1
Q
def of pathology
A
Pathology = study of _structural, bchmal, functional c_hanges in cells, tissues, organs that underlie dis
2
Q
def of disease
A
- – any deviation /interruption of the normal structure or function of a part, organ, sys of the body as manifested by characteristic symptoms and sign
3
Q
def of disorder
A
- Disorder – a derangement from abnormality of fucntion; a morbid physical or mental state
4
Q
Neoplasm
A
NEW ABNORMAL grth; specifically new grth of tissue in which the grth is uncontrolled and progressive
5
Q
- 4 aspects of dis process
A
- Etiology: cause
- Pathogenesis: sequence o_f cellular, biocehmical or molecular even_ts that occur after a tissue is damaged. Can be different in different population
- Morphologic changes: s_tructural alterations that occur_ in cells and organs that are characteristic of a disease or diagnostic of an etiologic process
- Clinical manifestations = fctal consequences of the changes that lead to clinical manifestations (signs and symptoms)
6
Q
- Defining the ______ and _____ is essential to understand the dis and the tx
A
etiology
pathogenesis
7
Q
- Injury to ___ and to the ____ lead to tissue and organ injury, which determines the morphologic and clinical patterns of the disease.
A
cells and ECM
8
Q
Our organs are in homeostasis with the stress placed on it. Increases, decreases or changes in stress on the organ can result in ________\_
A
Our organs are in homeostasis with the stress placed on it. Increases, decreases or changes in stress on the organ can result in growth adaptations.
9
Q
what are adaptiations?
A
adaptations are REVERSIBLE responses to REPEATED pathologic or physioglic stress, where NEW STEADY states are acheived to allow the cell to continue to survive and function.
10
Q
What are our growth adaptations?
A
- Increase in stress => Hyperplasia/hypertrophy
- Decrease in stress => Atrophy
- Changes in stress=> Metaplasia
- Dysplasia
- Aplasia
- Hypoplasia
REMEMBER THESE ARE REVERSIBLE
11
Q
What is cell injury?
A
a cell is going to undergo injury when it can no longer normally adapt to to stress, is deprirved of nutrients or mutations affect the cell
12
Q
Is cell injury reversible?
A
is reversible up to a certain point, but if the stimulus persists or is severe enough from the beginning, the cell suffers irreversible injury => cell death.
13
Q
Cell death is usually d/t
A
- ischemia (reduced blood flow),
- infection,
- toxins
- or it can be a normal process in embryogenesis/dev/homeostasis
14
Q
- Pathways of cell death: ____, ____ or ______
A
- necrosis
- apoptosis
- nutrient deprivation can trigger adaptive responses that can cause cell death
15
Q
What are the stages of progressive impairment following insults
A
Adaptatation => cell injury (3) => cell death (3)
cell injury: can not longer adapt, deprived of nutrients or mutations affect parts of cell. irreversible at first, but if stimilus is severe enough or persists long enough=> cell death, which is irreversible (via necrosis, apoptosis, nutrient deprivation triggers adaptations that cause CD)
16
Q
- _____________ colors myocardium magenta to see stages of progessive impairment after insults
- how did the myocardium adapt
- what can we see on histology that will tell us that injury is reversible?
- how did the myocardium adapt
A
Tri phenyl tetrazolium colors myocardium magenta to see this
- Hypertrophy d/t increase WL
- Cell swelling and fat accumulation: NO gross/microscopic changes
17
Q
Describe
hypertrophy and hyperplasia
these are adaption to _______ in stress
What types of cells can undergo each?
Describe subcategories
A
Both types of adaptations to INCREASE IN STRESS:
- Hypertrophy: increase in the size of the cells => increase in the size of the organ by activating genes to increase PROTEIN SYNTHESIS of the cell (increase size of cytokeleton) and make new organelles. Dividing cells undergo both hyperplasia nad hypertophy. Non-dividing cells can ONLY undergo hypertropphu.
- Physiologic hypertropgy: occurs d/t increase demand (working out), _mechnical stretch o_r hormones and GF
- Pathologic hypertrophy: occurs d/t excessive GF and hormones
- Hyperplasia: increase in number of cells that occurs in cell that are capable of DIVIDING cells via making new cells from stem cells OR proliferation of mature cells by GF.
