PATOLOGIA 2 RESPOSTA, ADAPTAÇAO LESAO E MORTE

Prévia do material em texto

18/03/20
1
Patologia
Conteúdo:
§ Resposta celular
§ Adaptação celular
§ Lesão celular
§ Morte celular
Profa.	
  Dra.	
  Daiani Cristina	
  Cilião Alves	
  Haddad
Ní
ve
ld
e	
  
ad
ve
rs
id
ad
e
da
s	
  c
on
di
çõ
es
(n
ív
el
de
	
  st
re
ss
	
  ce
lu
la
r,	
  
gr
av
id
ad
e
da
	
  in
jú
ria
)
Homeostase
– Função celular normal
Adaptação/alteração celular fisiológica ou
patológica,	
  pequena injúria reversível
-­‐ Função celular pouco comprometida.
Injúria irreversível,	
  morte celular
– Função celular ausente.
Fontes de	
  stress	
  celular:	
  isquemia,	
  infecção,	
  toxinas,	
  resposta imune,	
  etc.	
  	
  
PATOLOGIA	
  – Resposta	
  celular
PATOLOGIA	
  – Resposta	
  celular
Estágios na resposta celular ao estresse e estímulos nocivos.
PATOLOGIA	
  – Adaptação	
  celular
Hipertrofia e
ñ atividade funcional
Hiperplasia Atrofia
Metaplasia
Fisiológica
Patológica
Células musculares lisas
do	
  útero durante a	
  
gravidez; Cardiomiócitos em
quadro de	
  Hipertensão.
Hipertrofia:
3Cellular Adaptations to Stress
cells have a limited capacity to divide. Hypertrophy and 
hyperplasia also can occur together, and obviously both 
result in an enlarged (hypertrophic) organ.
Hypertrophy can be physiologic or pathologic and is caused 
either by increased functional demand or by growth factor 
or hormonal stimulation.
• The massive physiologic enlargement of the uterus 
during pregnancy occurs as a consequence of estrogen-
stimulated smooth muscle hypertrophy and smooth 
muscle hyperplasia (Fig. 1–3). In contrast, in response to 
increased demand the striated muscle cells in both the 
skeletal muscle and the heart can undergo only hyper-
trophy because adult muscle cells have a limited capac-
ity to divide. Therefore, the chiseled physique of the 
avid weightlifter stems solely from the hypertrophy of 
individual skeletal muscles.
• An example of pathologic cellular hypertrophy is the 
cardiac enlargement that occurs with hypertension or 
aortic valve disease (Fig. 1–2).
The mechanisms driving cardiac hypertrophy involve 
at least two types of signals: mechanical triggers, such as 
stretch, and trophic triggers, which typically are soluble 
mediators that stimulate cell growth, such as growth factors 
and adrenergic hormones. These stimuli turn on signal 
transduction pathways that lead to the induction of a 
number of genes, which in turn stimulate synthesis of 
many cellular proteins, including growth factors and struc-
tural proteins. The result is the synthesis of more proteins 
and myofilaments per cell, which increases the force gener-
ated with each contraction, enabling the cell to meet 
increased work demands. There may also be a switch of 
contractile proteins from adult to fetal or neonatal forms. 
For example, during muscle hypertrophy, the α-myosin 
heavy chain is replaced by the β form of the myosin heavy 
chain, which produces slower, more energetically econom-
ical contraction.
Whatever the exact mechanisms of hypertrophy, a limit 
is reached beyond which the enlargement of muscle mass 
clinical impact. Whether a specific form of stress induces 
adaptation or causes reversible or irreversible injury 
depends not only on the nature and severity of the stress 
but also on several other variables, including basal cellular 
metabolism and blood and nutrient supply.
In this chapter we discuss first how cells adapt to stresses 
and then the causes, mechanisms, and consequences of the 
various forms of acute cell damage, including reversible 
cell injury, subcellular alterations, and cell death. We con-
clude with three other processes that affect cells and tissues: 
intracellular accumulations, pathologic calcification, and 
cell aging.
CELLULAR ADAPTATIONS TO STRESS
Adaptations are reversible changes in the number, size, 
phenotype, metabolic activity, or functions of cells in 
response to changes in their environment. Physiologic adap-
tations usually represent responses of cells to normal stimu-
lation by hormones or endogenous chemical mediators 
(e.g., the hormone-induced enlargement of the breast and 
uterus during pregnancy). Pathologic adaptations are 
responses to stress that allow cells to modulate their struc-
ture and function and thus escape injury. Such adaptations 
can take several distinct forms.
Hypertrophy
Hypertrophy is an increase in the size of cells resulting in 
increase in the size of the organ. In contrast, hyperplasia (dis-
cussed next) is characterized by an increase in cell number 
because of proliferation of differentiated cells and replace-
ment by tissue stem cells. Stated another way, in pure 
hypertrophy there are no new cells, just bigger cells 
containing increased amounts of structural proteins and 
organelles. Hyperplasia is an adaptive response in cells 
capable of replication, whereas hypertrophy occurs when 
Figure 1–3 Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid uterus (left) that 
was removed for postpartum bleeding. B, Small spindle-shaped uterine smooth muscle cells from a normal uterus. C, Large, plump hypertrophied 
smooth muscle cells from a gravid uterus; compare with B. (B and C, Same magnification.) 
A B C
C H A P T E R 1 Cell Injury, Cell Death, and Adaptations2
Figure 1–1 Stages in the cellular response to stress and injurious stimuli. 
NORMAL CELL
(homeostasis)
ADAPTATION
Stress
Inability
to adapt
CELL INJURY
Injurious
stimulus
Mild,
transient
Severe,
progressive
REVERSIBLE
INJURY
IRREVERSIBLE
INJURY
CELL
DEATHNECROSIS APOPTOSIS
Figure 1–2 The relationship among normal, adapted, reversibly injured, and dead myocardial cells. The cellular adaptation depicted here is hypertrophy, 
the type of reversible injury is ischemia, and the irreversible injury is ischemic coagulative necrosis. In the example of myocardial hypertrophy (lower 
left), the left ventricular wall is thicker than 2 cm (normal, 1–1.5 cm). Reversibly injured myocardium shows functional effects without any gross or light 
microscopic changes, or reversible changes like cellular swelling and fatty change (shown here). In the specimen showing necrosis (lower right) the trans-
mural light area in the posterolateral left ventricle represents an acute myocardial infarction. All three transverse sections of myocardium have been 
stained with triphenyltetrazolium chloride, an enzyme substrate that colors viable myocardium magenta. Failure to stain is due to enzyme loss after cell 
death. 
Cell death
Reversibly injured
myocyte
Cell injury
Normal myocyte
Adapted
myocyte
(hypertrophy)
Adaptation:
response to
increased load
adaptation, achieving a new steady state and preserving 
viability and function. The principal adaptive responses 
are hypertrophy, hyperplasia, atrophy, and metaplasia. If the 
adaptive capability is exceeded or if the external stress is 
inherently harmful, cell injury develops (Fig. 1–1). Within 
certain limits, injury is reversible, and cells return to a stable 
baseline; however, if the stress is severe, persistent and 
rapid in onset, it results in irreversible injury and death of 
the affected cells. Cell death is one of the most crucial events 
in the evolution of disease in any tissue or organ. It results 
from diverse causes, including ischemia (lack of blood 
flow), infections, toxins, and immune reactions. Cell death 
also is a normal and essential process in embryogenesis, 
the development of organs, and the maintenance of 
homeostasis.
The relationships among normal, adapted, and revers-
ibly and irreversibly injured cells are well illustrated by the 
responses of the heart to different types of stress (Fig. 1–2). 
Myocardium subjected to persistent increased load, as in 
hypertension or with a narrowed (stenotic) valve, adapts 
by undergoing hypertrophy—an increase in the size of the 
individual cells and ultimately the entire heart—to gener-
ate the required higher contractile force. If the increased 
demandis not relieved, or if the myocardium is subjected 
to reduced blood flow (ischemia) from an occluded coro-
nary artery, the muscle cells may undergo injury. Myocar-
dium may be reversibly injured if the stress is mild or the 
arterial occlusion is incomplete or sufficiently brief, or it 
may undergo irreversible injury and cell death (infarction) 
after complete or prolonged occlusion. Also of note, stresses 
and injury affect not only the morphology but also the 
functional status of cells and tissues. Thus, reversibly 
injured myocytes are not dead and may resemble normal 
myocytes morphologically; however, they are transiently 
noncontractile, so even mild injury can have a significant 
Hipertensão,	
  válvula
estenótica
Infarto agudo
do	
  miocárdio,
PATOLOGIA	
  – Adaptação	
  celular
Fisiológica
Patológica
-­‐ FISIOLÓGICA HORMONAL:
Hiperplasia do	
  epitélio
glandular	
  da mama	
  durante
a	
  puberdade e gravidez.
-­‐ FISIOLÓGICA
COMPENSATÓRIA:
Hepatócitos após
hepatectomia
Hiperplasia:
Hepatectomia
Hiperplasia
fisiológica
compensatória
(hepatócitos)
Cirrose hepática
Hiperplasia
patológica
(fibroblastos)
PATOLOGIA	
  – Adaptação	
  celular
18/03/20
2
Fisiológica
Patológica
Útero diminui de	
  
