Autophagy= Digestion of cell s own substances. Lysosome

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Cell Responses 4.Sub - cell Injury
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Lecture Plan

• Alterations in cell organelles or the
  cytoskeleton
• Lysosomal catabolism
• Induction (hypertrophy) of smooth endoplasmic
  reticulum
• Mitochondrial alterations
• Cytoskeletal abnormalities
• Cytokeratin
• Neurofilaments
• Others
• Kartageners syndrome
• Wiskott-Aldridge Syndrome

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Lysosomes

• Primary Lysosomes Phagosomes (containing
  pathogen/material to be digested) ? phagolysosome
• Two ways of Proteolysis in the Lysosomes
• Autophagy Digestion of cells own substances
• Lysosome Autophagic vacuole
  Autophagolysosome
• Eg Atrophy, Cell injury, cell remodeling
• Heterophagy Digestion of material ingested from
  out-side
• Pinocytosis- Soluble smaller molecules( Cell
  drinking)
• Endocytosis- Particulate matter( Cell eating)

4
Lysosomes

• Lysosomal enzymes digest Carbohydrates Proteins
  but not all Lipids
• The un-digested Lipids and pigments (carbon or
  tattoo)? RESIDUAL BODIES (Lipofuscin)

Anthracotic (carbon) pigment
What is the difference between Russell and
Residual bodies?
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Yellow-brown granular pigment lipochrome
(Lipofuscin) in the hepatocytes (particularly
liver and heart) as residual bodies of
lipochrome What is the significance if it is lot
?
Lysosomes
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Lysosomal disorders

• Hereditary
• Enzyme deficiency ? Accumulation of the
  Substrate/metabolite ?Severe abnormalities
• Pompes disease
• Gauchers disease
• Drugs alter the Lysosomal functions
• ?Intra-Lysosomal pH- CHOLOROQUINE
• ?Tissue damage in Auto-immune diseases
  (Rheumatoid Arthritis)
• At the same time causes - Toxic Myopathy
  (?accumulation of Glycogen Phospholipids in
  cells)

7
The large pale cells contain an accumulated
storageproduct crumpled paper appearance of
cytoplasmWhat is the name for the cells?
Lysosomal disorders
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Induction of Smooth ER

• Most of the chemicals metabolized in SER in
  Liver - P-450 mixed function oxidase system by
• ?
• oxidative demethylation
• Substances metabolized- Antiepileptic
  (phenobarbitone)
• Others detoxified by same enzymes Alcohol,
  Steroids, Carcinogens, Insecticides toxic
  substances are also formed (Oxygen free radicals)
• Patients on antiepileptic also consume
  alcohol?Tolerance to alcohol leads to increased
  consumption?Hypertrophy of SER ? breakdown of
  medication?Sub-therapeutic levels of
  Antiepileptic

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Mitochondrial Alterations

• Most important role of mitochondria is in Cell
  injury- Apoptosis
• Diseases cause changes in Size, Shape, Number of
  the Mitochondria
• Mega mitochondria are seen in
• Alcoholic Liver disease
• Genetic disorders
• Mitochondrial Myopathies
• Tumors( Benign)- ONCOCYTOMAS ( with eosinophilic
  granular cytoplasm)

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Cytoskeletal abnormalities

• Cytoskeletal Proteins
• Thin Filaments- ACTIN ( 6-8 nm)
• Intermediate filaments ( 10 nm)
• Thick filaments-MYOSIN (15 nm)
• Microtubules (20-25nm)
• Non-polymerized / Non filamentous proteins
• The abnormalities in the Cytoskeleton are
  manifested as
• Functional defects intracellular organelle
  movement cell locomotion Phagocytosis
• Structural defects- ?intra cellular deposits of
  fibrillar material
• 1. Thin filaments (Actin and the regulatory
  proteins)
• Drugs Toxins ? bind and inhibit the
  polymerization of Actin (Cytochalacin B
  Phalloidin from Amanita phalloides)
• 2. Thick filaments (Microtubules) essential for
  leukocyte migration phagocytosis
• defects cause IMMOTILE CILIA SYNDROME OR
  KARTAGENERS SYNDROME (Lungs- Bronchiectasis,
  Sinuses- Chronic sinusitis, Situs inversus, male
  sterility)

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Cytoskeletal abnormalities

• 2. Thick filaments (Microtubules) contd
• Effect of Drugs bind to and inhibit the assembly
  of microtubules
• A) Colchicine metaphase arrest of mitosis-
  useful in Karyotyping also Rx of acute attacks
  of Gout- inhibit neutrophil migration and
  phagocytosis of urate crystals)
• B)Vinca alkaloids ( Vincristine Vinblastine)
  as Anti-cancer drugs
• 3. Intermediate filaments form flexible
  intra-cellular network
• Five classes
• A. Keratin filaments (normally produced by
  epithelial cells)
• In diseases like Alcoholic hepatitis, parenchymal
  cells (hepatocytes ) produce it Mallory body /
  Alcoholic hyaline
• What is this ?

What is this ?
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Cytoskeletal abnormalities

• 3. Intermediate filaments contd
• B. Neurofilaments (normal in neurons but seen in
  Diseases like Alzheimers as Neurofibrillary
  tangles)
• C. Desmin filaments in muscle cells
• D. Vimentin filaments in connective tissue cells
• E. Glial filaments in glial cells (what are
  they?)

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Cytoskeletal abnormalities

• Disorders affect intermediate filaments
• Mutations in the intermediate filament genes
  cause myopathies, neurological disorders and
  skin diseases
• WISKOTT- ALDRIDGE SYNDROME
• WAS gene ( X q chromosome)?WASp facilitates the
  nuclear translocation of NF- kB ?important role
  in lymphoid development
• Mutations of gene ? defective IL-2 expression
  and T-cell proliferation
• Clinically eczema , thrombocytopenia and
  immuno-deficiency