Cell Homeostasis YR1 Lecture 1H 2019 PDF

Cell Homeostasis Dr David A Mahns Director of Research Engagement School of Medicine Western Sydney University [email protected] Objectives To appreciate that homeostasis operates at the level of cells as well as organs and whole body systems. To understand how cells are able to homeostat...

Cell Homeostasis Dr David A Mahns Director of Research Engagement School of Medicine Western Sydney University [email protected] Objectives To appreciate that homeostasis operates at the level of cells as well as organs and whole body systems. To understand how cells are able to homeostatically regulate their: - Volume - Electrolyte composition - pH - Metabolic rate Basic principal , of constant environment. ‘Milieu Interieur’Claude Bernard 1878 Physiological systems act to maintain constancy of the internal environment. Structure  c150, Galen treaties of anatomy  c1235, 1st European medical school founded.  c1510, Leonardo da Vinci dissects humans  1543, Vesalius’ De Humani Corporis Fabrica. Chemistry  1869, 63 elements  1714, Mercury thermometer, Fahrenheit Scale.  1848, William Kelvin  Kelvin Scale. 2nd Law of Thermodynamics -- increasing entropy Starting point ; Body temperature 37oC Variations appeared in abnormal/diseased sates increased disorder question ? Homeostasis Walter Cannon c 1934 Homeo - sameness # Stasis - standing still Homeostasis - the body’s ability to maintain a relatively constant internal environment despite changes in the external environment. familie the number for exam Average young 70 kg male 60% water (i.e. 42 L) 18% protein 15% fat 7% mineral Fluid within is the Cells in the & in the distributed outside the cells , intetitial space vasculature 3 -- 3. main compartments. - - equilibrum between those There is moves three of that a that flow governs water/ion between the , the. compartments TOTAL BODY WATER (60% body weight, 42 L) 1/3 EXTRACELLULAR 20% body weight 2/3 In the all INTRACELLULAR 40% body weight 28 L 14 L Osmolarity cell membranes : salties the of all. osmolarity ECF = osmolarity ICF = 290-300 mOsm/kg Plasma, 5% wgt, 3.5 L EXTRACELLULAR (14 L) Interstitial fluid 1/4 3/4 INTRACELLULAR (28 L) 15% body weight 10.5 L capillary walls cell membranes Alons & flid more according asmality Sodium * G Potassium (d) reversed Nat & It cell into the > is ↓ ↑ Vascular space Intentitial space to Sodium ; there across the WHICH epithelial MEANS ↳ The equilibrium membrane is a in spaces approximates Extracellular& institial the equilibrium see what youspace in molecule make discordued H20 in ↓ NaCl → Dissociates 1 Mole. water-s + Na + Cl → 2 Moles osmotic active ions Too Shoe obspace - normal saltty-small/die ∆ in [Ion]out ↓ ∆ [osmotically active solutes] ↓ movement of H20 ion concentration change ↓ outside ∆ in cell volume in SO WHAT ? N Relationship between the similariti and the Lysis of RBC Normal plasma ion concentration Safety Margin 290 - 180 But may vary in distal tissue eg - Exercising Muscle fingers wal ↓ outside more + + - ↑[K , Cl ] ↓[Na ] ↑ movement sitting  ∆ osmolarity Osmolarity ↑ external environment - Metabolic disturbance N - O ‘Safety Margin’ - Cl Normal plasma ion concentration Osmolarity ‘Safety Margin’ Safety Margin 290 - 180 But may vary in distal tissue eg - Exercising Muscle - ↑[K+, Cl-] ↓[Na+]  ∆ osmolarity - Water influx into active Metabolic disturbance more salty Schools Out - Robert Opio ↓Glucose 6 Dehydrogenase ↓ ↓NADPH production ↓ ↑ enzyme / protein degradation ‘Oxygen stress’ ↓ ↑ cell lysis Osmolarity Safety Margin (Contracted to left) Pathway chain Schools Out - Robert Opio ↓Glucose 6 Dehydrogenase ↓ ↓NADPH production ↓ ↑ enzyme / protein degradation ‘Oxygen stress’ ↓ ↑ cell lysis (glucose is isosmotic) & Dehydrated Isosmotic → same osmolality 0.9% saline (0.15M NaCl) vs 1.8% urea & infection Hyposmotic → lower osmolality 0.45% saline vs 0.9% saline ↓salt - Heart & & Hyperosmotic → higher osmolality 1.8% saline vs 0.9% saline femid balone Tonicity – effects on cell volume hypotonic isotonic hypertonic H2O H2O How does water move? Movement of H20  Passive diffusion a) Across membrane - every all H20 H20 water - b) Aquaporin Remin i. AQP1 - all tissues ii. AQP2 - Inducible kidney - Hormone - vasopressin  ↑ water retention Direction of flow (Jx) is always down the chemical potential difference Why does water move? Movement of H20  Driving forces a) Water Concentration [H20] - [H20] v.v. high ~56 Molar vary little in the dilute physiological solutions  Osmolarity (1/[H20]) or [osmotically active solutes] in dilute solutions the H20 gradient across cell membrane α osmolarity across the membrane. ξOsmoin – ξOmso Out  OSMOSIS: the movement of H2O driven by osmotic gradients. Movement