Cell Injury : Adaptations 09/12/2010

Atrophy
 *A PEN ID*
o Aging
o Pressure (Increased)
Atrophy of renal cortex and medulla in
hydronephrosis
 Thick pancreatic duct secretions in cystic fibrosis
occludes umen causing increase luminial back pressure
o Endocrine function decreased
 Decreased hormones hitting targeted tissue
o Nutrients (Decreased)
 People with marasmus
o Innervation (decreased)
Ex. Loss of nerves function to a muscle will cause that
muscle to waste away because of no function (also goes
with decreased work load)
o Work Load Decreased
o Decreased blood flow (not included in A PEN ID)
 Cerebral palsy due to atherosclerosis of carotid artery
 Atrophy will cause decreased protein syn and increased protein
degradation
 will also cause breakdown of organelles
o organelles and cytosol will form autophagic vacuoles which
will fuse with lysosomes which will be used for enzymatic
degradation
 Some lipids will be undigested and will become
lipofuscin (this is undigestable)
***Brown Atrophy*** caused by accumulation of
lipofuscin and comes from the cell membrane.
 **menopause ovary goes to atrophy
Hypertrophy
Causes
o Increased work load (exercise/weight training)
 Left ventricular Hypertrophy is caused by increased
afterload or preload
 Can occur during high blood pressure
 Mechanism
 Induction of genes for increase syn of
proteins, growth factors and nuclear
transcription
o There is also an increase in cytosol
and other organelles
 Skeletal muscle  weight training)
 Smooth Muscle  can be caused by obstruction
 Ex – urinary bladder
 Surgical removal of an organ can cause the other organ
(if there is two like the kidney) to grow to compensate
o cytomegalovirus
Hyperplasia (increase in normal cells)
 Causes
o Hormones Stimulation
 Examples
 Acromegaly  increase in growth hormone and
insulin growth factor 1
 Endometrial Gland Hyperplasia
 Increase in estrogen
 o Increase estrogen in males 
gyecomasta
 Benign Prostatic Hyperplasia (BPH)
 Increase in dihydrotestosterone
o Too many glands
 Polycythemia
 Increase in erythropoietin
o Chronic Irritation
 Increased scratching leads to thickened epidermins
 Smokers have increased mucous in brochial tubes
 Alcoholics have cirrorihis of the liver
o Chemical imbalance:
 Hypocalcemia stimulates Parathryoid gland hyperplasia
 Iodine defiency causes hyperplasia of thyroid
o Virus
 HPV  warts (hyperplasia of epidermis)
Metaplasia (change of one normal cell to a different type of cell)
very common in epithelium and connective tissue
*metaplasia can lead to dysplasia (change from good to
cancer)
 Types
o Squamous Metaplasia
 Columnar to Squamous
 Seen in respiratory mucosa due to smoking and
air pollution (can also be caused due to Vit A
Defiency)
 Seen in cervix due to increase pH in vagina
 And in cervix during puberty
o Columnar Epith. Metaplasia
 Squamous to columnar
 Occurs at the lower end of the esophagus during
acid reflux disease (columnar protects better to
acid than squamous)
 There is an increase of goblet cells to deal
with the increase of acid
 Called Barrett’s esophagus
o Symptoms – pain and burning in
epigastic region
o Columnar to Columnar
 Seen in Helicobacter pylori  gastric ulcers
 Increase of goblet cells and paneth cells to help
