Introduction to pathology Flashcards
Define
a) Pathology
b) Aetiology
c) Pathogenesis
a) The study of disease, a disturbance of homeostasis occuring whenever there is damage to cells
b) The causes of disease
c) How diseases develop, what happens to diseased tissues/cells
What does the consequence of loss of homeostasis in a cell depend on? (6)
Type of injury
Duration
Severity
Type of cell
Capacity to adapt
The genetic makeup
Ways cells can adapt (5)
Atrophy (reduce complexity, digestion of cellular proteins by the proteasome system and autophagy)
Hypertrophy (increase in size of the cell)
Hyperplasia (increase in cell number)
Metaplasia (reversible change from one differentiated cell to another)
Dysplasia (changes in shape and size of cell - don’t always return to normal)
Apoptosis vs necrosis
Apoptosis: Programmed cell death. Cell shrinkage, membrane blebbing, nuclear fragmentation, chromosome condensation and DNA fragmentation. Intrinsic pathway - cell kills itself because it senses cell stress. Extrinsic pathway - cell is signalled to kill itself (Fas/Fas ligand). Activate caspase proteolytic pathway (BOTH APOPTOSIS AND NECROSIS DO THIS)
Necrosis: Pathological process (not present in normal cells, while apoptosis is natural). Loss of membrane integrity and uncontrolled release of cellular contents into extracellular space. Uncontrolled cell death. Induces inflammatory response. Involves sheets of cells (whereas apoptosis involves single cells)
ROS and cell injury
Oxidative enzymes in the mitochondria, ER, cytosol, plasma membrane, cause formation of reactive oxygen species (O₂·-, OH·). Alternatively, inflammation, radiation, xenobiotics, reperfusion injury, cause formation of ROS. ROS causes damage in the cell: DNA oxidation (mutations/breaks), protein oxidation (problems in enzyme activity/folding), fatty acid oxidation (disrupts plasma membrane and organelles). Normally ROS are removed by glutathione, catalase and SOD (superoxide dismutase) and can deal with normal cell levels of ROS, but not if there is excess
Diagram of potential conseqiences of a harmful stimulus
Consequence of loss of ATP
Effectsare very rapid and very detrimental. If the mitochondria have reduced oxygen supply, there will be less oxidative phosphorylation, hence less ATP generation. This causes i) Less action of the Na+/K+ pump, so there is an increase in the influx of Ca2+, H₂O and Na+, an increased efflux of K+, causing ER and cellular swelling and blebbing ii) Increased aerobic glycolysis, so decreased glycogen, increased lactic acid, and decreased pH (which will cause clumping of nuclear chromatin) iii) Ribosome detachment and so decreased protein synthesis. All of these consequences can lead to necrosis of the cell.
The heat shock response
The heat shock factor monomer (HSF-1) is bound by heat shock proteins (hsp70, hsp40 and hsp90). When there is heat, proteins don’t fold properly and the heat shock proteins are released form HSF-1 and bind the unfolded proteins. HSF-1 then forms a trimer with other HSF-1 monomers, then the trimer enters the nucleus and activates the transcription of more hsp genes. There is preconditioning as even minor heat stress causes an increase in hsp transcription, hence the cell is prepared for if there is more extreme heat stress
The unfolded protein response
Ensures the rate of protein synthesis doesn’t exceed the protein folding capacity of the cell.
If a folded protein experiences stress, it will unfold. The detection of unfolded proteins causes, first, an increase in the synthesis of chaperones (eg heat shock proteins to repair/stabilise unfolded proteins). There will then be a decrease in protein translation. Next, ubiquitin will bind to the proteasome, causing degradation of the remaining unfolded proteins. If this is not sufficient, the last resort is to activate caspases and induce apoptosis
The stress kinase response
Important signalling pathways include the Jun N-terminal kinase (JNK), or the stress-activated protein kinase (SAPK) pathway. Also the p38 kinase pathway. These are activated by many stimuli, such as osmotic or oxidative stress, heat, UV and ionising radiation, physical stretching, and DNA cleavage. The pathways regulate the activity of numerous transcription factors (an important one being AP-1) that reprogram cell transcription. There is cross talk between the pathways to coordinate the outcome. The pathways modulate descisions (whether apoptosis should occur, or proliferation, differentiation, inflammation, or cytokine production)
The activation of stress activated kinases causes the phosphorylation of transcription factors. These assemble as homodimers, heterodimers and multimers and promote the transcription of genes with binding sites for AP-1 (see image)
