Cellular Response to Injury: Adaptation Flashcards
Stages and dynamic evolution of cell injury and response
Normal cell–> stress or injurious stimulus–> either adapt, or if unable to adapt, cell injury–> cell injury either reversible or irreversible.
If irreversible–> necrosis or apoptosis
Causes of cell injury
O2 deprivation (hypoxia/ischemia)
Physical agents
Chemicals, toxins, drugs
infectious agents
immunologic reactions/dysfunction
genetic derrangement
nutritional deficiencies and inbalances
workload imbalance
ageing
Adaptive response to injury/stress
Increased cellular activity–> hypertrophy or hyperplasia
Decreased cellular activity–> atrophy
Altered cell type/position–> metaplasia or dysplasia
Cell response/adpation for different cell populations
Continuously replicating cells (labile cells): respond to injury with renewal
Quiescent/stable cells (hepatocytes, osteoblats): can restore proliferative activity in response to demand. NB: skeletal muscle cells count as permanent cells, but satellite cells provide some regenerative capacity.
Non-dividing cells: permanent cells (post-mitotic) e.g. neurons
Hypertrophy
increase in cell size–> increase in size of organ
Increased size due to increased synthesis of structural components (mostly proteins).
In non-dividing cells (e.g. mycocardial fibres), increased tissue is ONLY due to hypertrophy (no hyperplasia)
In many organs, hypertrophy and hyperplasia can co-exist and contribute to increased size.
Physiologic hypertrophy
caused by increased functional demand or by stimulation by hormones and growth factors
1) increased workload is most common stimulus for muscle hypertrophy
2) hormonal stimulation i.e. uterine enlargement in pregnancy and mammary gland enlargement and activity in lactation.
Pathologic hypertrophy
i.e. in the heart.
Myocardium, in response to increased workload (i.e. chronic hemodnamic overload from hypertension or valvular defects/lesions) can adapt by hypertrophy. Thickening of LV, inter-ventricular septum and RV wall. Alternatively, if myocardium gets injured–> cell death.
Molecular pathways of cardiomyocyte hypertrophy
mechanical stretch, agonists (i.e. angiotensin) and growth factors will all signal transduction pathways to activate transcription factors to essentially ensure cardiac hypertrophy in an effort to increase mechanical performance and decrease work load.
In dog: myocardial hypertrophy often caused by pulomnary atery valvular stenosis. Stricture leads to obstruction of blood from from RV to pulm. artery. Increase the pressure, increase the wordload in RV–> prominent hypertrophy.
Feline hypertrophic cardiomyopathy
frequent in cats- young adult and middle aged males are predisposed. Usually have congestive heart failure (CO is low and body becomes congested with fluid due to an inability of heart to match venous return)
10-20% have posterior paresis due to saddle thrombosis. Saddle thrombus: impediment of blood flow can give rise to a thromboembolism at aorta/iliac bifurcation. This results in ischemia in the hind-limbs–> paresis/paralysis.
Hyperplasia
Increase in organ size d/t increase in cell numbers
Response to: hormones/growth factors
“compensatory hyperplasia”–> regeneration subsequent to tissue injury and loss
Liver compensatory hyperplasia–> a dog with liver cirrhosis can have nodular regenerative hyperplasia subsequent to chronic liver damage. Hepatocytes divide upon injurious stimulus/stress–>can reactivate proliferation.
Molecular mechanisms in response to hepatocyte loss: transcription factors, anti-apoptotic factors, DNA replication, cellular proliferation.
Hormone induced hypertrophy/hyperplasia
excessive and/or persistent estrogenic stimulation and an ovary with a persistent CL with increased progesterone can lead to cystic endometrial hyperplasia. This results in a diffuse alteration of the mucosal surface. Pre-disposes bitch to development of pyometra.
Prostate enlargement: hormone related, but precise mechanisms unknown. Androgen removal by castration causes atrophy of prostate. Administration of estrogens causes prostate enlargement due to synergistic action of estrogen and testosterone. Estrogen is responsible for muscular hyperplasia, testosterone responsible for epithelial hyperplasia.
Thyroid gland hyperplasia (goiter): due to maternal dietary iodine deficiency during prengancy. Deficiency in I–> inadequate T4 synthesis–>decreased serum levels of T4 and T3–> feedback on hypothal.–> stimulates TRH secretion–> stim. pituitary to release TSH–> proliferative stimulus for thyroid follicular cells.
Atrophy
reduced size of an organ or tissue resulting from a decrease in cell numbers. Can be physiologic or pathologic.
Physiologic atrophy
common during normal development, ageing and upon decrease in functional demand (likely mediated by withdrawal of hormone stimulation)
Embryonic structures undergo atrophy during fetal development nb: notochord remains as remnant in nucleus pulposus of intervertebral discs.
Thymus–> age related decrease in size resulting from apoptosis-related depletion of lymphoid cells in crotex
Uterus–> decrease in size after parturition
Mammary gland–> decrease in size after end of lactation
Pathologic atrophy
depending on underlying cause can be local or generalized
Decreased nutrient supply/starvation: protein/energy malnutrition–> depletion of adipose stores–> skeletal muscle used as energy source–>muscle atrophy
Deficient blood supply: results in tissue hypoxia
Decreased workload/disuse: atrophy of muscle mass in immobilized limbs
Denervation atrophy: damage to motor neurons or axons –> rapid atrophy of muscle fibers.
Pressure atrophy: expanisve lesion–>pressure on tissue–> impaired local Q with subsequent hypoxia/iscehmia. Example: hydrocephalus- prominent dilatation of lateral ventricles caused by accumulation of fluid–>compressiong of brain parenchyma–>atrophy
Loss of endocrine stimulation: prolonged corticosteroid therapy–> negative feedback on HPA–>decreased ACTH production–> decreased trophic stimulation of adrenal cortex–> adrenocortical atrophy
Metaplasia
Reversible change–>one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. May represent an adaptive substitution of cells that are sensitive to stresss by cell types better able to withstand adverse environment.
Most common epithelial metaplasia is from columnar to squamous.
