Seven broad causes of cell and tissue injury
1) Physical agents (burns, etc.) 2) Chemicals and drugs 3) Infectuous pathogens 4) Immunologic reactions 5) Genetic mutations 6) Nutritional imbalances 7) Hypoxia and Ischemia
What are the meaning, difference, and causes of hypoxia and ischemia?
Hypoxia means that the cell or tissue isn't receiving adequate oxygen. Ischemia refers to injury that is related to hypoxia caused by some problem with blood circulation. Inadequate blood supply (bleeding, hematopoiesis problem), lung disease, heart failure, shock are most important causes.
What are the molecular and signaling responses to hypoxia?
Hypoxia induced HIF1-alpha and beta (Hypoxia Inducible Factor). HIF1 is a transcription factor for erythropoietin (EPO), vascular endothelial growth factor (VEGF), glucose transporters, and glycolytic enzymes.
Why is oxygen critical for life, and how may it be harmful?
All cells in the body are critically dependent on ATP, and O2 is used to create ATP. O2 also leads to ROS (reactive oxygen species), which are harmful to the body (obviously a minor side effect vs the alternative).
How long do different cells live through ischemic injury?
Neurons: 3-5 minutes, cardiac myocytes, hepatocytes, renal epithelium: 0.5 - 2 hours; soft tissue, skin, skeletal muscle: several hours.
What are the reversible cellular effects of hypoxia?
Hypoxia stops mitochondrial ATP production within 1 minute. Decreased ATP -> decreased Na pump function -> influx of Na, Ca, H2O, efflux of K -> cell swells. Decreased ATP -> increased glycolysis -> increased lactic acid -> decreased pH. Other effects: detachment of ribosomes, decreased protein synthesis, lipid deposition.
What are the irreversible cellular effects of hypoxia?
Opening of pores on the mitochondrial membrane (mitochondrial permeability transition pore) allow efflux of H+ into cytoplasm and degrades the concentration gradient across the christae. Low cytoplasmic pH activates lysosomal enzymes (pH 4-5). Degradation of DNA and protein. Influx of Ca (10,000x more Ca outside than inside, very sensitive)-> activates lipases and proteases.
How are hypoxic cells further damaged by oxygen radicals?
O2 is routinely administered to patients suffering from hypoxia/ischemia in order to raise O2 levels. This extra concentration is harmful to the cells in the alveolar spaces in the lung because the high O2 produces oxygen radicals (ROS). Hypoxic tissues are often infiltrated by PMNs, which have enzymes (myleoperoxidases) that produce ROS (often as normal, anti-pathogen function). Hypoxic conditions in cells can drive cleavage & activation of xanthine oxidase, which then produces ROS when blood supply and O2 levels return to norm.
How does SOD help eliminate ROS?
SOD combines ROS into peroxides and normal O2
What are three bad reactions of peroxide (H2O2)?
1) Spontaneous breakdown to hydroxyl radicals. 2) Fenton reaction - ferrous (Fe2+) ion produces hydroxyl radicals and ferric ion. 3) Haber-Weiss reaction - superoxide radical reacts with peroxide to produce hydroxyl radicals.
What are two good reactions of peroxides that eliminate the ROS hazard?
1) Spotaneous reaction of two peroxides to form H2O and O2. 2) Catalysis by Glutathione Peroxidase with GSH to reduce hydroxyls or peroxides to H2O.
What are the most significant targets of ROS?
Cellular membranes, proteins, DNA, and RNA.
What four characteristics do burn outcomes largely depend on?
1) Total surface area burned 2) Depth of the burn - partial vs full thickness 3) Whether lungs were impaired (by heat or smoke/particulates/chemicals) 4) Promptness of treatment. Survivability is also impaired by advancing age (35+).
How quickly does the airway respond to serious burn injury?
Critical, life threatening airway problems may be delayed for days after the initial burn injury. Swelling that results from burns to the throat result in edema that takes time to progress to life threatening stage.
What are complications resulting from burns?
Neurogenic shock, fluid loss, infection (Psuedomonas, Staph), Hypermetabolic state (need lots of calories to recover), Anemia
What are symptoms and consequences of exertional heat stroke?
1) Hot, dry skin 2) Usually lactic acidosis (over exertion) 3) May lead to ATN (acute kidney injury, hypoxia of kidney), DIC (disseminated intravascular coagulation), multi organ failure Rhabdo??
What are the symptoms and consequences of classic heat stroke (non-exertional)?
1) Hot dry skin 2) No lactic acidosis, but respiratory alkalosis (hyperventilation) 3) May lead to hypotension, coma. ATN and DIC are very uncommon.
What are the consequences of hypothermia?
1) May lead to coma or death. Metabolism in brain is inadequate. 2) Freezing of cells, causes local salt concentrations to markedly increase. 3) Poor perfusion of tissues - vasoconstriction, increased blood viscosity.
Three ways that electrical injury may lead to death
1) Heat Production 2) Disruption of cardiac nerve transmission. 3) Cell damage from electroporation of salts across membranes.