - Molecular and morphologic changes - Clinical manifestations: signs and symptoms Pathology attempts to understand what causes disease; it studies the pathogenesis, meaning the mechanism through which a disease progresses i.e. what happens to the cell, tissue, and body when there is a disease. Pathology also studies morphological and molecular changes, this is the topic of anatomopathology (morphological changes associated with pathological condition). Lastly, pathology studies the clinical manifestations (signs and symptoms) of the disease. Why do we have to study general pathology? Pathology is the bridge that connects basic science to clinical practice. The cause (etiology) and mechanism (pathogenesis) of disease bridges the gap between basic science (cells and molecules) and clinical practice (signs and symptoms of a disease). Knowing why we have a disease and its mechanism helps us in clinical practice. Sometimes, knowledge is not enough to cure a disease. For example, cystic fibrosis, we know that there is a mutation that affects ion channels, but this is not enough information to cure people of the disease. It is necessary to understand the mechanism through which a disease manifests in order to target it in the treatment of the patient. Rudolf Virchow, the father of modern pathology: Every disease starts from the disease of a cell type. This is a concept that was not so clear in the past. The first person who saw the connection between disease and problems associated with a single cell in the body was Rudolph Virchow. He was the father of pathology. There is a famous quote: “omnis cellula e cellula”, meaning “every cell stems from another cell”. In the past, it was not clear that a disease could affect a single cell, then the tissue, and finally the entire organism. He was the first to understand that the whole organism was not sick, only a few cells were. He observed that diseases are changes in normal cells that then develop in the entire organism. He promoted the use of microscopes for medical doctors (which was unusual), in order to understand the problem inside the damaged tissues. He also started to promote research and started to collect data (very important to have research activity with a method and to make systematic observations). 1 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi Virchow will be revisited because he made other discoveries in pathology. He was the first to sense inflammatory cells inside tumors, so he understood that tumors were made of many different cell types, including inflammatory cells. Professor Mantovani published a research paper around 20 years ago that was entitled “Inflammation and Cancer, back to Virchow”. Virchow was really the first one to understand this connection; Prof. Mantovani then picked up this line of research to find that macrophages were detrimental for tumor growth. Virchow will also appear in the vascular pathology part of the course. He was the first to understand what causes thrombosis as well as pulmonary embolism, the latter of which is a dangerous situation where a thrombus inside the veins of the legs travel up the bloodstream and arrive in the lung. Cellular responses to stress and noxious stimuli: What are the cellular responses to stress? If we start with normal cells in a homeostatic state, how do they respond to different kinds of stress? A cell in a homeostatic state can be subject to stress. This stress can be physiological or from pathological stimuli; overall, we call this stress “injury”. Normal cells can typically adapt to a stressful situation; this response is called adaptation. Adaptation means that our cells, when subject to stress, can change in some way to reach a homeostatic state. If the injury to a cell is mild (low, transient), the injury is reversible; meaning that it is possible for the cell to reach a homeostatic state again. If the injury is severe, i.e. a progressive situation, the cells undergo irreversible injury, which leads to cell death (can happen in different ways, e.g. necrosis or apoptosis). Adaptations: How do we define adaptation? It is a reversible change. On the test at the end of the year, a question will often be asked to the effect of: which of the following statements exemplifies “reversible” change? Change can be seen in the size of the cells, the number of cells, the phenotype of cells (i.e. change in the differentiation program of the cells), even the metabolic activity and function of the cells. As mentioned before, adaptational changes can happen in different ways: in response to changes in their physiological state or to pathological stimuli. 2 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi Why do cells adapt? Because the cells have to reach a new steady state (different from the initial one), to allow survival of the cells and the whole organism. To the right is a simple drawing depicting the different kinds of cellular adaptation that we can find in our body. In the center of the drawing, there is a normal bronchial epithelial cell. Hypertrophy means you have one cell but it gets bigger (increase in the size of the cell, not in the number). Hyperplasia means an increase in the number of the cells. Normally in tissue, to increase its function, you have both conditions (hyperplasia and hypertrophy). The opposite situation (when you have a decrease demand), is atrophy (meaning that you have a decrease in the size of the cell). Atrophy in a tissue can be a decrease in the size of the cell but also in the number (there is no differentiation like with hyperplasia and hypertrophy). There are also other terms like metaplasia, which means you have a change in the phenotype of the cells (in this case, change in the differentiation