Cell adaptation 2.pptx

Cell adaptation Dr Nor Hidayah Abu Bakar, MD, M.Path (Anat Path), FP UniSZA Strictly for instructional  Learning objectives Describe the cellular adaptation to various types of injury De...

Cell adaptation Dr Nor Hidayah Abu Bakar, MD, M.Path (Anat Path), FP UniSZA Strictly for instructional  Learning objectives Describe the cellular adaptation to various types of injury Describe hyperplasia, hypertrophy, atrophy and metaplasia (mechanism and causes) Describe hyperplasia and metaplasia as precursors to neoplasia  Cellular response to injury Normal cell Severe, progressive injurious stimulus Mild, transient stress injurious stimulus Reversible cell injury Irreversible Adaptations cell injury Atrophy Degeneration Unable Subcellular Hypertrophy Hyperplasia to adapt alterations Metaplasia Intracellular Dysplasia accumulations Stress removed Stimulus removed Normal cell Repair and Cell death restored healing  Cellular adaptation The cell forms the basic structural and functional unit of a tissue/ organ. Every cell has a narrow range of structure and function – homeostasis. When the cells are subjected to stress – they undergo certain structural and functional adjustment - increase, decrease or change in stress. The adaptation can be: – Physiological in response to physiologic needs – Pathological in response to stress or pathologic injury allow cells to modulate their structure and function and escape injury. Changes are reversible (number, size, phenotype, metabolic activity, functions)  Classification of cells Cells in the body are divided according to their proliferative capacity into: – Labile cells – Stable cells – Permanent cells  Labile cells Continuously dividing throughout life under normal physiologic conditions. Can easily regenerate after injury Contain a pool of stem cells Eg of organs: epidermis, gastrointestinal tract, respiratory tract, vagina, cervix, uterine endometrium, haemopoietic cells of bone marrow, cell of lymph node and spleen.  Stable cells Decreased or lose ability to proliferate after adolescent but able to multiply in response to stimuli. Eg: parenchymal cells of organs like liver, kidney, pancreas, adrenal and thyroid, mesenchymal cells like smooth muscle cells, fibroblasts, vascular endothelial cells, bone and cartilage cells.  Permanent cells Lose ability to proliferate around the time of birth injury always lead to scar in the organ Eg: neurons, striated muscle (cardiac muscle, skeletal muscle)  Cell cycle Resting - G0 (Gap 0) – Quiescent (cells are out of cycle and not dividing) Interphase – G1 (Gap 1) Daughter cells after mitosis PRE- synthetic, growth and accumulation of nutrients – S Phase (synthesis) Duplication of chromosomes – G2 (Gap 2) PRE-mitotic (growth and accumulation of nutrients) M Phase (mitosis) Major processes in adaptation  Hyperplasia Increased number of cells in an organ/ tissue which leads to increased volume of the organ. Occurs in labile and stable cells – capable of synthesizing DNA.  Mechanism of hyperplasia 1. Proliferation of mature cells, stimulated by growth factors. 2. Increased output of new cells from tissue stem cells. Eg: After partial hepatectomy, liver cells produce growth factors and activate signaling pathways that stimulate cell proliferation. But if the proliferative capacity of the liver cells is compromised, (in some forms of hepatitis causing cell  Types Types of of hyperplasia hyperplasia Physiologic hyperplasia Pathologic hyperplasia – Hormonal hyperplasia – Due to excessive hormonal due to the action of hormones stimulation or excessive or growth factors when there effects of growth factors on is a need to increase target cells functional capacity of hormone sensitive organs – Compensatory hyperplasia after damage or resection.  Example of physiological hyperplasia Hyperplasia of female breast at puberty and during pregnancy. Normal breast tissue Breast tissue during pregnancy  Example of physiological hyperplasia Proliferative activity of normal endometrium after a normal menstrual cycle. Example of physiological hyperplasia Regeneration of liver following partial hepatectomy – compensatory hyperplasia.  