tamanho logo	
  após
o parto.
Ateroscletorse leva a	
  
diminuição do	
  
suprimento sanguíneo.
Atrofia:
C H A P T E R 1 Cell Injury, Cell Death, and Adaptations4
after a normal menstrual period there is a burst of 
uterine epithelial proliferation that is normally tightly 
regulated by stimulation through pituitary hormones 
and ovarian estrogen and by inhibition through proges-
terone. However, a disturbed balance between estrogen 
and progesterone causes endometrial hyperplasia, 
which is a common cause of abnormal menstrual 
bleeding. Hyperplasia also is an important response of 
connective tissue cells in wound healing, in which pro-
liferating fibroblasts and blood vessels aid in repair 
(Chapter 2). In this process, growth factors are produced 
by white blood cells (leukocytes) responding to the 
injury and by cells in the extracellular matrix. Stimula-
tion by growth factors also is involved in the hyperplasia 
that is associated with certain viral infections; for 
example, papillomaviruses cause skin warts and mucosal 
lesions composed of masses of hyperplastic epithelium. 
Here the growth factors may be encoded by viral genes 
or by the genes of the infected host cells.
An important point is that in all of these situations, the 
hyperplastic process remains controlled; if the signals that initi-
ate it abate, the hyperplasia disappears. It is this responsiveness 
to normal regulatory control mechanisms that distin-
guishes pathologic hyperplasias from cancer, in which the 
growth control mechanisms become dysregulated or inef-
fective (Chapter 5). Nevertheless, in many cases, pathologic 
hyperplasia constitutes a fertile soil in which cancers may 
eventually arise. For example, patients with hyperplasia of 
the endometrium are at increased risk of developing endo-
metrial cancer (Chapter 18).
Atrophy
Shrinkage in the size of the cell by the loss of cell substance is 
known as atrophy. When a sufficient number of cells are 
involved, the entire tissue or organ diminishes in size, 
becoming atrophic (Fig. 1–4). Although atrophic cells may 
have diminished function, they are not dead.
Causes of atrophy include a decreased workload (e.g., 
immobilization of a limb to permit healing of a fracture), 
can no longer compensate for the increased burden. When 
this happens in the heart, several “degenerative” changes 
occur in the myocardial fibers, of which the most important 
are fragmentation and loss of myofibrillar contractile ele-
ments. The variables that limit continued hypertrophy and 
cause the regressive changes are incompletely understood. 
There may be finite limits of the vasculature to adequately 
supply the enlarged fibers, of the mitochondria to supply 
adenosine triphosphate (ATP), or of the biosynthetic 
machinery to provide the contractile proteins or other cyto-
skeletal elements. The net result of these changes is ven-
tricular dilation and ultimately cardiac failure, a sequence 
of events that illustrates how an adaptation to stress can 
progress to functionally significant cell injury if the stress is not 
relieved.
Hyperplasia
As discussed earlier, hyperplasia takes place if the tissue 
contains cell populations capable of replication; it may 
occur concurrently with hypertrophy and often in response 
to the same stimuli.
Hyperplasia can be physiologic or pathologic. In both situa-
tions, cellular proliferation is stimulated by growth factors 
that are produced by a variety of cell types.
• The two types of physiologic hyperplasia are (1) hormonal 
hyperplasia, exemplified by the proliferation of the glan-
dular epithelium of the female breast at puberty and 
during pregnancy, and (2) compensatory hyperplasia, in 
which residual tissue grows after removal or loss of part 
of an organ. For example, when part of a liver is resected, 
mitotic activity in the remaining cells begins as early as 
12 hours later, eventually restoring the liver to its normal 
weight. The stimuli for hyperplasia in this setting are 
polypeptide growth factors produced by uninjured 
hepatocytes as well as nonparenchymal cells in the liver 
(Chapter 2). After restoration of the liver mass, cell pro-
liferation is “turned off” by various growth inhibitors.
• Most forms of pathologic hyperplasia are caused by exces-
sive hormonal or growth factor stimulation. For example, 
Figure 1–4 Atrophy as seen in the brain. A, Normal brain of a young adult. B, Atrophy of the brain in an 82-year-old man with atherosclerotic 
disease. Atrophy of the brain is due to aging and reduced blood supply. Note that loss of brain substance narrows the gyri and widens the sulci. The 
meninges have been stripped from the bottom half of each specimen to reveal the surface of the brain. 
BA
Adulto	
  jovem Idoso	
  (82	
  anos)
3Cellular Adaptations to Stress
cells have a limited capacity to divide. Hypertrophy and 
hyperplasia also can occur together, and obviously both 
result in an enlarged (hypertrophic) organ.
Hypertrophy can be physiologic or pathologic and is caused 
either by increased functional demand or by growth factor 
or hormonal stimulation.
• The massive physiologic enlargement of the uterus 
during pregnancy occurs as a consequence of estrogen-
stimulated smooth muscle hypertrophy and smooth 
muscle hyperplasia (Fig. 1–3). In contrast, in response to 
increased demand the striated muscle cells in both the 
skeletal muscle and the heart can undergo only hyper-
trophy because adult muscle cells have a limited capac-
ity to divide. Therefore, the chiseled physique of the 
avid weightlifter stems solely from the hypertrophy of 
individual skeletal muscles.
• An example of pathologic cellular hypertrophy is the 
cardiac enlargement that occurs with hypertension or 
aortic valve disease (Fig. 1–2).
The mechanisms driving cardiac hypertrophy involve 
at least two types of signals: mechanical triggers, such as 
stretch, and trophic triggers, which typically are soluble 
mediators that stimulate cell growth, such as growth factors 
and adrenergic hormones. These stimuli turn on signal 
transduction pathways that lead to the induction of a 
number of genes, which in turn stimulate synthesis of 
many cellular proteins, including growth factors and struc-
tural proteins. The result is the synthesis of more proteins 
and myofilaments per cell, which increases the force gener-
ated with each contraction, enabling the cell to meet 
increased work demands. There may also be a switch of 
contractile proteins from adult to fetal or neonatal forms. 
For example, during muscle hypertrophy, the α-myosin 
heavy chain is replaced by the β form of the myosin heavy 
chain, which produces slower, more energetically econom-
ical contraction.
Whatever the exact mechanisms of hypertrophy,a limit 
is reached beyond which the enlargement of muscle mass 
clinical impact. Whether a specific form of stress induces 
adaptation or causes reversible or irreversible injury 
depends not only on the nature and severity of the stress 
but also on several other variables, including basal cellular 
metabolism and blood and nutrient supply.
In this chapter we discuss first how cells adapt to stresses 
and then the causes, mechanisms, and consequences of the 
various forms of acute cell damage, including reversible 
cell injury, subcellular alterations, and cell death. We con-
clude with three other processes that affect cells and tissues: 
intracellular accumulations, pathologic calcification, and 
cell aging.
CELLULAR ADAPTATIONS TO STRESS
Adaptations are reversible changes in the number, size, 
phenotype, metabolic activity, or functions of cells in 
response to changes in their environment. Physiologic adap-
tations usually represent responses of cells to normal stimu-
lation by hormones or endogenous chemical mediators 
(e.g., the hormone-induced enlargement of the breast and 
uterus during pregnancy). Pathologic adaptations are 
responses to stress that allow cells to modulate their struc-
ture and function and thus escape injury. Such adaptations 
can take several distinct forms.
Hypertrophy
Hypertrophy is an increase in the size of cells resulting in 
increase in the size of the organ. In contrast, hyperplasia (dis-
cussed next) is characterized by an increase in cell number 
because of proliferation of differentiated cells and replace-
ment by tissue stem cells. Stated another way, in pure 
hypertrophy there are no new cells, just bigger cells 
containing increased amounts of structural proteins and 
organelles. Hyperplasia is an adaptive response in cells 
capable of replication, whereas hypertrophy occurs when 
Figure 1–3 Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid uterus (left) that 
was removed for postpartum bleeding. B, Small spindle-shaped uterine smooth muscle cells from a normal uterus. C, Large, plump hypertrophied 
smooth muscle cells from a gravid uterus; compare with B. (B and C, Same magnification.) 
A B C
3Cellular Adaptations to Stress
cells have a limited capacity to divide. Hypertrophy and 
hyperplasia also can occur together, and obviously both 
result in an enlarged (hypertrophic) organ.
Hypertrophy can be physiologic or pathologic and is caused 
either by increased functional demand or by growth factor 
or hormonal stimulation.
• The massive physiologic enlargement of the uterus 
during pregnancy occurs as a consequence of estrogen-
stimulated smooth muscle hypertrophy and smooth 
muscle hyperplasia (Fig. 1–3). In contrast, in response to 
increased demand the striated muscle cells in both the 
skeletal muscle and the heart can undergo only hyper-
trophy because adult muscle cells have a limited capac-
ity to divide. Therefore, the chiseled physique of the 
avid weightlifter stems solely from the hypertrophy of 
individual skeletal muscles.
• An example of pathologic cellular hypertrophy is the 
cardiac enlargement that occurs with hypertension or 
aortic valve disease (Fig. 1–2).
The mechanisms driving cardiac hypertrophy involve 
at least two types of signals: mechanical triggers, such as 
stretch, and trophic triggers, which typically are soluble 
mediators that stimulate cell growth, such as growth factors 
and adrenergic hormones. These stimuli turn on signal 
transduction pathways that lead to the induction of a 
number of genes, which in turn stimulate synthesis of 
many cellular proteins, including growth factors and struc-
tural proteins. The result is the synthesis of more proteins 
and myofilaments per cell, which increases the force gener-
ated with each contraction, enabling the cell to meet 
increased work demands. There may also be a switch of 
contractile proteins from adult to fetal or neonatal forms. 
For example, during muscle hypertrophy, the α-myosin 
heavy chain is replaced by the β form of the myosin heavy 
chain, which produces slower, more energetically econom-
ical contraction.
Whatever the exact mechanisms of hypertrophy, a limit 
is reached beyond which the enlargement of muscle mass 
clinical impact. Whether a specific form of stress induces 
adaptation or causes reversible or irreversible injury 
depends not only on the nature and severity of the stress 
but also on several other variables, including basal cellular 
metabolism and blood and nutrient supply.
In this chapter we discuss first how cells adapt to stresses 
and then the causes, mechanisms, and consequences of the 
various forms of acute cell damage, including reversible 
cell injury, subcellular alterations, and cell death. We con-
clude with three other processes that affect cells and tissues: 
intracellular accumulations, pathologic calcification, and 
cell aging.
CELLULAR ADAPTATIONS TO STRESS
Adaptations are reversible changes in the number, size, 
phenotype, metabolic activity, or functions of cells in 
response to changes in their environment. Physiologic adap-
tations usually represent responses of cells to normal stimu-
lation by hormones or endogenous chemical mediators 
(e.g., the hormone-induced enlargement of the breast and 
uterus during pregnancy). Pathologic adaptations are 
responses to stress that allow cells to modulate their struc-
ture and function and thus escape injury. Such adaptations 
can take several distinct forms.
Hypertrophy
Hypertrophy is an increase in the size of cells resulting in 
increase in the size of the organ. In contrast, hyperplasia (dis-
cussed next) is characterized by an increase in cell number 
because of proliferation of differentiated cells and replace-
ment by tissue stem cells. Stated another way, in pure 
hypertrophy there are no new cells, just bigger cells 
containing increased amounts of structural proteins and 
organelles. Hyperplasia is an adaptive response in cells 
capable of replication, whereas hypertrophy occurs when 
Figure 1–3 Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid uterus (left) that 
was removed for postpartum bleeding. B, Small spindle-shaped uterine smooth muscle cells from a normal uterus. C, Large, plump hypertrophied 
smooth muscle cells from a gravid uterus; compare with B. (B and C, Same magnification.) 
A B C
3Cellular Adaptations to Stress
cells have a limited capacity to divide. Hypertrophy and 
hyperplasia also can occur together, and obviously both 
result in an enlarged (hypertrophic) organ.
Hypertrophy can be physiologic or pathologic and is caused 
either by increased functional demand or by growth factor 
or hormonal stimulation.
• The massive physiologic enlargement of the uterus 
during pregnancy occurs as a consequence of estrogen-
stimulated smooth muscle hypertrophy and smooth 
muscle hyperplasia (Fig. 1–3). In contrast, in response to 
increased demand the striated muscle cells in both the 
skeletal muscle and the heart can undergo only hyper-
trophy because adult muscle cells have a limited capac-
ity to divide. Therefore, the chiseled physique of the 
avid weightlifter stems solely from the hypertrophy of 
individual skeletal muscles.
• An example of pathologic cellular hypertrophy is the 
cardiac enlargement that occurs with hypertension or 
aortic valve disease (Fig. 1–2).
The mechanisms driving cardiac hypertrophy involve 
at least two types of signals: mechanical triggers, such as 
stretch, and trophic triggers, which typically are soluble 
mediators that stimulate cell growth, such as growth factors 
and adrenergic hormones. These stimuli turn on signal 
transduction pathways that lead to the induction of a 
number of genes, which in turn stimulate synthesis of 
many cellular proteins, including growth factors and struc-
tural proteins. The result is the synthesis of more proteins 
and myofilaments percell, which increases the force gener-
ated with each contraction, enabling the cell to meet 
increased work demands. There may also be a switch of 
contractile proteins from adult to fetal or neonatal forms. 
For example, during muscle hypertrophy, the α-myosin 
heavy chain is replaced by the β form of the myosin heavy 
chain, which produces slower, more energetically econom-
ical contraction.
Whatever the exact mechanisms of hypertrophy, a limit 
is reached beyond which the enlargement of muscle mass 
clinical impact. Whether a specific form of stress induces 
adaptation or causes reversible or irreversible injury 
depends not only on the nature and severity of the stress 
but also on several other variables, including basal cellular 
metabolism and blood and nutrient supply.
In this chapter we discuss first how cells adapt to stresses 
and then the causes, mechanisms, and consequences of the 
various forms of acute cell damage, including reversible 
cell injury, subcellular alterations, and cell death. We con-
clude with three other processes that affect cells and tissues: 
intracellular accumulations, pathologic calcification, and 
cell aging.
CELLULAR ADAPTATIONS TO STRESS
Adaptations are reversible changes in the number, size, 
phenotype, metabolic activity, or functions of cells in 
response to changes in their environment. Physiologic adap-
tations usually represent responses of cells to normal stimu-
lation by hormones or endogenous chemical mediators 
(e.g., the hormone-induced enlargement of the breast and 
uterus during pregnancy). Pathologic adaptations are 
responses to stress that allow cells to modulate their struc-
ture and function and thus escape injury. Such adaptations 
can take several distinct forms.
Hypertrophy
Hypertrophy is an increase in the size of cells resulting in 
increase in the size of the organ. In contrast, hyperplasia (dis-
cussed next) is characterized by an increase in cell number 
because of proliferation of differentiated cells and replace-
ment by tissue stem cells. Stated another way, in pure 
hypertrophy there are no new cells, just bigger cells 
containing increased amounts of structural proteins and 
organelles. Hyperplasia is an adaptive response in cells 
capable of replication, whereas hypertrophy occurs when 
Figure 1–3 Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid uterus (left) that 
was removed for postpartum bleeding. B, Small spindle-shaped uterine smooth muscle cells from a normal uterus. C, Large, plump hypertrophied 
smooth muscle cells from a gravid uterus; compare with B. (B and C, Same magnification.) 
A B C
PATOLOGIA	
  – Adaptação	
  celular
Metaplasia:
5Cellular Adaptations to Stress
epithelium. Metaplasia need not always occur in the direc-
tion of columnar to squamous epithelium; in chronic gastric 
reflux, the normal stratified squamous epithelium of the 
lower esophagus may undergo metaplastic transformation 
to gastric or intestinal-type columnar epithelium. Metapla-
sia may also occur in mesenchymal cells but in these situ-
ations it is generally a reaction to some pathologic alteration 
and not an adaptive response to stress. For example, bone 
is occasionally formed in soft tissues, particularly in foci of 
injury.
loss of innervation, diminished blood supply, inadequate 
nutrition, loss of endocrine stimulation, and aging (senile 
atrophy). Although some of these stimuli are physiologic 
(e.g., the loss of hormone stimulation in menopause) and 
others pathologic (e.g., denervation), the fundamental cel-
lular changes are identical. They represent a retreat by the 
cell to a smaller size at which survival is still possible; a 
new equilibrium is achieved between cell size and dimin-
ished blood supply, nutrition, or trophic stimulation.
The mechanisms of atrophy consist of a combination of 
decreased protein synthesis and increased protein degradation 
in cells.
• Protein synthesis decreases because of reduced meta-
bolic activity.
• The degradation of cellular proteins occurs mainly by 
the ubiquitin-proteasome pathway. Nutrient deficiency and 
disuse may activate ubiquitin ligases, which attach mul-
tiple copies of the small peptide ubiquitin to cellular 
proteins and target them for degradation in protea-
somes. This pathway is also thought to be responsible 
for the accelerated proteolysis seen in a variety of cata-
bolic conditions, including the cachexia associated with 
cancer.
• In many situations, atrophy is also accompanied by 
increased autophagy, with resulting increases in the 
number of autophagic vacuoles. Autophagy (“self-eating”) 
is the process in which the starved cell eats its own 
components in an attempt to survive. We describe this 
process later in the chapter.
Metaplasia
Metaplasia is a reversible change in which one adult cell type 
(epithelial or mesenchymal) is replaced by another adult cell type. 
In this type of cellular adaptation, a cell type sensitive to a 
particular stress is replaced by another cell type better able 
to withstand the adverse environment. Metaplasia is 
thought to arise by reprogramming of stem cells to differ-
entiate along a new pathway rather than a phenotypic 
change (transdifferentiation) of already differentiated cells.
Epithelial metaplasia is exemplified by the squamous 
change that occurs in the respiratory epithelium of habitual 
cigarette smokers (Fig. 1–5). The normal ciliated columnar 
epithelial cells of the trachea and bronchi are focally or 
widely replaced by stratified squamous epithelial cells. The 
rugged stratified squamous epithelium may be able to 
survive the noxious chemicals in cigarette smoke that the 
more fragile specialized epithelium would not tolerate. 
Although the metaplastic squamous epithelium has survival 
advantages, important protective mechanisms are lost, such as 
mucus secretion and ciliary clearance of particulate matter. 
Epithelial metaplasia is therefore a double-edged sword. 
Moreover, the influences that induce metaplastic change, if per-
sistent, may predispose to malignant transformation of the epi-
thelium. In fact, squamous metaplasia of the respiratory 
epithelium often coexists with lung cancers composed of 
malignant squamous cells. It is thought that cigarette 
smoking initially causes squamous metaplasia, and cancers 
arise later in some of these altered foci. Since vitamin A is 
essential for normal epithelial differentiation, its deficiency 
may also induce squamous metaplasia in the respiratory 
Figure 1–5 Metaplasia of normal columnar (left) to squamous epithe-
lium (right) in a bronchus, shown schematically (A) and histologically (B). 
B
Normal
columnar
epithelium
Basement
membrane
Squamous
metaplasia
A
SUMMARY
Cellular Adaptations to Stress
• Hypertrophy: increased cell and organ size, often in 
response to increased workload; induced by growth 
factors produced in response to mechanical stress or 
other stimuli; occurs in tissues incapable of cell division
• Hyperplasia: increased cell numbers in response to hor-
mones and other growth factors; occurs in tissues whose 
cells are able to divide or contain abundant tissue stem 
cells
• Atrophy: decreased cell and organ size, as a result of 
decreased nutrient supply or disuse; associated with 
decreased synthesis of cellular building blocks and 
increased breakdown of cellular organelles
• Metaplasia: change in phenotype of differentiated cells, 
often in response to chronic irritation, that makes cells 
better able to withstand the stress; usually induced by 
altered differentiation pathway of tissue stem cells; may 
result in reduced functions or increased propensity for 
malignant transformation
Metaplasia do	
  epitélio colunar
(à esquerda)	
  para epitélio
escamoso (à direita)	
  em um	
  
