Cellular adaptation to stress, regeneration, and wound healing. A12-A15

Question 1

A/12. Pathomechanisms and caracteristics of atrophy and hypertrophy, organ examples

Definition of atrophy, on a celullar and organ level

Causes of atrophy (6) and their organ examples.

Answer 1

Atrophy: This means reduction in size and reduced cell content. (↓ cell size (autophagy and ubiquitin‐proteasome degradation) and ↓ cell number (apoptosis)) i.

• Cell level: it means shrinkage of organelles and decreased number of organelles.
• Organ level, it means shrinkage of the cells and loss of cells.
• There is reprogramming of the cell. The changing environment may induce apoptosis, but it will try to survive in a smaller form.

Causes:

1. Reduced use or function: Muscle and bone atrophy in a cast.
2. Inadequate oxygen/nutrition supply.
   
   • Cerebral Vascular Disease, chronic brain ischemia causes diffuse atrophy, widening of the sulci.
   • Nutmeg liver, atrophy around the central veins
3. Persistent cell injury.
   
   • Atrophy of the mucous membrane in chronic gastritis.
4. Aging.
5. Physiologic involution
   
   • ​​Atrophy of the thymus in adults
   • Atrophy of the uterus after menopause (growth factor removal)
6. Pathological atrophy
   
   • ​mechanical damage,
   • radiation
   • malnutrition
   • ageing.

Question 2

A/12. Pathomechanisms and caracteristics of atrophy and hypertrophy, organ examples

Hypertrophy,

General definition and causes

Answer 2

Hypertrophy: An adaptation of post-mitotic cells, increasing in size. Seen commonly in muscle cells. Polyploidy of 2n, 4n, up to hundreds of copies of the DNA can be created in order to facilitate protein synthesis at an increased rate.

• May occur alone - in muscle tissue, or with hyperplasia - uterine growth in pregnancy.
• Also occurs in Nerves, which are post-mitotic.

Causes:

• Increased physical demand of the tissue (muscle)
• Growth factor and cytokine signaling.

Question 3

A/12. Pathomechanisms and caracteristics of atrophy and hypertrophy, organ examples

Cardiac hypertrophy and specific types

Answer 3

Concentric hypertrophy: occurs in response to increased Resistance

1. Hypertension
2. Aortic stenosis
3. Aortic coarctation

Eccentric hypertrophy: dilation that occurs in response to blood backflow or congestion.

1. Mitral insufficiency
2. Aortic insufficiency

Terminal dilation: occurs after concentric hypertrophy has reached its maximum, and the heart relies on the Frank-Starling stretch mechanims to increase cardiac output and overcome increased resistance.

Cor Pulmonale: RV hypertrophy, caused by

• Emphysema, alveolar septa destruction, decreased capillary cross sectional area, increased resistance.
• Fibrosis of the lung, due to toxins, or as in Coal Miner’s Pneumoconiosis
• Pulmonary embolism
• Vasculitis
• Chest deformations:
  
  • Scoliosis
  • Obesity

Cor Pulmonale, RV hypertrophy, will eventually cause pulmonary sclerosis, as this is meant to be a low presssure system, and the increased pressure will promote atherosclerosis of the system, exacerbating the problem, eventually leading to right sided heart failure, or hyaline deposits into the alveoli and ARDS.

LV concentric: more than 12mm

LV eccentric (dilation): less than 10mm

RV concentric: more than 4mm

RV eccentric:: less than 3mm

Question 4

A/12. Pahtomechanisms and caracteristics of atrophy and hypertrophy, organ examples

Describe the Consequences of LV hypertrophy.

Answer 4

LV hypertrophy:

1. Diastolic failure. The heart cannot relax properly to allow sufficient filling. This can lead to
2. Atrial dilation and stasis –> thrombii generation
3. Chronic ischemic heart disease.
4. Renal failure, from Hyaline Arteriolosclerosis. Nephrosclerosis or arteriolosclerosis. In a vessel, if there is a pressure overload, there is damage of the endothelial cells and hyalinic arteriolosclerosis develops because they trap plasma proteins from the circulation. The lumen is narrowed and this makes renal failure. The angio‐renin system is normalized by the other kidney.
5. Apoplexy. A hemorrhage caused by extremely high blood pressure. 200 mmHG pressure has high risk of apoplexia. Normally with sports, however, one can have such high pressures. In the case of people with Charcot‐Bouchard aneurysm though, that makes them more sensitive for rupture.
   
   • Charcot‐Bouchard aneurysm of brain vasculature (usually in the lenticulostriate arteries of the basal ganglia), rupture causes syncope and subsequent paralysis.
   • Associated with chronic hypertension
   • Leads to cerebral hemorrhage → hemorrhagic stroke
6. Eccentric hypertrophy, terminal dilation of the left ventricle. This is due to Frank‐Starling mechanism. Irreversible.

Question 5

A/12. Pathomechanisms and caracteristics of atrophy and hypertrophy, organ examples

Describe the Causes and Consequences of Right Ventricular hypertrophy.