of the epithelial cell). There is also dysplasia, which is not considered an adaptation, even if it is listed in the above drawing. Why is it not an adaptation? Because it is the first step towards neoplastic transformation i.e. there is an abnormal growth and differentiation of the cell. It is important to remember it is still a reversible situation (just not an adaptation). Adaptive responses: The following might help to remember some of terms mentioned: Note that adaptive responses can be the result of increased stimulation, increased demand, altered nutrition state, etc. All of which can happen because of increased muscle activity, increased growth factors, increased hormones, too much food or too little. Cellular adaptations: As we have seen, cells can adapt in size or number, or change their differentiation state like in metaplasia or dysplasia. Not every cell type can undergo all these though, it depends on the cell type that is stressed. In our body, we can divide our cells into 3 different types: 3 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi - Labile cells → cells that are continuously run through the cell cycle, continuously dividing (like the cells of epidermis, mucosae), every day we renew these cells - Quiescent cells or stable cells → best example are hepatocytes (cells of liver), these cells are outside the cell cycle (so they are in the zero state) but they can easily re-enter the cell cycle when necessary (when there is stimulation or requirement) and undergo cell division and proliferate - Permanent cells → mainly neurons and cardiac myocytes. They are outside the cell cycle and terminally differentiated cells so they can’t divide anymore. These can’t proliferate, so we can’t have a hyperplasia of a permanent cell type (but maybe you can have a hypertrophy of the tissue). In summary, the kind of adaptation we have in a tissue depends on the cell type present in that tissue. Hypertrophy: NOT NUMBER OF CELLS Hypertrophy is an increase in the size of cells. If you have an increase in the size of all the cells in the tissue, there will be an increase in the size of the tissue or the organ. You won’t have more cells, but bigger cells. They are bigger because the cells start to produce more intracellular components, which means more protein synthesis to produce additional proteins inside the cytoplasm. In some situations, an increase in organ size can be due to both hypertrophy and hyperplasia (for instance, if you have a tissue that is made of both stable and permanent cells). In this case, permanent cells can undergo hypertrophy while stable cells undergo hyperplasia. Or cells can do both (increase in size and number). Normally, if you have an increase in demand, hypertrophy will occur in cells that can’t divide (permanent cells). Physiologic hypertrophy: In our body, we can have situations where hypertrophy happens in a physiological way. 1) Skeletal muscles in response to increase workload - If we increase the demand of an organ, we will produce either more hormones or growth factors, which will lead to physiological hypertrophy. - Typically, hypertrophy happens in striated muscle cells. When we increase our workload, the skeletal muscle cells cannot divide and so they undergo hypertrophy. 2) Heart for chronic hemodynamic overload (hypertension or faulty valves) - Hypertrophy can also happen when there is hypertension or problems in the artery walls. Hypertrophy that starts as physiological hypertrophy can become pathological hypertrophy. 4 07-10-2021 - - Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi In the heart, there can be a physiological situation that induces hypertrophy of the heart. In the beginning, it is a physiological situation because the heart tries to cope with the increased pressure and the muscle cells become bigger. But in the end (if you don’t down regulate the pressure and don’t cure hypertension), it will become a pathological condition. The heart chamber will become larger and larger, however there is a limit, and once crossed, the problem becomes pathological. The mechanism is as follows: the muscle cells become larger because they start to synthetize more proteins, more myofilaments, which leads to an overall increase in muscle. In the heart, it can lead to very serious problems (also sudden death, because some patients don’t realize they have a problem and the situation becomes fatal). Hypertrophy resulting from pathological injury (hypertension): The images above show pathological hypertension. Both are images of the left ventricle, we can see how big the wall of the ventricle is. This is the due to systemic hypertension, so it is very important to know if you have hypertension. If hypertension is not treated, you can have a pathological situation that leads to scarring, as is the case after a myocardial infarction (seen in the picture on the right). What happens after a myocardial infarction? Some cells of the heart will die because of ischemia. These dead cells (seen in the white portion of the heart) form a scar where there was necrosis of the heart. The scars are fibrotic tissue, not heart tissue, which means it’s nonfunctional. So the heart grows larger in order to regain functionality, which ultimately leads to pathological hypertrophy. So hypertrophy can be due to hypertension, but can also be a secondary condition after myocardial infarction (because there are less cells working, the heart becomes larger). The image to the immediate left (with green background), shows how the left ventricle wall can become much bigger in a hypertensive patient (far right section). 