brônquio.
PATOLOGIA	
  – Adaptação	
  celular
Lesão celular:
§ Causas
§ Características bioquimicas e	
  morfológicas
§ Mecanismos
PATOLOGIA	
  – Lesão	
  emorte	
  celular
Estágios na resposta
celular ao estresse e	
  
estímulos nocivos:
Lesão
celular
Hipóxia
Agentes
químicos
Agentes
infecciosos
Resposta
imunológica
Fatores
genéticos
Desbalanço	
  
nutricional
Agentes	
  
físicos
Envelheci-­‐
mento
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Causas	
  das	
  lesões	
  celulares
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Características bioquímicas e	
  morfológicas na	
  lesão	
  celular
§ A lesão celular é resultante de diferentesmecanismos bioquímicos
que agem em vários componentes celulares essenciais.
§ Componentes celulares mais frequentemente lesados por
estímulos nocivos:
ü Mitocôndrias,
ü Membranas celulares,
ü Maquinaria de síntese e empacotamento de proteínas,
ü DNA.
§ Qualquer estímulo nocivo pode, simultaneamente, iniciar
múltiplos mecanismos que lesam as células.
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Mecanismos da lesão celular:
18/03/20
3
Mecanismos de	
  lesão celular:	
  
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
ERO:	
  Espécies	
  reativas	
  de	
  oxigênio.	
  
