BIOL131 - Lec 1-Cellular pathology.pdf

BIOL131 Introduction to Biomedical Science Cellular pathology ‘the phenomena of a particular disease are brought about by a series of cellular changes’’ - Virchow Cerebral infarct & brain necrosis Dr Rachael Rigby: [email protected] Pathology Pathology is the scientific study of caus...

BIOL131 Introduction to Biomedical Science Cellular pathology ‘the phenomena of a particular disease are brought about by a series of cellular changes’’ - Virchow Cerebral infarct & brain necrosis Dr Rachael Rigby: [email protected] Pathology Pathology is the scientific study of causes and effects of disease Encompasses: • Histology and cytology • Microbiology • Haematology • Clinical chemistry • Clinical genetics Normal cell structure and function • Functional units of living organisms • Human body is a clone of 1013 cells • Same genetic material – genes switched ‘on’ or ‘off’ in different cell types • Cells are adaptable to changing environment - within physiological limits • Different cell types vary in their ability to adapt and survive Pathological processes • Adaptation - may result in abnormal cell growth • Abnormal cell growth - such as dysplasia or neoplastic growth R. Virchow - ‘’all disturbances of function and structure in disease are due to cellular abnormalities and the phenomena of a particular disease are brought about by a series of cellular changes’’ • Cell death – may occur due to lack of adaptation • Healing - stimulated by a pathological stress such as physical injury, collagen deposition in scar tissue • Genetic and immune factors - affect a cell/organ ability to adapt to environmental stresses leading to different susceptibilities to disease Schultz M. Photo quiz. Emerg Infect Dis [serial on the Internet]. 2008 Sept Pathological stimuli cause cellular stresses Environmental changes outside the acceptable physiological range Examples: • Osmotic stress (water and electrolyte/salt concentrations) • temperature stress • oxygen / energy deprivation • Injury, infection • any disruption of homeostasis… Gives rise to the cell stress response…. Adaptive response during cell stress • Improves cell survival in adverse environment • Alterations in metabolism e.g. • Fasting - fatty acids mobilised from adipose tissue • Calcium lack - calcium mobilised from bone matrix • Liver enzymes induced to metabolise drugs • Physiological adaptive responses include:  cellular activity  cellular activity – cell/tissue atrophy Morphological change – metaplasia, Restitutive Wound Healing Adaptive response during cell stress  ‘housekeeping’ genes (normal structural proteins)  Cell stress genes (cell-organising/ protective functions) e.g. heat shock proteins (HSPs), NF-kB, AP-1 → high degree of evolutionary conservation → essential to cell survival Protection in times of cellular stress • Heat shock proteins (HSPs) act as chaperones: protect proteins, assist refolding, prevent protein aggregation • Ubiquitin – targets protein for destruction by specific proteases (proteasome) • Chronic stress results in visible aggregates of constituents known as inclusion bodies e.g. Lewy body (aggregations of a-synuclein) in nerve cells Adaptive response during cell stress Increased functional demand may result in: • → Hyperplasia: increase in number of tissue cells due to increased cell Normal breast epithelium Hyperplastic breast epithelium division • → Hypertrophy: increase in size of existing cells, matched by increase in functional capacity May be physiological: • endometrial lining during menstrual cycle (hyperplasia) • skeletal muscle fibres of athletes (hypertrophy) Colonic epithelial hyperplasia • The normal colon has a smooth lining of single layer epithelial cells and short crypts. Epithelial hyperplasia increases the number of cells present resulting in deeper crypts. → 4x Transient epithelial hyperplasia may help expel intestinal pathogens. 4x Prostate hyperplasia Benign prostatic hyperplasia (BPH) •20% of males age 40 •70% at age 60 •90% at 80 •Hyperplasia of prostate cells •BPH not risk factor or precursor for prostatic carcinoma Lesovaya et al. 2015 Oncotarget 6(12) 9718 Inability to adapt may result in irreversible cell damage • Leads to pathological death • Apoptosis (programmed cell death) • Necrosis Cell targets include: • Cell membranes • Mitochondria • Cytoskeleton • Cellular DNA Apoptosis Responsible for elimination of unwanted/damaged cells Four phases: 1) Induction/signalling - antiapoptotic proteins Bcl-2 2) Effector - ‘point of no return’ → mitochondrial permeability 3) Degradation - proteases (caspases) → morphology 4) Phagocytic - cell fragments are engulfed and removed Abou-Ghali and Stiban 2015 Saudi Journal of Biological Sciences 274(6) Apoptosis in vitro cells Apoptosis as a normal cell process • Immune system – removal of autoreactive immune cells • Intestinal cell turnover • Embryogenesis and development - larval forms & evolutionary background Apoptosis in digit development in a mouse paw Radtke and Clevers 2005 Science 307, 1904 Apoptosis as a pathological disease • Under-active pro-apoptotic pathways and/or over-active antiapoptotic pathways can promote cancer Cancer e.g. p53 Cancer Molecular Biology of the cell: Lodish et al 6th Ed. p936 and 1107-1111 e.g. Bcl 2 Necrosis Triggers: any acute stressor e.g. metabolic stress, hypoxia, absence of nutrients, trauma Receptorinteracting serine/threonineprotein kinase Poly(ADP-ribose) polymerase Common molecular mechanisms that result in necrosis: • Reduction in ATP → swelling of internal membranes (‘cloudy swelling’), reduced biosynthesis •  cytosolic calcium (Ca++) → activate protein kinases, phospholipases • Reduction in ability to scavenge ROS (reactive oxygen species) • Plasma membrane integrity and cytoskeleton compromised • Cells swell, lyse and burst Hou et al. 2013 Cell Death & Disease 4(12):e966 Examples of pathological stimuli that cause necrosis • Hypoxia - reduction or absence of normal oxygen supply to an organ • Specific chemical agents - carbon tetrachloride (CCl4) or paracetamol • Hypoxia → death of an area of tissue → INFARCTION Myocardial Infarction = Heart attack Cerebral infarct & brain necrosis https://webpath.med.utah.edu/CINJHTML/CINJ024.html Restriction in blood supply (ischemia) leads to necrosis Anaerobic metabolism Failure of Ionic Pumps Cellular Swelling Accumulation of metabolic intermediates Inflammatory Response Oxidative Stress Further Ionized Calcium Influx Acute ischaemia & reperfusion injury Alizan et al 2006; Plast. Reconstr. Surg. 117: 1024 Apoptosis vs. Necrosis Apoptosis Necrosis Shrinking of cytoplasm Swelling of cytoplasm Condensation of nucleus Swelling & disintegration of organelles Blebbing of plasma membrane, maintains integrity Loss of plasma membrane integrity Formation of membrane-bound vesicles Loss of membrane integrity Tightly regulated process Loss of ion homeostasis Energy (ATP) dependant – does not occur at 4oC Passive process - occurs at 4oC Very little inflammatory response Cell contents release = Inflammatory response Non-random degradation of DNA (ladder pattern after agarose gel electrophoresis) Random digestion of DNA (smear after agarose gel electrophoresis) Gel electrophoresis Apoptosis Non-random degradation of DNA = ladder pattern on agarose gel electrophoresis Necrosis Random digestion of DNA = smear on agarose gel electrophoresis