with reducing the acidity
**inflamed epithelium undergoes metaplasia
Cell Injury : Aging 09/12/2010
Aging causes the decline of normal function of the cell such as
 Reduced mitochondrial oxidation phosphorylation
o Cannot make ATP
 Decreased protein synthesis for structure, enzymes and receptors
 Reduced capability to repair chromsomes
 **reasons
o programmed
 cell has self trigger/ biological clock (or gene) to do so
o environmental
 incomplete replication of chromosomes (as seen in
telomere shortening)
 wear and tear of the cell will cause errors during repair
 Werner’s Sydrome
 Premature aging of cell due to defective
Helicase (repairs and replicates)
 free radicals
*also progessive loss of dna, which is replicated by
telomerase) causes decreased cell function, growth and
death
 cancer triggers telomerase to divide more
Free Radicals
 Caused by loss of Vit E & Glutathione Peroxidase (located in
PPP and neutralizes H202)
 Accumulation of Lipofuscin occurs
Cell Injury (THE BIG ONE) 09/12/2010
Causes of Cell Injury (PIG CHIN)
 Physical Injury
 Infectious agent
 Genetic problems
 Chemical agent
 Hypoxia (MOST COMMON and IMPORTANT)
 Immunological reactions
 Nutritional Imbalance

Hypoxia
Inadequate oxygen leads to decreased production of ATP
o Need O2 for oxidative phosphorylation because O2 is an
electon acceptor from the ETC (last step of Oxidative Phosph)
Symptoms: cyanosis, confusion, cognitive impairment, and lethargy
Causes:
o ISCHEMIA
Decreased arterial blood flow and venous outflow
 Caused by coronary artery atherosclerosis,
decreased cardiac output, thrombosis of splenic
vein
 Results in atrophy, infarction, and organ dysfunction
o Hypoxemia
 Decreased Pao2
 Pao2  pressure keeping O2 in blood
  Occurs in high altitudes
 Respiratory Acidosis also causes decreased
Pao2 because increase in Co2
 Caused by paralysis of diaphragm,
bronchitis, and depression of brainstem
(drugs or trauma)
 Ventilation Problems
 No oxygen to alveoli
 Respiratory Distress Sydrome (RDS)
 The blood is going in but the blood is not getting
oxygenated
 Perfusion (blood flow) problem
 Oxygen is there but no blood
 Causes
o Pulm embolism
 Diffusion Problems
 Decreased diffusion of O2 b/w capillaries
and alveoli
o Causes  interstitial fibrosis, pulm
edema
o Hemoglobin Abnormalities
 Anemia
 Decrease production of Hemoglobin (iron
deficieny)
 Increase Destruction of RBC
 Decrease production of RBC (aplastic anemia)
 **Normal Pao2 and Sao2
 Methemoglobinemia
  Fe3+ cant go back to Fe2+
 Caused by defect in cytochrome b5
reductase
 Fe3+ cant bind with oxygen
 SHIFT OF THE OXYGEN DISSOCIATIVE CURVE TO
THE LEFT because of lack of O2
**sym** - chocolate blood and cyanosis
o Treatment  methylene blue
Decreased Sao2 (average percentage of O2 in
blood)
o Carbon Monoxide Poisoining
 Competes with O2 at hemoglobin binding sites
 SHIFTS CURVE TO THE LEFT
 Inhibits cytochrome oxidase in ETC
**Symptoms**
 Cherry Red Discoloration of Blood and skin
 Headache
 Dizziness
 Coma
 Lactic Acidosis
**Treatment**
 100% oxygen mask
Mitochondrial Causes of ATP Depletion
 CO and Cyanide inhibit cytochrome oxidase in ETC  less ATP
 o Comes from house fires
o CNS and CVS depression
o Increases Lactic Acid
 Brown Fat/Uncoupling
Consequence due to Hypoxia  NO ATP!!