Mecanismos de	
  lesão celular:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Depleção de ATP:
§ Principais causas de depleção de ATP:
• Redução de oxigênio e nutrientes,
• Danos mitocondriais,
• Ação de algumas toxinas (ex., cianeto).
§ Célula se torna incapaz de realizar funções que
dependem de ATP.
§ A privação de O2 ou glicose, pode levar a injúria
reversível, e se o quadro se manter, ocorre necrose.
§ Produção de ATP (mitocôndria): -­‐ fosforilação oxidativa
-­‐ via glicolítica
Mecanismos de	
  lesão celular:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Depleção de ATP:
Consequências morfológicas
e funcionais da diminuição
de ATP intracelular durante a
lesão.
Mecanismos de	
  lesão celular:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Dano Mitocondrial:
§ Danificadas por:
• éCa2+	
  citosólico,
• ERO,
• ê Oxigênio,	
  
• Mutações nos genes	
  
mitocondriais.	
  
§ Quadro pode evoluir:
• Depleção de ATP, levando a
necrose.
• Vazamento de proteínas
mitocondriais levando a apoptose.
Extravasamento	
  
de	
  proteínas	
  
pró-­‐apoptóticas
Mecanismos de	
  lesão celular:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Influxo de Cálcio:
§ Cálcio: normalmente mais
concentrado fora da célula, ou
dentro de organelas como o
retículo endoplasmático.
§ Lesões: ativa enzimas diversas:
• Danificam a célula e seus
componentes.
• Ativam a via apoptótica.
Mecanismos de	
  lesão celular:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Acúmulo de ERO (stress oxidativo):
§ Modificação covalente de proteínas,
lipídeos e ácidos nucléicos.
§ Lesão celular e morte por necrose ou
apoptose.
ERO (radical livre derivado do oxigênio/ Espécies reativas de
oxigênio):
§ Produzidos: normalmente nas células durante a respiração e
geração de energia mitocondrial.
§ Degradados e removidos: pelas celulas de defesa.
18/03/20
4
Mecanismos de	
  lesão celular:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Aumento da permeabilidade das
membranas celulares:
§ Afeta membranas: plasmáticas,
lisossomais, mitocondriais.
§ Geralmente leva a necrose mas pode
ocorrer apoptose.
Mecanismos de	
  lesão celular:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Acúmulo de danos ao DNA e proteínas
anormalmente dobradas:
§ Ativação da apoptose.
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Morte	
  celular	
  
Necrose:
C H A P T E R 1 Cell Injury, Cell Death, and Adaptations6
cell, resulting in necrosis. Cellular contents also leak 
through the damaged plasma membrane into the extra-
cellular space, where they elicit a host reaction (inflam-
mation). Necrosis is the major pathway of cell death in 
many commonly encountered injuries, such as those 
resulting from ischemia, exposure to toxins, various 
infections, and trauma. When a cell is deprived of 
growth factors, or the cell’s DNA or proteins are 
damaged beyond repair, typically the cell kills itself by 
another type of death, called apoptosis, which is charac-
terized by nuclear dissolution without complete loss of 
membrane integrity. Whereas necrosis is always a patho-
logic process, apoptosis serves many normal functions and is 
not necessarily associated with pathologic cell injury. Further-
more, in keeping with its role in certain physiologic processes, 
apoptosis does not elicit an inflammatory response. The mor-
phologic features, mechanisms, and significance of these 
two death pathways are discussed in more detail later 
in the chapter.
CAUSES OF CELL INJURY
The causes of cell injury range from the gross physical 
trauma of a motor vehicle accident to the single gene defect 
that results in a nonfunctional enzyme underlying a 
Figure 1–6 Cellular features of necrosis (left) and apoptosis (right). 
Apoptotic
body
Condensation
of chromatin
Membrane blebs
Phagocyte Phagocytosisof apoptotic cells
and fragments
Reversible
injury
Progressive
injury
Inflammation
Recovery
NORMAL
CELL
NORMAL
CELL
NECROSIS
APOPTOSIS
Swelling of
endoplasmic
reticulum and
mitochondria
Membrane blebs
Myelin
figures
Amorphous densities
in mitochondria
Breakdown of
plasma membrane,
organelles, and
nucleus; leakage
of contents
Cellular
fragmentation
Myelin
figure
OVERVIEW OF CELL INJURY 
AND CELL DEATH
As stated at the beginning of the chapter, cell injury results 
when cells are stressed so severely that they are no longer 
able to adapt or when cells are exposed to inherently dam-
aging agents or suffer from intrinsic abnormalities (e.g., in 
DNA or proteins). Different injurious stimuli affect many 
metabolic pathways and cellular organelles. Injury may 
progress through a reversible stage and culminate in cell 
death (Fig. 1–1).
• Reversible cell injury. In early stages or mild forms of 
injury the functional and morphologic changes are 
reversible if the damaging stimulus is removed. At this 
stage, although there may be significant structural and 
functional abnormalities, the injury has typically not 
progressed to severe membrane damage and nuclear 
dissolution.
• Cell death. With continuing damage, the injury becomes 
irreversible, at which time the cell cannot recover and 
it dies. There are two types of cell death—necrosis and 
apoptosis—which differ in their mechanisms, morphology, 
and roles in disease and physiology (Fig. 1–6 and Table 1–1). 
When damage to membranes is severe, enzymes leak 
out of lysosomes, enter the cytoplasm, and digest the 
Tumefação generalizada da
célula e suas organelas
Bolhas na membrana plasmática
Densidades	
  	
  amorfas	
  na	
  mitocôndria
Rompimento	
  das	
  membranas	
  
do	
  núcleo,	
  das	
  organelas	
  e	
  
plasmática	
  e	
  extravasamento	
  
de	
  conteúdo
Alterações
morfológicas da	
  lesão
celular que	
  culminam
em necrose:
Inflamação
Recuperação
Injúria
reverssível
Figuras	
  	
  de	
  	
  
mielina
Injúria
progressiva
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
C H A P T E R 1 Cell Injury, Cell Death, and Adaptations6
cell, resulting in necrosis. Cellular contents also leak 
through the damaged plasma membrane into the extra-
cellular space, where they elicit a host reaction (inflam-
mation). Necrosis is the major pathway of cell death in 
many commonly encountered injuries, such as those 
resulting from ischemia, exposure to toxins, various 
infections, and trauma. When a cell is deprived of 
growth factors, or the cell’s DNA or proteins are 
damaged beyond repair, typically the cell kills itself by 
another type of death, called apoptosis, which is charac-
terized by nuclear dissolution without complete loss of 
membrane integrity. Whereas necrosis is always a patho-
logic process, apoptosis serves many normal functions and is 
not necessarily associated with pathologic cell injury. Further-
more, in keeping with its role in certain physiologic processes, 
apoptosis does not elicit an inflammatory response. The mor-
phologic features, mechanisms, and significance of thesetwo death pathways are discussed in more detail later 
in the chapter.
CAUSES OF CELL INJURY
The causes of cell injury range from the gross physical 
trauma of a motor vehicle accident to the single gene defect 
that results in a nonfunctional enzyme underlying a 
Figure 1–6 Cellular features of necrosis (left) and apoptosis (right). 
Apoptotic
body
Condensation
of chromatin
Membrane blebs
Phagocyte Phagocytosisof apoptotic cells
and fragments
Reversible
injury
Progressive
injury
Inflammation
Recovery
NORMAL
CELL
NORMAL
CELL
NECROSIS
APOPTOSIS
Swelling of
endoplasmic
reticulum and
mitochondria
Membrane blebs
Myelin
figures
Amorphous densities
in mitochondria
Breakdown of
plasma membrane,
organelles, and
nucleus; leakage
of contents
Cellular
fragmentation
Myelin
figure
OVERVIEW OF CELL INJURY 
AND CELL DEATH
As stated at the beginning of the chapter, cell injury results 
when cells are stressed so severely that they are no longer 
able to adapt or when cells are exposed to inherently dam-
aging agents or suffer from intrinsic abnormalities (e.g., in 
DNA or proteins). Different injurious stimuli affect many 
metabolic pathways and cellular organelles. Injury may 
progress through a reversible stage and culminate in cell 
death (Fig. 1–1).
• Reversible cell injury. In early stages or mild forms of 
injury the functional and morphologic changes are 
reversible if the damaging stimulus is removed. At this 
stage, although there may be significant structural and 
functional abnormalities, the injury has typically not 
progressed to severe membrane damage and nuclear 
dissolution.
• Cell death. With continuing damage, the injury becomes 
irreversible, at which time the cell cannot recover and 
it dies. There are two types of cell death—necrosis and 
apoptosis—which differ in their mechanisms, morphology, 
and roles in disease and physiology (Fig. 1–6 and Table 1–1). 
When damage to membranes is severe, enzymes leak 
out of lysosomes, enter the cytoplasm, and digest the 
Morte	
  celular	
  
Apoptose:
Alterações morfológicas
da	
  lesão celular que	
  
culminam em apoptose.
Bolhas na membrana plasmática
Condensação da cromatina
Corpos apoptóticos
Fagócito Fagocitose da célula e
corpos apoptóticos
Fragmentação celular
Lesão
reversível
Eventos
limiares
Lesão
irreversível
(Necrose)
•Inchaço;
•Alterações na membrana plasmática (bolhas e distorções);
•Alterações mitocondriais (edema, densidades amorfas);
•Acúmulo de vacúolos lipídicos;
•Hipertrofia do RE (separação e desagregação de polissomos)
•Disfunção mitocondrial;
•Rompimento da membrana plasmática.
•Extravasamento	
  de	
  conteúdo	
  celular;
•Inflamação;
•Eosinofilia	
  citoplasmática;
•Citoplasma	
  vacuolado;
•Cariólise;
•Picnose;
•Cariorréxis
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Características morfológicas das	
  lesões	
  celulares
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Necrose – alterações nucleares
Características morfológicas das	
  lesões	
  celulares
18/03/20
5
De	
  
