PCL 301

1. PCL 301 ADEYEMI OC, 26/1/2015.

2. 1. NORMAL CELL AND ADAPTED CELL

3. CELL ADAPTATION • Cell adaptations are reversible changes in number, size, phenotype, metabolic activity or functions of a cell- not same as cell injury. • Physiologic- hormonal/ endogenous chemical mediators (breast development at puberty) or Pathologic- response to stress- modulation of activity to escape injury • Types; hypertrophy, hyperplasia, atrophy, metaplasia

4. CELL ADAPTATION: Hypertrophy • Stimuli- signal transduction pathways- induction of genes- stimulation of cellular protein synthesis, growth factors and structural proteins- ↑myofilaments and proteins per cell hence improved performance. • Possible switch in contractile protein from α-myosin heavy chain to β-myosin heavy chain which has better ergonomical contractions • Adaptations are not perfectly elastic

5. CELL ADAPTATION: Hypertrophy An increase in size of cells (due to increase structural proteins and organelles) resulting in increase in the size of the organ. • Cells have limited ability to divide. • Physiologic- enlargement of striated skeletal and heart muscles in adults due to exercise, or Pathologic- enlargement of cardiac muscles due to hypertension or aortic valve disease

6. CELL ADAPTATION: Hyperplasia • An increase in cell number. May occur with hypertrophy (e.g. gravid uterus) and due to similar stimuli. • Cells must be able to divide and regulate replication.

7. CELL ADAPTATION: Atrophy • Shrinkage in the size of the cell by the loss of cell substance • Functions may diminish but cells are not dead • Due to decreased workload, loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation (menopause)and aging (senile atrophy) • Mechanism: decreased protein synthesis (↓metabolic activity) and increased protein degradation (ubiquitin-proteasome pathway) e.g. cancer cachexia • Atrophy is accompanied by autophagy- starved cells eating its components in an attempt to find nutrients and survive.

8. CELL ADAPTATION: Metaplasia • Reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type. • Genetic reprogramming of stem cells rather than modification of already differentiated cells. • Respiratory epithelium of habitual smokers’ normal columnar cells are replaced by squamous epithelium- loss of mucus secretion and ciliary clearance of particulate matter • Influences that induce metaplastic transformations if persistent may increase risk for malignant transformation of epithelium. • Note gastric epithelium, in chronic gastric reflux, changes from squamous to columnar

9. SELF ASSESSMENT • Write short notes on the following, defining terms and differentiating with examples between physiologic and pathologic types of each adaptation; • Hypertrophy • Hyperplasia • metaplasia • In chronic gastric reflux, the gastric epithelium is transformed/ adapts, which of the following is true of the adaptation A. It is an irreversible change where adult cell types are replaced by a different cell type B. There is a genetic reprogramming of stem cells without modification of adult differentiated cells C. The adult cells are modified D. All of the above E. A and C only • At puberty, glandular epithelium of the female breast undergoes A. Hormonal hyperplasia B. Compensatory hyperplasia C. Hormonal hypertrophy D. All of the above E. A and C only

10. 2. CELL INJURY AND CELL DEATH • Cell injury occurs when cells are stressed so severely that they are no longer able to adapt/ exposed to inherently damaging agents/ suffer from intrinsic abnormalities. • Reversible cell injury- functional and morphological changes are reversible if damaging stimulus is removed. • Cell death occurs when injury becomes irreversible and can be necrosis or apoptosis- both differ in morphology, mechanisms, and roles in disease and physiology.

11. 2. CELL INJURY AND CELL DEATH: Causes

12. 2. CELL INJURY AND CELL DEATH: Morphologic alterations in injured cells • Reversible cell injury: cell swelling, fatty change, plasma membrane blebbing and loss of microvilli, mitochondrial swelling, dilation of the endoplasmic reticulum and eosinophilia. • Necrosis: increased eosinophilia; nuclear shrinkage, fragmentation, and dissolution; breakdown of plasma membrane and organellar membranes; myelin figures, leakage and enzymatic digestion of cellular contents. • Apoptosis: nuclear chromatin condensation; formation of apoptotic bodies (fragments of nuclei and cytoplasm)

