Physicological Adaptations to Pathologies

PHYSICOLOGICAL ADAPTATIONS TO PATHOLOGIES Adaptation Hyperplasia • ↑ cell numbers (↑organ size) • DNA synthesis and mitosis • Physiological: o Hormonal e.g. uterus in pregnancy o Compensatory e.g. liver regeneration after partial resection • Pathological: o Hormonal e.g. pituitary tumour producing ACTH → adrenal growth of Cushing disease o Growth factor e.g. HPV induced warts • Often accompanies hypertrophy Hypertrophy • ↑cell size (↑organ size) i.e. no new cells • Synthesis of intracellular structural components (e.g. more myofilaments per cell) • In non-dividing cells (e.g. myocardial fibers) • Physiological e.g. skeletal muscle fibres from physical work • Pathological e.g. cardiac muscle in hypertension or valve defects Atrophy • ↓size and number of cells (↓organ size) • Physiological e.g. thymus involution after birth • Pathological e.g. decreased workload, denervation, ischaemia, malnutrition, endocrine hypofunction, ageing, compression (e.g. adjacent tumour) Metaplasia • Original ‘adult’ (differentiated) cell type is replaced by another type better suited to stress • Reversible • Undesirable – can lead to cancer • Pathological o E.g. squamous metaplasia in bronchial airways (smoking) – normally ciliated columnar o E.g. Intestinal metaplasia in oesophagus (gastro- oesophageal reflux disease) Living with cell injury Intracellular accumulation • Fat → excessive mutated substrate + insufficient mutated enzymes • Carbon dust → foreign substrate + absent enzyme • E.g. steatosis = lipid (fat) in hepatocytes → lobular architecture distorted by marked macroveiscular steatosis that expands and distorts hepatocyte cytoplasm Steatosis • Fatty change caused by an accumulation of triglycerides, mainly in liver (major organ of fat metabolism) • Disruption of fat metabolic pathway due to: alcohol abuse, NASH (insulin resistance syndrome), anorexia and malnutrition • Complications: with progressive steatosis, there is inflammatory hepatocyte destruction (steatohepatitis) → scaring → cirrhosis → risk of hepatocellular carcinoma E.g. Early atherosclerosis • Lipid in arterial wall macrophages • Subintimal accumulation of foamy cells (lipid laden macrophages) that form fatty streaks, which can evolve to atheroma complicated by thrombus Ageing • Accumulation of genetic and metabolic damage: increased susceptibility for carcinogenesis • Loss of replicative capacity: telomeric shortening of chromosomes Senescene • Terminal non-dividing cell state • Finite number of divisions for each somatic cell • Mechanism: telomeres (repetitive DNA sequence at the end of chromosomes  ‘protective cap’) → due to inherent ‘rules’ of DNA replication, telomeres progressively shorten with each cell division → eventual shortening to a critical length blocks further cell division = senescence → inherent counting mechanism o Telomerase: enzyme with own RNA template that extends shortened telomeres, expressed in stem cells and cancerous cells → overcomes normal restrictions on cell replicative capacity Death • Particularly harmful injury • Reversible: cell swelling with disturbed cell membranes • Irreversible: profound mitochondrial and cell membrane dysfunctions Causes of cell death • O2 deprivation (ischaemia) • Physical e.g. trauma, radiation, temp extremes • Chemical agents e.g. drugs • Infection • Immunological reactions • Genetic derangements • Malnutrition Pathogenesis of cell death: mitochondrial damage → depletion of ATP → accumulation of oxygen-derived free radicals (oxidative stress) → defects in membrane permeability • Oxidative stress o Free radical: chemical species with single unpaired electron in its outer orbit o Unstable: energy released to adjacent molecules, converting them to further free radicals o Small amounts usually from mitochondria removed by homeostasis o ↑ amounts from mitochondrial dysfunction o Harmful effects on cell membranes, proteins and DNA • Defects in membrane permeability (affects all cell membranes) o Cytoplasmic membrane damage ▪ Loss of osmotic balance with extracellular fluid ▪ Influx of water and ions ▪ Loss of proteins, enzymes, coenzymes, RNA and metabolites needed for ATP o Lysosomal membrane damage ▪ Leakage of enzymes into cytoplasm (e.g. DNases, proteases) – auto-digestion Necrosis – unscheduled (pathological) cell death • Results in membrane disruption → cell contents leak due to inflammation Apoptosis – programmed cell death • Physiological or pathological • Scheduled: enzymes degrade own DNA and proteins • Cytoplasmic membrane remains intact (cell breaks up into small membrane bound bodies containing cytoplasm, organelles and nuclear fragments) • Bodies phagocytosed by macrophages before their contents leak → no inflammation • Adjacent healthy cells replace deleted cells by migration or cell division Physiological apoptosis (removing unwanted cells) 1. Programmed destruction of cells during embryogenesis 2. Hormone-dependent involution in adult e.g. endometrial cell breakdown in menstrual cycle 3. Cell deletion in proliferating populations e.g. intestinal epithelium to maintain constant number 4. Elimination of cells that are past their purpose e.g. neutrophils after acute inflammation Pathological apoptosis (removing damaged cells) 1. Cell death after DNA injury e.g. radiation and cytotoxic drugs, mild to moderate thermal injury (if more severe → necrosis) 2. Cell injury by viruses e.g. viral hepatitis B/C 3. Cell elimination after duct obstruction (organ atrophy) e.g. pancreas, salivary gland, kidney blocked by stone