Coagulação
De	
  
Liquefação
Caseosa Gordurosa
Fibrinoide
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Necrose
Necrose:
Características morfológicas das	
  lesões	
  celulares
Lítica:	
  hepatite	
  viral
Gomosa:	
  sífilis	
  tardia
Gangrenosa:	
  membros
Esteatonecrose:	
  adipócitos
C H A P T E R 1 Cell Injury, Cell Death, and Adaptations10
B
I
N
A
Figure 1–9 Coagulative necrosis. A, A wedge-shaped kidney infarct (yellow) with preservation of the outlines. B, Microscopic view of the edge of 
the infarct, with normal kidney (N) and necrotic cells in the infarct (I). The necrotic cells show preserved outlines with loss of nuclei, and an inflamma-
tory infiltrate is present (difficult to discern at this magnification). 
Figure 1–10 Liquefactive necrosis. An infarct in the brain showing 
dissolution of the tissue. 
MORPHOLOGY
• Coagulative necrosis is a form of necrosis in which the 
underlying tissue architecture is preserved for at least 
several days (Fig. 1–9). The affected tissues take on a firm 
texture. Presumably the injury denatures not only struc-
tural proteins but also enzymes, thereby blocking the pro-
teolysis of the dead cells; as a result, eosinophilic, anucleate 
cells may persist for days or weeks. Leukocytes are 
recruited to the site of necrosis, and the dead cells are 
digested by the action of lysosomal enzymes of the leu-
kocytes. The cellular debris is then removed by phagocy-
tosis. Coagulative necrosis is characteristic of infarcts 
(areas of ischemic necrosis) in all of the solid organs 
except the brain.
• Liquefactive necrosis is seen in focal bacterial or, 
occasionally, fungal infections, because microbes stimulate 
the accumulation of inflammatory cells and the enzymes 
of leukocytes digest (“liquefy”) the tissue. For obscure 
reasons, hypoxic death of cells within the central nervous 
system often evokes liquefactive necrosis (Fig. 1–10). 
Whatever the pathogenesis, the dead cells are completely 
digested, transforming the tissue into a liquid viscous mass. 
Eventually, the digested tissue is removed by phagocytes. 
If the process was initiated by acute inflammation, as in a 
bacterial infection, the material is frequently creamy yellow 
and is called pus (Chapter 2).
• Although gangrenous necrosis is not a distinctive 
pattern of cell death, the term is still commonly used in 
clinical practice. It usually refers to the condition of a limb, 
generally the lower leg, that has lost its blood supply and 
has undergone coagulative necrosis involving multiple 
tissue layers. When bacterial infection is superimposed, 
coagulative necrosis is modified by the liquefactive action 
of the bacteria and the attracted leukocytes (resulting in 
so-called wet gangrene).
• Caseous necrosis is encountered most often in foci of 
tuberculous infection. Caseous means “cheese-like,” 
referring to the friable yellow-white appearance of the 
area of necrosis (Fig. 1–11). On microscopic examination, 
the necrotic focus appears as a collection of fragmented 
or lysed cells with an amorphous granular pink appearance 
in the usual H&E-stained tissue. Unlike with coagulative 
necrosis, the tissue architecture is completely obliterated 
and cellular outlines cannot be discerned. The area of 
caseous necrosis is often enclosed within a distinctive 
inflammatory border; this appearance is characteristic 
of a focus of inflammation known as a granuloma 
(Chapter 2).
• Fat necrosis refers to focal areas of fat destruction, typi-
cally resulting from release of activated pancreatic lipases 
into the substance of the pancreas and the peritoneal 
cavity. This occurs in the calamitous abdominal emergency 
known as acute pancreatitis (Chapter 16). In this disorder, 
pancreatic enzymes that have leaked out of acinar cells 
§ Arquitetura do órgão é geralmente mantida por algum tempo.
§ Infiltrado inflamatório.
§ Uma área localizada de necrose de coagulação é chamada de
infarto, exceto no cérebro.
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Necrose da coagulação:
Lesão Desnatura enzimas Bloqueando a	
  proteólise
A. Infarto renal. B, Aspecto microscópico da borda do infarto, com rim normal (N) e células necróticas no
infarto (I), mostrando contornos preservados, com ausência de núcleos e um infiltrado inflamatório
C H A P T E R 1 Cell Injury, Cell Death, and Adaptations10
B
I
N
A
Figure 1–9 Coagulative necrosis. A, A wedge-shaped kidney infarct (yellow) with preservation of the outlines. B, Microscopic view of the edge of 
the infarct, with normal kidney (N) and necrotic cells in the infarct (I). The necrotic cells show preserved outlines with loss of nuclei, and an inflamma-
tory infiltrate is present (difficult to discern at this magnification). 
Figure 1–10 Liquefactive necrosis. An infarct in the brain showing 
dissolution of the tissue. 
MORPHOLOGY
• Coagulative necrosis is a form of necrosis in which the 
underlying tissue architectureis preserved for at least 
several days (Fig. 1–9). The affected tissues take on a firm 
texture. Presumably the injury denatures not only struc-
tural proteins but also enzymes, thereby blocking the pro-
teolysis of the dead cells; as a result, eosinophilic, anucleate 
cells may persist for days or weeks. Leukocytes are 
recruited to the site of necrosis, and the dead cells are 
digested by the action of lysosomal enzymes of the leu-
kocytes. The cellular debris is then removed by phagocy-
tosis. Coagulative necrosis is characteristic of infarcts 
(areas of ischemic necrosis) in all of the solid organs 
except the brain.
• Liquefactive necrosis is seen in focal bacterial or, 
occasionally, fungal infections, because microbes stimulate 
the accumulation of inflammatory cells and the enzymes 
of leukocytes digest (“liquefy”) the tissue. For obscure 
reasons, hypoxic death of cells within the central nervous 
system often evokes liquefactive necrosis (Fig. 1–10). 
Whatever the pathogenesis, the dead cells are completely 
digested, transforming the tissue into a liquid viscous mass. 
Eventually, the digested tissue is removed by phagocytes. 
If the process was initiated by acute inflammation, as in a 
bacterial infection, the material is frequently creamy yellow 
and is called pus (Chapter 2).
• Although gangrenous necrosis is not a distinctive 
pattern of cell death, the term is still commonly used in 
clinical practice. It usually refers to the condition of a limb, 
generally the lower leg, that has lost its blood supply and 
has undergone coagulative necrosis involving multiple 
tissue layers. When bacterial infection is superimposed, 
coagulative necrosis is modified by the liquefactive action 
of the bacteria and the attracted leukocytes (resulting in 
so-called wet gangrene).
• Caseous necrosis is encountered most often in foci of 
tuberculous infection. Caseous means “cheese-like,” 
referring to the friable yellow-white appearance of the 
area of necrosis (Fig. 1–11). On microscopic examination, 
the necrotic focus appears as a collection of fragmented 
or lysed cells with an amorphous granular pink appearance 
in the usual H&E-stained tissue. Unlike with coagulative 
necrosis, the tissue architecture is completely obliterated 
and cellular outlines cannot be discerned. The area of 
caseous necrosis is often enclosed within a distinctive 
inflammatory border; this appearance is characteristic 
of a focus of inflammation known as a granuloma 
(Chapter 2).
• Fat necrosis refers to focal areas of fat destruction, typi-
cally resulting from release of activated pancreatic lipases 
into the substance of the pancreas and the peritoneal 
cavity. This occurs in the calamitous abdominal emergency 
known as acute pancreatitis (Chapter 16). In this disorder, 
pancreatic enzymes that have leaked out of acinar cells 
§ Digestão das células mortas, resultando na transformação do
tecido em umamassa viscosa líquida.
§ Geralmente em infecção bacteriana ou fúngica, que estimulam o
acúmulo de leucócitos e a liberação de enzimas dessas células.
§ Ex: Pus.
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Necrose de	
  liquefação:
Infarto no	
  cérebro,	
  mostrando a	
  
