Cellular adaptations to stress / cell injury & death

Pathology
Pathology is literally the study (logos) of suffering (pathos) process as to:

Etiology (its cause) Pathogenesis (mechanisms of its development) Morphologic changes (the structural alterations induced in the cells and organs of the body ) Clinical significance (functional consequences of the morphologic changes )

The goals of this course is to defined and describe in general terms: - physiological adaptations, - reversibly and irreversibly injury - cell death

Virtually all forms of organ injury start with molecular or structural alterations in cells (Rudolf Virchow)
Cellular dysfunction tissue and organ injury clinical disease

Cellular Responses to Stress

Adaptation, reversible injury, and cell death can be considered stages of

progressive impairment of the cell's normal function and structure
2004 Elsevier Downloaded from: Robbins & Cotran Pathologic Basis of Disease

Summary of tissue response to environmental change. Adaptive responses allow cells to survive in the face of a change in the cellular environment. Failure to adapt is associated with cell damage or cell death.

Downloaded from: Robbins & Cotran Pathologic Basis of Disease

Cellular Responses to Injury

Nature and Severity of Injurious Stimulus Altered physiologic stimuli: Cellular Response Cellular adaptations:

Increased demand, increased trophic Hyperplasia, hypertrophy stimulation (e.g. growth factors, hormones) Decreased nutrients, stimulation Chronic irritation (chemical or physical) Reduced oxygen supply; chemical injury; microbial infection Atrophy Metaplasia Cell injury:

Acute and self-limited

Progessive and severe (including DNA damage)

Acute reversible injury

Irreversible injury cell death Necrosis Apoptosis

Mild chronic injury Metabolic alterations, genetic or acquired Prolonged life span with cumulative sublethal injury

Subcellular alterations in various organelles Intracellular accumulations; calcifications Cellular aging

Various Types of Adaptations

cells may undergo various adaptations in physiological and pathological conditions controlled by complex molecular mechanisms common types of cellular adaptations
1. 2. 3. 4. 5. 6. 7. hypertrophy hyperplasia atrophy metaplasia dysplasia intracellular accumulations pathological calcifications a. dystrophic calcification b. metastatic calcification

Mechanism of cellular adaptation

up or down regulation of specific cellular receptors involved in metabolism of certain components.
induction of new protein synthesis by the target cell (ex: response of muscle cells to increased physical demand) induction of cellular proliferation (responses of the endometrium to estrogens) switch by cells from producing one type of a family of proteins to another or markedly overproducing one protein (cells producing various types of collagens and extracellular matrix proteins in chronic inflammation and fibrosis).

These adaptations involve all steps of cellular metabolism of proteins: receptor binding, signal transduction, transcription, translation,
or regulation of protein packaging and release.

Cellular Adaptations

Size

Number

Type

Atrophy Disuse 2. Loss of endocrine stimulation 3. Denervation 4. Inadequate nutrition 5. Ischemia

1.

Hypertrophy

Hyperplasia

Metaplasia

Dysplasia

Intracellular Accumulations

Calcifications Dystrophic Metastatic

1. Hyperplasia

Definition: increase the number of cells (proliferation) in an organ or tissue --> increased volume of the organ or tissue The increase of number is achieved not only by proliferation of the existent cells but also by the development of new cells from stem cells. may sometimes co-exist with hypertrophy
Hyperplasia takes place if the cellular population is capable of synthesizing DNA, thus permitting mitotic division

Tissue

X Epithelial Connective Nerve Muscle

Connective Tissue Proper

Cartilage

Bone

Blood

X Skeletal

X
Cardiac Smooth

Loose Connective Tissues

Dense Connective Tissues

Regenerating Capability Good

Moderate
Areolar Adipose Reticular Dense regular Dense Irregular Elastic Poor None

Hyperplasia

classified as: physiologic - hormonal: increase the functional capacity of a tissue (e.g., breast and uterus during normal menstrual cycle and pregnancy) - compensatory: increases tissue mass after damage or partial resection (regeneration of
liver following partial hepatectomy or wound healing)

pathologic - excessive hormonal stimulation (BPH, endometrial hyperplasia) or growth factors (hyperplastic epithelium in papillomaviruses
infections)

Normal breast

Breast in lactation

Normal

Hyperplastic

Prostatic hyperplasia

Normal

Achantosis

Achantosis

2. Hypertrophy

increase in the size of cells enlargement of the organs (the hypertrophied organ has no new cells, just larger cells) increase the function mostly seen in cells that cannot divide, i.e., - skeletal muscle (strength training) - cardiac muscle (hypertension) changes usually revert to normal if the stimulus is removed mediated by different mechanisms (increased
workload, hormonal stimulation and growth factors stimulation the synthesis of more structural components).