13. 2. CELL INJURY AND CELL DEATH: Differentiating Necrosis and Apoptosis

14. 2. CELL INJURY AND CELL DEATH: Mechanism of Injury

15. 2. CELL INJURY AND CELL DEATH: Reversible and irreversible injury

16. 2. CELL INJURY AND CELL DEATH: Apoptosis A Regulated mechanism of cell death that serves to eliminate unwanted and irreparably damaged cells, with the least possible host reaction • Characterized by: enzymatic degradation of proteins and DNA, initiated by caspases; and recognition and removal of dead cells by phagocytes Initiated by two major pathways: • Mitochondrial (intrinsic) pathway is triggered by loss of survival signals, DNA damage and accumulation of misfolded proteins (ER stress); associated with leakage of pro-apoptotic proteins from mitochondrial membrane into the cytoplasm, where they trigger caspase activation; inhibited by anti-apoptotic members of the Bcl family, which are induced by survival signals including growth factors. • Death receptor (extrinsic) pathway is responsible for elimination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes; is initiated by engagement of death receptors (members of the TNF receptor family) by ligands on adjacent cells

17. Self Assessment • List the mechanisms of Cell injury and cell death giving a brief description of each • Describe • Ischemic and Hypoxic injury • Ischemia-Reperfusion Injury • Chemical Injury • What are the causes of Apoptosis in physiologic and pathologic conditions?

18. 3. INFLAMMATION AND REPAIR- Signs • Rubor: redness due to increased blood flow and vasodilation • Calor: heat due to increase blood flow • Tumor: swelling from inflammatory edema • Dolor: pain from swelling and presence of inflammatory mediators • Function laesa: loss of function due to main and structural necrosis

19. 3. INFLAMMATION AND REPAIR- Acute Inflammation A series of reactions of vascularized tissue to injury • Defends against foreign substances, dispose of dying or dead tissue, immobilize injured area or compartmentalize injured area • Depends on severity of injury, immune status and temperature

20. 3. INFLAMMATION AND REPAIR- Acute Inflammation

21. 3. INFLAMMATION AND REPAIR- Acute Inflammation • Immediate vasoconstriction– 1hour gradual vasodilation, hemostasis, mast cell degranulation, margination of WBC, Large scale neutrophil response– later Hemoconcentration from edema, ischemia, interaction with chemical mediators, emigration of larger WBCs, initiation of complement system • Abscess, ulcers, cellulitis, pseudomembranous inflammation

22. 3. INFLAMMATION AND REPAIR- Chronic Inflammation Recurrent inflammation prior to completion of repair or resolution Cellular aspect: • Macrophages predominate, features monocytes, giant cells, fibroblasts and lymphocytes • CD8+ T-killer and CD4+ delayed hypersensitivity • Leads to hypertrophic scarring (build up of type I collagen in chronic inflammation/healing)

23. 3. INFLAMMATION AND REPAIR- Chronic Inflammation Granulomatous inflammation- a granuloma is an abnormal structure built from at least two activated macrophages adhering to one another-may be called epithelioid cells • Granulomas may be formed with caseation (typical in fungal infections, TB), suppuration (pus, typical in infections that involve the lymph nodes- brucellosis, plague), around foreign bodies (splinters, sutures, mucus plugs in cystic fibrosis) etc.

24. 3. INFLAMMATION AND REPAIR- Regeneration and Repair • Inflammation resolves when nonstructural cells are lost after inflammation/ damaged cells have been regenerated or repaired by fibrous tissue • Labile cells/ continuous replicators e.g. skin, gut, hemopoietic cells • Stable cells have little proliferation without injury, but can divide rapidly if necessary eg liver, renal parenchymal tissue • Permanent cells – healed by scarring eg brain, heart

25. 3. INFLAMMATION AND REPAIR- Regeneration and Repair • Tissue repair • 1.Fibroplasia/ fibrous repair: formation of granulation tissue, infiltration of fibroblasts, collagen laid down in random pattern (can be manipulated artificially) • 2.Maturation and remodeling: scar matures, scar remodels (due to stress)- usually is more fragile than tissue it replaces.

26. 3. INFLAMMATION AND REPAIR- Regeneration and Repair • Surgical wounds • 1. healing by primary intention- wound has neatly apposed edges, no big scar is left • 2. healing by secondary intention- granulation tissue is formed from bottom up since edges are not apposed, big scar. • Factors responsible for wound healing: growth factors eg platelet derived growth factor, epidermal growth factor, fibroblast growth factor, transforming growth factor, TNF/Cachectin etc.

