Cell Injury and Death

Learning Outcomes

• Identify stimuli that may cause cell injury
• Comprehend possible cellular responses to injury
• Interrelate types of reversible injury with clinical context
• Interrelate types of irreversible cell injury with clinical context
• Understand the complications and clinical manifestations of cell death

Cause of Cell Injury

• Hypoxia refers to low oxygen levels in cells
• Ischemia is the deprivation of blood supply; it can lead to infarction, a type of necrosis caused by oxygen deprivation

Susceptibility of Cells to Ischemic Injury

• Low susceptibility: Fibroblasts, epidermis, and skeletal muscle can withstand ischemia for many hours
• Intermediate susceptibility: Myocardium (heart muscle), hepatocytes, and renal epithelium can withstand ischemia for 30 minutes to 2 hours
• High susceptibility: Neurons can only withstand ischemia for 3-5 minutes

Physical Agents

• Trauma is a cause of cell injury
• Atmospheric pressure that is too high or too low can cause cell injury
• Extreme temperature can cause cell injury
• Radiation can cause cell injury
• Electricity shock can cause cell injury

Chemical Agents

• Poison is a cause of cell injury
• Drugs can cause cell injury by causing side effects
• Alcohol can cause cell injury
• Carcinogens can cause cell injury
• Some chemical agents can cause liver injury

Biological Agents

• Bacteria can cause cell injury
• Viruses can cause cell injury
• Fungus can cause cell injury
• Parasites can cause cell injury

Immunological Reactions

• Hypersensitivity states: The body is too reactive, leading to conditions like allergies, asthma, and diarrhea, can cause cell injury
• Autoimmunity: The immune system attacks the body's own cells due to false recognition of self-antigens, triggering inflammatory responses that can cause cell injury

Other Causes

• Genetic defects can cause cell injury
• Nutritional imbalance can cause cell injury
• Obesity can cause cell injury
• Starvation can cause cell injury

Types of Cell Injury

• Cellular adaptation and homeostasis are intertwined aspects of cell health

Reversible Changes

• Excess isotonic fluid influx causes this.
• Derangement of the cell membrane also causes this.
• Individual cells swell with sodium and water vacuoles.

Fatty Change

• Chemical substances and toxins (like alcohol) initiate it.
• Hypoxia also causes this.
• Conditions such as starvation and wasting diseases can trigger this change.
• Metabolic disorders (DM) also contibute to this change.
• Characteristics of this change: there will be an abnormal accumulation of fat within cells, Intracellular fat vacuoles will arise and the nucleus will be displaced and this can be found in the liver, heart muscle, and renal tubule

Hyaline Degeneration

• It arises when smooth muscle is replaced by fibrous connective tissue.
• Tissues appear pink and homogeneously eosinophilic.
• The tissue takes on a glassy or hyaline appearance.

Intracellular Accumulation

• Lysosomal storage causes this.
• Occurs when there is a deposition of pigment
• Lipofuscin: This is a pigment of ageing.
• Lipofuscin appears as brownish yellow patches
• Hemosiderin comes from the breakdown of haemoglobin.
• It appears yellow/brown because it is due to presence of RBC
• When hemosiderin reacts with Prussian blue dye it appears light blue.

Sublethal Nuclear Damage

• Sublethal is below death.
• There are no morphological changes associated with this.
• It is heritable if it occurs in germ cells (sex cells).
• Can cause neoplasia if it occurs in somatic cells.

Irreversible Changes

• Apoptosis is programmed cell death

Necrosis (Cell Death)

• UV or ionizing radiation can cause this. (e.g. radiotherapy)
• Cytotoxic T cells can cause this.
• Cell-mediated immunity can cause this.
• Drugs can cause this.
• Tumor cell death can cause this.
• Programmed cell destruction during embryonic development can cause this
• Normal cell turnover in adult organs can cause this.

Physiological / Pathological

• Only pathologic is physiological with the culmination of irreversible cell injury

Affected Cells

• Single cells are affected within living tissues
• Sheets of cells die together

Effects

• No acute inflammation
• Phagocytosis by adjacent cells
• Preservation of tissue structure
• Loss of body function follows this.
• Acute inflammation follows this.
• Release of cell content follows this.
• Leaking of enzymes from organs follows this.
• Effects of repair and regeneration follows this.
• Dystrophic calcification follows this.
• Infection follows this.

Process

• Genetic changes initiate this.
• DNA is fragmented by endonuclease which cause this.
• Chromatin and cytoplasm condensation occurs during this.
• There is formation of apoptotic bodies during this.
• Apoptotic bodies are phagocytosed by adjacent cells.

Autolysis

• Structural disintegration occurs due to digestion by lysosomal hydrolases of the necrotic cells.

