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1 Pathology Week 1 – Cellular Adaptation, Injury and Death

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1 Pathology Week 1 – Cellular Adaptation, Injury and Death Pathology week 1 – Cellular adaptation, injury and death Cellular responses to injury Cellular Responses to Injury Nature and Severity of Injurious Stimulus Cellular Response Altered physiologic stimuli: Cellular adaptations: • ↑demand, ↑ trophic stimulation (e.g. growth factors, hormones) • Hyperplasia, hypertrophy • ↓ nutrients, stimulation • Atrophy • Chronic irritation (chemical or physical) • Metaplasia Reduced oxygen supply; chemical injury; microbial infection Cell injury: • Acute and self-limited • Acute reversible injury • Progessive and severe (including DNA damage) • Irreversible injury → cell death Necrosis Apoptosis • Mild chronic injury • Subcellular alterations in organelles Metabolic alterations, genetic or acquired Intracell accumulations; calcifications Prolonged life span with cumulative sublethal injury Cellular aging Hyperplasia - response to increased demand and external stimulation - ↑ number cells - ↑ volume of organ - often occurs with hypertrophy - occurs if cells able to synthesize DNA – mitotic division - physiologic or pathologic Physiological hyperplasia A) hormonal – ↑ functional capacity tissue when needed (breast in puberty, uterus in pregnancy) B) compensatory - ↑ tissue mass after damage/resection (post-nephrectomy) Mechanisms: - ↑ local production growth factors or activation intracellular signaling pathways o both → production transcription factors that turn on cellular genes incl those encoding growth factors, receptors for GFs, cell cycle regulators →→ cellular proli feration - in hormonal hyperplasia hormones may act as growth factors - ↑ tissue mass secondary to proliferation and development of new cells from stem cells Pathological hyperplasia - mostly due to xs hormonal stimulation or GFs o endometrial hyperplasia (xs oestrogen), BPH - abnormal but controlled because if hormonal stimulation removed then hyperplasia regresses - but can turn into cancerous proliferation (endometrial cancer) - in wound healing proliferation of fibroblasts and blood vessels aids repair - certain viruses can cause hyperplasia → HPV – warts Hypertrophy - response to ↑ functional demand or hormonal stimulation - ↑ size of cells → ↑ size of organ (no new cells), due to ↑ synthesis structural components - occurs in nondividing cells (eg myocardium) - physiologic or pathologic - usually due to ↑ workload (striated muscle) - in heart due to chronic haemodynamic overload (HTN or valve disease) - ↑ number myofilaments per cell - hormonally causes hypertrophy AND hyperplasia in pregnant uterus 1 Mechanisms: - heart: signal transduction pathways – stimulate synthesis of cellular proteins o genes induced incl. encoding transcription factors, growth factors (IGF-1, TGF-1), and vasoactive agents (alpha-adrenergic agonists, endothelin-1, angiotensin II) o may switch from adult to fetal or neonatal forms some genes only found in early development reappear in hypertrophy eg ANF - triggers: mechanical or tropic (eg IGF1, angiotensin II) - cardiac hypertrophy reaches point where unable to compensate for ↑ burden → heart failure - limiting factors for hypertrophy: vascular supply, ↓ oxidative capacities of mitochondria, ↓ protein synthesis, cytoskeletal alterations Atrophy - shrinkage in size of cells by loss of structural components of cell - adaptive response, may lead to cell death - apoptosis may be induced by same signals causing atrophy - physiologic atrophy: common in early development (thyroglossal duct) o uterus post delivery - pathologic atrophy: local or generalised ↓ workload (atrophy of disuse) – POP: ↓ cell size, then ↓ cell no’s; with bone resorption – osteoporosis o loss of innervation (denervation atrophy) – carpal tunnel o ↓ blood supply – arterial occlusive disease/ischaemia: brain o inadequate nutrition (protein/calorie malnutrition – muscle breakdown – cachexia chronic inflammation overproduction TNF – appetite suppression and atrophy o loss of endocrine stimulation – endocrine/reproductive glands, breast – loss oestrogen o aging (senile atrophy) – cell loss in permanent cells: brain, heart o pressure (tissue compression) – tumours: ischaemia Mechanisms: - affects balance between protein synthesis and degradation - lysosomes contain acid hydrolases and other enzymes that degrade endocytosed proteins - ubiquitin and proteasome pathway responsible for degradation of many cytosolic and nuclear proteins (proteins conjugated to ubiquitin then degraded with the proteasome – this pathway responsible for accelerated proteolysis in cachexia - glucocorticoids and thyroid hormone stimulate proteasome-mediated protein degradation, insulin opposes these actions - cytokines eg TNF can ↑ muscle