Lecture 11 - Kapila - Adaptations 23 Sep 2006

Cell Proliferation and Adaptation Kusum Kapila September 2006

Normal growth Growth – increase in size by synthesis of specific tissue components Differentiation – process by which cell develops a special function which distinguishes it from parent cell

Cells encounter many stresses as a result of changes in their internal and external environment. Patterns of response to this stress constitutes the cellular basis of disease If cell able to withstand injury or the stress removed in time - cell injury is reversible and the cell is restored to its original structure and function. Persistent sublethal stress – leads the cell to adapt to reversible injury which has its morphological counterpart Severe stress leads to cell death

Cell adaptation Cells are adaptable within physiological limits. Cells can respond to injury by producing cell stress proteins, which protect from damage and help in recovery. Increased demands are met by hypertrophy and hyperplasia. Reduced demand is met by atrophy. Cell loss from tissues can be achieved by programmed cell death (apoptosis). Tissues can adapt to demand by a change in differentiation known as metaplasia.

Cellular Adaptations: Growth adaptations: Hyperplasia, Hypoplasia, Hypertrophy, Atrophy, Metaplasia, Dysplasia, Neoplasia.

Degenerations: (Accumulations) Hydropic change (cell swelling/edema) Fatty Change Hyaline Change Pigment storage – wear & tear..

Adaptations Cells may undergo various adaptations in physiological and pathological conditions. Stress may be -increased functional,work or metabolic demand. -excessive endocrine stimulation. -persisting tissue injury. The following are common adaptations -atrophy -hyperplasia -hypertrophy -metaplasia -dysplasia

Atrophy Decrease in the size and function of cell / organ Adaptive response On restoration of normal condition cells resume their function May culminate in cell death

Physiologic atrophy – common in early development -notochord -thyroglossal cyst -thymus ADULT

CHILD

Atrophy

(Decrease in size of cells)

Physiologic: Developmental – e.g.. Thyroglossal duct Uterus following parturition

Pathologic: Decreased workload – Disuse atrophy of muscles Loss of innervation – Denervation atrophy Decreased blood supply – Brain atrophy Malnutrition – marasmus, extreme cachexia. Loss of endocrine support – endocrine glands. Ageing: Senile atrophy

Atrophy Pathologic atrophy – focal or general • Reduced functional demand (disuse atrophy) - cast for bone fracture - prolonged bed rest 6. Denervation atrophy - damage to nerves – muscle atrophy

Atrophy

.Diminished blood supply - ischemia to tissue eg kidney - brain atrophy, adult life

Pathologic Atrophy 2. Insufficient nutrients - protein calorie malnutrition (marasmus) - cachexia – patients with

- chronic inflammatory disease - cancer - TNF

Atrophy Pathologic Atrophy 2.

Loss of endocrine stimulation

-

Removal of anterior pituitary -

-

TSH, ACTH, FSH

atrophy of thyroid, adrenal cortex, ovaries - Menopause – lack of estrogen - atrophy of endometrium, vaginal epithelium, breast - androgen dependent carcinoma of prostate partially regresses with testosterone antagonists.

Atrophy Pathologic Atrophy 6. Persistent cell injury Chronic inflammation atrophy mucosa in chr.gastritis villous atrophy – celiac disease Pressure CHF – central liver cells enlarging benign tumour 9. Aging (senile atrophy) - seen in tissues with permanent cells heart brain

Normal Brain surface:

Atrophy – Senile / Alzheimer's

Atrophy of un-descended testes

Testicular AtrophyNo spermatogenic activity seen

Mechanism of Atrophy Incompletely understood Affects balance between protein synthesis and degradation Increased protein degradation plays a key role

Anamolies of organogenesis Agenesis (aplasia) – complete failure of development of an organ, renal, thymus, anencephaly Atresia – failure of development of a lumen in a normal tubular structure – esophagus, biliary, urothelial Hypoplasia – incomplete growth of organ Dysgenesis/dysplasia – renal Ectopia/heteropia/choristomasdevelopment of mature tissue is an inappropriate site.

Adaptations - Hypertrophy Hypertrophy--increase in the size of cells which results in enlargement of the organs. No new cells but larger cells due to synthesis of more structural components – proteins. Dividing cells -both hyperplasia/hypertrophy Non-dividing cells-hypertrophy–cardiac,skeletal muscle These changes usually revert to normal if the cause is removed

Hypertrophy can be classified as: physiologic pathologic

Hypertrophy •

Physiologic (hormonal) hypertrophy - puberty – hypertrophy of juvenile sex organs - lactation – breast (estrogen, prolactin) - Exogenous anabolic steroids – muscle hypertrophy - Endogenous over production of TSH – goitre - Uterus during pregnancy (hyperplasia and hypertrophy)

Pregnant uterus

hyperplasia and

Hypertrophy Increased functional demand - exercise muscle size - heart – eject blood under pressure - hypertension - aortic outflow obstruction - Kidney (loss ofnormal

normal

Mechanism of Hypertrophy Final steps in messenger and ribosomal /RNA and protein Transcriptional regulation DNA replication can be independently regulated by different growth factors.

