Introduction to Disease: Cell Injury

Question 1

Causes Of Cell Injury

Answer 1

Vascular
Inflammatory
Traumatic
Autoimmune
Metabolic
Infection
Neoplastic
Degenerative
Idiopathic
Congenital

Question 2

Cellular response depends on

Answer 2

• nature of the injury
• its duration
• its severity

Question 3

cellular response to injury

Answer 3

1. adaptation - hyperplasia / hypertrophy
2. acute cell injury - irreversible cell death necrosis or apoptosis / reversible
3. intracellular accumulations
4. pathologic calcification
5. cellular aging

Question 4

what are the 4 types of cellular injury stimuli, and what is the response (adaptation/injury/accumulation/aging)?

Answer 4

1. altered physiologic stimuli –> adaptation
   - demand –> hypertrophy/hyperplasia
   - nutrients –> atrophy
   - chronic irritation –> metaplasia
2. chemical microbial injury –> injury
   - acute and self limited –> reversible
   - progressive and severe - DNA damage –> irreversible injury cell death
   - chronic and mild
3. metabolic, genetic/acquired –> intracellular accumulations
4. prolonged life span, cumulative sublethal injury –> cellular aging

Question 5

Describe the mechanisms by which cells become injured

Answer 5

1. free radicals,
2. chemicals,
3. viruses
4. hypoxia
5. autoimmunity
6. irradiation

Question 6

Describe the mechanisms by which cells become damaged (auto)

Answer 6

1. mitochondrial damage – ATP depletion/ free radicals
2. increase in cytosolic calcium – activates cellular enzymes
3. defective membrane permeability – enzymatic digestion of cellular components due to lysosomal / loss of cellular components due to membrane damage
4. DNA damage – activation of proapoptic proteins

= MCMD

Question 7

Describe the mechanisms by which cells become damaged (auto) - 1. mitochondrial

Answer 7

= ischaemic and hypoxic injury

i) first point of attack = cell’s aerobic resporation = decrease ATP. how?
- - membrane trasnport defect = Ca Na water gain / K loss. = cell swelling
- - anaerobic glycolysis increased = decrease glycogen, increase lactic acid, decrease pH = clumping of nuclear chromatic

ii) disrupt interaction between ER and ribosomes - ribosomal detachment - affects protein synthesis

Question 8

Describe the mechanisms by which cells become damaged (auto) - 2. Ca influx

Answer 8

activation of enzymes that damage cellular componsnts and trigger apoptosis.

Question 9

Describe the mechanisms by which cells become damaged (auto) - 3. free radical induced cell injury - ROS

Answer 9

Free radical may be generated within cells by-

1. Reduction-oxidation reactions
2. absorption of radiant energy (e.g. UV light,, x-rays)
3. enzymatic metabolism of exogenous chemicals and drugs (e.g. CCL4)
4. activated leukocytes during inflammation

ROS are produced normally in cells during mitochondrial respiration and energy generation, but they are degraded and removed by cellular defense systems.

if accumulated cause:
membrane damage
protein modification
DNA damage –> mutations

Question 10

Describe the mechanisms by which cells become damaged (auto) - 4. membrane damage

Answer 10

due to hypoxia - affect ATP - sffect transport and PSPL synthesiss

due to increase in cytosolic Ca - activate protease and phosoplipase

due to ROS - affect lipid peroxidation - PSPL loss

all leading to membrane damahe]ge

Question 11

Describe the mechanisms by which cells become damaged (auto) - 5. misfolded proteins

Answer 11

The presence of misfolded proteins in the ER is detected by sensors in the
ER membrane, such as the kinase IRE-1, which form oligomers that are activated by phosphorylation. This triggers an adaptive unfolded protein response,
which can protect the cell from the harmful consequences of the misfolded proteins. When the amount of misfolded proteins is too great to be corrected,
excessive activation of ER sensors activates the mitochondrial pathway of apoptosis and the irreparably damaged cell dies; this is also called the terminal
unfolded protein response.

Question 12

Two patterns of reversible cell injury :

Answer 12

1. Cellular swelling

2. fatty change.

Question 13

Reversible cell injury : Ultrastructural changes

Answer 13

1. plasma membrane alterations, such as blebbing, blunting, and loss of microvilli
2. mitochondrial changes, including swelling and the appearance of small amorphous densities
3. dilation of the endoplasmic reticulum, with detachment and disaggregation of polysomes, intracytoplasmic myelin figures
4. nuclear alterations, with disaggregation of granular and fibrillar elements.

Question 14

define necrosis

Answer 14

A sequence of morphologic changes that follow cell death in living tissue, resulting from the progressive degradative action of enzymes on the lethally injured cell.

Autolysis = lysosomes of dead dells . Their cellular membranes fall apart, and cellular enzymes leak out and ultimately digest the cell

Heterolysis = lysosomes of immigrant leukocytes recruited as part of the inflammatory reaction.