dissolução do	
  tecido.
11Mechanisms of Cell Injury
Figure 1–11 Caseous necrosis. Tuberculosis of the lung, with a large 
area of caseous necrosis containing yellow-white (cheesy) debris. 
Figure 1–12 Fat necrosis in acute pancreatitis. The areas of white chalky 
deposits represent foci of fat necrosis with calcium soap formation 
(saponification) at sites of lipid breakdown in the mesentery. 
Figure 1–13 Fibrinoid necrosis in an artery in a patient with polyarteritis 
nodosa. The wall of the artery shows a circumferential bright pink area 
of necrosis with protein deposition and inflammation. 
Leakage of intracellular proteins through the damaged cell 
membrane and ultimately into the circulation provides a means 
of detecting tissue-specific necrosis using blood or serum samples. 
Cardiac muscle, for example, contains a unique isoform of 
the enzyme creatine kinase and of the contractile protein 
troponin, whereas hepatic bile duct epithelium contains a 
temperature-resistant isoform of the enzyme alkaline phos-
phatase, and hepatocytes contain transaminases. Irrevers-
ible injury and cell death in these tissues result in increased 
serum levels of such proteins, and measurement of serum 
levels is used clinically to assess damage to these tissues.
SUMMARY
Morphologic Alterations in Injured Cells and Tissues
• Reversible cell injury: cell swelling, fatty change, plasma 
membrane blebbing and loss of microvilli, mitochondrial 
swelling, dilation of the ER, eosinophilia (due to decreased 
cytoplasmic RNA)
• Necrosis: increased eosinophilia; nuclear shrinkage, frag-
mentation, and dissolution; breakdown of plasma mem-
brane and organellar membranes; abundant myelin figures; 
leakage and enzymatic digestion of cellular contents
• Patterns of tissue necrosis: Under different conditions, 
necrosis in tissues may assume specific patterns: coagula-
tive, liquefactive, gangrenous, caseous, fat, and fibrinoid.
and ducts liquefy the membranes of fat cells in the peri-
toneum, and lipases split the triglyceride esters contained 
within fat cells. The released fatty acids combine with 
calcium to produce grossly visible chalky white areas (fat 
saponification), which enable the surgeon and the patholo-
gist to identify the lesions (Fig. 1–12). On histologic exami-
nation, the foci of necrosis contain shadowy outlines of 
necrotic fat cells with basophilic calcium deposits, sur-
rounded by an inflammatory reaction.
• Fibrinoid necrosis is a special form of necrosis, visible 
by light microscopy, usually in immune reactions in which 
complexes of antigens and antibodies are deposited in 
the walls of arteries. The deposited immune complexes, 
together with fibrin that has leaked out of vessels, produce 
a bright pink and amorphous appearance on H&E prepara-
tions called fibrinoid (fibrin-like) by pathologists (Fig. 
1–13). The immunologically mediated diseases (e.g., poly-
arteritis nodosa) in which this type of necrosis is seen are 
described in Chapter 4.
MECHANISMS OF CELL INJURY
Now that we have discussed the causes of cell injury and 
the morphologic changes in necrosis, we next consider in 
more detail the molecular basis of cell injury, and then 
illustrate the important principles with a few selected 
examples of common types of injury.
The biochemical mechanisms linking any given injury 
with the resulting cellular and tissue manifestations are 
complex, interconnected, and tightly interwoven with 
many intracellular metabolic pathways. Nevertheless, 
§ “caseoso”: semelhante a queijo;
§ Encontrada comumente em focos de tuberculose;
§ Arquitetura tecidual alterada;
§ Células rompidas ou fragmentadas e restos granulares amorfos
encerrados dentro de uma borda inflamatória nítida;
§ Típica de granulomas.
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Necrose caseosa:
Necrose caseosa.	
  Pulmão tuberculoso
11Mechanisms of Cell Injury
Figure 1–11 Caseous necrosis. Tuberculosis of the lung, with a large 
area of caseous necrosis containing yellow-white (cheesy) debris. 
Figure 1–12 Fat necrosis in acute pancreatitis. The areas of white chalky 
deposits represent foci of fat necrosis with calcium soap formation 
(saponification) at sites of lipid breakdown in the mesentery. 
Figure 1–13 Fibrinoid necrosis in an artery in a patient with polyarteritis 
nodosa. The wall of the artery shows a circumferential bright pink area 
of necrosis with protein deposition and inflammation. 
Leakage of intracellular proteins through the damaged cell 
membrane and ultimately into the circulation provides a means 
of detecting tissue-specific necrosis using blood or serum samples. 
Cardiac muscle, for example, contains a unique isoform of 
the enzyme creatine kinase and of the contractileprotein 
troponin, whereas hepatic bile duct epithelium contains a 
temperature-resistant isoform of the enzyme alkaline phos-
phatase, and hepatocytes contain transaminases. Irrevers-
ible injury and cell death in these tissues result in increased 
serum levels of such proteins, and measurement of serum 
levels is used clinically to assess damage to these tissues.
SUMMARY
Morphologic Alterations in Injured Cells and Tissues
• Reversible cell injury: cell swelling, fatty change, plasma 
membrane blebbing and loss of microvilli, mitochondrial 
swelling, dilation of the ER, eosinophilia (due to decreased 
cytoplasmic RNA)
• Necrosis: increased eosinophilia; nuclear shrinkage, frag-
mentation, and dissolution; breakdown of plasma mem-
brane and organellar membranes; abundant myelin figures; 
leakage and enzymatic digestion of cellular contents
• Patterns of tissue necrosis: Under different conditions, 
necrosis in tissues may assume specific patterns: coagula-
tive, liquefactive, gangrenous, caseous, fat, and fibrinoid.
and ducts liquefy the membranes of fat cells in the peri-
toneum, and lipases split the triglyceride esters contained 
within fat cells. The released fatty acids combine with 
calcium to produce grossly visible chalky white areas (fat 
saponification), which enable the surgeon and the patholo-
gist to identify the lesions (Fig. 1–12). On histologic exami-
nation, the foci of necrosis contain shadowy outlines of 
necrotic fat cells with basophilic calcium deposits, sur-
rounded by an inflammatory reaction.
• Fibrinoid necrosis is a special form of necrosis, visible 
by light microscopy, usually in immune reactions in which 
complexes of antigens and antibodies are deposited in 
the walls of arteries. The deposited immune complexes, 
together with fibrin that has leaked out of vessels, produce 
a bright pink and amorphous appearance on H&E prepara-
tions called fibrinoid (fibrin-like) by pathologists (Fig. 
1–13). The immunologically mediated diseases (e.g., poly-
arteritis nodosa) in which this type of necrosis is seen are 
described in Chapter 4.
MECHANISMS OF CELL INJURY
Now that we have discussed the causes of cell injury and 
the morphologic changes in necrosis, we next consider in 
more detail the molecular basis of cell injury, and then 
illustrate the important principles with a few selected 
examples of common types of injury.
The biochemical mechanisms linking any given injury 
with the resulting cellular and tissue manifestations are 
complex, interconnected, and tightly interwoven with 
many intracellular metabolic pathways. Nevertheless, 
§ Áreas de destruição de gordura que ocorre como resultado da
liberação de lipases pancreáticas ativadas na cavidade
abdominal, como na pancreatite aguda.
§ Os ácidos graxos liberados combinam-­‐se com o cálcio,
produzindo áreas brancas gredosas (argilosa)
macroscopicamente visíveis (saponificação da gordura).
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Necrose gordurosa:
Necrose gordurosa: As áreas de depósitos
gredosos, brancas, representam focos de
necrose gordurosa.
11Mechanisms of Cell Injury
Figure 1–11 Caseous necrosis. Tuberculosis of the lung, with a large 
area of caseous necrosis containing yellow-white (cheesy) debris. 
Figure 1–12 Fat necrosis in acute pancreatitis. The areas of white chalky 
deposits represent foci of fat necrosis with calcium soap formation 
(saponification) at sites of lipid breakdown in the mesentery. 
Figure 1–13 Fibrinoid necrosis in an artery in a patient with polyarteritis 
nodosa. The wall of the artery shows a circumferential bright pink area 
of necrosis with protein deposition and inflammation. 
Leakage of intracellular proteins through the damaged cell 
membrane and ultimately into the circulation provides a means 
of detecting tissue-specific necrosis using blood or serum samples. 
Cardiac muscle, for example, contains a unique isoform of 
the enzyme creatine kinase and of the contractile protein 
troponin, whereas hepatic bile duct epithelium contains a 
temperature-resistant isoform of the enzyme alkaline phos-
phatase, and hepatocytes contain transaminases. Irrevers-
ible injury and cell death in these tissues result in increased 
serum levels of such proteins, and measurement of serum 
levels is used clinically to assess damage to these tissues.
SUMMARY
Morphologic Alterations in Injured Cells and Tissues
• Reversible cell injury: cell swelling, fatty change, plasma 
membrane blebbing and loss of microvilli, mitochondrial 
swelling, dilation of the ER, eosinophilia (due to decreased 
cytoplasmic RNA)
• Necrosis: increased eosinophilia; nuclear shrinkage, frag-
mentation, and dissolution; breakdown of plasma mem-
brane and organellar membranes; abundant myelin figures; 
leakage and enzymatic digestion of cellular contents
• Patterns of tissue necrosis: Under different conditions, 
necrosis in tissues may assume specific patterns: coagula-
tive, liquefactive, gangrenous, caseous, fat, and fibrinoid.
and ducts liquefy the membranes of fat cells in the peri-
toneum, and lipases split the triglyceride esters contained 
within fat cells. The released fatty acids combine with 
calcium to produce grossly visible chalky white areas (fat 
saponification), which enable the surgeon and the patholo-
gist to identify the lesions (Fig. 1–12). On histologic exami-
nation, the foci of necrosis contain shadowy outlines of 
necrotic fat cells with basophilic calcium deposits, sur-
rounded by an inflammatory reaction.
• Fibrinoid necrosis is a special form of necrosis, visible 
by light microscopy, usually in immune reactions in which 
complexes of antigens and antibodies are deposited in 
the walls of arteries. The deposited immune complexes, 
together with fibrin that has leaked out of vessels, produce 
a bright pink and amorphous appearance on H&E prepara-
tions called fibrinoid (fibrin-like) by pathologists (Fig. 
1–13). The immunologically mediated diseases (e.g., poly-
arteritis nodosa) in which this type of necrosis is seen are 
described in Chapter 4.
MECHANISMS OF CELL INJURY
Now that we have discussed the causes of cell injury and 
the morphologic changes in necrosis, we next consider in 
more detail the molecular basis of cell injury, and then 
illustrate the important principles with a few selected 
examples of common types of injury.
The biochemical mechanisms linking any given injury 
with the resulting cellular and tissue manifestations are 
complex, interconnected, and tightly interwoven with 
many intracellular metabolic pathways. Nevertheless, 
§ Típica de reações imunes com imunocomplexos em combinação
com fibrina na parede de vasos;
§ Aparência amorfa e róseo-­‐brilhante, pela coloração de H&E.
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Necrose fibrinoide:
Necrose fibrinoide na artéria. A parede
da artéria mostra área circunferencial de
necrose, rósea-­‐brilhante, com
inflamação (núcleos escuros dos
neutrófilos).
18/03/20
6
Apoptose
de	
  /	
  cair
Mecanismo de	
  morte celular no	
  qual a	
  célula degrada seu próprio
DNA	
  e suas próprias proteínas,	
  de	
  maneira ordenada e sem levar a	
  
inflamação.
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Conhecida como:	
  
“morte celular programada"
Apoptose
Eliminação de	
  células
não mais necessárias
Eliminação de	
  células
indesejáveis ou potencialmente
danosas ao organismo
Apoptose:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Fisiológica
Patológica
Apoptose:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
§ Eliminar células que não são
mais necessárias.
§ Manter um número constante
das várias populações
celulares nos tecidos.
§ Elimina células que são lesadas
de modo irreparável, limitando
a lesão tecidual paralela.
• Desenvolvimento
embrionário:
• Involução de	
  órgãos
por privação hormonal:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Apoptose fisiológica:
• Perda celular em
populações celulares
proliferativas:
• Eliminação de	
  linfócitosautorreativos
potencialmente
nocivos:	
  