 Decrease in pH cause of lactic acidosis (reversible)
 Increase of pfk1 because of low citrate (from Krebs Cycle)
o Increase in Glycolosis (reversible)
 Cell Swelling because of Sodium retention in cell cause of no NaK-
ATPase pump (reversible)
o Causes more water to go inside the cell
 Decrease protein syn(reversible)
 Impaired Ca-ATP pump  (irreversible )
o More Ca2+ in cytosol
 Leads to phospholipase increase and organelle
permeability
 Esp in the mitochondria and release
cytochrome c which will activate apotosis
 Proteases damage to cytoskelaton
 Karyolysis
 Cytoskelaton abnormality (irreversible)
o Mallory Bodies
 Oxygen free Radicals formation (irreversible)
o Reduced oxygen species
  Irreversible Cell Injury Clinically
o Intermediate filaments are used as markers for tumors
 Keratin Filaments – Epitheial cells
 Neurofilaments – neurons
 Desmin – muscles
 Vimentin – conn. Tissue
 Glial filaments – astrocytes
o *Hepatitis -> increase AST/ALT
o *Myocardial Infarction -> increase in Troponin I
o *Skelatal Muscle -> increase in Creatinine Kinase
o *Exocrine Pancreas injury -> Amylase lipase
Nuclear Change
 Pyknosis
o Shrinkage and condensation of nuclear chromatin
 irreversible
 Karyolosis
o The dissolution of the nucleus; loss of basophilia
 Karyorrhexis
o The breakup of condesnsed chromatin into small dense
fragments in a necrotic cell
Free Radical Cell Injury 09/12/2010
Free Radical  chemical compound with a single unpaired electron in
outer orbit
 Causes damage to cell membrane  leads to death
The human body makes oxygen derived electrons:
 Radiation, inflammation, oxygen toxicity, chemicals, repersion
injury
o Hydrogen peroxide H202
 Made from high levels of oxygen
o Superoxide anion radical O2-
 Made from damaged mitochondra
 Made from high levels of oxygen
 Made from xanthine oxidase
o Hydroxyl free radical OH-
 Made from radiation
 If there is no gluthione peroxidase
 Made from high levels of oxygen
Antioxidants such as Vit E (preventes lipid peroxidation of cell
membrane) & A deactivate free radicals by donating their electrons to it
Trasnferrin, ceruloplasmin bind with free radicals
Superoxide dismutase, Gluthathione peroxidase, and catalase converts it to
O2 and H20

Clinical scenario
 Myocardial infarcation  tissue necrosis
o Oxygenated blood coming in will generate free radicals
via neutrophils
Cell Death 09/12/2010
Reversible  irreversible  cell death

Cell death occurs when cells or tissues are unable to adapt to injury
Necrosis
Death of group of cells accompanied by inflammatory infiltrate
 Coagulation Necrosis
o Structure is intact, cell outline is fine
o Absence of nuclei or kayolysis (fading chromatin)
o Seen in all organs except the BRAIN
o Occurs because of hypoxia (usually from infarction)
 Which leads to denaturing of proteins because of
increase lactic acidosis
 Kidney, brain and spleen will have a paler look because
of the increased density
 Lungs and bowels will have a reddish look because of
loose tissue
 Occurs in hemorrahic shock
o A lot of eosinophils
o Necrotic area will eventually become fibrotic
Gangrene  Anoxic injury can come from atheroschleoris,
colon cancer and diabetes
 Dry Gangrene (frost bite) or can also come from
patients with diabetes mellitus
 When dry gangrene gets infected with clostridium
perfringens (gas gangrene –cracking noise is
made by crepitant tissue while patient is moving)
it leads to wet gangrene which is liquefactive
 Liquefactive necrosis
o Necrotic tissue becomes liquidish
 o Mechanism: lysosomal enzymes released by nectrotic
cells and neutrophils cause liquefaction
o BRAIN
Caused by autocatalytic effected of hydrolytic enzymes