Question 15

Morphologic Appearance of Necrotic Cells

Answer 15

Necrosis is characterized by changes in the cytoplasm and nuclei of the injured cells.

I. CYTOPLASMIC CHANGES

• Increased eosinophilia
  loss of ribosomal basophilia
  Binding of Eosin to denatured proteins [Arg/Lys]
• Glassy appearance (loss of glycogen)
• Moth-eaten vacuolated appearance (enzymatic degradation of organelles)

II. NUCLEIC CHANGES

• pyknosis = shrinkage of nucleus (increase basophilia)
• karyolysis = nuclear fading and dissolution due to DNAases and RNAases
• karyorrehxis = fragmentation of nucleus

Question 16

Fates of necrotic cells

Answer 16

1. replaced by myelin figures - which are phagocytosed or degraded into fatty acids which bind to calcium salts resulting in calcification of cell
2. or digested by emzumes and disappearing cells

Question 17

List the types of necrosis.

Answer 17

1. Coagulative (myocardial infarction)
2. Liquefactive necrosis
3. Caseous (tuberculosis)
4. Gangrene (ischaemic injury to digits, bowel)
5. Fibrinoid (hypertension)
6. Fat necrosis (trauma, pancreatitis)

CCFFGL = cool country for foolish goats living

Distinctive Types of Necrosis
Vary according to
1. different types of tissue effected 2. nature of causative agent
3. predominance of further enzymatic changes in the necrotic cells

Question 18

Coagulative Necrosis

Answer 18

• most common in hypoxic death of cells in all tissues except the brain i.e. kidney, heart, adrenals
  
  • result from denaturation of proteins
    Gross: pale & firm, demarcated from uninvolved tissue
    Histology : affected cells → acidophilic opaque mass with loss of nucleus but basic cellular outline & tissue architecture are preserved

Question 19

Liquefactive Necrosis

Answer 19

Focal bacterial lesions → powerful enzymes completely digest the cell & transform into a proteinaceous fluid.
hypoxic deaths of brain tissue

Gross : soft, become cystic fluid with debris and fluid
Histology : amorphous eosinophilic fluid with complete destruction of cells

Question 20

Caseous Necrosis

Answer 20

Combination of coagulative & liquefactive necrosis in the centre of tuberculous infection due to lipopolysaccharides of capsule of Mycobacterium tuberculosis

Histo: Pink, amorphous, granular debris (barely visible dead cells which are not totally liquefied with no cellular outline preserved)
- enclosed within granulomatous inflammation reaction

Gross: Soft, friable, yellow-white debris resembling clumped cheesy material.

Question 21

Enzymatic Fat Necrosis

Answer 21

• seen in acute haemorrhagic pancreatitis (acute pancreatic necrosis)
  
  • result from release of powerful enzymes from injured acinar cellsi.e. Protease → digest the cell membrane → necrosis

      lipase → split triglycerides→ FFA → combine with calcium in blood→ calcium salts ← serum calcium ↓
    
       elastase → destroy vessel wall → haemorrhage

Gross - Amorphous, opaque, chalky-white deposits in pancreas and fat around it.
Histology - Amorphous, granular, basophilic deposits (saponification areas) on the shadowy outlines of necrotic fat cells, surrounded by inflammatory cells; Areas of h’ges present.

Question 22

Gangrenous Necrosis

Answer 22

• coagulative necrosis, modified by liquefactive necrosis, caused by bacteria and attracted leucocytes.
  Sites - lower limbs, appendix, gall bladder, intestines.

Dry gangrene - coagulative necrosis is predominant. e.g. ischemia without infection

Wet gangrene - liquefactive necrosis is predominant. e.g. with infection

Question 23

Fibrinoid necrosis

Answer 23

• occurs in 
  1. Immune reactions (complexes of antigens and antibodies deposited in the walls of blood vessels)
  2. Severe hypertension. 
  Gross: No specific gross appearance

Histology: bright pink, amorphous appearance called fibrinoid (fibrin-like) due to Deposited immune complexes combination with plasma proteins 

Question 24

Define APOPTOSIS

Answer 24

Programmed cell death.
Tightly regulated cell suicide programme.