of H20  Driving forces b) Hydrostatic Pressure. hydrostatic P difference across cell walls ≈ 0  no significant effect on H2O flow. NB:hydrostatic Pressure differences cross capillary walls are critical in determining movement of fluids between Intra vascular and Extra cellular (interstitual) compartments. Starling forces ξOsmoin – ξOmso Out Starlings Forces * B/P will drive it into your hydrostatic pressure slightly ⑦ Intra – Vascular (Capillary) , profile wation so within the ah extracellular space - Governing H20 movement Latter lectures Extra cellular (Interstitual) [Na,Cl, K etc] [Na,Cl, K etc] Hydrostatic Pressure 25 mmHg Hydrostatic Pressure -2 mmHg I vascular space ↓ drive ions ↓ protein ↓ Hydrostatic Pressure -2 mmHg Colloid osmotic pressure Low High [Plasma Protein] [Plasma Protein] 0.1 mmHg 25mmHg In Cell movement prese d KEY POINT H20 movement driven by: - [Ion] - [Protein] H20 Flux Hydrostatic P ≈ Colloid Osmotic P ≈ equilibrium  lymphatics Hydrostatic P > Colloid Osmotic P Ultra - Filtration Regulating intracellular ion concentrations Inside [Na+] [K+] mOsm 15 > 4.5 mM 290 = mOsm 290  Na+/K+ATPase - 3Na+ OUT - 2 K+ IN - ATPADP - Outside Na+/K+ATPase ATP dependent (1/3 energy expenditure) 3 Na+ out 2 K+ in 2 consequences: Potassiu Sodium , t e cherrich ⑭ i) ↓[Electrolyte]  ↓water content ii) Electrogenic (-ve charge Inside) Na+/K+ATPase ATP dependent (1/3 energy expenditure) ① we sati 3 Na+ out 2 K+ in 2 consequences: i) ↓[Electrolyte]  ↓water content ii) Electrogenic (-ve charge Inside) Responses to cell shrinking - Regulatory volume increase - Short term responses Increasing extra cellular osmolarity e.g., hypovolemia dehydration ↓ salty , O O Tro G com Responses to cell shrinking - Regulatory volume increase - Long term responses (hours-days) Increasing (Hyper) extra cellular osmolarity e.g., hypovolemia dehydration During sustained dehydration hours /days Accumulation of impermeant solutes (trapped in cell) De novo production: – Sorbitol, inositol – Formed by the break down glucose by aldose reductase » aldose reductase induced by cell shrinkage Transport / accumulation within cell: – upregulation of Na+/ Inositol/ betaine / taurine co-transporters Responses to cell shrinking - Regulatory volume increase - Long term responses (hours-days) BEWARE : Re-hydration practices Accumulation of impermeant solutes (Sorbitol, inositol, Betaine, Taurine)  hyperosmolality Rapid fluid replacement  immediate uptake into cells Oedema / swelling of all tissues  spinal cord / brain stem  compression of cord  brain damage Responses to cell Swelling - Regulatory volume decrease - Short term responses O O O jous Swelling  ↑K+ / Cl- efflux (outward movement) ↓ Osmo inside  normalise cell size pH 7 Alkaline B (acid) - hydrogen low negative logarithm of the hydrogen ion concentration in a solution. Range Cell pH (7 Dietary excess  ↑[H+] Metabolism  ↑[H+]. 3 - 4. 5) Normal cellular pH Maintained  7.4 Marked changes in [H+]  changes in enzymatic activity Excess H+ ions bound by buffers: » Intracellular protein » phosphate » bicarbonate » ammonia be ad water e H+ + Pr12-  Pr11H+ + HPO42-  H2PO4H+ + HCO3- H2O + CO2 NH3 + H+  NH4+ ④then en Homeostatic control mechanisms 3 components: – Sensor: responds to stimuli – Control centre: determines set point, analyses input and determines appropriate response – Effector - provides means for control centres response. Feedback mechanisms Homeostasis maintained through either: – Negative feedback mechanisms opposes response to stimulus – Positive feedback mechanisms enhances response to stimulus Negative Feedback Systems Negative feedback mechanisms – predominant mechanism for homeostatic control – maintain physiological functions within narrow ranges – control events which require continuous adjustment for moment-to-moment wellbeing e.g. control of BP, blood glucose regulation. heart ~ stop Positive Feedback Systems Positive feedback mechanisms – usually control infrequent events that are self perpetuating and explosive – do not control events which require continuous adjustments to promote moment-to-moment well-being e.g. uterine contractions (explosive Homeostatic imbalance Most diseases and/or disorders result from homeostatic imbalance With aging: – body organs and control systems become less efficient – internal environment becomes less and less stable – greater risk of illness/injury Homeostatic imbalance ↓ reception in With aging: Na+ / H20 Balance – – – – hyptotham Age 30 - 40 total-body water 55 to 60% Age 75 - 80 total-body water 50 percent, with ↓ thirst mechanism diminishes with age, ↓ maximal urinary concentrating ability,  ↑ risk for dehydration Other examples: BP regulation Type II (late onset) diabetes