generated by neuroglial cells produces a cystic space
o Abscess (bacterial infection)
 Caused by hydrolytic enzymes by neutrophils
 Caseous necrosis
o Cheesy like material
 Caused by release of lipids from cell wall of
mycobacterium TB and fungi after immune destruction
of macrophages (T Lymphocytes and interferon gamma)
o Microscopic features
 Acellular material in the center surrounded by activated
macrophages, cd4 helper t cells, and
multinucleated giants cells
 Enzymatic Fat Necrosis
o Usually attacks the pancreas and omentum
Due to alcoholism that stems from acute pancreatitis
 Also obesity
o Mechanism:
 Activation of pancreatic lipase which hydrolyzes the
triglycerides in fat cells which releases fatty acids
 Fatty acids combines with calcium to form a
soapy type substances
 Process called saponification
o Basophilic stain
 Traumatic Fat Necrosis
o Breast tissue
  Not enzyme mediated
 Fibrinoid Necrosis
o Necrosis around small blood vessels
 Deposits proteinaceous material on the damaged vessel
wall due to damaged basement membrane
 Diseases: malignant hypertensionan
Apotosis
 Programmed cell death
 Normal pathological process
o Occurs to muellerian cells in males and setoli and females
o Endometrial cells during withdrawal of estrogen and
progesterone in menstrual cycle
o Death of tumor or virus after targeted by CD8 T Cells
o Removal of acute inflammatory cells from healing sites
o Removal of misfolded proteins
o Thymus
o Renewal of GIT
o **surrounded cells/tissues not affect
 Mechanisms
o Extrinsic  Requires TNF (Tumor Necrosis Factor) and
activation of caspases
o Intrinsic
 Mitochondrial leakage of cytochrome c into cytosol
(calcium) and activation of caspases
 Genes
  BCL2
 Chromosome 18
o Inbitits apoptosis
 Prevents leakage of
cytochrome c
 TP53 suppressor gene
 Guardian cell
o Arrests cell in G1 phase to repair DNA
damage
 If damage is too severe
activates BAX gene (apotosis
gene) to inactivate BCL2 gene
to make cell undergo apoptosis
o Caspases
 Inactive proenzymes (proteases and endonucleases)
that are activated by extrinsic or intrinsic sysmtem to
produce apoptosis
 Endonucleases  nuclear pyknosis
 Proteases  cytoskeleton breakdown
 Cytoplasmic buds filled with nuclear fragments,
mitochondria and condense protein fragments attach to
cell membrane
 Apoptotic bodies form by breaking off cytoplasmic
buds
 Apoptotic bodies undergo phagocytosis by
neighboring cells
Intracellular Accumulation 09/12/2010
Accumulation of various substances in the cell due to metabolic
abnormalities
Fatty Liver
o Accumulation of trigylercides (VLDLs) in the hepatocytes
o Cause: ALCOHOL
 Increases the syn of triglycerides
 Mored DHAP to G3P in glycolosis
 Free fatty acids binds to G3P to make
TG
 Less TG being secreted out
 More NADH being converted to DHAP
 Alcohol Metabolism cause more Acetyl CoA to form
 Excess Acetyl CoA gets stores as FA to TG
 **does not become oxidized to ketones
o no beta oxidation: alcohol causes
mitochondrial dysfunction
 TG are not packaged to VLDL because of Decreased
syn of Apo B100
 Once too much damage fibrosis and cirrohis will occur
and it is irreversible
o LIVER GROSS:
 Enlarged liver with yellow discoloring
o Liver Microsopic
 Nucleus pushed to the periphery
**Fatty Cardiac muscle can also occur
o Causes
  severe anemia and diphteria (myocarditis) (inhibits
Beta Oxidation)
IRON
o Occurs in iron overload diseases such as hemochromatosis
(chromosomal defect)
 Causes:
 Excess iron intake
 Left Heart Failure  Pulm Congestion
 Rupture with phagocytosis of RBCs
 Hemoyltic Anemia
 Blood Transfusions
 Impaired utilization of iron
 Excess hemosiderin (break down product of
ferritin and RBC)