- Physiologic hyperplasia: occurs d/t :
- GF/hromones in hormone sensitive organs that need to increase fx
- damaged/resectied tissue that needs to recover
- Pathologic hyperplasia: occurs d/t excessive hormones/GF and viruses. reversible if imbalance is fixed but can lead to CANCER/DYSPLASIA
- Physiologic hyperplasia: occurs d/t :
18
Q
- Cells that can divide may respond to stress by undergoing …
A
hyperplasia
hypertrophy
19
Q
Physiologic hypertrophy example
A
- Working out => causes muscle fibers to hypertrophy
- Uterus undergoes hypertophy d/t hormones in pregnancy
20
Q
Generally, hyperplasia and hypertrophy occur together. An example would be a uterus during pregnancy.
There is an exception
A
- permanent tissues (skeletal and cardiac muscle and nerves). These ONLY undergo hypertrophy because they cannot make new cells.
21
Q
The most common stimulus for cardiac muscle hypertrophy is
A
FAULTY VALVES AND HTN THAT CAUSE AN increase in hemodynamic load
22
Q
_________ is reversible if ____________ is fixed and can lead to cancer and dysplasia
A
Pathological hyperplasia
hormone imbalance
23
Q
Ex of pathologic hyperplasia
A
24
Q
- __________are the main trigger for physiologic hypertrophy
- ________ are the main trigger for pathologic hypertrophy.
A
- Mechanical sensors are the main trigger for physiologic hypertrophy
- GF and hormones are the main trigger for pathologic hypertrophy.
25
What is the molecular **pathogenesis** for **cardiac hypertrophy?**
* 1. PAthological stressors: Mechanical sensors (+ by increased WL), GF (TGF-B, IGF1 and FGF) and physioligical stresstors: vasoactive agonists (a-adrenergic AGO, endothelin-1 and angiotensin II) =\> detect pathologic =\> +
* 2. + Hypertrophic signal transduction pathways:
* A. GCPR G-proteins (+ in pathologic hypertrophy)
* B. P13K/AKT (+ in physioloic hypertrophy, like working out)
* 3. Pathways activate transcription factors (**GATA4, NFAT, and MEF2**) =\>
1. Increase the synthesis of m proteins = hypertrophy!
2. Switch of adult contractile proteins -\> fetal or neonatal forms
1. The genes can be switched back to the fetal form: alpha isoform of the myosin heavy chain is replaced by B isoform =\> producing slower, energy saving contractions
3. express genes only expressed during early development =\> products participate in the cellular response to stress (ANP, ANF, cardiac alpha actin) =\> increases mechanical performance and decreases workload
4. Increase production of growth factors to postively regulate hypertrophy
* Adaptive changes can non longer keep up with the stress and the heart begins to give up =\> regressive changes in the myocardial fibers (lysis and loss of contractile elements) and myocyte death occur
26
how can we prevent h**ypertrophy of \<3**
* **NFAT, GATA4, MEF2 inhibitors**
27
What cause hyperplasia?
**1. Make new cells from stem cells**
**2. GF-driven proliferation of mature cells**
28
What are examples of **physiologic hyperplasia?**
1. female breast (glandular epithelial cells) is an example of hormonal hyperplasia and hypertrophy at puberty/preg in response to hormonal cues.
2. Compensatory hyperplasia in liver regeneration and bone marrow
1. BM: blood loss/hemolysis=\> causes activation of EPO =\> increase in the red cell progenitors
29
**Examples of**
* Pathologic hyperplasia
* 1. **Endometrial hyperplasia:** balance between estrogen and progesterone fucks up =\> increase estrogen production =\> pathologic hyperplasia of endometrial glands =\> a_bnormal menstrual bleeding_
* 2. **BPH**: d/t too many androgens
30
Decrease stress causes atrophy (an adaption). Describe this process.
