Cellular Injury Study Guides

ATP Depletion ATP is produced by  Oxidative phosphorylation of ADP in mitochondria.  Glycolytic pathway using glucose from circulation or hydrolysis of intracellular glycogen Causes of ATP depletion  reduced supply of oxygen and nutrients  mitochondrial damage  actions of some toxins (e.g., cyanide).  The activity of plasma membrane ATP-dependent sodium pumps is reduced, resulting in intracellular accumulation of sodium and efflux of potassium.  There is a compensatory increase in anaerobic glycolysis in an attempt to maintain the cell’s energy sources  Failure of ATP-dependent Ca2+ pumps leads to influx ofCa2+, with damaging effects on numerous cellular components, lschemia M itochond rion .J. Oxidative pho,spho,1ryll.ation ·! i .J.Na pump 1 Influx of Ca 2+ H 2 O, and Na + t Efflux of K.+ J ER swellingi C,ellular sw,ell1ing Loss of m1icrovrn i Blebs ,�t t�TP i t Anaerobic glycollysis i I-Glycogen t i tLactic _,...., ,JplH acid Detachm1ent of 1ribosom1es ! i i Protei1n C umping of nuclear chromatin © Elsevier. l(;ilimar et. al: Robbins Basic Pathology Be - www.stude1n1lc:o111sult.corn synthesis Extraceillular Ca 2+ M itochondrion lncreas,ed ATPase Phospholipa.s,e Endop,lasmic �eticulum tic c.a 2 + Protease Disruption Decreased Decre,ased phosphohpids of membrane, ATP and cytoskel,etal pr,oteins. 1 Endonuclease Nucleus chromatin dam age 1 Mlembrane dam1age © E1lsevier. Kiumar et al: Robbins BasJc P.athotogy 8e - w-ww.,;;b.lden1tco1rnsu1lt.rom Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Free radicals  extremely unstable chemical species with a single unpaired electron in an outer orbital.  in cells they attack nucleic acids, cellular proteins and lipids.  Initiate autocatalytic reactions Reactive oxygen species (ROS)  produced normally in cells but they are degraded and removed by cellular defense systems.  Increased production  ineffective scavenging systems excess of free radicals oxidative stress MITOCHONDRION PHAGOSOME ; + NO D2 -..�02 -----...... ONOOPeroxynitrite SOD Fenton reaction Mitochondria lncomple,t,e reduction Inflammation Radliati:0111 -c::::- Fenton � reaction GIENERATtON OF REACTIVE OXYGEN SPECIES 1 r-::::::7 � Che,m· cals ���� �===;>�==�� Bepertusion Hlydroxy1 Hydrogen Superoxide injuiry radical perox11de z !Reactive oxygen species REMI01 'VAL OF FREE RADICALS PA�HOL10GIC EFFECTS OF R 10S: CELL INJURY AND DEATH Antioxidant mechanisms: • SOD (in mitochondria) ROS react with: • Fatty acids __,. oxidati1on iiiiiiiiJ11o­ converts 02 ....,. H202 ge111eration of lipid • G1u· athione peroxidase peroxidases ,-+- disrupfon o,f (in mitochondria) l les plasma membrane, organe,converts OH • ....,. H202 •Proteins....,.. oxidation III loss • Cata ase (in peroxisomes) of enzymatic activity. abnormal converts H20:2 ....,. H20 + 0 folding • DNIA. _.. oxidation ..- mutations, breaks © E sevier. Kit.umir et al: Robbins Basic Pathology Be� www.stude11itr:o111s11J1lt.com mechanisms to remove free radicals  Endogenous or exogenous antioxidants (e.g., vitamins E, A, and C, and βcarotene)  iron and copper can catalyze the formation of ROS.  The levels of these reactive metals are reduced by binding of the ions to storage and transport proteins (e.g., transferrin, ferritin, lactoferrin, and ceruloplasmin), thereby decreasing the formation of ROS. Examples of damage by free radicals  Ischemia-reperfusion  chemical injury  radiation injury  toxicity from oxygen and other gases  cellular aging  microbial killing by phagocytic cells  tissue injury caused by inflammatory cells. Summary of Mechanisms of Cell Injury  ATP depletion  Mitochondrial damage  Influx of calcium  Accumulation of reactive oxygen species  Increased permeability of cellular membranes  Accumulation of damaged DNA and misfolded proteins: triggers apoptosis EXAMPLES OF CELL INJURY AND NECROSIS Ischemic and Hypoxic Injury  diminished blood flow to a tissue The fundamental biochemical abnormality  reduced supply of oxygen  reduced intracellular generation of ATP  failure of many energy-dependent cellular systems, including  ion pumps  depletion of glycogen stores  reduction in protein synthesis.  Decrease cellular function If hypoxia continues  worsening ATP depletion  loss of microvilli and the formation of "blebs"  Swelling of the entire cell and its organelles (mitochondria, ER)  increased concentrations of water, sodium, and chloride and a decreased concentration of potassium.  If oxygen is restored, all of these disturbances are reversible If ischemia persists  severe swelling of mitochondria  extensive damage to plasma membranes  swelling of lysosomes  Massive influx of calcium into the cell may occur.  Death is mainly by necrosis, but apoptosis also contributes.  The cell's components are progressively degraded  widespread leakage of cellular enzymes into the extracellular space.  dead cells may become replaced by large masses composed of phospholipids in the form of myelin figures.  then either phagocytosed by leukocytes or degraded further into fatty acids that may become calcified. Ischemia-Reperfusion Injury  Exacerbation of cell injury after reperffuson into ischemic tissue Ischemia-Reperfusion Injury mechanism  Increased supply of oxygen  increase in the production of ROS  because of :  Mitochondrial damage leads to incomplete reduction of oxygen  action of oxidases in leukocytes, endothelial cells, or parenchymal cells.  Decraese cellular antioxidant defense mechanisms by ischemia Ischemia-Reperfusion Injury mechanism  Ischemic injury is associated with inflammation  increased influx of leukocytes and plasma proteins.  The products of activated leukocytes may cause additional tissue injury  Activation of the complement system may also contribute to ischemiareperfusion injury.  Deposit of some antibodies in ischemic tissues for unknown reasons