o Causes free radical and organ
dysfunction like cirrhosis and increase
in serum ferritin (is deficient in iron
anemia)
 Golden brown apperences in
tissue
 Blue when stained with Prussian
Blue stain
**can lead to heart failure and
dibates mellitus (Bronzed Diabetes)
 Patient will be hyperglycemic
 **Can also be caused of anemia of chronic
disease
Billirubin
o Two Causes:
 Obstruction in the flow of bile
 Hemolysis of hemolytic anemia
 Will cause yellow discoloration in the body
If it enteres the basal ganglia of brain it can cause
permanent damage
Cholesterol
o Excess will cause Xanthomas (yellow plaque in the skin)
o And Ecess will cause Artheromatous Plaque (narrows the
artery)
 Gives a yellow plaque with crystals
Glycogen Storage Disease
o Most Common Defect is defiency of Glucose 6 Phosphatase
 Glycogen cannot break down back to glucose
 Causes Hepatomegaly
Gaucher’s Disease
 Defiency in Glucocerebrosidase
 Sea blue cytoplasm in bone marrow
 Increase in glucocerebrosides in lysosomes
 Sym: splenomegaly, anemia, and neurological
problems
Melanin
o Occurs in addisons disease
 Decrease of Adrenal Cortex leads to more ACTH
production
 Can lead to melanomas
Anthracotic Pigment
o Coal Worker’s pneumoconiosis
  Phagocytosis of black anthracotic pigament (coal dust)
by dust cells
 Lymph node will be black
 The pigment is black but has no major
organ dysfunction
Hyaline Change
o Glassy, pink change in the ECM
 Intracellular hyaline deposit  Russell body – protein
deposit
 Found in plasma cell
 Mallory body  alcoholic hyalnine
 Found in hepatocytes
o Made up of intermediate filaments
 Extracellular Hyaline deposit
 Wall of the artery in long standing diabetes
mellitus and hypertension
 Sometimes leak out proteins because of
much pressure
o Leakage of fibrin
 Amyloidosis also has hyaline like deposit
 Multiple myeloma
o Hyaline like deposit in the glomeruli of
the kidney
Amyloid:
 Fibrilar protein that forms deposits in interstial tissue
due to organ dysfunction
 Abnormal tissue folding
 Beta pleated sheet
 Amyloid Light (AL)
 Derived from light chains
 Amyloid associated (AA)
 Derived from serum associated amyloid
 Beta Amyloid (AB)
 Derived from amyloid precursor protein
(chromosome 21)
 TYPES
 Systemic
o Similary tissues involved
o Primary
 Ass/ with multiple myeloma
 AL dispoition
o Secondary (reactive)
 AA Amyloid
 Ass with chronic inflammation
 Localized
o Confined to single organ
 Ex. Alzheimers
 Hereditary
o Auto Recessive involving AA
Pathological Calcification 09/12/2010
Abnormal Calcium Salts in tissue
 Some magnesium and iron will be present also
Dystrophic
 Deposit of calcium phosphate in necrotic tissue
o NORMAL SERUM CALCIUM AND PHOSPHATE
 Seen in coagulative, caseous and enzymatic fat
necrosis
 See a psammona body
 Examples
 Chronic pancreatitis: enzymatic fat
 Artherosclerotic: coagulative
 Cytomegalovirus infection Periventricular :
caseous
 Occurs in aorta

 Mechanism
o Calcium of the dead cells binds to the phospholipid of the cell
membrane
o Phosphate binds to calcium of cell membrane forming
microcystals
o The microcystals deposit
Metastatic
 Deposition of Calcium and Phosphate in Normal Tissue
Cause:
 Increase serum calcium and/or phosphate
  Hypercalcemia (primary hyperparathyroidism
(solitary adenomas or multiple endocrine
neoplasia) or maglinant tumor (multiple
myelonma lymphoma)
 Increase in vit D
 Paget’s Disease
 Hyperphosphatemia (renal failure (leads to
secondary hyperparathyroidism), primary
hypoparathryoidism)
 Excess phophate makes calcium go into
normal tissue
 Calcification of renal tubular basement mebrane in
collecting ducts (nephrocalcinosis)
 Causes nephrogenic diabetes and renal failure