27. Self Assessment • INSTRUCTION: Choose the option that best suits the statement and the explanation after it. • The statement is true: the explanation is true and explains the statement • The statement is true: the explanation is true, but does not explain the statement • The statement is false: the explanation is a true statement. • The statement is false: the explanation is false • The options do not apply • Rubor is redness: and it is due to swelling and presence of inflammatory mediators. • Cellulitis is an acute inflammation state: the inflammatory process includes immediate vasoconstriction resulting from hemostasis, margination of white blood cells, and later hemoconcentration resulting from edema, ischemia and interaction with chemical mediators. • Chronic inflammation usually heals without any scarring involved: this is due to build up of type I collagen in chronic inflammatory conditions • Granulomas may be formed with caseation in Tuberculosis patients: this is usually due to the mycobacterium infested cells dying to leave a cheese like structure • Inflammation does not resolve: this typically occurs if no cells are lost or if damaged cells have been regenerated or repaired by fibrous tissue • Labile cells and stable cells heal by proliferation, while permanent cells heal by scarring: this observed difference is due to dissimilar abilities to detect divine signals

28. NEOPLASIA AND ITS CLINICAL ASPECTS • Tumors- an abnormal mass of tissue which may be solid or fluid filled • Cancers- malignant neoplasms, invade and spread to remote sites (metastasize) • Benign tumors- do not spread but represents a risk • Cancers from epithelium (carcinomas), from mesoderm (sarcomas)

29. NEOPLASIA AND ITS CLINICAL ASPECTS: Diagnosis • Laboratory based- histologic and cytologic methods eg pap smear; immunohistochemistry to determine origin/categorize/determine target therapy; flow cytometry; molecular diagnosis/molecular profiles/tumor markers.

30. NEOPLASIA AND ITS CLINICAL ASPECTS: Neoplasm • They don’t facilitate homeostasis, grow more rapidly than surrounding tissue, are unregulated. • Anaplasia- ugly cells/ markers for cancer or pre-cancer • Neoplasia- a new, useless organ produced by cells having mutation • Dysplasia-pre-cancer cells in an epithelium, without invasion

31. NEOPLASIA AND ITS CLINICAL ASPECTS • Squamous cell carcinoma- arise anywhere there is a stratified squamous epithelium, either healthy (skin, oesophagus, mouth) or metaplastic (endocervix, bronchi) • Adenocarcinomas- arise anywhere there are glands, even single celled glands(goblet cells) • Spindle cell sarcomas- arise where there is connective tissue • Leukemias and Lymphomas- cells resemble blood precursors, don’t stick tightly together

32. NEOPLASIA AND ITS CLINICAL ASPECTS: Causes • Both benign and metastatic are clonal overgrowths of cells having multiple/ cumulative genetic injury • Several genes are mutated or over expressed e.g. epidermal growth factor b receptor, basic fibroblast growth factor, cathepsin B etc. • Telomerase expression, Vascular endothelial growth factor (for blood supply) etc. • Triggers include chemicals, environmental factors,

33. NEOPLASIA AND ITS CLINICAL ASPECTS: characters • Relatively unregulated proliferation • Failure to mature • Transplantability • Immortality • Loss of contact inhibition • Loss of serum and anchorage requirement • Loss of density-dependent growth inhibition

34. 4. NEOPLASIA AND ITS CLINICAL ASPECTS: Clinical Aspect Malignant and benign tumors through: • Location and impingement on adjacent structures • Functional activity- hormone synthesis, development of paraneoplastic syndromes • Bleeding and infections when tumor ulcerates through adjacent surfaces • Symptoms from rupture or infarction • Cachexia or wasting

35. 4. NEOPLASIA AND ITS CLINICAL ASPECTS: Clinical Aspect Local and hormonal effect: • Location- a 1cm benign pituitary adenoma, can compress and destroy surrounding normal gland leading to serious hypopituitarism. • Hormone production is common with benign or malignant neoplasms arising in endocrine glands e.g. B-cell adenoma of the pancreatic islets may produce sufficient insulin to cause fatal hypoglycemia.

36. 4. NEOPLASIA AND ITS CLINICAL ASPECTS: Clinical Aspect Cancer Cachexia: • Progressive loss of body fat and lean body(unlike in starvation) mass accompanied with profound weakness, anorexia, and anemia. • Likely due to cytokines e.g. TNF, IL-1, interferon-ᵞ, and leukemia inhibitory factor. • Responsible for a third of cancer deaths

37. 4. NEOPLASIA AND ITS CLINICAL ASPECTS: Clinical Aspect • Para-neoplastic syndromes • Symptom complexes in cancer-bearing individuals that can not readily be explained, either by local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue from which the tumor arose • Earliest symptom of occult neoplasm, represents significant problems/ may be lethal, mimics metastatic disease and confounds treatment.

38. 4. NEOPLASIA AND ITS CLINICAL ASPECTS: Clinical Aspect • Grading and staging: • Low to high grade, or four categories/ descriptive e.g. well-differentiated, mucin-secreting adenocarcinoma of the stomach. Grading is not as significant as clinical staging. • Staging- based on size of primary lesion, extent of spread to regional lymph nodes, and the presence or absence of blood-borne metastases e.g. TNM- T0(in situ lesion), N0(no nodal involvement), M0(no distant metastasis)-numbers range from 0-4.