5 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi In the image here, we have a section of normal heart tissue on the left. And on the right, we see how much bigger the fibers can become in a hypertensive heart. Physiologic adaptation vs. pathology: Adaptation is usually a physiological response but, in some cases, a pathological situation can develop (the amount of adaptation that can occur has its limits). Failure to adapt can lead to a pathological condition like cardiac hypertrophy. We see that after a myocardial infarction, there is a big portion of the ventricle that is dead, which leads to hypertrophy due to the lack of function in the affected portion of the heart. Physiological hypertrophy – normal: There are other situations where hypertrophy is physiological. During pregnancy, there is hypertrophy of the muscle fibers of the uterus from hormonal stimulation. In the image to the left, we see the normal size of the uterus and the size of the uterus after the end of the pregnancy. This change in size is due to an increase in the dimensions of the muscle fibers. Normal After pregnancy 6 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi Question: During pregnancy, is there also hypertrophy of the skin? During pregnancy, skin undergoes hyperplasia (because skin cells are labile and continuously dividing, they adapt by increasing their number). Glands are also composed of cells that can divide so they undergo hyperplasia (i.e. not hypertrophy) or both hyperplasia and hypertrophy together (so there will be more cells and they will be larger). Microscopic physiological hypertrophy: In this image, we see a normal tissue on the left and a hypertrophic tissue on the right. Mechanisms of myocardial hypertrophy: This is a scheme of the mechanism that leads to myocardial hypertrophy. You may ask yourself, what are the mechanisms responsible for the increase in size? There are mechanical sensors, hormone receptors, and growth factor receptors. All these receptors induce a signal transduction cascade that will increase production of contractile proteins, increasing mechanical performance. The mechanism is the stimulation of receptors on the surface of the cells that will increase the production of contractile proteins, in order to increase cell size. Cardiac hypertrophy: Cardiac hypertrophy is a major cause of death. If there is no diagnosis, it is a risk factor for heart failure. There is group of inherited conditions that can lead to cardiac hypertrophy. One of them involves mutations in the genes of sarcomere proteins; the mutation leads to more production of these proteins which leads to bigger muscle cells. The most common mutation, however, involves beta-myosin heavy chain and myosin-binding protein C. Both mutations lead to the increase in the size of the cells. If you are lucky, you have symptoms like chest pain or atrial fibrillation but sometimes it is completely asymptomatic. The most unfortunate aspect of cardiac hypertrophy is that it is often asymptomatic, and it is a common cause of sudden cardiac death in young people (e.g. some soccer players undergo sudden death because of undiagnosed cardiac hypertrophy that are sometimes due to genetic conditions). 7 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi Hyperplasia: Hyperplasia means an increase in the number of the cells in tissue or organ after a stimulus. Often, it happens together with hypertrophy, the same stimulus that induces hypertrophy in one tissue or cell type induces hyperplasia in another. Hyperplasia occurs only in labile cells or stable cells (not permanent cells). It can be physiological or pathological. Physiological hormonal hyperplasia: Here is an example of a physiological condition. During a normal menstrual cycle, there is normal endometrium proliferation of the glands in the endometrium. Physiological hyperplasia (other examples): To the right, we see a type of hormonal hyperplasia (note that during pregnancy there is also hormonal hyperplasia of the glandular epithelium of the breasts). In the top image, normal breast tissue can be seen with glands. In the image below, we see hyperplasia of the cells that the glands are composed of. This also happens at puberty when there is growth of the breasts in young girls. Normally, you have hypertrophy of glandular epithelial cells. Hyperplasia can also be a compensatory situation. When you have the resection of a lobe of the liver, the remaining liver starts to grow; the hepatocytes that are normally outside the cell cycle re-enter the cell cycle and the remaining lobes start to get bigger to compensate for the lack of lobes. The same happens during the removal of a kidney; the remaining kidney becomes bigger (this is compensatory hyperplasia). Also, during a bone marrow donation, bone marrow can regenerate; this is also an example of compensatory hyperplasia. So hyperplasia can be physiological because of hormones (e.g. endometrial proliferation every month, or during a pregnancy with the hyperplasia of glandular epithelium). Or, it 8 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi can be compensatory like with the the resection of a portion of an organ, or the removal of one organ that exists in a pair, and the other one compensates (like in the case of the kidneys). Pathological hyperplasia (PPP): Hyperplasia can be pathological if there is excessive hormone or growth factor production. There are two very frequent examples: 1) endometrial hyperplasia which is caused by an imbalance of hormones regulating the menstrual cycle (note that hyperplasia also occurs during a normal menstrual cycle but here we are talking about an imbalance) and 2) prostatic hyperplasia (common in old men) due to abnormal stimulation of androgens, so the gland starts to grow and becomes larger. Both endometrial and prostatic hyperplasia are