CLASS: 10:00 – 11:00Scribe: Adam Baird

DATE: November 8, 2010Proof:

PROFESSOR: AndersonCELLULAR ADAPTATIONSPage1 of 8

  1. CELLULAR ADAPTATIONS [S1]
  2. Review last Friday’s lecture (11/5). Understand how cells react under stress.
  3. Today, we’ll talk about what cells do when they don’t die (i.e., how they adapt to their environment).
  4. CELLULAR ADAPTATIONS: ENVIRONMENAL FACTORS [S2]
  5. Environmental factors:
  6. Increased or decreased stimulation
  7. Growth hormones, tropic factors, etc.
  8. During last Friday’s lecture (11/5), we discussed how tropic hormones lead to apoptosis. However, tropic hormones don’t always lead to apoptosis; sometimes they just lead to an alteration in the cell (and the cell remains alive).
  9. Increased or decreased work
  10. Example: Weight lifting
  11. Decreased blood flow
  12. During last Friday’s lecture (11/5), we discussed ischemia and hypoxic injury.
  13. Example from last Friday’s lecture (11/5): The tubular collecting duct cells in the kidney section (where the kidney was dead but the rest of the collecting ducts were still alive)
  14. Abnormal materials
  15. Exposure to toxins, metabolite inhibitors, etc.
  16. Causes the cells to adapt to environment
  17. RESPONSE TO STRESS [S3]
  18. It’s important that stressed cells have the ability to adapt. If they don’t have the ability to adapt, it can lead to cell injury or cell death (necrosis).
  19. RESPONSE TO STRESS [S4]
  20. This figure is from the textbook.
  21. Upper left-hand corner:normal cells.
  22. Single layer of epithelial cells on a basement membrane.
  23. If one of the environmental factors (decreased blood flow, metabolic inhibitors, decreased growth factors, etc.) is present, the cells can result in atrophy, hypertrophy, hyperplasia, metaplasia, or dysplasia. (Note: Dysplasia is more appropriate to talk about in relation to neoplasia, because dysplasia is the “precursor” for neoplasia. We won’t talk about dysplasia and neoplasia today though.)
  24. ATROPHY [S5]
  25. Atrophy is the hrinkage in cell size by loss of structural components.
  26. Decreased growth factors
  27. Decreased oxygen
  28. Decreased metabolites
  29. Leads to a group of normal cells that get smaller (they lose their cellular components). The cells may not lose many ER, ribosomes, lysosomes, etc. though. The whole cell just gets smaller.
  30. ATROPHY [S6]
  31. Atrophy is the shrinkage in size of cell by loss of structural components.
  32. Atrophy can be caused by:
  33. Decreased work load
  34. Loss of innervation
  35. Diminished blood supply
  36. Inadequate nutrition
  37. Loss of endocrine stimulation
  38. DISUSE ATROPHY – SKELETAL MUSCLE [S7]
  39. Classic example: broken ankle. Little movement or exercise leading to disuse atrophy of the leg.
  40. DISUSE ATROPHOY – SKELETAL MUSCLE [S8]
  41. Here is the biopsy of the skeletal muscle (viewed from a cross section of the muscle fibers).
  42. Notice that most of the muscle fibers are “normal size”. Some are shrunken though, due to the biopsy preparation and processing. (Tissues are introduced to alcohols, which leads to dehydration. Then the tissues are infiltrated with paraffin, then rehydrated, and finally, stained.)
  43. Spreads among the “normal size” muscle fibers are the atrophied muscle fibers. These atrophied muscle fibers are still alive (they still have nuclei), but they are just smaller than normal. They don’t have to contract anymore because the muscles aren’t being used (caused by a broken ankle, for example), so they don’t make actin, myosin, etc.
  44. Notice the cell that has gone through necrosis, where some of the nuclei have broken down into smaller pieces.
  45. SENILE ATROPHY [S9]
  46. Another type of atrophy is senile atrophy.
  47. The brain on the left is a “normal” brain.
  48. The brain on the right is caused by senile atrophy (caused by dementia, Alzheimer’s disease, etc.)
  49. There is some death of the cells in senile atrophy, but for the most part, it just includes shrinkage of the cells.
  50. If some neurons die, the connecting neurons don’t have to work either, leading to the reduction of function over the entire brain.