* Decreased nutrient supply or disuse =\> leads to loss in the metabolic needs to maintain the cells at their current size =\> cell decreases protein synthesis and increases protein degradation
* =\> reduction in the size of an organ or tissue by _decreasing cell size and number_ =\>
* To decrease size (2):
* 1. Ubiquitin-proteosome degradation of cytoskeleton:
* + ubiquitin ligases =\> attach Ub to cell proteins =\> degraded in proteasomes
* 2. Autophagy of cellular components
1. Cell consumes its own components in vacuoles to reduce nutritional demand to match supply -\> fuse with lysosomes -\> lysosomes have hydrolytic enzymes necessary to break the organelles down.
* To decrease number of cells:
* **1. Apoptosis**
* loss of intracellular organelles. Atrophy can be physiologic or pathologic.
31
Types of atrophy
* 1. P**hysiological atrophy** common during development:
* notochord
* thyroglossal duct
* **Uterus after partuition**
* 2. **Pathological atrophy** has many causes and can be local or generalized:
* decreased WL
* Denervation atrophy
* Ischemia (decreased BS)
* Malnutrition
* **_Loss of endocrine stiumulation_**
* **Pressure**
32
2. Pathological atrophy has many causes and can be _local or generalized:_
* **decreased WL**
* **Denervation atrophy**
* Ischemia (decreased BS)
* Malnutrition
* Loss of endocrine stiumulation
* Pressure
* Decreased WL: no longer use muscle from BR or cast
* initially reversible but if prlonged, skeletal m fibers decrease in number and size =\> atropgy and bone resorption=\> _osteoporosis of disuse_
* Denervation atrophy:The loss of innervation to muscle fibers
33
2. Pathological atrophy has many causes and can be local or generalized:
* decreased WL
* Denervation atrophy
* **Ischemia (decreased BS)**
* **give example**
* **Malnutrition**
* Loss of endocrine stiumulation
* Pressure
Ischemia (decreased BS)
* _Senile atrophy:_ arthersclerosis in BV to brain and heart =\> atrophy of brain
Malnutrition:
* **Profound _protein-calorie_ malnutrition (marasmus**): the body eating the skeletal muscle for NRG after using other resrouces (fat tissue), resulting in _cachexia_
* In chronic inflammatory diseases, too much of inflammatory cytokines (TNF) _suppresses appetite and lipid depletion_ and =\> muscle wasting.
34
2. Pathological atrophy has many causes and can be local or generalized:
* decreased WL
* Denervation atrophy
* Ischemia (decreased BS)
* give example
* Malnutrition
* **Loss of endocrine stiumulation**
* **Pressure**
* Loss of endocrine stiumulation
* **Loss of hormones to hormone- responsive tissues** like the breast, uterus, and vagina=\> atrophy
* Ex. **menopause**
* Pressure
* Tissue compression can cause atrophy and compress surrounding uninvolved tissues. May be d/t ischemia.
35
conseques of menopause are d/t what?
**pathological atrophy: lo**ss of endocrine stimulation of the boobs, uterus and vagina cause ATROPGY
36
pressure (or compression of tissue) can cause what
pathological **atrophy**
37
* .\_\_\_\_\_\_\_\_\_\_ can be seen inside atrophic cells.
**LIPOFUSCIN GRANULES/residual bodies** (d/t autophagy that occurs to decrease cell size in atrophy), which makes tissue look brown
38
what is Metaplasia
how does it occur
most commonly involves?
* Change in stress and and most commonly, **chronic irritation,** on an organ leads to a R**EVERSIBLE change to a new cell type** (metaplstic cell) to better handle stress by **reprogramming of stem cells or undifferentiated mesenchymal cells in CT** =\> become new cells anme make new ones
* Most commonly involves s**urface epithelium**: (squamous, columnar or transitional/urothelium)
39
The metaplastic changes that occur can leads to what?
Cell that can better _protect against irritation and insult_, BUT
## Footnote
**Reduced function**
**Increase risk of cancer**
40
Most common type of metaplasia
* **: epithelium changing from columnar =\> _stratified_ squamous** (which protects:
41
What adaption occurs in the respiratory tract d/t
1. **chronic irritation (smoking)**
2. **Vit A deficiency**
3. **stones in salivary, bile and pancreatic glands**
from **columnar =\> stratified squamous**,
stratified squamous can better handle irritation and insult but it looses its specialized job (muscus secretion and ciliary action)
42
What cellular adaptation is most common in
Barrett esophagus
- Barrett esophagus = **goblet cell Metaplasia (_squamous to columnar typ_e)**
43
Baretts ESO can lead to what?
