PP Mechanisms of disease Stress and disease Homeostasis - Responsible for maintaining a constant, safe internal environment - Controlled by feedback loops o Negative feedback loop: temperature, blood glucose regulation o Positive feedback loop: platelet activation in blood vessel damage Allostasis - Adaption of homeostasis according to the environment/age - E.g. lots of stress over a long period of time increases BP, HR, Resp. for the constant need to be ready to flee Homeorhesis - Homeostasis changes within a lifespan - Continuous development of the human body changes the normal range of homeostasis - E.g. Paediatrics BP and HR is different to Geriatrics BP and HR Adaption to stressors The general adaptive syndrome for stressors categories adaption to stressors into 3 main phases: - Alarm o Release of catecholamines (adrenaline, nor-adrenaline) o Sympathetic nervous system response (BP increase, BGL increase, blood moves to limbs instead of stomach, HR increase, Resps increase) - Resistance o Removal of response or adaptation to stressor
o A new set point of Homeostasis o Allostasis changes according to environment - Exhaustion o Stressor or response overwhelms body o No longer able to return to homeostasis o Can cause death o Reduced response to stressor because continued response is harmful Effect of catecholamines short term stress response (ALARM 1) - Neural activation - Sympathetic nervous system activated - Adrenal medulla releases adrenaline - Increased CO, muscle blood flow, BGL, reduces GI tract activity The hypothalamic pituitary feedback loop long term stress response (ALARM 2) - Stressor releases Adrenocorticotrophic hormone (ATCH) - ACTH stimulates corticotrophin releasing hormone (CRH) which stimulates glucocorticoid release - Glucocorticoid inhibits ACTH and CRH Effects of corticosteroids long term stress (ALARM 2) - Supports the act of catecholamines - Supress immune response - Inhibit reproductive function Adrenaline important in Alarm phase Cortisol important in Resistance phase Generalised stress response Behavioural/Emotional - Anxiety - Depression - Increased substance abuse
- Mental exhaustion - Altered sleeping and/or eating problems - Increased irritability - Reduced concentration - Decreased productivity Physical - Increased pulse, BP Resps - Increased muscle tension - Nausea, vomiting, diarrhoea - Hyperglycaemia due to increased glucose in blood due to cortisol and/or sympathetic nervous system - Sweaty palms - Fatigue Cell injury Five causes of cell injury - Ischemia lack of blood flow to area/tissue - Nutritional deficiency problems - Infectious and immunological damage from kinin s, endotoxins, exotoxins, prostaglandins, leukotriene s - Chemical carbon monoxide, lead, paracetamol - Physical disruption to DNA, electrical activity Cell injury - Minor cell damage = reversible (recovers) due to: o Due to inadequate energy sources o Low Na/K pump activity o Intracellular accumulation of lipids, carbohydrates, proteins, pigments and calcium - Major cell damage = irreversible (permanently damaged or dies) due to: o Necrosis cell death due to lack of energy (nutrient or O 2 ), toxicity or physical damage. Four types: Coagulative Relatively solid mass, area maintains general tissue architecture, result of ischaemic damage
Liquefaction Cells liquefied, may form abscess or cyst, dissolved quickly, caused from rapid cell death Fat Tissue releases triglycerides, chalky white area of the tissue, trauma and pancreatitis cause, adipose dies and the gets digested Caseous Dead cells fenced off by WBC s, cells lose structure, persistent Gangrene Can be dry, green or gas, Due to ischemia o Apoptosis Programmed cell death. Occurs naturally by multiplying tissue where cell have limited lifespan, but can be triggered by damage Activation of suicide gene Involves the caspase enzyme - Cell susceptibility varies - Consequences of cell damage and death varies Cell adaption - Atrophy cells shrink in size - Hypertrophy cells increase in size - Hyperplasia increased number of cells - Metaplasia Replacement of cell type with another differentiation - Dysplasia Disorganisation of cells compared to normal Acute and chronic inflammation Purpose of inflammation - Destroy invaders/harmful agents - Limits spread of invaders - Prepare tissue for repair Cardinal signals of inflammation - Redness - Swelling - Heat - Pain - Loss of function
Acute inflammation 3 components of inflammatory response - Increased permeability - Recruitment of inflammatory cells - Phagocytosis of cell debris/chemical signals Vascular permeability Initial response in a spilt second is vasoconstriction in the arterioles, after that the arterioles vasodilate, increasing blood flow to the area. With vasodilation, an increased permeability in capillary beds allows necessary leukocytes and platelets to the site. Leukocytes include: - Mast cells containing histamine and prostaglandin - Macrophages - Neutrophils - Basophils - Eosinophils Chemical response Initial phase of inflammation is mediated by many chemicals: - Histamine o From mast cells, basophils and platelets o Stimulates vasodilation o Stimulates permeability of capillaries o Causes bronchoconstriction in the lungs in allergic reactions o Pain and itching - Serotonin o From platelets o Causes vasodilation o Causes vascular permeability (not as much as histamine) - Prostaglandins o Can be produced by all cells in body (esp. epithelial, fibroblasts) o Produced by aracadonic acid by COX o Potent stimulator of vasodilation o Stimulates permeability
- Leukotrienes o From leukocytes o C4, D4 and E4 cause permeability o B4 causes chemotaxis - Complement proteins (produced by liver) o C3a increased permeability o C5a increased chemotaxis - Kinin s o Bradykinin Forms clot Wound healing and platelets - Platelets get to injury - Bind to collagen - Release fibronectin to make matrix - Release growth factors Leukocytes and their functions Acute inflammation - Neutrophils o Arrive first o Eat bacteria and cell debris o Release free radicals to kill micro-organisms - Macrophages o Arrive later o Eat dead cells and debris o Release cytokines to alter behaviour and tissue function - Eosinophil s o Specialise in attacking parasites o Bind to microorganisms and release free radicals