  51. The brain on the right is…”your brain on drugs”.
  52. HYPERTROPHY [S10]
  53. Hypertrophy is the increase in cell size. Because each cell gets bigger, the entire tissue gets bigger as well.
  54. The main difference between hypertrophy versus hyperplasia is the “character of the cells”.
  55. Hypertrophy is seen in tissues where cells can’t divide.
  56. Heart muscle cells, for example, can’t divide. So for heart muscles cells to work harder, they have to get bigger.
  57. HYPERTROPHY [S11]
  58. There are two types of hypertrophy: physiologic hypertrophy and pathologic hypertrophy.
  59. Physiologic hypertrophy can be caused by:
  60. Hormonal stimulation
  61. Example: Uterus during pregnancy
  62. Pathologic hypertrophy can be caused by:
  63. Increased functional demand
  64. Example: High blood pressure, hypertension, valve stenosis, etc.
  65. HYPERTROPHY [S12]
  66. Here is a heart from autopsy. The top of the aorta has been cut off.
  67. Recall: The aortic valve has three cuffs. In this picture, the three cuffs are fused together. The cuffs are thick here too, due to calcification and fibrous connective tissue. This, then, is called “calcific aortic stenosis”. It is seen in older populations. There are no known underlying diseases associated with calcific aortic stenosis though.
  68. Over time, there is calcification and scar tissue formation, reducing the size of the hole that the blood flows through. The heart has to work extra hard to pump the blood supply for the whole body – and that’s a lot of blood in such a tiny hole! The result: a “Swartzeneggaer heart”.
  69. HYPERTROPHY [S13]
  70. Show in the picture is left ventricular hypertrophy. Notice the right ventricle, which is fairly normal in size and configuration. Notice the left ventricle, which is much bigger. This is compared to another heart from another patient.
  71. Inaudible question asked by student. Answer: Some people with aortic stenosis get “concentric hypertrophy”. These patients tend to get very big hearts and they tend to develop fibrosis among the heart cells, which is not reversible, unless it is identified early enough. (If you try to replace the aortic valve after the heart is full of fibrosis, the heart won’t go back to “normal”.) So, you have to replace the aortic valve before the heart gets too big and before the heart gets too much fibrosis. The problem: it’s unknown how to determine when the right time is to replace the aortic valve. It’s considered a surgical conundrum. Sometimes, though, once the aortic valve is replaced, there are better hemodynamics, and the heart cells gets smaller, but there is still scar tissue that continues to act as a “girdle” that keeps the heart from working at full efficiency.
  72. Another inaudible question asked by student. Answer: The patient in the IP lab (from Friday 11/5) who had the myocardium infarction had a history of hypertension, and hypertension is a risk factor for atherosclerosis. Hypertension leads to a big heart, but it also leads to increased coronary artery disease, and that’s why the patient ended up having an acute infarction.
  73. HYPERTROPHY [S14]
  74. On the left is a cell from a normal heart. On the right is a cell from a hypertrophy heart.
  75. In hypertrophy, each individual cell gets much bigger (more actin, more myosin, etc.). Because the cells are working so hard, large amounts of myosin must be produced to replace the myosin that gets worn out or injured over time. This called the “myosin turnover rate”.
  76. Lots of ER, high protein synthesis, etc. is needed to keep the heart working. Because the cells have to work so hard, the cells may eventually die out, leading to congestive heart failure.
  77. POSTPARTRUM UTERUS [S15]
  78. This is a woman who gave birth and then died due to some other complications.
  79. Notice that the uterus is still very big. Notice the ovaries on each size. Notice the kidneys too. The uterus should be smaller than the ovaries.
  80. The uterus isn’t a great example though, because smooth muscle cells can divide. So there are actually more cells in the uterus in addition to the larger cells (like a mixed hypertrophy/hyperplasia example).
  81. HYPERPLASIA [S16]
  82. Hyperplasia is the increase in the number of cells in an organ or tissue.
  83. In the same way that the heart tissue responds to stress by getting bigger, other organs respond to stress by producing more cells; more cells means a balance of workload between cells. Each cell does the same amount of work prior to hyperplasia (they don’t increase or decrease their workload). There is just more cells available to do work in response to the stress and demands.
  84. Example: Damaged liver. Your liver can make more cells in order to repair the tissue or to do more work.
  85. HYPERPLASIA [S17]
  86. There are two types of hyperplasia: physiologic hyperplasia and pathologic hyperplasia.
  87. Physiologic hyperplasia can be caused by:
  88. Hormonal stimulation
  89. Example: Breasts in pregnancy. (Normal breast have glands to make milk, with epithelial cells lining the glands. Nursing breasts have a hyperplasia of cells in the glands to make milk. Post-nursing breasts have cells that go through apoptosis.)