**_glandular cancers (adenocarcinomas)_**
44
* **_Connective tissue metaplasia_**
* **_what is it?_**
* **_What is an example_**
* **CT metaplasia:** The creation _of cartilage, bone, or adipose tissue_ in tissues that do not normally contain these elements.
* **_Myositis ossificans_** , an adaptation that occurs after intramuscular hemorrhage in where skeletal muscle -\> makes bone
45
What is the mechanism metaplasia occurs?
* **the reprogramming of stem cells or undifferentiated mesenchymal cells in CT.**
46
What 2 types of adaptations can lead to cancer?
**1. Metaplasia**
**2. Pathologic hyperplasia**
47
What adaptation occurs in mesenchymal cells?
1. Mesenchymal tissues (CT like bone, fat, BV, cartilage) can undergo **metaplasia**.
Ex. M**yositis ossificans:** bone is made from skeletal muscle
48
Q: When does injury occur to a cell?
Injury occurs when a cell cannot adapt to stress.
49
Reversible cell injury
* Occurs when?
* Reversible?
Reversible cell injury
* Occurs in the e**arly stages or mild forms** of cell injury.
* Reversible if **damaging stimulus is removed**
50
**Likelihood of injury** depends on what?
**1. Type of stress**
**2. How severe the stress is**
**3. Cell that is affected.**
51
* Neurons are _____ susceptible to hypoxia; skeletal muscle, on the other hand, \_\_\_\_\_\_\_\_\_\_.
* **Neurons** are very susceptible to hypoxia; skeletal muscle, on the other hand, **can withstand hypoxia for longer periods of time.**
52
* Hallmarks of **reversible injury i**nclude:
* 1. Reduced Oxphos =\> decrease in ATP
* 2. Decrease in ATP causes cellular swelling bc Na/K ATPase channels stop working =\> Na+ cannot move out of cell and water moves in.
* 3. Alters intracellular (mT and cytoskeleton) organnels
53
What cells are **VERY** sensitive to cell death?
***heart***
***CNS***
54
There are 2 types of cell death: what is the difference between the two?
1. Necrosis: when damage to MEMBRANES is severe, lysomal enzymes NTR cytoplasm =\> digest cell=\> contents leak out =\> _acute inflammatio_n due to _damage of the cell membrane_ and _a disruption in the homeostasis of ions_ =\> death of a LARGE group of cells.
* ALWAYS pathologic: never normally occurs
2. Apoptosis: N**RG*****-dependent,**genetically programmed* cell death of single cells or a _SMALL GROUP of_ cells that occurs**d/t damage to cells DNA/ misfolded proteins/ infections, pathological atrophy in paranchymal organs after duct obstruction. C**haracterized by nuclear dissolution, fragmentation of the cell***_without complete loss of membrane integrity_***, and rapid removal of the cellular debris
* No inflammation
* Pathologic OR physiologic
55
What is the process of necrosis?
Process: _ischemia_, exposure to _toxins_, _infection_, _trauma_ =\> damages cell membrane -\> lysosomal enzs enter cytoplasm =\> digest cell =\> morphologic changes (mito damage, destruction ATP) =\> cellular contents leak into ECM \> inflamm
56
APOPTOSIS is characterized by:
1. Apoptosis: a form of cell death characterized by nuclear dissolution, fragmentation of the cell ***_without complete loss of membrane integrity_***, and rapid removal of the cellular debris; SAVING THE DAY FROM INFLAMMATION :)
2.
57
1. Which cell death process can BOTH pathologic and physiologic?
2. Which CD process involves death of a large group of cells?
3. Which CD process is followed by acute inflamation and why?
4. Why CD process ocurs d/t damage of cells DNA or proteins?
1. Apoptosis
2. Necrosis
3. Necrosis because membrane is damage -\> lysomal enzymes to leak into cytoplasm -\> digest cell -\> damage mT and destroy ATP =\> causing cell contents to leak into ECM =\> inflammation
4. Apoptosis occurs d/t damage of cell DNA/proteins
58
What are causes of cell injury?