Answer 5

a. Causes:

1. Emphysema.
2. Chronic bronchitis
   
   • Chronic inflammation lyses lung tissue, causing some tissue loss and some fibrosis.
   • Stimulates mucous secretion which also increases resistance.
3. Bronchiectasis. Bronchiectasis is dilation of the bronchus and the caliber decreases towards the periphery. Caused by both chronic bronchitis and cystic fibrosis.
4. Cystic Fibrosis
5. Pneumoconiosis. Coal miner’s lung fibrosis.
6. Infectious diseases.
   
   • Tuberculosis makes granulomas, reduces parenchyma, makes increased resistance.
7. Vascular diseases.
   
   1. Thromboembolism. This is the most important.
   2. Vasculitis. For example Wegener’s vasculitis.
8. Deformities of the chest.
   
   • Scoliosis
   • Obesity

Consequences:

1. Nutmeg liver. Backward failure causing liver stasis and atrophy of the pericentral region
2. Pulmonary sclerosis. increased pulmonary pressure causing atherosclerosis of the system.

Question 6

A/13. Pathomechanisms and caracteristics of hyperplasia, organ examples

Answer 6

Hyperplasia: proliferation of cells within an organ. Hyperplasia usually occurs in conjunction with hypertrophy in organs that are capable

Causes:

1. Hormones:
   
   • Endometrial hyperplasia: an imbalance in mitosis promoting estrogen signaling and inhibitory progesterone signaling. Often occurs as a paraneoplastic syndrome
   • Prostate hyperplasia: condition in middle aged and old men, from testosterone signaling. Subsequently causes hypertrophy of the urinary bladder muscles.
   • Gynecomastia: from excess estrogen signaling due to liver failure or obesity storing excess estrogen.
   • Congenital Adrenal Hyperplasia: Excess androgens causing female virilization, hirsuitism.
2. Increased Demand:
   
   • ​Bone marrow hyperplasia: due to increased oxygen demands, living at high altitude, hemolysis, hypoxia of pulmonary origin.
   • Follicular hyperplasia. Lymph node hyperplasia in response to B cell proliferation.
3. Inflammation
   
   • ​Chronic cystitis. Endothelium of the urinary bladder proliferates to protect itself from chronic inflammation.

Question 7

A/14. Pathomechanisms and caracteristics of metaplasia, organ examples

Answer 7

Metaplasia: The conversion of one type of differentiated cell into another kind, in response to injury or enviromental change.

1. Bronchial squamous metaplasia: Respiratory epithelium changes from the columnar ciliated epithelium to stratified squamous. From smoking
2. Barett’s Esophagus: Stratified squamous epithelium of the esophagus changes to a glandular columnar epithelium that produces mucous.
3. Intestinal metaplasia of the stomach: Chronic gastritis, the gastric epithelium becomes more like the large intestine.
4. Keratomalacia: Vitamin A deficiency, causes a failure of differentiation of the conjuntiva and cornea. Where the normal columnar epithelium of the cornea is replaced with a stratified squamous keratinized tissue. Causes blindness.

Metaplasia increases the risk of dysplasia and subsequent neoplasia.

Metaplasia is often reversible _i_f the stimulus is removed.

Dysplasia: An expansion of immature cells (basal cells extending into the higher layers) with a corresponding decrease in the number and location of mature cells.

Question 8

A/15. Tissue repair and wound healing

what are the two major types of healing

Answer 8

1) Regeneration and 2) Repair by Fibrosis.

Embryonic healing involves true regeneration and heals without any scarring.

Normal wound healing inolves a degree of reapair along with fibrosis.

Question 9

A/15. Tissue repair and wound healing

What are the cell cycle check points?

What are the categories of cells, with regards to their proliferative ability?

Answer 9

Check points:

1. Restriction point: in G1, prior to G1/S checkpoint. Is there sufficient nutrients, cell size, and trophic signaling for mitosis to proceed?
2. G1 / S checkpoint. DNA checked for damage prior to DNA replication.
3. G2/M checkpoint. DNA checked for damage and for any un-duplicated DNA.
4. Metaphase/Anaphase checkpoint: Are chromosomes properly paired/aligned.

Cell categories:

1. Labile cells: Continuously dividing stem cells, producing cells that differentiate.
   
   • Epithelial cells, GI mucosal cells, Bone marrow.
2. Stabile cells: Cells that are in the G0 stage, but retain the capability to replicate in response to injury or mitotic stimulus.
   
   • Parenchymal cells of most solid organs. Hepatocytes, Kidney cells, Pancreas, Fibroblasts.
3. Permanent cells: Permanently postmitotic cells. Can only respond to injury by scarring or hypertrophy.
   
   • neurons, cardiac myocytes.
4. Stem cells - Cells that have lifelong proliferative capcity and can generate multiple differentiated cell types.
   
   1. ​Pluriopotent
   2. Multipotent
   3. Unipotent.
   4. iPSCs.

Question 10

A/15. Tissue repair and wound healing

Describe Regeneration

What are the major growth factors (8)

Answer 10

Regeneration: Tissue is returned to the normal state:

ECM framework and stem cell populations must be in tact. Small cuts in labile tissues or stabile tissues.

