Cell Adapt

7/30/2019 Cell Adapt

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Cellular adaptations, cell injury,and cell death

Monday Feb 7


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Terms

Etiology Pathogenesis

Morphologic changes Functional derangements and clinical

manifestations


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Hypertrophy

Figure removed for copyright reasons.Source: Figure 1.3 in [RC] Kumar, V., A. K. Abbas, and N. Fausto.

Robbins and Cotran Pathologic Basis of Disease. Philadelphia PA: Elsevier, 2005.ISBN: 0721601871.


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Hyperplasia

Photos removed for copyright reasons.


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Transmissible murine colonichyperplasia

Photo and diagram removed for copyright reasons.


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Photos removed for copyright reasons.Source: CD-ROM in [RC]. Control colon, H&E 200x

TMCH colon, H&E 200x TMCH colon, BrdU 200x


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Factors driving compensatoryhyperplasia

HGF from nonparenchymal cells acts via c-Metexpressed on hepatoctyes

TGF-alpha and EGF are also mitogenic forhepatocytes

IL-6 and TNF-alpha are produced early in hepaticregeneration, and are necessary for theproliferative response

A priming event is necessary for hepatocytes torespond to these cytokines and growth factors(degradation of ECM, release of norepinephrine,insulin, glucagon, etc.?)


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Resolution of compensatoryhyperplasia

TGF-beta is an important inhibitor,which is also produced bynonparenchymal cells in the liver

The adult stem cells of the liver donot appear to play an important rolein hyperplasia following partialhepatectomy


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Pathologic hyperplasia Hyperplasia constitutes a fertile soil in

which neoplasia may develop Hyperplasia in certain organs is a risk

factor for cancer But in tissues with a high turnover rate,hyperplasia may be a beneficial response

when mature cells are injured or killed,necessitating compensatory renewal


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Metaplasia

Figure removed for copyright reasons.

Source: Figure 1.6 in [RC].


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Reversible & irreversible injury

Figure by MIT OCW.

Normal CellNORM

AL

REVERSIBLECELLINJURY

IRREVERSIBLECELL

Injury

Necrosis

Clumping of

chromatin

Injury

Recovery

Death

Lysosome

rupture

Membraneblebs Swollen mitochondria

with amorphous densities

Swelling of endoplasmic

reticulum and loss of

ribosomes

Necrosis

Fragmentation of cell

membrane & nucleus

Nuclear

condensation

Myelin figures

Normal Cell

Swelling of endoplasmic

reticulum & mitochondria

N d


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Necrosis and apoptosis

NORMAL

Apoptotic

body

Phagocyte

Phagocytosis

of apoptotic cells

& fragments

Enzymatic digestion

& leakage of

cellular contents

NECROSIS

APOPTOSIS

Figure by MIT OCW.


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Feature Necrosis Apoptosis

Cell size Enlarged (swelling) Reduced (shrinkage)

Nucleus Pyknosis,

karyorrhexis,karyolysis

Fragmentation into

nucleosome sizefragments

Plasma membrane disrupted Intact, alteredstructure

Cellular contents Enzymaticdigestion, leakage

Intact, release inapoptotic bodies

Adjacentinflammation Frequent No

Physiologic orpathologic role

Always pathologic Often, but notalways, physiologic


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Cellular and biochemical sites of damage

Figure by MIT OCW.

ATP

Loss of

energy-dependent

cellular functions

Cell deathProtein breakdown

DNA damage

Enzymatic digestion

of cellular components

Loss of cellular

contents

MitochondriaPlasma membrane

Lysosome

Membrane DamageIntracellular

Ca2+

O2H2O2OH

-

Reactive Oxygen

Species

Injurious Stimulus

Ca

Ca

Ca

C f ATP d l ti


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Consequences of ATP depletion

Ischemia

Mitochondrion

Oxidative phosphorylation

ATP

Na pump

Influx of Ca++

H2O, and Na+

Efflux of K+

Glycogen Detachment of

ribosomes, etc.

pH

Clumping of

nuclear chromatinProtein synthesis

Lipid deposition

ER swelling

Cellular swelling

Loss of microvilliBlebs

Anaerobic glycolysis Other effects

Figure by MIT OCW.

Mit h d i l d f ti


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Mitochondrial dysfunction

Cytochrome c

H+

Apoptosis

Mitochondrial

membrane

Cytochrome c, other

pro-apoptotic proteins

ATP

production

Mitochondrial

permeability transition (MPT)

Mitochondrial injury or dysfunction

(Increased cytosolic Ca2+, oxidative stress, lipid peroxidation)

Figure by MIT OCW.

C 2+ i ll i j


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Ca2+ in cell injury

Increased cytosolic

Ca2+

Extracellular

Ca2+

Injurious agent

Endoplasmic

reticulumMitochondrion

ATPase

Decreased

ATP

Membrane damage

Phospholipase

Decreased

phospholipids

ProteaseEndonuclease

Disruption of

membrane and

cytoskeletal proteins

Ca2+

Ca2+Ca2+

Nucleus

chromatin

damage

Ca2+

Figure by MIT OCW.


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ROS in cell injury

Figure removed for copyright reasons.Source: Figure 1.14 in [RC].


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Necrosis


h ll


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Ischemic cell injury

Figure by MIT OCW.

Ischemia

Oxidativephosphorylation

Other effects

Basophilia ( RNP)

Nuclear changesProtein digestion

Membrane

injury

Mitochondria

Reversible Injury Irreversible Injury(Cell death)

Leakage of

enzymes

(CK, LDH)

Ca2+influx

Loss of

phospholipids

Cytoskeletalalterations

Free radicals

Lipid breakdown

Others

Intracellular

release andactivation of

lysosomal

enzymes

ATP Glycolysis

Detachment

of ribosomes

Protein

synthesis

Lipid

deposition

Glycogen

pH

Clumping of

nuclear chromatin

Napump

Influx of Ca2+

H2O, and Na+

Efflux of K+

Cellular swelling

Loss of microvilli

Blebs

ER swellingMyelin figures


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CCl4

+O2

Microsomal polyenoic fatty acid

CCl3

Membrane Damage to RER

SER

Chemical Injury

Lipid Radicals

Polysome Detachment

Fatty Liver

LIPID PEROXIDATION

Apoprotein Synthesis

Release of Products of Lipid Peroxidation

Autocatalytic spreadalong microsomal

membrane

Damage to Plasma Membrane

Permeability to Na+

, H2O, Ca2+

Inactivation of Mitochondria, Cell Enzymes,

and Denaturation of Proteins

Massive Influx of Ca2+

Cell Swelling

Figure by MIT OCW.


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Mechanisms of apoptosis



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Extrinsic pathway of apoptosis



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Intrinsic pathway of apoptosis



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Reticulum cell sarcoma modelB cell lymphoma

Reticulum cell sarcoma (RCS)MMTV-encoded superantigen

Syngeneic CD4+ Vb16+ T cells

Produce B cell growth factorsReverse immune surveillance

Th1 cytokines


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Normal spleen

Capsule of Spleen

White Pulp

Venus Sinus

Red Pulp

Trabeculum

Figure by MIT OCW.


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Photos removed for copyright reasons.Source: CD-ROM in [RC]. Normal spleen, H&E 100x RcsX spleen, H&E 100x Normal spleen, H&E 200x

RcsX spleen, H&E 200x Normal spleen, H&E 400x RcsX spleen, H&E 400x RcsX spleen, iNOS 400x RcsX spleen, activated caspase-3 400x

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