* 1. Hypoxia (_ischemia_, _decrease O2 content in blood d/t cardioresp failure,_ _Hb has a decrease O2 carrying capacity_ (occurs in anemia and CO poisoning) and s_evere blood loss_).
* 2. Genetic problems (def of functional proteins, damaged DNA or misfolded proteins)
* 3. Chemicals/drugs
* 4. Infectious agents
* 5. Immunological reactions (autoimmune diseases)
* 6. Nutritional excess (obesity, high cholesterol) or defieincy (protein-cal def), vit def, self-imposed (anorexia)
* 7. Physical agents (radiation, trauma, extreme temps, pressure changes)
59
how does **hypoxia** cause cell injury?
Hypoxia is low O2 delivery to tissue. However, Tissues are dependent on O2 because O2 is the electron-acceptor in the ETC. Accepting of electrons by O2 allows us to make ATP
* Thus; low O2 -\> **impair oxidative phosphorylation -\> low ATP** -\> cellular injury.
60
How are the effects different if hypoxia occurs gradually or sudden/if severe?
* If gradual, the **cell can adapt and *atrophy*,**
* But it it is sudden or severe, the cell can die.
61
**Morphological alterations in cell injury**
* All stresses and noxious influences exert effects FIRST at the ______ and then they progress to be able to be seen at the\_\_\_\_\_\_
**Morphological alterations in cell injury**
* All stresses and noxious influences exert effects FIRST at the **_molec/bchm level_** and then they progress to be able to be seen at the **structural level.**
62
* Cells may become rapidly _nonfctal_ after the onset of injury, but may still be viable (rever).
T or F?
TRUE
63
When do morphological changes become apparent when a cell is injured
**_Injury leads to loss of cell function_ BEFORE we can see morphological changes.**
* Morpholoical changes are detected ONLY after biochemical alterations have caused cell death. t
* he interval between injury and morphological changes depend on method of detection.
64
Which methods of detection detect injury first -last?
1. Ultrastructural changes
2. Light microscope changes
3. Gross morphologic changes are seen last.
All of these occur after biochemical reactions have occured that can cause cell death.
65
What morphological changes do we see with **REVERSIBLE** CELL INJURY on a **LIGHT MICROSPE and Ultrastructural changes**
Light microscope=\> cell swelling and fattty change
1. **Cell swelling:** if the first manifestation of all forms of injury because lack of ATP causes the cell not to maintain proper ion grandient, which then causes water flows INTO the cell.
* _Hydropic change or vacuolar degeneration_: peices of ER that are released as small vacules in the cytoplasm
* Increase _eosinophillic staining_ (d/t loss of cytplasmic staining, which binds blue) and increased denatured cytoplasmic proteins (binds red)
*Ultrastructural changes include:*
1. Changes in plasma membrane: blebbing, loss of microvillus
2. ER swells: causing ribosomes to pop off
3. mT swells
4. Changes in nucleus: chromatin clumps, granular and fibrrilar elements break up.
2. **Fatty change**: lipid vaculous appear in cytoplasm in cells mainly dept on fat metabolism (liver cells and heart cells)
66
Cell sweling is best seen on what level?
What does it look like?
ORGAN LEVEL, hard to see with light microscope
=\> organ is **swollen** causes some **pallor**, **increased _turgor_,** an_d **increased weight.**_
67
What is a morphological pattern of **non-lethal injury** we see in REVERSIBLE CELL INJURY.
**hydropic change** or **vacuolar degeneration:**
* small clear vacuoles may be seen in the cytoplasm which are from pieces of the ER that have been pinched off and released.
68
If myelin figures are present in ultrastructural changes of cell injury: is it reversible or irreversible?
IRREVERSIBLE!
is not assx with reversible cell injjury
69
Reversible injury shows increased _______ staining (more pronounced in necrosis)
**EOSINOphillic; d.t**
* Loss of cytoplasmic RNA (which binds blue dye, hematoxylin)
* Denatured cytoplasmic proteins (bind red dye, eosin)
*
70
A cell with alot of microvillus and no blebbing is?
normal
71
**what stage of injury:**
swollen mT
blebbing
lipid vaculous in cytoplasm
**EARLY cell injury (early because reversible)**
72
What is the characteristic signs of **atrophy**?
