A/12-15 CELLULAR ADAPTATION TO STRESS, REGENERATION, WOUND HEALING (Leiel) Flashcards
Define hypertrophy
Is an increase in the size of cells (which leads to an increase in the size of the organ) there are no new cells in hypertrophy, just the cells become bigger due to increased amount of structural proteins and organelles.
This is to be distinguished from hyperplasia, in which there is an increase in the cell number.
What may trigger hypertrophy?
The 2 processes occur as a response to either
- Mechanical trigger (increase in the functional demand)
- Trophic trigger (hormonal stimulation).
What determines if a cell responds with an hypertrophy or hyperplasia?
- If a cell is incapable of dividing (striated muscle of skeletal and cardiac muscle) then it responds with an hypertrophy
- If a cell is capable of replication it will go through hyperplasia.
Hypertrophy and hyperplasia can also occur together.
When is hypertrophy a physiologic and when is it a pathologic process?
Physiologic:
- Due to exercise (increase in the functional demand)
- Due to hormonal effect: Hypertrophy and hyperplasia of the uterus during pregnancy (estrogen), breast during lactation (estrogen, prolactin).
Pathologic:
- hypertrophy of the heart due to hypertension or aortic valve stenosis.
Cardiac hypertrophy pathogenesis
Cardiac myocytes are incapable of dividing.
Trophic stimuli → signal transduction pathway → induction of number of genes → synthesis of proteins and myofillaments → increase muscle mass and performance.
- There might be a change in the type of the contracticle protein: alpha myosin heavy chain is replaced by beta myosin heavy chain which is slower and more energetically economical contraction.
- The extent of the hypertrophy varies with the underlying cause, and may reach up to 1 kg.
What are the 2 groups of HDAC that are associated with hypertrophic pathway?
There are 2 groups of HDAC:
- Group I is pro-hypertrophic (up-regulation or loss of inhibition)
- Group II is anti-hypertrophic (loss of inhibition)
- The balance between the 2 will determine if the cell goes through hypertrophy or not.
The hormones that initiate the pathways are angiotensin 2, IGF-1, ANP, catecholamines etc.
What cause of cardic hypertrophy will result in what pattern of hypertrophy?
- Pressure overloaded ventricle developes concentric hypertrophy with increased wall thickness (parallel growing of the sarcomeres) which can even reduce the cavity diameter.
- volume overload: the sarcomeres grow in series so there is no increase in wall thickness but only the volume of the chamber increases.
What are the possible reasons that lead to myocyte contractile failure?
- The fetal isoform of proteins is less functional
- Intracellular handling of calcium ion leads to an impaired function
- The hypertrophy is not accompanied by an increase in the vascular supply, thus, there is a chronic ischemia that leads to deposition of fibrous tissue and limited relaxation of the heart.
For all these reasons, prolonged hypertrophy leads to cardiac decompensation.
Define atrophy.
Decrease of body or organ mass as a result of shrinkage of the size of the cells.
Atrophy can be a physiologic or a pathologic process.
Describe pysiological atrophy
Physiologic atrophy: is common during early development when certain embryonic structures undergo atrophy.
The signaling pathway that determines if the cell undergows atrophy or hypertrophy:
- “Survival siganl” = IGF-1 → PI3K → Akt →
- phosphorylation of FOXO → no activation of protein ligases → no degradation of proteins in proteasomes.
- Akt activates m-TOR → protein synthesis and hypertrophy).
In the absence of the survival signal, FOXO is not phosphorylated, thus, it activates ubiquitin ligases (Atrogin-1, Murf-1) that result in degradation of cells and atrophy.
What are the causes of pathologic atrophy?
- Atrophy of diseus: a decrease in the workload.
-
Denervation atrophy: Loss of innervation leads to muscle atrophy.
- diseases of motor neuron (e.g. Amyotrophic lateral sclerosis)
- trauma to peripheral nerve
- Decreased blood supply: can be the result of atherosclerosis.