Tissue

Epithelial

Connective

Nerve

Muscle

Connective Tissue Proper

Cartilage

Bone

Blood
Skeletal Cardiac Smooth

Loose Connective Tissues

Dense Connective Tissues

Regenerating Capability Good

Moderate
Areolar Adipose Reticular Dense regular Dense Irregular Elastic Poor None

Hypertrophy

Physiologic

Pathologic

Exercise

Adaptive

Compensatory

Normal heart

Hypertrophied heart

Hypertrophied and dilated heart

Hypertrophied heart

Normal uterus

Gravid uterus

Physiologic hypertrophy of the uterus during pregnancy. A, gross appearance of a normal uterus and a gravid uterus that was removed for postpartum bleeding,
Downloaded from: Robbins & Cotran Pathologic Basis of Disease

3. Atrophy

A shrinkage in the size of the cell due to decreased synthesis or increase of chatabolism, with possible reduction of functional capacity The cells are still alive and may return to original size if are stimulated by correct signals or may culminate with death Commonly, when atrophy occurs, the lost cells are replaced by either adipose or fibrous tissue, often maintaining the overall size of the organ. Should be distinguished by: - hypoplasia = incomplete growth of an organ - agenesis= complete failure to grow

Atrophy
Physiologic Denervation Pathologic

Disuse

Loss of endocrine stimulation

Inadequate nutrition

Ischemia

Atrophy associated with Alzheimers Disease

Denervation Atrophy

Loss of endocrine stimulation

http://www.wholewoman.com/newsletters/images/uterus_diagram.gif

Testicular atrophy

Atrophy associated with Malnutrition

http://membres.lycos.fr/spe edyz/billets/images/malnutri tion.jpg http://mazusy.blox.pl/resource/chuda.jpg

Atrophy of myocytes

Normal

Atrophy

4. Metaplasia

transformation or replacement of one adult cell type to another adult cell type, the most common: columnar to squamous also occurs in mesenchymal tissue (e.g., formation of bone in skeletal muscle) metaplastic changes usually result from chronic irritation changes seem to precede the development of cancer, in some instances

thought to arise from reprogramming of stem or undifferentiated cells that are present in adult tissue

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 November 2004 12:20 PM) 2004 Elsevier

Metaplasia of Respiratory Epithelium

Squamous metaplasia in bronchis

Collumnar to sq. ep Bronchial metaplasia

Metaplasia of Uterine Cervix

Metaplasia of Uterine Cervix At Higher Magnification

Metaplasia of Esophagus Epithelium Barretts Esophagus

Barretts Esophagus

5. Dysplasia
From Greek, roughly bad formation deranged cell growth varying of size, shape and organization of cells minor degrees are associated with irritation or inflammation most commonly associated with respiratory tract or uterine cervix potentially reversible often a precursor for cancer

the cells may undergo morphological transformation in witch increase rate of division is coupled with incomplete maturation of resultant cells Dysplastic cells May show loss of normal architectural relationship between the cells Tend to exhibit a high nuclear to cytoplasmic ratio Nuclei: irregular contour, increase of size, of hypercromasia Increase rate of mytotic activity

Grading of dysplasia is notoriously subjective and lacks intra- and interobserver reproducibility Different classification: - in 3 categories: slight moderate, severe - in 2 categories: low grade high grade

Cervix dysplasia

Colonic adenomatous polyp

6. Intracellular accumulations

develop when normal cellular constituents or products (e.g., water, lipids -TGL,FL, Colesterolproteins, carbohydrates- Gn) occur in excess - fatty changes in the liver, or heart genetic defects involving specific enzymes can result in the massive accumulation of some endogenous substances - lysosomal storage diseases

Accumulation of Pigments

Exogenous

carbon dust (anthracosis)

Endogenous

lipofuscin aging pigment in liver, heart, neurons, etc. hemosiderin lungs following congestive heart failure called hemosiderosis when found in a number of tissues and organs melanin bilirubin jaundice

Mechanisms of intracellular accumulations: (1) abnormal metabolism, as in fatty change in the liver; (2) mutations causing alterations in protein folding and transport, as in alpha1-antitrypsin deficiency; (3) deficiency of critical enzymes that prevent breakdown of substrates that accumulate in lysosomes, as in lysosomal storage diseases; and (4) inability to degrade phagocytosed particles, as in hemosiderosis and carbon pigment accumulation. Downloaded from: Robbins & Cotran Pathologic Basis of Disease