An active controlled process. and apoptotic fragments phagotysosed by neighbouring cells.
Enzymatic destruction of DNA and cytoskeleton
Cell membrane remains intact (no inflammation) but Cell components are broken down (apoptosis = “falling off”) and is phagocytised
Energy-dependent process

Question 25

Physiologic vs pathologic apoptosis

Answer 25

Physiological: important mechanism in development and normal cell turnover, removing redundant/damaged cells

Pathological: eliminates potentially harmful cells (e.g. mutated or virally-infected cells)

Question 26

Apoptosis: 2 Mechanisms are ____________ and ____________

Answer 26

1. mitochondrial intrinsic pathway

2. death receptor extrinsic pathway

Question 27

Apoptosis: Mechanisms

1. mitochondrial intrinsic pathway

Answer 27

In the mitochondrial pathway, BH3-only proteins, which are related to members of the Bcl-2 family, sense a lack of survival signals or DNA or protein damage.
These BH3-only proteins activate effector molecules that increase mitochondrial permeability. In concert with a deficiency of Bcl-2 and other proteins that
maintain mitochondrial permeability, the mitochondria become leaky and various substances, such as cytochrome c, enter the cytosol and activate caspases.
Activated caspases induce the changes that culminate in cell death and fragmentation.

A specific feature of apoptosis is the activation of several members of a family of cysteine proteases named caspases.

The process of apoptosis may be divided into an initiation phase, during which some caspases become catalytically active, and an execution phase, during which other caspases trigger the degradation of critical cellular components. Initiation of apoptosis occurs principally by signals from two distinct pathways: the intrinsic, or mitochondrial, pathway, and the extrinsic, or death receptor–initiated, pathway

The Intrinsic (Mitochondrial) Pathway of Apoptosis
This pathway of apoptosis is the result of increased mitochondrial permeability and release of pro-apoptotic molecules (death inducers) into the cytoplasm
Mitochondria are remarkable organelles in that they contain proteins such as cytochrome c that are essential for life, but some of the same proteins, when released into the cytoplasm (an indication that the cell is not healthy), initiate the suicide program of apoptosis.
The release of these mitochondrial proteins is controlled by a finely orchestrated balance between pro- and anti-apoptotic members of the Bcl family of proteins
Growth factors and other survival signals stimulate production of anti-apoptotic proteins, the main ones being Bcl-2, Bcl-x, and Mcl-1.
When cells are deprived of survival signals or their DNA is damaged, or misfolded proteins induce ER stress, sensors of damage or stress are activated. These sensors are also members of the Bcl family, and they include proteins called Bim, Bid, and Bad
The sensors in turn activate two critical (proapoptotic) effectors, Bax and Bak, which form oligomers that insert into the mitochondrial membrane and create channels that allow proteins from the inner mitochondrial membrane to leak out into the cytoplasm.
One of these proteins is cytochrome c, well known for its role in mitochondrial respiration. Once released into the cytosol, cytochrome c binds to a protein called Apaf-1 (apoptosis-activating factor-1
This complex is able to bind caspase-9, the critical initiator caspase of the mitochondrial pathway, and the enzyme cleaves adjacent caspase-9 molecules, thus setting up an auto-amplification process.

Question 28

Apoptosis: Mechanisms

1. Death receptor extrinsic pathway

Answer 28

In the death receptor pathway, signals from plasma membrane. receptors
lead to the assembly of adaptor proteins into a “death-inducing signaling complex,” which activates caspases, and the end result is the same.

This pathway is initiated by engagement of plasma membrane death receptors on a variety of cells.
Death receptors are members of the TNF receptor family that contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain because it is essential for delivering apoptotic signals.
The best-known death receptors are the type 1 TNF receptor (TNFR1) and a related protein called Fas (CD95)
The ligand for Fas is called Fas ligand (FasL).
When FasL binds to Fas, three or more molecules of Fas are brought together, and their cytoplasmic death domains form a binding site for an adapter protein that also contains a death domain and is called FADD (Fas-associated death domain). FADD that is attached to the death receptors in turn binds an inactive form of caspase-8 .
. The enzyme then triggers a cascade of caspase activation by cleaving and thereby activating other pro-caspases, and the active enzymes mediate the execution phase of apoptosis

Question 29

Which of the following is a major inducers of apoptosis by intrinsic pathways?

A. Cytotoxic T lymphocytes
B. Immunoglobulins mediated
C. Tumor necrosis factor
D. Receptor/ligand interactions
E. Withdrawal of growth factors/hormones

Answer 29

E.

Question 30

Apoptosis: The cellular alterations

Answer 30

1. Cell shrinkage
2. Chromatin condensation:
3. Formation cytoplasmic blebs and apoptotic bodies
4. Phagocytosis apoptotic of bodies by macrophages or by healthy adjacent parenchymal cells.

Question 31

Apoptosis: On histology

Answer 31

The apoptotic cell appears as a round or oval mass of intensely eosinophilic with dense nuclear chromatin.

Question 32

DISORDERS ASSOCIATED WITH INHIBITED APOPTOSIS

AND INCREASED CELL SURVIVAL :

Answer 32

carcinoma with p53 mutations,or hormone dependent
tumors – breast, prostate, ovary etc.
Autoimmune disorders.

Question 33

DISORDERS DUE TO INCREASED APOPTOSIS:

Answer 33

1) neurodegenerative diseases
2) ischemic injury and stroke.
3) virus-induced lymphocyte depletion.