pathological situations. Remember that these situations are still adaptations, which means they can regress. If the situation is diagnosed, you can decrease or inhibit the hormonal stimulation causing these problems and go back to a homeostatic state. Why is hyperplasia dangerous? When you see the term hyperplasia, it means more cells, not different cells. Which means there isn’t always an underlying pathological situation like cancer; with that said, hyperplasia can be fertile soil for cancer. A tumor arises from many mutations that accumulate in certain cell type. When you have excessive proliferation, the risk of accumulating mutations increases. This is why hyperplasia should be monitored very carefully; hyperplastic tissue can become a cancerous site. “Atypical hyperplasia” in the endometrium: If you have endometrial hyperplasia (atypical, not the normal kind), you have an increased risk of endometrial adenocarcinoma. This is because more cell division leads to a higher risk of mutation accumulation (especially in older individuals). ** Note that it is important to understand the difference between the term hyperplasia and the term tumor ** Mechanisms of hyperplasia: Which are the mechanisms of hyperplasia? 1) Growth factor-driven proliferation of mature cells 2) Proliferation of tissue stem cells Growth factors can induce the proliferation of cells. So, if more growth factors act on receptors, there is an increase in cell proliferation. You also have stem cells. Inducing the proliferation of the stem cell pool we have in our tissues is one of the main 9 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi mechanisms of hyperplasia. For example, in the liver, we have quiescent cells. If there is an injury to the liver, stem cells become activated. You also have cells of the immune system and endothelial cells that start to grow via angiogenesis. So, the growth of tissue is usually possible because of a pool of stem cells that are able to grow (giving rise to tissue). We also have hyperplasia of the bone marrow. If there is a problem, there are stem cells that will proliferate giving rise to all other cells. Atrophy: Atrophy means a decrease in cell size and a decrease in number. Again, it can be physiological or pathological. During fetal development, we have many structures that undergo atrophy. For example, after the delivery of a baby, there is a rapid decrease in the size of the uterus because there is atrophy of the muscle cells of the uterus. Causes of pathological atrophy: - - - ‘Use it or lose it’ Decreased workload (atrophy of disuse, skeletal muscle atrophy after immobilization) o If you decrease the workload, there is atrophy of the skeletal muscle cells; it is very common in patients when they stay in bed for a long time. It is a dangerous situation because if you lose muscle cells because they die, you can’t increase the number of muscle cells. Loss of innervation (denervation atrophy, metabolism of skeletal muscle is dependent on its nerve supply) o If you have a problem with the innervation of an organ, and you don’t have the correct neuronal stimulation, you will see a decrease in size of the organ. Diminished blood supply (e.g. brain and heart atrophy for atherosclerosis, senile atrophy) o If you have a problem in the blood arriving in the organ, you will see a decrease in size or number of cells. To the left is an example of what happens in the brain of a patient with atherosclerosis. This kind of atrophy is typical of aging. 10 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi Causes of pathological atrophy: Immobilization of a fracture may cause a decrease in the size of muscles surrounding the fracture. Likewise, a decrease in blood supply e.g. due to an ischemic event from atherosclerosis, may cause a decrease in the size of the affected kidney. Question: Will the ischemic event shown in image above cause hypertrophy in the other kidney? - Normally, yes, because if you have the lack of function of one kidney, the other one will undergo hyperplasia (more cells, kidney cells can replicate) Other causes of pathological atrophy include: - Inadequate nutrition: use of skeletal muscle proteins as a source of energy marked muscle wasting (cachexia) o Lack of nutrition: if you don’t have the right nutrition, you will degrade the skeletal muscle proteins. This normally happens in a terminal cancer patient (cachexia → the patient will degrade all the muscle proteins and become very thin; these proteins will be used for energy production). - Loss of endocrine stimulation: physiologic atrophy of the endometrium, vaginal epithelium, and breast due to loss of estrogen stimulation after menopause - Pressure: tissue compression by benign tumor can cause atrophy as a result of ischemia o If your muscle cells are dying, you can’t renew them (there are some stem cells in the muscle, but they are not able to generate entire muscle fibers). o We can have physiological atrophy when there is a loss of endocrine stimulation. So normally, after menopause, there will be atrophy of the endometrium, vaginal epithelium, and breast because there is no more estrogen stimulation. o There can also be compression, if there is the growth of a tumor (can also be benign), which leads to ischemia, which in turn leads to tissue atrophy. 