Adaptations - Hyperplasia Hyperplasia--increased number of cells in an organ or tissue. Hyperplasia may sometimes co-exist with hypertrophy. Hyperplasia can be classified as: Physiologic --hormonal (e.g., breast and uterus during pregnancy) --compensatory--regeneration of liver following partial hepatectomy. Various growth factors and interluekins are important in such hyperplasia. Pathologic--excessive hormonal stimulation / growth factors -endometrial hyperplasia -viral infection (papilloma viruses); neoplasms -wound healing/repair

Hyperplasia •

Hormonal stimulation - menstrual cycle - endometrial hyperplasia – menopause - gynecomastia (exogenous or endogenous) - benign prostate hyperplasia (androgens) - erythropoietin (renal ca) increases erythrocyte precursors in bone marrow.

Hyperplasia 2.

Increased functional demand

-high altitude residents O2 content – hyperplasia of bone marrow producing increased RBC’s due to increased erythropoietin-secondary polycythemia -Chronic blood loss -

RBC

-Chronic renal disease Ca absorption mobilisation of Ca from bones parathyroid hormone - parathyroid hyperplasia

Hyperplasia

3. -

-

Pathologic Persistent cell injury papilloma virus – warts Callus Chronic cystitis Cancerous hyperplasia

Mechanism of hyperplasia Increased local production of growth factors Activation of intracellular signalling pathways Production of transcription factors Turn on cellular genes, genes encoding factors, receptors for growth factors and cell cycle regulators Net result in cellular proliferation Apparently autonomous hyperplasia Eg.-psoriasis,Paget’s disease of bone, fibromatosis

Adaptations - Metaplasia transformation or replacement of one adult cell type to another adult cell type change from columnar to squamous cells in respiratory tract, uterine cervix from squamous to columnar in Barrett’s esophagitis. From columnar to columnar in chronic gastritis From transitional to squamous in bladder stones Metaplasia also occurs in mesenchymal tissue -formation of bone in skeletal muscle -bone, carilage, fat in tissues that normally do not have them

Gastric metaplasia of lower esophagus-Barrett’s esophagus

Examples of Metaplasia Original tissue tissue

Stimulus

Metaplastic

Ciliated columnar Epithelium of bronchial tree

Cigarette smoke

Squamous epithelium

Transitional epithelium of Bladder

bladder calculus

Squamous epithelium

Columnar epithelium in ducts

Trauma of calculus

Squamous

Fibrocollagenous tissue

Chronic trauma

Bone(osseous) tissue

Esophageal squamous Epithelium

Gastric acid

Columnar epithelium

Adaptations - Metaplasia Metaplastic changes usually result from chronic irritation. Metaplastic changes seem to precede the development of cancer, in some instances. Metaplasia is thought to arise from reprogramming of stem or undifferentiated cells that are present in adult tissue.

Dysplasia Dysplasia characterised by cellular proliferation with incomplete maturation of cells. - variations in size and shape - enlarged, irregular, hyperchromatic nuclei - disorderly arrangement of the cells within the epithelium

Squamous - epidermal actinic keratosis - bronchus - uterine cervix

Columnar - ulcerative colitis - endocervical epithelium

splasia – Squamous epithelium

Dysplasia – Columnar epitheli

Dysplasia Reflects persistance of injurious influences Can regress on cessation of stimulus Various grades Fine line of distinction between cancer Considered a preneoplastic lesionnecessary step in the multistep cellular evolution to cancer Dysplastic cell less differentiated than hyperplastic or metaplastic cell Not autonomous yet its replication is not as well regulated Adaptation does not stop with dysplasia – overshoots – transformation to a cancer cell.

CIN I

CIN II

CIN III

SCC

Neoplasia Abnormal, uncoordinated, excessive cell growth Persists after initiating stimulus has been withdrawn Assoc with genetic alterations Neoplastic cells influence behaviour of normal cells Neoplasia new growth Neoplasm lesion so produced

Intracellular Accumulation Intracellular accumulation develops when normal cellular constituents or products (e.g., water, lipids, proteins, carbohydrates) occur in excess. Fatty changes in the liver, or heart are two examples of this abnormal condition. Genetic defects involving specific enzymes can result in the massive accumulation of some endogenous substances, as seen in lysosomal storage diseases.

Intracellular Accumulation Accumulation of pigments: Exogenous--carbon dust (anthracosis) Endogenous-lipofuscin (aging pigment) in liver, heart, neurons, etc. hemosiderin--in lungs following congestive heart failure; called hemosiderosis when found in a number of tissues and organs bilirubin--in jaundice

Pathologic Calcification There are two general types of pathologic calcification: Dystrophic--deposition of calcium and other minerals in dead tissue (e.g., atherosoma in blood vessels, heart valves in elderly individuals, old tuberculosis lesions) Metastatic--calcium deposits in normal tissues in hypercalcemic states

Cellular Aging Many cell functions decline, and morphologic changes occur with aging. Aging is thought to be influenced by an intrinsic molecular program, called the "programmed aging hypothesis." It states that sequential shortening of telomeres (the natural ends of chromosomes) may lead to loss of genes, causing cellular aging.

Cellular Aging Aging is also thought to be influenced by cumulative effects of various extrinsic factors. Progressive effects of free radical damage throughout life may be an important factor in cellular aging. Free radicals can induce damage to mitochondria and DNA.