6. Mechanisms of Cell Death & Tissue Repair

Factors affecting cell injury

Nature, duration, severity

Cell type and adaptability

Activation of multiple mechanisms

Chemical injury mechanismss

Some directly target organelles

Some require metabolic activation

Some trigger an inflammatory response

Often very selective – based on kinetics

Ways infections destory cells

Bacterial toxins – lytic phospholipases

Viral replication – promotes cell lysis

Hypoxic Injury Characterisrtics

Anoxia

Loss of or dysfunctional hemoglobin

Poisoning

Respiratory/CVD

Example in Reversible Cell Injury

stunned or hibernating myocardium

Mechanisms of cell injury

Mitochondrial damage

Abnormal calcium homeostasis

DNA damage

Membrane damage

ER Stress

Oxidative stress

Enzyme Release from heart during cell injury

Myoglobin, CK-MB, Troponin, LDH, BNP

Enzyme Release from Liver during cell injury

AST, ALT, LDH, Alkaline Phosphatase

Enzyme Release from Pancreas during cell injury

Amylase, Lipase

3 distinct routes of cellular catabolism defined morphologically

apoptosis

autophagy

necrosis

2 Types of Necrosis

accidental necrosis

necropoptosis

Accidental Necrosis (passive process) Cause & Characteristics

Pathological (noxious stimuli)

Occurs synchronously in multiple cells

Early loss of membrane integrity

Generalized cell and nuclear swelling • Nuclear chromatin disintegration

Inflammatory reactions

Energy independent (dramatic irreversible drop in ATP)

Historically regarded as unregulated cell death

Coagulative necrosis

Infarction – necrosis caused by ischemia or anoxia (heart attack/stroke).

Tissue shows red stain indicating clot proteins (ie., fibrin), anoxic injury. Loss of blood supply

Liquefactive necrosis

Neuronal-brain

Fluid remains following digestion of necrotic tissue.

Caseous necrosis

Lung - tuberculosis

Combination of coagulative and liquefactive necrosis

Granulomas - Immune response

Fatty necrosis

Fat Necrosis Pancreas

“Production of soaps”

“Necrotic Fat Cells”

• Leak of digestive enzymes – lipase

• Release of fatty acids combine with minerals

Programmed Cell Death definition

Active process that depends on the execution of a defined sequence of signaling events

Dependent on genetically encoded signals or activities

‘programmed cell death’ and ‘apoptosis’ are not synonyms

Apoptosis

described a morphological aspect of cell death

Removal of damaged, senescent or unwanted cells

Critical in the maintenance of normal organ and tissue homeostasis

Important role in sculpting development (nervous system) and maintaining normal function of immune system

Apoptosis (active process) Characteristics

Physiological or pathological

Asynchronous process in single cells

Genetically controlled

Cell rounding up, reduction of volume

Condensation of nuclear contents (DNA laddering)

Late loss of membrane integrity and little ultrastructural damage to cytoplasmic organelles

Evokes little inflammatory response

Energy dependent

Autophagy Characteristics

Self-digestive process

Cytoplasmic and intra-cellular organelles sequestered into double membrane vesicles

Fuse with lysosomes for digestion

Does not display chromatin condensation

Caspase-independent

3 major categories of autophagy

Macroautophagy

Microautophagy

Chaperone-Mediated Autophagy

What trigger autophagy

Nutrient deprivation

Autophagy paradox

Paradoxically- ‘point-of-no-return’ - extensive activation can result in cell death

Autophagy purpose

Activity enables cells to restore sufficient energy levels and promotes viability

Early satges of tissue repair are cleaned up how

area ‘cleaned up’ by phagocytosis – WBC (neutrophils)

Occurs within minutes

Over few days – phagocytes begin to accumulate (macrophages derived from monocytes)

What provides blood supply for reconstruction

New growth of tiny blood vessels (endothelial cells)

What is granulation tissue?

Proliferating blood vessels – meshwork of tiny capillaries

Several days post-injury

What is fibrous tissue

scar

Fibroblasts: What to they do

proliferate and synthesize collagen – tough fibrous protein which binds together (scar)

Late tissue repair includes

Fibrous tissue, fibroblasts

Days to weeks

Examples of tissues that can regenerate

liver, skin

Tissues with no regenerative capacity

heart muscle, CNS – however evidence this may not be completely true)

Tissue repair: summary

Phagocytes clean up the debris.

New blood vessels grow in.

Some tissues may regenerate.

Scarring may occur

Tissue adaptations: Metabolic Responses

hydrophobic swelling

fatty acid change

protein accumulation

Tissue adaptations: Growth Responses

trophy

hypertrophy

hyperplasia

metaplasia