• Morte de	
  células
que já tenham
cumprido seu
papel:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Apoptose patológica:
§ Lesão de DNA,
§ Acúmulo de proteínas anormalmente dobradas,
§ Infecções,
§ Atrofia patológica no parênquima de órgãos após obstrução de ducto.
Apoptose:	
  
Aspectos morfológicos:
§ Diminuição do	
  volume	
  
celular;
§ Fragmentação do	
  
núcleo;
§ Condensação da
cromatina;
§ Projeções na
membrana plasmática;
§ Formação de	
  corpos
apoptóticos;
§ Fagocitose.
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
19
A
po
pt
os
is
of
 m
ul
tip
le
 c
on
se
rv
ed
 d
om
ai
ns
 o
f 
th
e 
Bc
l-2
 f
am
ily
). 
Th
ey
 
in
 t
ur
n 
ac
tiv
at
e 
tw
o 
pr
o-
ap
op
to
tic
 m
em
be
rs
 o
f 
th
e 
fa
m
ily
 
ca
lle
d 
Ba
x 
an
d 
Ba
k,
 w
hi
ch
 d
im
er
iz
e,
 in
se
rt
 in
to
 t
he
 m
ito
-
ch
on
dr
ia
l 
m
em
br
an
e,
 a
nd
 f
or
m
 c
ha
nn
el
s 
th
ro
ug
h 
w
hi
ch
 
cy
to
ch
ro
m
e 
c 
an
d 
ot
he
r m
ito
ch
on
dr
ia
l p
ro
te
in
s 
es
ca
pe
 in
to
 
th
e 
cy
to
so
l. 
Th
es
e 
se
ns
or
s 
al
so
 i
nh
ib
it 
th
e 
an
ti-
ap
op
to
tic
 
m
ol
ec
ul
es
 B
cl
-2
 a
nd
 B
cl
-x
L 
(s
ee
 fu
rt
he
r 
on
), 
en
ha
nc
in
g 
th
e 
le
ak
ag
e 
of
 m
ito
ch
on
dr
ia
l p
ro
te
in
s.
 C
yt
oc
hr
om
e 
c,
 to
ge
th
er
 
w
ith
 s
om
e 
co
fa
ct
or
s,
 a
ct
iv
at
es
 c
as
pa
se
-9
. 
O
th
er
 p
ro
te
in
s 
th
at
 le
ak
 o
ut
 o
f m
ito
ch
on
dr
ia
 b
lo
ck
 th
e 
ac
tiv
iti
es
 o
f c
as
pa
se
 
an
ta
go
ni
st
s 
th
at
 fu
nc
tio
n 
as
 p
hy
si
ol
og
ic
 in
hi
bi
to
rs
 o
f a
po
p-
to
si
s.
 T
he
 n
et
 re
su
lt 
is
 th
e 
ac
tiv
at
io
n 
of
 th
e 
ca
sp
as
e 
ca
sc
ad
e,
 
ul
tim
at
el
y 
le
ad
in
g 
to
 n
uc
le
ar
 fr
ag
m
en
ta
tio
n.
 C
on
ve
rs
el
y,
 if
 
ce
lls
 a
re
 e
xp
os
ed
 t
o 
gr
ow
th
 f
ac
to
rs
 a
nd
 o
th
er
 s
ur
vi
va
l 
si
gn
al
s,
 t
he
y 
sy
nt
he
si
ze
 a
nt
i-a
po
pt
ot
ic
 m
em
be
rs
 o
f 
th
e 
Bc
l-2
 f
am
ily
, t
he
 t
w
o 
m
ai
n 
on
es
 o
f 
w
hi
ch
 a
re
 B
cl
-2
 i
ts
el
f 
an
d 
Bc
l-x
L. 
Th
es
e 
pr
ot
ei
ns
 a
nt
ag
on
iz
e 
Ba
x 
an
d 
Ba
k,
 a
nd
 
th
us
 l
im
it 
th
e 
es
ca
pe
 o
f 
th
e 
m
ito
ch
on
dr
ia
l 
pr
o-
ap
op
to
tic
 
pr
ot
ei
ns
. C
el
ls
 d
ep
ri
ve
d 
of
 g
ro
w
th
 fa
ct
or
s 
no
t o
nl
y 
ac
tiv
at
e 
th
e 
pr
o-
ap
op
to
tic
 B
ax
 a
nd
 B
ak
 b
ut
 a
ls
o 
sh
ow
 r
ed
uc
ed
 
le
ve
ls
 o
f 
Bc
l-2
 a
nd
 B
cl
-x
L, 
th
us
 f
ur
th
er
 t
ilt
in
g 
th
e 
ba
la
nc
e 
to
w
ar
d 
de
at
h.
 T
he
 m
ito
ch
on
dr
ia
l p
at
hw
ay
 s
ee
m
s 
to
 b
e 
th
e 
pa
th
w
ay
 t
ha
t 
is
 r
es
po
ns
ib
le
 f
or
 a
po
pt
os
is
 i
n 
m
os
t 
si
tu
a-
tio
ns
, a
s 
w
e 
di
sc
us
s 
la
te
r.
Th
e 
D
ea
th
 R
ec
ep
to
r 
(E
xt
rin
sic
) 
Pa
th
wa
y 
of
 A
po
pt
os
is
M
an
y 
ce
lls
 e
xp
re
ss
 s
ur
fa
ce
 m
ol
ec
ul
es
, c
al
le
d 
de
at
h 
re
ce
p-
to
rs
, t
ha
t 
tr
ig
ge
r 
ap
op
to
si
s.
 M
os
t 
of
 t
he
se
 a
re
 m
em
be
rs
 o
f 
th
e 
tu
m
or
 n
ec
ro
si
s 
fa
ct
or
 (
TN
F)
 r
ec
ep
to
r 
fa
m
ily
, 
w
hi
ch
 
co
nt
ai
n 
in
 t
he
ir
 c
yt
op
la
sm
ic
 r
eg
io
ns
 a
 c
on
se
rv
ed
 “
de
at
h 
do
m
ai
n,
” 
so
 n
am
ed
 b
ec
au
se
 i
t 
m
ed
ia
te
s 
in
te
ra
ct
io
n 
w
ith
 
ot
he
r 
pr
ot
ei
ns
 in
vo
lv
ed
 in
 c
el
l d
ea
th
. T
he
 p
ro
to
ty
pi
c 
de
at
h 
re
ce
pt
or
s 
ar
e 
th
e 
ty
pe
 I 
TN
F 
re
ce
pt
or
 a
nd
 F
as
 (C
D
95
). 
Fa
s 
lig
an
d 
(F
as
L)
 is
 a
 m
em
br
an
e 
pr
ot
ei
n 
ex
pr
es
se
d 
m
ai
nl
y 
on
 
ac
tiv
at
ed
 T
 l
ym
ph
oc
yt
es
. 
W
he
n 
th
es
e 
T 
ce
lls
 r
ec
og
ni
ze
 
Fa
s-
ex
pr
es
si
ng
 t
ar
ge
ts
, F
as
 m
ol
ec
ul
es
 a
re
 c
ro
ss
-li
nk
ed
 b
y 
Fa
sL
 a
nd
 b
in
d 
ad
ap
to
r 
pr
ot
ei
ns
 v
ia
 t
he
 d
ea
th
 d
om
ai
n.
 
Th
es
e 
in
 t
ur
n 
re
cr
ui
t 
an
d 
ac
tiv
at
e 
ca
sp
as
e-
8.
 I
n 
m
an
y 
ce
ll 
ty
pe
s 
ca
sp
as
e-
8 
m
ay
 c
le
av
e 
an
d 
ac
tiv
at
e 
a 
pr
o-
ap
op
to
tic
 
m
em
be
r 
of
 t
he
 B
cl
-2
 f
am
ily
 c
al
le
d 
Bi
d,
 t
hu
s 
fe
ed
in
g 
in
to
 
th
e 
m
ito
ch
on
dr
ia
l 
pa
th
w
ay
. 
Th
e 
co
m
bi
ne
d 
ac
tiv
at
io
n 
of
 
bo
th
 p
at
hw
ay
s 
de
liv
er
s 
a 
le
th
al
 b
lo
w
 t
o 
th
e 
ce
ll.
 C
el
lu
la
r 
pr
ot
ei
ns
, 
no
ta
bl
y 
a 
ca
sp
as
e 
an
ta
go
ni
st
 c
al
le
d 
FL
IP
, 
bl
oc
k 
ac
tiv
at
io
n 
of
 c
as
pa
se
s 
do
w
ns
tr
ea
m
 o
f 
de
at
h 
re
ce
pt
or
s.
 
In
te
re
st
in
gl
y,
 s
om
e 
vi
ru
se
s 
pr
od
uc
e 
ho
m
ol
og
ue
s 
of
 F
LI
P,
 
an
d 
it 
is
 s
ug
ge
st
ed
 t
ha
t 
th
is
 i
s 
a 
m
ec
ha
ni
sm
 t
ha
t 
vi
ru
se
s 
us
e 
to
 
ke
ep
 
in
fe
ct
ed
 
ce
lls
 
al
iv
e.
 