**Autophagy and decreased protein synthesis**
73
What processes underlie **m_orpholical changes_** seen in **necrosis**?
What is the hallmark?
Necrosis: when damage to membrane is severe, lysosomal enzymes enter the cytoplasm, causing:
1. Cells _protein denaure_
2. Lethal injured cell undergoe**s _enzymatic digestion_**
Membraen is destroyed, causing =\> contents leak out of leaky membranes and enzymes from its own lysosome that digest cell =\> acute inflammation (hallmark)
74
How soon can we detect necrosis?
Histologically= hours (4-12
but, because contents leaked, within 2 hours we can detect ezymes and proteins in BLOOD
75
What are distinctive morphological featuers of necrosis?
**1. NEctrotic cells are more eosinophiliic on HE stain**
**2. Appear glassy d/t glycogen loss**
**\*\*\* Cell size: enlarged d/t swelling**
_3. **Cytoplasm is vacuolated**_
4. Dead cells are replaced by large masses of phospholipid called _**myelin figure**s_ that come from damaged cell membranes.
* Then, eaten by other cells =\> broken down into FA, which can be calcified into calcium soaps
**5. Breakdown of membranes**
6. **Leakage and enzymatic digestion** of cellular contents
7. c**hanges in nucleus**
76
what changes in morphological changes in nucleus do we see in necrosis?
Nuclear changes occur d**/t breakdown of DNA.**
1. **_Karyolysis (nuclear fading)_**: endonucleases (DNAase/RNAse) degrade DNA=\> causing basophila of chromatin to fade"
2. **_Pyknosis (nuclear shrinkage)_**: nucleus shrinks =\> chromatin condenses into a solid, shrunken mass=\> basophil increases. This is also seen in apop.
3. **_Karyorrhexis (nuclear fragmentation)_** the pyknotic nucleus fragments and then w/in a day or 2 the cell disappears.
77
Cmopare morphological changes of necrosis and apoptosis
Cell size:
Nucleus:
PM:
Cell contents:
Inflammation
Physiologic or pathologic?
78
What are the 4 patterns of tissue necrosis?
1. Coagulative necrosis
2. Liquifactive necrosis.
3. Caiseous necrosis
4. Fibrinoid necrosis.
79
Coagulative necrosis
faetures and typically caused by
* **Coagulative necrosis**
* Tissue r**emains firm** and preserved for a few days to weeks d.t **coagulation**.
* **Structure proteins AND degradative enzymes** are affected, therefore, the tissue is able to remain for a while
* **_eosinophilic**_, _**anucleate_** cells observed
* Dead cells are eventually removed by via: phagocytosis from leukocytes & lysosomal enzy.
* Typically caused by an obstruction of a blood vessel that leads to the tissue -- *except brain*. The affected area is called an *infarct*.
*
80
where is one place coagulative necrosis does not occur
brain
81
a localized area of coagulative necrosis is called what
**infarct**
82
* Liquefactive necrosis is characterized by what?
* **Characterized by digestion of the dead cells that turns the dead tissue into a YELLOW liquid viscous mass (pus) t**ypically from bacterial and fungal infections, bc they recruit alot of leukocytes
83
* Liquifactive necrosis is characteristic of what?
1. bacterial and fungal infection
2. Hypoxic death of CNS cells: only one that occurs in brain
84
* Caseous necrosis
* aka
* Often seen in:
* aka cheese like
* Soft, friable necrotic tissue that looks like cheese
* Often seen in: granulomatous inflammation of TB (most common) or a fungal infection.
85
On microscopic examination, **caseous necrosi**s looks like?
fragmented and lysed cells and granular debris inside of a distinct inflammatory border called a **granuloma**
86
What is helpful in fat necrosis to allow the surgeon localize the lesion
White-chalky fat saponification formed from **FA-Ca2+.**
87
* Fibrinoid necrosis
* characteristic of:
* How is it formed?