Example of pathological hyperplasia Endometrial hyperplasia following oestrogen and progesterone imbalance Normal endometrium Endometrial hyperplasia  Example of pathologic hyperplasia Benign nodular prostatic hyperplasia in old age men due to hormonal stimulation by androgen From a young man showing uniform texture of gland Prostatic hyperplasia From an elderly man showing Normal prostate irregular hyperplastic nodules. This would cause obstruction  Example of pathological hyperplasia Skin warts (hyperplastic epithelium) in response to papillomavirus infection due to stimulation by growth factor by viral genes or by the genes of the infected cells. Normal skin Viral wart  Hypertrophy Increase in cell size of cells → an increase in the size of the affected organ. Due to the synthesis and assembly of additional intracellular structural components. Permanent cells/ non-dividing cells undergo hypertrophy only. Dividing cells (stable cells/ quiescent cells) undergo both hypertrophy and hyperplasia.  Mechanism of hypertrophy Synthesis of newer cellular proteins or excessive secretion of growth factors  Types Types of of hypertrophy hypertrophy Physiological Pathological hypertrophy hypertrophy – Occur in response to increased – Increased functional workload or disease state in a cells with limited capacity for division. demand – Eg: Hypertrophy of cardiac muscle in – Increased stimulation by systemic hypertension and aortic growth factors and valve stenosis (chronic hormones. haemodynamic overload) leading to left ventricular hypertrophy – Initially, cardiac hypertrophy improves function, but over time this adaptation often fails, setting the stage for heart failure and other significant forms of heart disease  Example of physiologic hypertrophy Small Enlarged uterus in spindle- shaped pregnancy: uterine smooth Oestrogen hormone muscle ↓ cells (normal Stimulation of oestrogen uterus). receptors on smooth muscle Large, plump ↓ hypertrop Increased smooth muscle proteins hied smooth ↓ muscle Increase in size of cells and organ cells from a gravid Normal Pregnant uterus uterus uterus  Example of physiological hypertrophy Striated muscle cells in the heart and skeletal muscle of weightlifter undergo hypertrophy in response to increased demand (limited capacity to divide). Skeletal muscle hypertrophy in response to exercise  Example of pathological hypertrophy Hypertrophy of cardiac muscle in hypertension and valvular disease: heart pumping under pressure in hypertension and increase volume load in valvular diseases Example of pathological hypertrophy Myocardium in hypertensive heart disease  Atrophy Reduction in the size of an organ or tissue due to a decrease in cell size and number. Early in the process, atrophic cells and tissues have diminished function, but cell death is minimal. Later, the cell die by apoptosis.  Mechanism of atrophy Reduced trophic signals Decrease protein synthesis Degradation of cellular proteins by ubiquitin- proteasome pathway Increased autophagy (increase autophagic vacuoles) Some of the cell debris within the autophagic vacuoles may resist digestion and persist in the cytoplasm as membrane-bound residual bodies – lipofuscin granules  Types of Types of atrophy atrophy Physiological atrophy Pathological atrophy – during normal development – Decrease workload (Disuse) – after parturition. atrophy – Loss of innervation (denervation) atrophy – Diminish blood supply (senile) atrophy – Inadequate nutrition (Starvation) atrophy – Loss of endocrine stimulation – Pressure atrophy  Example of physiological atrophy – Atrophy of gravid uterus post pregnancy – Atrophy of thymus in adult life – Atrophy of lymphoid tissue with age – Atrophy of gonads after menopause Gravid uterus post pregnancy  Example of pathological atrophy Decreased workload (Disuse) atrophy : – Wasting of muscles of limb immobilised cast Loss of innervation (denervation) atrophy: – Muscle atrophy in Poliomyelitis Motor neuron disease Transected nerve  Example of pathological atrophy Diminished blood supply (Senile/ ischaemic) atrophy Gradual decrease in blood supply – atherosclerosis – atrophy of the brain small atrophic kidney in atherosclerosis of renal artery Normal brain Atrophic brain  Example of pathological atrophy Inadequate nutrition (Starvation) atrophy: in cancer patients and in patients with chronic inflammatory diseases Profound protein-calorie malnutrition (marasmus) → utilization of skeletal muscle proteins as a source of energy after other reserves such as adipose stores have been depleted →muscle wasting (cachexia). In some cases, chronic overproduction of the inflammatory cytokine TNF →appetite suppression and lipid depletion→muscle atrophy.  