proteolysis this way - atrophy often accomp by ↑↑ in no. of autophagic vacuoles (membrane-bound vacuoles in cell containing fragments of cell components into which lysosomes discharge their hydrolytic contents – digested - some of cell debris resists digestion – persist in membrane-bound bodies in the cytoplasm eg lipofuscin granules – brown colour in tissue (brown atrophy) Metaplasia - reversible change where one adult cell type is replaced by another type - may be adaptive to withstand chronic stress such as chemical or physical irritants - most common epithelial metaplasia: columnar to squamous resp tract due to chronic irritation (smoking) resp tract due to Vit A deficiency salivary, pancreatic, biliary stones o squamous epithelium withstands more stress but resp tract protective mucus lost o may go on to malignant transformation - metaplasia from squamous to columnar Barretts, due to increase acid (go on to adenoCa) - connective tissue metaplasia – formation cartilage, bone or adipose in tissues not normally containing these o myositis ossificans post # Mechanisms: - reprogramming of stem cells that exist in normal tissues or of undifferentiated matrix components present in connective tissue - differentiation of stem cells due to signals by cytokines, GFs and ECM components 2 - certain cytostatic drugs cause disruption of DNA methylation patterns and can transform mesenchymal cells from one type (fibroblast) to another (muscle, cartilage) Cell Injury and Cell Death - reversible injury: initially functional and morphological changes that are reversible if damaging stimulus removed o ↓ oxidative phosphorylation o ATP depletion o cellular swelling (change in ion conc’s and water influx) - irreversible injury and death: with continuing damage o apoptosis (not always assoc with cell injury) and necrosis (always pathological) - causes of cell injury: o hypoxia → ↓aerobic oxidative respiration (incl CO, anaemia) cf ischaemia – loss of blood supply with ↓ O 2 and metabolic substances ie glucose → more rapid/severe cell injury) o physical agents – mechanical trauma, burns, cold, pressure, radiation, electric shock o chemical agents (gluc/salt if hypertonic, ↑↑ O 2, poisons, pollutants, insecticides, CO, asbestos, drugs, EtOH) o infectious agents o immunological reactions (anaphylaxis) o genetic derangements (Downs, Sickle cell, enzymes) o nutritional imbalances (starvation, anorexia, obesity) - morphology: o reversible: swelling ER and mitochondria, clumping chromatin o irreversible: swelling ER, loss ribosomes, lysosome rupture, membrane blebs, myelin figures, swollen mitochondria, nuclear condensation (pyknosis) o necrosis: fragmentation cell membrane and nucleus (karyorrhexis) then dissolution nucleus (karyolysis) Features of Necrosis and Apoptosis Features of Necrosis and Apoptosis Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis → karyorrhexis → Fragmentation into nucleosome size fragments karyolysis Plasma membrane Disrupted Intact; altered structure, especially orientation of lipids Cellular contents Enzymatic digestion; may leak out Intact; may be released in apoptotic bodies of cell Adjacent Frequent No inflammation Physiologic or Invariably pathologic (culmination Often physiologic, means of eliminating unwanted cells; may pathologic of irreversible cell injury) be pathologic after some forms cell injury, esp DNA damage Cellular and biochemical sites of damage in cell injury 3 Mechanisms of Cell Injury - cellular response to injurious stimuli depends on type of injury, duration and severity - consequences of cell injury depend on type, state and adaptability of injured cell – cell nutritional status and metabolic needs important in response to injury o ?genetic polymorphisms affect response - biochemical mechanisms: o cell injury results in abnormalities of 1 + of 5 cellular components: aerobic respiration (mitochondrial oxidative phosphorylation/ATP) maintenance of cell membrane integrity protein synthesis intracellular cytoskeleton integrity of genetic apparatus Intracellular mechanisms: 5 pathways 1) ATP depletion o enzymatic metabolism chemicals/drugs - ↓ synthesis/ATP depletion due to ischaemic and eg carbon tetrachloride toxic injury o redox reactions as part of normal o ATP made by glycolysis (anaerobic, metabolism (respiration) inefficient) + oxidation o transition metals (iron, copper) phosphorylation in mitochondria catalyze free radical formation (aerobic, efficient) o NO acts as free radical o hypoxia → glycolysis/glycogen depletion, ↑ lactate, acidosis - free radicals unstable – decay spontaneously o ATP also for membrane transport, o antioxidants block free radical maintain ion gradients, protein synth formation or scavenge them (Vit E, A, C, glutathione) 2) mitochondrial damage o reactive forms metals minimized by - directly (hypoxia/toxins)
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