  90. Pathologic hyperplasia can be caused by:
  91. Viral induced
  92. Example: Papillomavirus. (Virus that proliferate epithelial skin cells, causing a wart.)
  93. Excessive hormonal stimulation
  94. Example: Prostate. (Hormonal stimulation of the prostate leads to prostatic hyperplasia.)
  95. PROSTATIC HYPERPLASIA [S18]
  96. Here is an autopsy section of a prostate.
  97. Notice the nodules. These are hyperplastic nodules.
  98. However, the nodules are not tumors; it is not prostate cancer.
  99. The nodules are caused by hormone imbalance, causing stimulation of cell growth.
  100. The cells respond to testosterone/estrogen balance. As men get older, this testosterone/estrogen balance gets altered, resulting in prostatic hyperplasia.
  101. PROSTATIC HYPERPLASIA [S19]
  102. Here is a histological slide showing the prostatic hyperplasia nodules.
  103. Notice that the cells are piled up on each other (shown by the red arrows) instead of a nice, single layer, like a pseudostratified layer.
  104. Notice the infolding. This is not normal. The glands make infoldings to increase surface area, so that the cells stick to it. Notice that the gland is nearly completely filled with prostatic epithelial cells.
  105. METAPLASIA [S20]
  106. Metaplasia is a little different. It still involves cells responding to stress though.
  107. METAPLASIA [S21]
  108. Metaplasia is a reversible change where one differentiated cell type converts to another differentiated cell type.
  109. Example: Ciliated columnar epithelium. (Recall: This is the epithelium that lines the respiratory tract, trachea, bronchi, etc.) Smoking damages epithelial cells. These cells, then, change from the normal, adult, differentiated cell type to squamous epithelium. Note: it isn’t a transition from the ciliated columnar epithelium to a squamous epithelium; instead, smoking produces a signaling cascade that tells the stem cells/reserve cells/basal cells in the epithelial cell to mature into a different cell. It’s not a transformation. It’s one cell type transitioning through the reserve cell into a different cell type.
  110. METAPLASIA [S22]
  111. Irritation causes damage to the columnar epithelial cells (in the respiratory tract, for example), causing a complicated signaling cascade (involving Vitamin A and Vitamin A receptors).
  112. There has been a lot of research as to how this process works (i.e., why the stem cells quit turning into a ciliated columnar epithelial cells and begins to be formed into a squamous epithelial cell).
  113. In essence, the process reprograms the phenotypic maturation of the reserve cell and produces a different cell type.
  114. SQUAMOUS METAPLASIA - BRONCHUS [S23]
  115. Here is a sample of a bronchus of a smoker.
  116. Notice the ciliated columnar epithelia on the left. Notice the squamous epithelia on the right. The key: it is the stem cells/reserve cells/basal cells along the bottom that transition into the squamous epithelia cells rather than ciliated columnar cells.
  117. The squamous epithelial cells want to be normal; they want to be ciliated columnar epithelial cells. They are getting a signal to be squamous epithelial cells though. That signal comes from smoking, for example, or other forms of irritation.
  118. This is a reversible process. Once a patient stops smoking, for example, the cells eventually go back to normal (although it may take a while).
  119. KIDNEY STONE [S24]
  120. Here is an autopsied kidney. Notice the large stone in it. Notice that the stone is rough and jagged.
  121. Recall: the lining of the renal pelvis (where the urine pools before it goes down the ureter, onto the bladder, and out through the urethra) is made of transitional epithelia. Notice the nice layer of basal cells along the bottom. These grow up to be transitional epithelial cells.
  122. The kidney stone, however, causes squamous metaplasia.
  123. TRANITIONAL EPITHELIUM [S25]
  124. Here is what the lining of the renal pelvis should look like. It should be transitional epithelium.
  125. SQUAMOUS METAPLASIA [S26]
  126. Here is what the lining of the renal pelvis looks like with squamous metaplasia.
  127. Notice that there are a bunch of inflammatory cells here though. The kidney stone has caused some irritation and inflammation. The basal cells are changed so that they mature into squamous epithelial cells.
  128. SQUAMOUS METAPLASIA [S27]
  129. This is the same picture as before, just at a higher magnification
  130. The basal cells (which should be a nice, single layer) are disrupted by the kidney stone. As a result, squamous cells are made in excess to act as a callus (protection).
  131. METAPLASIA SUMMARY [S28]
  132. Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type.
  133. If a surface is irritated, a callus is formed (like when your hands forms calluses from lifting weights). In addition to squamous metaplasia (which forms a callus), there are other types of metaplasia.