* Characteristic of: : **malignant HTN or vasculitis**
* Fibrinoid necrosis is is a special type of necrosis seen in immune reactions that involve blood vessesls: Ag- Ab complexes deposit in the walls of the arteries (type 3 hypersensitivity
* Deposits of immune complexes + fibrin that leaked out =\> a bright pink staining in H/E stains called **fibrinoid**.
88
* Fat necrosis
* **NOT A PATTERN OF NECROSIS!**
* Adipose tissue that undergoes necrosis
* In acute pancreatitis, pancreatic lipases or MO are released into pancrease or peritoneal cavity -\> cause the release of TAGS from FA , which then combine with Ca2+ to produce a chalke white appearance (**saponification)**
89
What is Gangrenous necrosis
Not A PATTERN, but coagulative necrosis that occurs in a extremity/limb and involves many tissue.
90
When is gangraneous necrosis considered "**wet gangrene"?**
If gangrenous tissue becomes infected w bacteria, it can cause liquefactive necrosis as well =\> wet gangrene
91
* \_\_\_\_\_\_: thought to be most important in *physiologic* muscle hypertrophy
* **PI3K/AKT:** thought to be most important in *physiologic* muscle hypertrophy
92
* ***_EXAM QUESTION: A 68 year old obese, post-menopausal women experiences abdominal pain. A biopsy of her uterus is obtained and shows increased proliferation of endometrial tissue and presence of glands. What is the underlying mechanism of this hyperplasia?_***
* ***_: increased levels of estrogen; NOT GF_***
93
* In cancer and chronic infections, it is the *\_\_\_ that suppresses appetite* and depletes lipid stores, thus causing there to be wasting of the muscle tissue =\> **atrophy**
**TNF**
94
* What happens if necrotic cells are not taken back up by leukocytes?
**dystrophic calcification:** Ca2+ and other minerals deposit =\> calcified
95
Parts of cell damaged most freq:
* **mT**, **cell mems**, machinery of protein synth/packaging, DNA
96
* Responses to injurous stimilu depend on what:
* Consequences of injury depend on:
* Responses to injurous stimilu depend on what: type, severity and duration of injury
* Consequences of injury depend on: _type_, _state_ and how well the injured cell can adapt
97
Cell injury occurs d.t one of 5 essential elements:
1. **ATP production** via aerobic respiration in mT
2. I**ntegrity of mT (**indep on ATP production)
3. **Integrity of plasma membrane,** which maintains ion and osmotic homeostsis
4. **Protein synthesis, folding, degradation and refolding**
5. **Genetics**
98
In general, what happens if you have a decreased of ATP?
Decreased ATP =\> _failure of NRG-dependent function_s =\> reversible injury=\> _fundamental cause of necrosis_; associated with hypoxic and toxic injury,
99
How is ATP made?
* Oxidative phosphorylation of ADP (via reducing O2 in the ETC) in mT
* Glycolytic pathway: uses glucose from body fluids or hydrolysis of glycogen to make ATP (no O2 needed)
100
* Depletion of ____ of ATP has profound effects on the critical cellular systems:
5-10%
101
* Hypoxia or toxic injury causes a decrease of oxidative phosphorylation -\> decreases ATP production-\>
Depletion of ATP causes what?
1. **Activity of Na/K ATPase pump is reduced**.
1. Allows influx of H20 and Na+ and K+ efflux=\> causes the cell to swell, dilation of the ER, loss of microvilli and blebs.
2. **Cellular energy metabolism is altered: increase in anaerobic glycolyis**
1. Decrease in ATP =\> Increase of AMP =\> anerobic glycolysis: makes ATP by metabolizing glycogen -\> glucose (depleting glycogen stores), increases lactic acid production and decreases pH =\> causes clumping of nuclear chromatin & decrease activity of enzymes
3. **Activity of Ca pump is reduced**
1. =\> increased influx of Ca =\> many damaging effects.
4. With greater amounts of ATP loss: **ribosomes detach from ER=\> decrease in protein synthesis**
5. **Misfolding of proteins**
1. These then accumulate in the ER = cause an _unfolded stress response_ =\> causes _ER stress response =\> c_auses _cell injury and death_
102
What happens if ATP depletion persists
If ATP depletion goes on long enough, there will be enough **damage to the mito and lysosomal membranes** that will cause the cell to go into **necrosis**.