Anthracosis

Lipofuscin

Myocardial cells with lipofuscin

Icterus

http://www-medlib.med.utah.edu/WebPath/CINJHTML/CINJ049.html

Hemosiderin in the liver

Liver congenital glycogenosis

Sudan III

Liver steatosis

Fatty liver. A, Schematic diagram of the possible mechanisms leading to accumulation of triglycerides in fatty liver. Defects in any of the steps of uptake, catabolism, or secretion can result in lipid accumulation. B, High-power detail of fatty change of the liver. In most cells, the well-preserved nucleus is squeezed into the displaced rim of cytoplasm about the fat vacuole. (B, Courtesy of Dr. James Crawford, Department of Pathology, Yale University School of Medicine, New Haven, CT.)

Downloaded from: Robbins & Cotran Pathologic Basis of Disease

Hyaline degeneration of the fibrous tissue

thick, eosinophilic collagen fibers few fibroblasts

7. Pathological calcification
abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts 2 forms: dystrophic :

in injured tissues, areas of necrosis (atheroma in blood vessels, heart valves in elderly individuals, old tuberculosis lesion) normal serum levels of calcium and absence of derangements in calcium metabolism macro: as fine, white granules or clumps, often felt as gritty deposits

micro: basophilic, amorphous granular, sometimes clumped, appearance

Metastatic
deposition of calcium salts in otherwise normal tissues in hypercalcemic states principally affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins.

nephrocalcinosis

Cellular Responses to Injury

Nature and Severity of Injurious Stimulus Altered physiologic stimuli: Cellular Response Cellular adaptations:

Increased demand, increased trophic Hyperplasia, hypertrophy stimulation (e.g. growth factors, hormones) Decreased nutrients, stimulation Chronic irritation (chemical or physical) Reduced oxygen supply; chemical injury; microbial infection Atrophy Metaplasia Cell injury:

Acute and self-limited

Progessive and severe (including DNA damage)

Acute reversible injury

Irreversible injury cell death Necrosis Apoptosis

Mild chronic injury Metabolic alterations, genetic or acquired Prolonged life span with cumulative sublethal injury

Subcellular alterations in various organelles Intracellular accumulations; calcifications Cellular aging

Reaction of cells to injury

Common pathological stimuli causing cell injury

General principals regarding cellular response to the injury

Response depends on nature of injury, duration and severity Consequences of injury depend on cell type

Morphological changes detectable by MO may occur much later than functional lesion Although different agents may have different initial cellular targets, the final pathways are ofen similar

Targets of injurious stimuli

Aerobic respiration Loss of ATP Sodium pump failure water enters cell cell swells Membranes Defect in permeability water enters cell cell swells and even death Synthetic mechanism Enzymatic and structural proteins are not synthesized cell swells Genetic apparatus DNA and RNA changes Inherited or acquired If enzymes deficient substrate accumulates cell swells

Main cellular mechanism of cell injury

ATP depletion Loss of calcium homeostasis Oxidative stress (excess Reactive Oxygen Species - ROS) Damage of mitochondria and increase permeability of membrane

Downloaded from: Robbins & Cotran Pathologic Basis of Disease

Reversibile cellular
injury

generalized swelling of the cell and its organelles blebbing of the plasma membrane; detachment of ribosomes from the endoplasmic reticulum; and clumping of nuclear chromatin

Explain the differences between reversible and irreversible cell injury.

.

REVERSIBLE

IRREVERSIBLE Irreversible mitochondrial damage Massive peroxidation due to due to uncontrolled chain reaction Uncontrolled ROS; inflammation Uncontrolled calcium influx Loss of amino acids

Loss of ATP Phospholipid breakdown PLPase activation Increase in ROS Release of calcium from storage site Altered metabolism

Necrosis

Gross irreversible cellular injury Passive process since does not require gene involvement ore new protein synthesis Triggers or elicits a marked inflammatory response (liberation of lysosomal enzymes, digestion of cell mb., disruption of cells, influx of macrphages due to release of chemotactic factors an removal of debris) DNA fragmentation is haphazard with smudge pattern on electrophoresis Must be differentiated by autolysis

General and cellular characteristic

Nuclear changes:
Pyknosis the shrinkage of the nucleus into a small deeply basophylic or black clumps of chromatin Karyorrhexis a fragmentation of the nucleus into multiple small black dots or pieces Karyolysis the fading of the nucleus, less and less basophilic until it disappears

