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Leicester Warwick Medical School

CELL INJURY

Introduction

General considerations……Adapt or die!Reaction patterns in a given cell/tissue is often limitedDegree of injury is a function of type, duration and severity of insult

Types of insult - hypoxia

Ischaemia Local e.g. embolus Systemic e.g. cardiac failure Hypoxaemia Oxygen problems e.g. altitude Haemoglobin problems e.g. anaemia Oxidative phosphorylation E.g. cyanide poisoning

Types of insult - chemical

Many of the common poisons (arsenic, cyanide, mercury) interfere with cellular metabolism. If ATP levels drop below critical levels, affected cells will die. The list of pharmaceuticals that may have toxic effects on cells is enormous. Some act directly, but most have their effect through breakdown metabolites. Metabolism of alcohol (a type of drug) to acetaldehyde is one example.

Types of insult - infections

Fungi, Rickettsiae, Bacteria and Viruses E.g. viruses can take over protein translation machinery and subvert it entirely to the production of new virions.

Types of insult - Physical

Direct Physical Effects Exposure of tissue to extreme heat or cold results in direct injury that is often irreversible, resulting in a pattern of coagulative necrosis (see later). Sudden changes in pressure can cause cellular disruption (e.g. a hammer blow to the thumb). Electrical currents can cause direct breakdown of cellular membranes that may be irreversible.


Types of insult –immune Inflammatory mediators such as interferons and interleukins can alter both gene expression and cellular metabolism. The effects are designed to help cells combat an infectious process, but the resulting stress to the cells can be highly injurious and sometimes deadly. Activation of complement can result in direct attack on a cell's surface membrane. Cytotoxic T-cells and NK cells can mediate a direct attack on a target cell's and initiate the self-destruct cascade within a target cell.

Types of insult - nutrition

Dietary insufficiency of protein, vitamins and/or minerals can lead to injury at the cellular level due to interference in normal metabolic pathways. Dietary excess can likewise lead to cellular and tissue alterations that are detrimental e.g. fat is the biggest offender, or excess ingestion of "health supplements"

Causes of cell injury - summary

Hypoxia Chemical Physical Infection Immune Nutritional deficiency (or excess!)

Principle structural targets for cell damage

Cell membranes Plasma membrane Organelle membranes DNA Proteins Structural Enzymes Mitochondria oxidative phosphorylation

Pathogenesis of cell injury - hypoxia

Reversible Loss of ATP Failure of Na/K pump Anaerobic metabolism Increased lactic acid and phosphate Reduced protein synthesis

Pathogenesis of cell injury - hypoxia

Irreversible Massive intra-cytoplasmic calcium accumulation Enzyme activation

Pathogenesis of cell injury - general

Reduced ATP synthesis/mitochondrial damage Loss of calcium homeostasis Disrupted membrane permeability Free radicals


Free radicals
Highly reactive, unstable chemicals Associated with cell injury Chemicals/drugs, reperfusion injury, inflammation, irradiation, oxygen toxicity, carcinogenesis

Free radicals

Free radical generation occurs by….Absorption of irradiationE.g. OH•, and H•Endogenous normal metabolic reactionsE.g. O2-•, and H2O2Transition metalsE.g. Fe+++ nitrous oxidean important paracrine-type mediator that helps regulate vascular pressure Toxins e.g. carbon tetrachloride

Free radicals

Free radicals are removed by….Spontaneous decayAnti-oxidantsE.g. Vitamin E, vitamin A, ascorbic acid, glutathioneStorage proteinsE.g. transferrin, ferritin, ceruloplasminEnzymesCatalase, SOD, glutathione peroxidase

Free radicals

Injure cells by…..Membrane lipid peroxidationAutocatalytic chain reactionInteraction with proteinsProtein fragmentation and protein-protein cross-linkageDNA damageSingle strand breaks (genomic and mitochondrial)

General protective mechanisms

Heat shock response genes comprise a large group of genes expression is up-regulated in the face of cell stressors and serve to protect proteins from stress-related damage "clean up" damaged proteins from the cell. Many tissues and organs can survive significant injury if they are "pre-stressed" Ways to exploit this phenomenon to improve organ transplantation and tissue repairs are being tested in clinical trials.