Occurs in Labile tissues: from proliferation and differentiation of the stem cells.

Occurs in Stabile tissues: Depends on Growth factor and Cytokine activation of their receptors (kinase or GPCRs) to induce proliferation and regeneration of the parenchymal cells.

Growth factors:

1. VEGF - Endothelial proliferation, revascularization
2. PDGF - chemokine and mitogen for leukocytes, fibroblasts, stimulates ECM synthesis
3. FGF - chemokine and mitogen for fibroblasts, ECM secretion.
4. TGF-beta - chemokine for leukocytes and fibroblasts, stimulates ECM deposition, anti-inflammatory
5. TGF-alpha - hepatocyte growth factor, epithelial cells too
6. HGF - hepatocyte and epithelial cell mitogen
7. EGF - fibroblast and keratinocyte mitogen and chemokine
8. KGF - keratinocyte mitogen and chemokine

Question 11

A/15. Tissue repair and wound healing

Question 12

A/15. Tissue repair and wound healing

When does scar formation occur

What are the steps.

Answer 12

Scar formation, aka Repair with fibrosis : Occurs when the ECM is disrupted, or permanent cells are destroyed.

Steps of scar formation in Skin.

1. Coagulation - immediate,
2. Inflammation - 24 hours
3. Debridement - 1 to 3 days
4. Migration and proliferation - over a few weeks.
   
   1. Epithelialization - parenchymal regeneration re-connecting the disrupted edges.
   2. Angiogenesis - revascularization
   3. Fibroplasia
   4. Remodelling
   5. Contration

Question 13

A/15. Tissue repair and wound healing

What are the multiple roles of the Extracellular matrix in wound healing

What are the components of ECM

Answer 13

1. ​Mechanical support
2. Active cell signaling, via integrin receptors.
   
   1. Can be inhibit or stimulate proliferation
   2. Can control cell differentiation
3. Sequesters cytokines and growth factors (low affinity GF and cytokine receptor, increases local concentrations)

Components:

Interstitial Matrix:

1. Collagen
2. Elastin
3. Proteoglycans
4. Hyaluronic acid

Basement membrane:

1. Type 4 collagen
2. Proteoglycans
3. Laminin

Question 14

A/15. Tissue repair and wound healing

What is Healing by First Intention and Healing by Second Intention

Answer 14

Healing by First Intention: Surgical wound healing. Healing of a clean, uninfected, precisely cut wound.

1. in 24 hours, neutrophils migrate to the clot
2. Re-epithelialization occurs, forming a thin continuous epithelial layer
3. Day 3, Nuetrophils are replaced by macrophages, and epithelialization continues
4. Granulation tissue forms, Fibroblasts depositing elastin, re-vascularization is occuring, and myofibroblasts are invading/differentiating.
5. Granulation tissue then fills the wound, and neovascularization is established
6. During week 2, continuous collagen accumulation and fibroblast proliferation
7. By one month collagen I has replaced most collagen III, and the scar is made entirely of connective tissue, covered by normal epidermis. Note, first intention healing does not involve significant scar retraction.

Healing by second intention:

• Occurs with more extensive tissue loss, abscesses, ulcers, infarcts.
• Involves both regeneration and scarring.
• involves a more intense inflammatory response
• More abundant granulation tissue, bigger scar.
• Involves much greater wound contraction.

Question 15

A/15. Tissue repair and wound healing

Notes on healing in specific organs.

Types of defects in scar formation

Answer 15

i. Kidney:

1. Tubular epithelium: Regenerates if basement membrane is intact
2. Glomeruli: Do not regenerate.

ii. Lung:

1. If the basement membrane is intact, there is complete regeneration.
2. If the basement membrane is not intact, there is fibrosis.

iii. Heart.

1. Myocardium: Does not regenerate.
2. Endocardium: Repair and vascularization of valves.

iv. Nervous System.

1. CNS: No regeneration of axons possible.
2. Peripheral: Axonal regeneration if cut edges are in perfect alignment. Otherwise, axonal proliferation.

v. Liver.
1. Both scarring and proliferation.

Question 16

A/15. Tissue repair and wound healing

Types of defects in wound healing

Answer 16

Would dehiscence. Bursting open of a wound. It occurs after
mechanical stresses (vomiting, coughing, sneezing) especially in abdominal
surgery.

Incisional hernia. A late consequence of a weak abdominal scar.

Ulceration. Poor vascularization, trophic (nutritional) disturbances.

Keloid formation. Excessively large hypertrophic scar, extending beyond original wound borders.

Dupuytren’s contracture. An inherited disorcer causing excessive scar contraction.

Question 17

Types of collagen

Answer 17

Type I: skin, tendon, vascular ligature, organs, bone (main component of the organic part of bone)

Type II: cartilage (main collagenous component of cartilage)

Type III: reticulate (main component of reticular fibers), commonly found alongside type I.

Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane.

Type V: cell surfaces, hair and placenta