Cytoplasmic changes:
Increase pink cytoplasm (eosinophilic, glassy) less RNA Generalized swelling of organelles (ER, mitochondria) Disruption of ribosomes Autophagy (lysis of the cells own contents) Phagocytosis of deteriorating organelles by lysosomes

Types of necrosis

Coagulative necrosis Liquefactive Casseous Gangrenous Fibrinous Gummatous Fat

1. Coagulative necrosis

Most common type Cause is most often from sudden loss of blood supply to an organ (ischemia)

Heart an kidney (end arteries with limited collateral circulation) Adrenal glands

Resuls of denaturation of proteins Early stages preservation of tissue architecture Histology

General architecture well preserved Progressive nuclear condensation with eventual dissappearance of stainable nuclei Increased pink cytoplasm (eosinophilic,glassy) with ghost -like structures

Splenic infarct

Adrenal gland

Acute myocardial infarction

2. Liquefactive necrosis

Characterized by digestion of tissue Gross= affected tissue is liquified Histology: softening and liquefaction of tissue Typical of organs in which the tissues have a lot of lipid (such as brain cerebral infarct) Also in suppurative infections (pus formation)

Liquefied tissue debris and intense inflammatory response of PMN= abcess

abcess

Liquefactive necrosis in the liver

3. Caseous necrosis

Gross cheese-like (caseous) consistency Combines features of coagulative and liquefactive necrosis Histology:
Architecture not preserved Amorphous pink, granular material Few nuclei but no ghost-like appearance

Occurs as a part of granulomatous inflammation (most often seen in tuberculosis)

tuberculosis lesions

4. Gangrenous necrosis

Extensive Most often due to interaction of blood supply to lower extremities or bowel (secondary to vascular occlusion) Most often associated with bacterial infections Wet gangrene (complicated by liquefaction necrosis) Dry gangrene (coagulative necrosis without liquefaction)

dry gangrene

wet gangrene

5. Fibrinoid necrosis

Often associated with immune-mediated vasculitis Connective tissue and muscle replacement by homogenous pink material resembling fibrin

Ex: deposition of fibrin like material in the arterial walls

Histology:
Smudgy pink appearance in vascular walls Necrosis may or may not be present

Fibrinoid necrosis of placenta

6. Gummatous necrosis

Seen in granulomatous inflammation such as tertiary syphilis Gross: rubbery Histology:

No architecture Pink with few nuclei

Gumatous necrosis in liver

Tertiary siphilistypical gumma

7. Fat necrosis

Traumatic type (following severe injury to tissue with high fat content: breast) Hystology:

Necrotic fat cells, acute inflammation, hemorrhage, calcium soap formation, lipid-laden macrophages

Enzymatic type
Pancreas (complication of acute hemorrhagic pancreatitis) Proteolytic and lipolytic enzymes diffuse into the inflamed tissue of pancreatic parenchyma Can attract calciumfatty acids form calcium salts (saponification soap formation)

Apoptosis

Greek term meaning falling away from

(involutional process similar to physiological loss of leaves from a tree).

Programmed physiological cell death tha removes unwanted cells Helps to maintain homeostasis and growth in tissue Has subtle cellular damage (with enzymes causes nuclear condensation and fragmentation)

Important mechanism for the removal of cells with irreparable AND damage

by free radicals, viruses, cytotoxic immune mechanisms If fails then can lead to cancers, viral infections and autoimmune diseases

Plays a role in wound healing Also important mechanismm for physiologic cell removal during embryogenesis and in programmed cell cycling (menstruation)

Morphological features

Tendency to involve single isolated cells or small clusters

Changes which lack inflammatory response

Blebbing of plasma membrane Cytoplasmic shrinkage and increased pink staining chromatin condensation and fragmentation Budding of cell and separation of membrane-bound apoptotic bodies phagocytosis of apoptotic bodies by macrophages and adyacent normal cells

apoptosis is a dynamic process energy dependent

Summary overview of apoptotic process

http://www-medlib.med.utah.edu/WebPath/CINJHTML/CINJ054.html

Apoptosis of myocardial cells

Apoptosis of liver cells

Summary-differences between apoptosis and necrosis

APOPTOSIS

NECROSIS
cells swell and "explode" disorderly DNA fragmentation no caspase activation inflammation caused by lack of ATP

cells shrink orderly DNA fragmentation (ladders) caspase activation (cascade) no inflammation requires ATP

phagocytosis (no body)

necrotic "corps" persists