11 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi Mechanisms of Atrophy: The most common mechanism of atrophy is a decrease of metabolic activity. Protein synthesis will decrease and protein degradation will increase by the proteasome pathway. There is also another mechanism called autophagy. If you are starving, your cells start to digest themselves. Autophagy is also a mechanism of cell death (first step). Metaplasia: The last adaptation is metaplasia. It is a reversible change in the differentiation of the cell type which happens in epithelia or mesenchymal cells. In this adaptation, a differentiated cell type is substituted by another. The most common example of this is the epithelial metaplasia of the respiratory tract which is due to chronic irritation (normally due to cigarette smoke). The normal epithelium (pseudostratified respiratory epithelium) is replaced by a stratified squamous epithelium. This happens because the tissue is continuously subject to this irritation (from the toxins present in the smoke), inducing inflammation of the tissue. Hence, the cells change their differentiation program and start to become a stratified squamous epithelium. Why does this happen? Because this tissue is more resistant than the other to the inflammatory condition. This is dangerous because the individual will be losing very important mechanisms of protection against external pathogens: the cilia and the mucosal cells (individual will be unable to produce mucus and will not have cilia, which is very important for the first mechanism of defense against pathogens). The cilia, with the mechanical work and mucus, are able entrap the pathogens. Smoking induces the loss of these very first mechanisms of defense of the respiratory tract. This situation can predispose the individual to a mutation because changing the differentiation of the cells means changing their program, and so their proliferation. This can be a predisposing situation to accumulate mutation. Smoke is a very important risk for lung cancer. It has been demonstrated that smoking induces the growth of lung cancer. This happens because this chronic irritation can start to induce a change in differentiation of the tissue. It is important to remember that metaplasia of a tissue is a reversible situation. This means if you stop smoking, your epithelium can return to the normal situation. 12 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi In the drawing above, we can see that the normal epithelium can change and become squamous epithelium. Metaplasia of esophageal epithelium: Another common condition is called Barrett’s esophagus (or Barrett’s metaplasia). It can happen in the mucosa of the esophagus. There is a transformation of the normal mucosa into an internal-like mucosa, due to gastric acid from gastric reflux. This is a situation that can revert (so if you stop this acid reflux in your esophagus, you can revert the situation). But if it goes undiagnosed, this is a place where the situation could become cancerous (very dangerous cancer type). We see in the image to the immediate right that the wall of the esophagus is completely changed; it takes on the appearance of an intestinal-like wall. Why does it happen? Because it is more resistant to acid production. Mechanisms of metaplasia: What is the mechanism of metaplasia? It is the reprogramming of the stem cells. The stem cells that we have in our tissue - which usually generate normal epithelial cells - change their differentiation program due to molecules produced in inflammatory situations, for instance cytokines. Cytokines are the main molecules that induce inflammation, it is the mechanism through which leukocytes communicate with one another. The same cytokines can induce the reprograming of epithelial stem cells. ** Remember: metaplasia is an adaptation, which means a reversible situation. ** 13 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi Key concepts – cellular adaptations to stress: Here are the key concepts that we have to remember (the mechanisms should also be remembered): - Hypertrophy = increase in cell and organ size, often in response to increased workload, induced by growth factors produced in response to mechanism stress or other stimuli, occurs in tissues incapable of cell division - Hyperplasia = increase in cell number in response to hormones and other growth factors, occurs in tissues whose cells are able to divide or contain abundant tissue stem cells - Atrophy = decrease in cell and organ size, as a result of decreased nutrient supply or disuse, associated with decreased synthesis of cellular building blocks and increased breakdown of cellular organelles - Metaplasia = change in the phenotype of these cells, often in response to chronic irritation, that makes cells better able to withstand the stress, usually induced by altered differentiation pathway of tissue stem cells, may result in reduced functions or increased propensity for malignant transformation ** Remember: both hyperplasia and metaplasia can be the soil from where a cancer can arise ** Epithelial dysplasia: Dysplasia is a potentially reversible process but it is the first step towards neoplasia. ** Remember for the exam that dysplasia is NOT an adaptation. ** New, uncontrolled growth of cells Back to the scheme: Again, we go back to the scheme. We have described what happens when there is stress. The mechanisms of adaptation need to be remembered. In the next lesson, we will talk about cell injury and describe reversible and irreversible injury. And then, we will describe the mechanisms of cell death. Practice questions: The answer is metaplasia. 14 07-10-2021 Sbobinator’s name: Anahita Nabavi Reviewer’s name: Theresa Crupi The first one is correct, because the muscle cells of the myometrium are not undergoing replication: they increase in size (hypertrophy). The female breast at puberty undergoes hyperplasia. The liver following partial resection undergoes compensatory hyperplasia. The ovary following menopause undergoes physiological atrophy. The cervix with chronic inflammation undergoes metaplasia (because you have a chronic inflammatory situation). 15