Th
e 
de
at
h 
re
ce
pt
or
 
pa
th
w
ay
 is
 in
vo
lv
ed
 in
 e
lim
in
at
io
n 
of
 se
lf-
re
ac
tiv
e 
ly
m
ph
o-
cy
te
s 
an
d 
in
 k
ill
in
g 
of
 t
ar
ge
t 
ce
lls
 b
y 
so
m
e 
cy
to
to
xi
c 
T 
ly
m
ph
oc
yt
es
.
Ac
tiv
at
io
n 
an
d 
Fu
nc
tio
n 
of
 C
as
pa
se
s
Th
e 
m
ito
ch
on
dr
ia
l a
nd
 d
ea
th
 re
ce
pt
or
 p
at
hw
ay
s l
ea
d 
to
 th
e 
ac
tiv
at
io
n 
of
 th
e 
in
iti
at
or
 c
as
pa
se
s,
 c
as
pa
se
-9
 a
nd
 -8
, r
es
pe
c-
tiv
el
y.
 A
ct
iv
e 
fo
rm
s 
of
 t
he
se
 e
nz
ym
es
 a
re
 p
ro
du
ce
d,
 a
nd
 
th
es
e 
cl
ea
ve
 a
nd
 th
er
eb
y 
ac
tiv
at
e 
an
ot
he
r s
er
ie
s 
of
 c
as
pa
se
s 
th
at
 a
re
 c
al
le
d 
th
e 
ex
ec
ut
io
ne
r 
ca
sp
as
es
. T
he
se
 a
ct
iv
at
ed
 c
as
-
pa
se
s c
le
av
e 
nu
m
er
ou
s t
ar
ge
ts
, c
ul
m
in
at
in
g 
in
 a
ct
iv
at
io
n 
of
 
nu
cl
ea
se
s 
th
at
 d
eg
ra
de
 D
N
A
 a
nd
 n
uc
le
op
ro
te
in
s.
 C
as
pa
se
s 
al
so
 d
eg
ra
de
 c
om
po
ne
nt
s 
of
 t
he
 n
uc
le
ar
 m
at
ri
x 
an
d 
cy
to
-
sk
el
et
on
, l
ea
di
ng
 to
 fr
ag
m
en
ta
tio
n 
of
 c
el
ls
.
M
ec
ha
ni
sm
s 
of
 A
po
pt
os
is
A
po
pt
os
is
 r
es
ul
ts
 fr
om
 th
e 
ac
tiv
at
io
n 
of
 e
nz
ym
es
 c
al
le
d 
ca
sp
as
es
 
(s
o 
na
m
ed
 b
ec
au
se
 th
ey
 a
re
 c
ys
te
in
e 
pr
ot
ea
se
s 
th
at
 c
le
av
e 
pr
ot
ei
ns
 a
ft
er
 a
sp
ar
tic
 r
es
id
ue
s)
. T
he
 a
ct
iv
at
io
n 
of
 c
as
pa
se
s 
de
pe
nd
s 
on
 a
 fi
ne
ly
 tu
ne
d 
ba
la
nc
e 
be
tw
ee
n 
pr
od
uc
tio
n 
of
 
pr
o-
 a
nd
 a
nt
i-a
po
pt
ot
ic
 p
ro
te
in
s.
 T
w
o 
di
st
in
ct
 p
at
hw
ay
s 
co
nv
er
ge
 o
n 
ca
sp
as
e 
ac
tiv
at
io
n:
 t
he
 m
ito
ch
on
dr
ia
l 
pa
th
w
ay
 
an
d 
th
e 
de
at
h 
re
ce
pt
or
 p
at
hw
ay
 (
Fi
g.
 1
–2
2)
. A
lth
ou
gh
 t
he
se
 
pa
th
w
ay
s 
ca
n 
in
te
rs
ec
t, 
th
ey
 a
re
 g
en
er
al
ly
 in
du
ce
d 
un
de
r 
di
ff
er
en
t c
on
di
tio
ns
, i
nv
ol
ve
 d
iff
er
en
t m
ol
ec
ul
es
, a
nd
 se
rv
e 
di
st
in
ct
 r
ol
es
 in
 p
hy
si
ol
og
y 
an
d 
di
se
as
e.
Th
e 
M
ito
ch
on
dr
ia
l (
In
tr
in
sic
) 
Pa
th
wa
y 
of
 A
po
pt
os
is
M
ito
ch
on
dr
ia
 c
on
ta
in
 s
ev
er
al
 p
ro
te
in
s 
th
at
 a
re
 c
ap
ab
le
 o
f 
in
du
ci
ng
 a
po
pt
os
is
; 
th
es
e 
pr
ot
ei
ns
 i
nc
lu
de
 c
yt
oc
hr
om
e 
c 
an
d 
ot
he
r p
ro
te
in
s t
ha
t n
eu
tr
al
iz
e 
en
do
ge
no
us
 in
hi
bi
to
rs
 o
f 
ap
op
to
si
s.
 T
he
 c
ho
ic
e 
be
tw
ee
n 
ce
ll 
su
rv
iv
al
 a
nd
 d
ea
th
 i
s 
de
te
rm
in
ed
 b
y 
th
e 
pe
rm
ea
bi
lit
y 
of
 m
ito
ch
on
dr
ia
, w
hi
ch
 is
 
co
nt
ro
lle
d 
by
 a
 fa
m
ily
 o
f m
or
e 
th
an
 2
0 
pr
ot
ei
ns
, t
he
 p
ro
to
-
ty
pe
 o
f w
hich
 is
 B
cl
-2
 (F
ig
. 1
–2
3)
. W
he
n 
ce
lls
 a
re
 d
ep
ri
ve
d 
of
 g
ro
w
th
 fa
ct
or
s a
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th
er
 su
rv
iv
al
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gn
al
s,
 o
r a
re
 e
xp
os
ed
 
to
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ge
nt
s 
th
at
 d
am
ag
e 
D
N
A
, o
r 
ac
cu
m
ul
at
e 
un
ac
ce
pt
ab
le
 
am
ou
nt
s 
of
 m
is
fo
ld
ed
 p
ro
te
in
s,
 a
 n
um
be
r 
of
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en
so
rs
 a
re
 
ac
tiv
at
ed
. T
he
se
 s
en
so
rs
 a
re
 m
em
be
rs
 o
f 
th
e 
Bc
l-2
 f
am
ily
 
ca
lle
d 
“B
H
3 
pr
ot
ei
ns
” 
(b
ec
au
se
 th
ey
 c
on
ta
in
 o
nl
y 
th
e 
th
ir
d 
Fi
gu
re
 1
–2
1 
M
or
ph
ol
og
ic
 a
pp
ea
ra
nc
e 
of
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po
pt
ot
ic
 c
el
ls.
 A
po
pt
ot
ic
 
ce
lls
 (s
om
e 
in
di
ca
te
d 
by
 a
rro
w
s)
 in
 a
 n
or
m
al
 c
ry
pt
 in
 th
e 
co
lo
ni
c 
ep
ith
el
iu
m
 
ar
e 
sh
ow
n.
 (T
he
 p
re
pa
ra
tiv
e 
re
gi
m
en
 fo
r 
co
lo
no
sc
op
y 
fre
qu
en
tly
 in
du
ce
s 
ap
op
to
sis
 in
 e
pi
th
el
ia
l c
el
ls,
 w
hi
ch
 e
xp
la
in
s 
th
e 
ab
un
da
nc
e 
of
 d
ea
d 
ce
lls
 
in
 th
is 
no
rm
al
 ti
ss
ue
.) 
N
ot
e 
th
e 
fr
ag
m
en
te
d 
nu
cl
ei
 w
ith
 c
on
de
ns
ed
 c
hr
o-
m
at
in
 a
nd
 t
he
 s
hr
un
ke
n 
ce
ll 
bo
di
es
, s
om
e 
w
ith
 p
ie
ce
s 
fa
llin
g 
of
f. 
(C
ou
rte
sy
 o
f D
r. 
Sa
nj
ay
 K
ak
ar
, D
ep
ar
tm
en
t 
of
 P
at
ho
lo
gy
, U
ni
ve
rs
ity
 o
f C
al
ifo
rn
ia
 S
an
 F
ra
nc
isc
o, 
Sa
n 
Fr
an
cis
co
, C
al
if.)
18/03/20
7
Apoptose:	
  
Aspectos bioquímicos:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
§ Ativação das	
  Caspases.
§ Quebra do	
  DNA	
  e Proteína.
§ Alterações da Membrana e Reconhecimento pelos Fagócitos.
Eletroforese de	
  DNA
A:	
  células viáveis
B:	
  apoptose “escadas”
C:	
  necrose “difuso”	
  
Apoptose:	
  
Aspectos bioquímicos:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Ativação das Caspases:
§ Caspase: enzima da família de cisteína proteases.
• “c” = cisteína protease (enzima com cisteína no sítio ativo).
• “aspase” = habilidade em clivar resíduos de ácido aspártico.
§ Funcionalmente dividida em dois grupos:
• Desencadeador: caspase-­‐2, -­‐8, -­‐9, -­‐10.
• Executor: caspase-­‐3, -­‐6, -­‐7.
§ Pró-­‐enzimas inativas (zimogênios): devem sofrer clivagem
enzimática para tornarem-­‐se ativas.
§ Caspases ativas (clivadas):marcador de células em apoptose.
Apoptose:	
  
Mecanismos:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Início da	
  apoptose: por sinais originados de	
  duas vias distintas:
Fosfolipídios do	
  folheto da	
  
membrana interno para	
  o	
  externo
Apoptose:	
  
Distúrbios Associados à Apoptose Desregulada:
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
§ Distúrbios associados com apoptose defeituosa e aumento da
sobrevida celular:
• Permite a sobrevida de células anormais, com consequências.
• Ex: -­‐ câncer devido a mutações no gene p53.
• -­‐ pode ser a base dos distúrbios autoimunes.
§ Distúrbios associados com o aumento da apoptose e morte celular
excessiva:
• Doenças neurodegenerativas: perda de grupos específicos de
neurônios, devido mutações e proteínas anormalmente dobradas.
• Lesão isquêmica: infarto miocárdico e acidente vascular cerebral.
• Morte de células infectadas por vírus: muitas infecções virais.
Autofagia:	
  
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
§ Processo no qual a célula digere seu próprio conteúdo.
§ Mecanismo de sobrevivência em períodos de privação de
nutrientes, reciclando os conteúdos digeridos.
Fagolisossomo
PATOLOGIA	
  – Lesão	
  e	
  morte	
  celular
Característica Necrose Apoptose
Tamanho celular Aumentado (tumefação)	
   Reduzido (retração)
Núcleo Picnose,	
  cariorrexe e
cariólise
Fragmentação em fragmentos
do	
  tamanho nucleossomas
Membrana
plasmática
Rompida Intacta;	
  estrutura alterada,
especialmente a orientação dos	
  
lipídios
Conteúdos celulares Digestão enzimática;
podem extravasar da célula
Intactos;	
  podem ser	
  liberados
em corpos apoptóticos
Inflamação adjacente Frequente Nenhuma
Papel fisiológico ou
patológico
Invariavelmente patológico
(finalização da lesão celular
irreversível)
Frequentemente fisiológico
(eliminação de células
indesejadas);	
  pode ser	
  
patológica (após algumas formas
de	
  lesão,	
  especialmente lesão de	
  
DNA).