Example of pathological atrophy Endocrine atrophy: Hormone-responsive tissues (eg breast and reproductive organs) are dependent on endocrine stimulation for normal metabolism and function. The loss of oestrogen stimulation after menopause → atrophy of the endometrium, vaginal epithelium, and breast. Similarly, the prostrate atrophies following chemical or surgical castration. Pressure atrophy: An enlarging benign tumor can cause atrophy in the surrounding uninvolved tissues - probably due to ischaemic changes (compression of blood supply by the expanding mass).  Metaplasia A reversible change: one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. A cell sensitive to particular stress is replaced by another cell type better able to withstand the adverse environment. Occurs in response to abnormal stimuli, reverts back to normal on removal of stimulus.  Mechanism of metaplasia Reprogramming of tissue stem cells. Colonization by differentiated cell populations from adjacent sites. Both are stimulated by signals generated by cytokines, growth factors, and extracellular matrix. Types of metaplasia Divided into 2: – Epithelial – Mesenchymal  Epithelial metaplasia More common type. Patchy or diffuse. Replaced by stronger but less specialised epithelium. 2 types: – Squamous metaplasia. – Columnar metaplasia.  Example of squamous metaplasia More common. Cause: Chronic irritation, smoking Common metaplasia: In bronchus of chronic smoker – Ciliated columnar epithelium to squamous Normal bronchial Metaplastic squamous epithelium epithelium – Adv:stratified squamous epithelium able to survive the noxious chemicals in cigarette Squamous epithelium smoke – Disadv:important protective mechanisms are lost (mucus secretion and ciliary clearance of particulate matter) In uterine endocervix in prolapse uterus and in old age. Columnar epithelium – Simple columnar epithelium to squamous.  Example of squamous metaplasia – In gall bladder in chronic cholecystitis and oestrogen therapy. Simple columnar epithelium to squamous. – In prostate in chronic prostatitis and oestrogen therapy. Simple columnar epithelium to squamous. Normal prostate gland Squamous metaplasia  Example of squamous metaplasia – In renal pelvis and urinary bladder in chronic infection and stones. transitional epithelium to squamous – in vitamin A (retinoic acid) deficiency: squamous metaplasia in nose, bronchi, urinary tract, lacrimal and salivary glands, cornea(keratomalacia) Retinoic acid regulates gene transcription directly through nuclear retinoid receptors, which can influence the differentiation of progenitors derived from tissue stem cells.  Example of columnar metaplasia Columnar metaplasia (from squamous) in Barrett’s oesophagus due to gastric acid reflux.  Example of columnar metaplasia Intestinal metaplasia in healed chronic gastric ulcer Conversion of pseudostratified ciliated columnar epithelium in chronic bronchitis and bronchiectasis to columnar type.  Connective tissue metaplasia Formation of cartilage, bone, or adipose cells (mesenchymal tissues) in tissues that normally do not contain these elements Not associated with increased cancer risk. Osseous metaplasia: – In arterial wall in old age (Monkeberg’s medial calcific sclerosis) – In soft tissues in myositis ossificans – In cartilage of larynx and bronchi in elderly people – In scar of chronic inflammation of prolonged duration – In the fibrous stroma of tumour – leiomyoma Cartilaginous metaplasia: – In healing of fractures, in area with undue mobility.  Other Other types types of of metaplasia metaplasia Apocrine metaplasia Tubal metaplasia Clear cell metaplasia Mucinous metaplasia Fat metaplasia  Hyperplasia and Metaplasia as precursors to neoplasia Increased cell division associated with hyperplasia → ↑ risk of acquiring genetic aberrations → uncontrolled proliferation and cancer. Thus, pathologic hyperplasia constitutes a fertile soil in for cancer development. If the response to stimuli causing hyperplasia and metaplasia become uncontrolled or persistence, the growth mechanism become dysregulated → malignant transformation. E.g. Patients with endometrial hyperplasia are at increased risk for endometrial cancer. E.g. squamous cell carcinoma arising from the metaplastic squamous epithelium of the bronchial mucosa in a heavy smoker. E.g. metaplasia from squamous to columnar epithelium in Barret oesophagus may progress to adenocarcinoma of oesophagus.  From hyperplasia to carcinoma Endometrial hyperplasia Normal endometrium Endometrial carcinoma  From metaplasia to carcinoma Grades of dysplasia in bronchial epithelium. (A) Normal two-layered epithelium; (B) squamous metaplasia; (C) mild dysplasia; (D) moderate dysplasia; (E) severe dysplasia; (F) carcinoma in situ.