Heterolysis

• Digestion occurs by immigrant leukocytes.

Observation

• Cell size reduces due to shrinkage during apoptosis.
• Cell Size enlarges due to swelling during Necrosis (Cell Death)

Nucleus

• During Apoptosis fragmentation of the nucleus is into nucleosome-size fragments
• The nucleus will follow these stwps during necrosis: pyknosis, karyorrhexis, karyolysis and finally there will be abscence of nucleus

Plasma membrane

• The membrane remains intact during during Apoptosis
• The structure is altered: Orientation of lipid changes can occur during Apoptosis
• The membrane becomes disrupted during necrosis

Cellular Contents

• Enztmatic digestion occurs in Necrosis
• Intact during Apoptosis
• Will be released in apoptotic bodies during Apoptosis
• Cell content will leak ous of the cell during Necrosis

Morphological Types of Necrosis

• Coagulative Necrosis (most common)
• A result of ischemia
• Certain toxic insults, such as certain chemicals
• Extreme heat

Microscopic Morphology (Histology)

• Coagulation and clumping of cellular proteins
• The denaturation of proteins occurs
• There are No hydrolytic enzymes
• There is No hydrolysis
• The architecture of the tissue is generally retained for several days
• Acidophilic “tombstone”
• The nuclei show granular debris
• Presence of a well-demarcated zone of necrotic tissue surrounded by an inflammatory response: this zone is area where the ischemic insult occurred

Gross Morphology

• The segment of tissue that has died will contrast against surrounding well vascularized tissue
• Tissue Will be dry on a cut surface
• The tissue may later turn red due to inflammatory response

Examples

• Solid organs such heart
• the Myocardium

Liquefaction Necrosis

• Caused by bacterial or fungal infection
• Is caused by ischemic injuries
• The microorganisms release enzymes to degrade cells
• Hydrolytic enzymes will liquify cells
• The microorganisms cause local damage and causes cells to be lysed, causing a fluid phase

Contains necrotic cell debris and macrophages filled with phagocytosed material

• Loss of tissue structure occurs
• A creamy yellow liquid known as Pus should be present: As lots of leukocytes are found to be dead
• As lots of leukocytes are found to be dead
• Cystic infarct of brain is an example of tissue that has undergone Necrosis

Caseous Necrosis

• Found in the centre of foci of tuberculosis infections
• The tissue shows characteristic granulomatous wall, that is made of Peripheral mantle of lymphocytes

Combines features of both coagulative and liquefactive necrosis

Disappearance of cellular outline oosinophilic

• Contain granular debris is associated with this.

Gross morphology characteristics

• The tissue looks cream cheese like

• Soft, granular and yellowish in colour

• Histotoxic effects of lipopolysaccharides present in the capsule of the Mycobacterium Tuberculosis

  Enzymatic acute Pancreatitis, causes fat necrosis of pancreas:

• Pancreatic enzymes leaking out of acinar cells and ducts cause this.

• fat cell membranes in the peritoneum are liquified

• Lipases split the TAG in fat cells to fatty acid this is caused.

• Grossly visible chalky white areas (fat saponification) are produced.

Traumatic fat necrosis in breast:

• Lipids released from fat cells and Provoke a chronic inflammatory happens following

• There is fat provokes chronic inflammatory

• An Indurated mass mass is then produced the tissue dies.

• The Necrosed fat cells start to appear cloudy

• The surrounding tissue shows an inflammatory reaction

• The formation of calcium soaps is identified in the tissue section

• Chalky Patches occurs during pancreatitis

• Fat appears ellowish-white with firm compos.

Fibrinoid Necrosis

• Immunologic tissue injury such as
• The vessel wall shows brightly pink amorphous material and nuclear fragments of necrosed neutrophils

Autophagy

• Autophagy refers to lysosomal digestion of the cell's own components.
• Cellular organelles are packed into cytoplasmic autophagic vesicles (autophagosomes).
• Adaptive response during nutrient deprivation occurs.
• Host defense mechanisms exist against microbes
• Dysregulation can cause diseases such as such as cancers, inflammatory bowel disease etc.

Pathogenesis of cell injury Factors

• Type can cause injury.

Duration of Injury

• Cell type is a factor that can cause cell injury
• the state of the cell can be a factory for cell injury
• the cell's ability to adapt can determine outcome of cell injury
• Effects are exerted at the molecular or biochemical levels
• Results of injury depends in cell ability to response to stimulus and duration, biochemical derangement
• Intracellular aerobic respiration
• Mitochondria structure
• Enzymatic and structural protein
• Genetic appratus alterations and damage can affect cell injury

Stages of Cell Injury

• Minutes become hours after injury.
• Changes happen on light microscope or on gross examination (organ examination).