- Hormonal effect: an abnormaly high or low levels of hormones.
- Atrophy due to pressure: (corset liver, aneurysm of aorta, Pressure of benign tumors, Cryptorchidism, Hydronephrosis)
- Inadequate nutrition: Cachexia, marasmus, profound protein-calorie malnutrition causes the use of skeletel muscles as soure of calorie. (AIDS, tumors, anorexia nervosa)
- aging (senile atrophy)
What is Osteoporosis?
How does the peak bone mass maintained?
- Increased porosity (empty spaces) of skeleton resulting from a reduction in bone mass (bone atrophies).
- The peak bone mass is maintained by appropriate nutrition, physical exercise, vitamine D and genetic factors.
- A decrease of the peak bone mass is called osteoporosis.
Describe the causes of primary osteoperosis
Primary:
-
Postmenopausal: in the presence of estrogen: OPG increases → OPG binds to RANKL → decreased differentiation of osteoclasts precursores into mature ones.
- If estrogen decreases, and moreover, IL-1 and IL-6 increases → increased osteoclasts activity
-
Senile (after the age of 75)
- Decreased replicative activity of osteoprogenitor cells
- Decreased synthetic activity of osteoblasts
- Decreased biologic activity of matrix-bound growth factors
- Reduced physical activity
Describe the secondary osteoporosis
Can occur at every age and in male and female equally and is due to the following:
-
Endocrine disorders:
- Hyperparathyroidism
- Hypo/hyerthyroidism
- Hypogonadism
- Diabetes
- Addison disease
-
Neoplasia:
- Multiple myeloma
- carcinomatosis
-
Gastrointestinal:
- Malnutrition
- Malabsorption
- Hepatic insufficiency
- Vitamin C, D deficiences
- Rheumatologic diseases
-
Drugs:
- Anticoagulants
- Corticosteroids
- Anticonvulsants
- Chemotherapy
-
Miscellaneous
- Immobilisation
- Osteogenesis imperfecta
- Anemia
Describe Alzheimer disease and its pathogenesis
- The most common cause of dimensia in the elderly.
- Risk increases with increased age.
- The disease in caused by the accumulation of aβ-peptide in the brain. This peptide is derived from a group of membrane proteins called amyloid-precursore protein (APP) which can be processed in 2 ways, one of them which is done by the enzyme γ-secretase and leads to the formation of this peptide and to its accumulation since it cannot be cleared by the blood. The plaques generated inhibit the function of neurocytes and cause inflammation, injury and death of neurons.
What are the cellular changes that occur durind atrophy?
- Decrease in cellular function, along with a decrease in cellular function
- Change in cellular component: nuclei becomes pyknotic, fewer mitochondria and ER.
- Protein degradation by the ubiquitin ligase system
- Activation of the apoptotic machinary
The biochemical pathway of atrophy
If a survival signal (IGF-1) is present:
- IGF-1 → PI3K → Akt
- → mTOR → protein synthesis
- → phosphorylates Foxo (Inactivation).
- The result is a downregulation of ubiquitin ligases, thus, there is no protein degradation and no atrophy.
In the absence of a survival signal, Akt is no present, so that Foxo is dephosphorylated and active.
Active Foxo leads to upregulation of ubiquitin ligases that target proteins to degradation by proteasomes, leading to an atrophy of the tissue.
What is hyperplasia?
An increase in the cellular number that takes place if the cell population is capable of replication.
What are the cuses hyperplesia?
-
Increased functional demand
- At high altitude, low atmospheric O2 pressure induces compensatory hyperplasia of the bone marrow
- compensatory hyperplasia that occurs when an organ is removed
- follicular hyperplasia
- parathyroid hyperplasia
-
Hormonal stimulation
- The hormonal stimulation can lead to physiologic or pathologic hyperplasia which is the result of excessive hormonal or growth factor stimulation.
- Chronic inflammation