Cell injury - morphology

Reversible

Irreversible

Cell injury - morphology
Light microscopy Cytoplasmic changes Nuclear changes

Cell injury - morphology

Abnormal accumulations Lipid Protein

Necrosis

Definition Death of groups of contiguous cells in tissue or organ Patterns Coagulative Liquefactive Caseous Fat necrosis (gangrene) (Infarct) Red/haemorrhagic White

Coagulative necrosis

Cells have died but the basic shape and architecture of the tissue endures Most common manifestation of ischaemic necrosis in tissues. Affected tissue maintains solid consistency. In most cases the necrotic cells are ultimately removed by inflammatory cells. The dead cells may be replaced by regeneration from neighboring cells, or by scar (fibrosis).

Coagulative necrosis

Necrosis
Normal

Coagulative necrosis

Liquefactive necrosis
Complete dissolution of necrotic tissue. Most commonly due to massive infiltration by neutrophils (abscess formation). Release of reactive oxygen species and proteases Liquefaction is also characteristic of ischaemic necrosis in the brain.

Liquefactive necrosis

Caseous necrosis
Accumulation of amorphous (no structure) debris within an area of necrosis. Tissue architecture is abolished and viable cells are no longer recognizable. Characteristically associated with the granulomatous inflammation of tuberculosis. Also seen in some fungal infections.

Caseous necrosis

Fat necrosis
Results from the action of lipases released into adipose tissue. pancreatitis, trauma. Free fatty acids accumulate and precipitate as calcium soaps (saponification). These precipitates are grossly visible as pale yellow/white nodules Microscopically, the digested fat loses its cellular outlines. There is often local inflammation

Caseous necrosis

Fat necrosis



Gangrene ("gangrenous necrosis")
Not a separate kind of necrosis at all, but a term for necrosis that is advanced and visible grossly. If there's mostly coagulation necrosis, (i.e., the typical blackening, desiccating foot which dried up before the bacteria could overgrow), we call it dry gangrene. If there's mostly liquefactive necrosis (i.e., the typical foul-smelling, oozing foot infected with several different kinds of bacteria), or if it's in a wet body cavity, we call it wet gangrene.

Gangrenous necrosis

Infarction
An area of ischaemic necrosis in a tissue or organ White Arterial occlusion in most solid tissues Red/haemorrhagic Venous occlusion Loose tissues Dual blood supply Previously congested

White infarct

Red infarct

Apoptosis - basics

is a distinct reaction pattern which represents programmed single-cell suicide. Cells actually expend energy in order to die. Derived from Greek "falling off" (as for autumn leaves) Apoptosis is "the physiological way for a cell to die", seen in a variety of normal situations.

Apoptosis - morphology

Necrosis: pathological response to cellular injury. Chromatin clumps, mitochondria swell and rupture, membrane lyses, cell contents spill, inflammatory response triggered Apoptosis DNA cleaved at specific sites - 200 bp fragments. Cytoplasm shrinks without membrane rupture Blebbing of plasma and nuclear membranes Cell contents in membrane bounded bodies, no inflammation

Apoptosis - normal

A stain for apoptotic cells in the developing paw of a foetal mouse.

Apoptosis -pathological

Graft-versus-host disease in colonic mucosa

Apoptosis - triggers

Withdrawal of growth stimuli E.g. growth factors Death signals E.g. TNF and Fas DNA damage p53 plays an important role

Apoptosis - mechanisms

Extrinsic factors E.g. by members of the TNF family Intrinsic mechanisms E.g. hormone withdrawal

Summary

This talk has covered….Causes of cell injuryCellular targetsPathogenesisMorphology of cell injuryPatterns of necrosisApoptosis

Final thought… Our lives are filled with joys and strife, And what is death but part of life? Will come the day that we must die, And leave behind those learning why.