  134. Glandular metaplasia
  135. Transformation from squamous cells to glandular cells
  136. Example: Gastroesophageal reflux disease, also known as GERD.
  137. Your stomach is full of acid and is lined by glandular cells that secret mucous and bicarbonate. Your esophagus has squamous metaplasia, forming a callus-like surface. What happens when you burp, or when you have reflux, and that acid moves up into your esophagus? The acid hits the squamous metaplasia in your esophagus and it hurts! Why? Because there’s nothing there to protect the esophagus. So, the reserve stem cells start producing other cells that secret mucus and bicarbonate to help protect the esophageal lining.
  138. In summary, glandular metaplasia in the basal portion of your esophagus is formed with a layer of mucus to protect it from the stomach’s acid.
  139. Specifically, this is called “Barrett’s esophagus”, which is just a form of glandular metaplasia (where cells go from squamous to glandular, as opposed to the previous examples, where cells go from ciliated columnar or transitional to squamous).
  140. Metaplasia is simply the body’s reaction to a constant irritation, reprogramming the cells to react accordingly.
  141. CELLULAR ADAPTATIONS [S29]
  142. Cells need to be able to adapt to stress (either by atrophy, hypertrophy, hyperplasia, or metaplasia) so that they don’t die.
  143. Cell adaptations are the “first step” of balancing homeostasis. Hopefully, the cells react effectively.
  144. Hyperplasia, metaplasia, or hypertrophy isn’t thought to be precursors to cancer though.
  145. One exception: “Barrett’s esophagus” is a precursor of cancer. Patients that have “Barrett’s esophagus” may be more prone to develop cancer in that same area. So, in this case, metaplasia isn’t something that is “good”. In most other cases, metaplasia is “good”.
  146. One additional note: Nearly every older man (age 70 – 80) has some degree of prostatic hyperplasia (simply because of the testosterone/estrogen hormone imbalance). They are also more likely to have foci of a prostatic tumor. These men have an 80% chance of having a focal prostatic tumor. These men usually don’t die from it though; they will die from something else. The key: it’s not the prostatic hyperplasia that leads to the prostatic tumor. It’s something else – and we’ll discuss it later.
  147. Another additional note: The body reacts to smoke by making squamous epithelial cells (which is a good thing), except, mucus is still produced and no cilia are present to pull it out of the respiratory tract. So, gravity pulls the mucus down into the lungs; that’s why chronic smokers are always coughing. Even though the squamous metaplasia is a reaction to the irritation, and it’s not really a “bad thing”, it’s certainly not a “perfect situation”. The cells would be much better to go back to the ciliated columnar epithelium.
  148. CELLULAR ACCUMULATIONS [S30]
  149. INTRACELLULAR ACCUMULATIONS [S31]
  150. Besides reacting to stress (by changing cell morphology, for example), cells can “suck things up and store them away”. When this happens, normal cellular constituents (like lipids, proteins, glycogen carbohydrates, etc.) or abnormal material (like carbon, silicon, asbestos, bacteria etc.) builds up in the cells.
  151. So, the cells will sometimes phagocytose material and package it up into their lysosomes, storing the material away so that it doesn’t cause any harm.
  152. FATTY CHANGE [S32]
  153. Cells can also accumulate fat.
  154. Fat can either be of two types:
  155. Lipid in macrophages
  156. Example: Atherosclerosis.
  157. Patients that have atherosclerosis usually have high lipid levels in their blood (hypercholesterolemia). The macrophages try to “chew up” the lipid in hopes to get rid of it before it causes a problem. Unfortunately, the cells get full of lipid though; they get constipated. These cells are called “foam cells”.
  158. Lipid in parenchyma cells
  159. Example: Alcoholic Fatty Liver
  160. Alcohol causes reversible injury to the hepatocytes, keeping them from correctly metabolizing fat. As a result, the fat builds up.
  161. FATTY LIVER [S33]
  162. Figure of a normal cell (hepatocyte) on the left.
  163. Figure of an alcoholic fatty liver cell on the right.
  164. Alcohol alters the metabolism and stops the synthesis of protein. Recall: lipids have to be bound to a protein (forming a lipoprotein) in order for it to be processed. So if the liver cell can’t make enough protein, it can’t bind to the lipid to form the lipoprotein.
  165. The problem with fatty liver:
  166. Too much lipid going in
  167. Not enough lipid going out
  168. EARLY FATTY CHANGE – LIVER [S34]
  169. Histological section of a (relatively) normal liver cell (after one or two beers, for example).
  170. Recall: Tissues have to be processed through alcohols for histological slide.