103
How can we damage the mT?
* **1. Oxygen deprivation**
* **2. Increase Ca2+ in cytosol**
* **3. ROS**
Thus, they mT is sensitive to ALL **types of injury (hypoxia and toxins**
104
What are the 3 major consequences of mito damage?
* 1. Formation of a **mitochondrial permeability transition pore:** disrupts electrical potential of the mT, so that we cannot make ATP via Oxphos =\> which can then lead to necrosis.
* 2. Creation of **ROS** d/t problem with oxphos
* 3. Outer mitochondrial membrane increases in permeability, **releases Cytochrome C**, which can then activate caspases and + intrinsic pathway of apoptosis.
105
Influx of Ca and Loss of Ca homeostasis: how does it cause cell injury?
Usually, cytoplasm has low concentrations of Ca2+ because it is stored in _ER and mT,_ protecting us from damage.
1. When toxins or ischemia is detected, intracellular Ca2+ is released from the **mT and ER** at first, then later there is an extracellular influx of Ca2+ into the cell d/t a leaky plasma membrane. Increased cytosolic Ca2+ then causes:
1. Causes mitochondria permeability transition pores to open --\> failure to generate ATP
2. Activate enzymes that damages the cell
1. **Phospholipases** --\> membrane damage
2. **Proteases** --\> breaks down membrane and cytoskeleton proteins
3. **Endonucleases** --\> DNA and chromatin fragmentation
4. **ATPases** --\> faster loss of ATP
3. Direct activation of **apoptosis via caspases**
106
What is
* ***_One of the structural components of the mitrochondrial permeability transition pore?_***
**Cyclophillin D**
107
Barrett's esophagus is an example of what kind of metaplasia?
Squamous to columnar (**columnar metaplasia)**
## Footnote
**\*Metaplasias are named for what it turns into**
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* Mechanisms of membrane damage
* ROS and lipid peroxidation
* Decreased phospholipid synthesis
* Via hypoxia or mitochondrial dysfunction.
* Affects all cellular membranes including the membranes of the organelles.
* Increased phospholipid breakdown
* Via activation of Ca dependent phospholipases by increased levels of calcium.
* Phospholipid breakdown leads to an increase in lipid breakdown products (Free fatty acids, Acyl carnitine, Lysophospholipids) which have a detergent effect on the membrane. They can also insert/exchange into the membrane and change the permeability and electrophysiologic alterations.
* Cytoskeletal abnormalities
* Increased Ca++ levels cause proteases to attack the cytoskeleton and allow it to detach from the membrane.
* This allows the expanding membrane to detach and stretch/rupture while it is expanding.
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In reversible cell injury: there is cell swelling, membrane blebbling and swelling of the RER, decreasing protein synthesis.
**Eventually, once the membrane is damaged, the cell undergoes IRREVERSIBLE DAMAGE.**
* Consequences of membrane damage
* mt
* plasma membrane
* lysosome
* Mitochondrial membrane damage --\> Opening of the transition pore
* Decreased ATP generation and release of Cytochrome C that trigger apoptosis
* Plasma membrane damage --\> Loss of osmotic balance and cellular contents including the compounds needed for making ATP again.
* Leaky plasma membranes are bad
* Injury to lysosomal membranes --\> leakage of enzymes into cytoplasm and activation of acid hydrolases in the acidic intracellular pH of the injured cell
* RNAses, DNAses, proteases, phosphatases, glucosidases.
* Leads to necrosis.
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What IDAble morphalogical/biochemial changes to we see with irreversible injury?
none because no definition
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* What 2 morphological changes consistently represent irreversible changes in cell injury?
* I**nability to reverse mitochondrial dysfunction** (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury and profound problems with membrane function. Injury to lysosomal membranes results in the enzymatic dissolution of the injured cell that is characteristic of necrosis.
* **Leakage of intracellular proteins** through the damaged cell membrane and ultimately into the circulation provides a means of detecting tissue-specific cellular injury and necrosis using blood serum samples.
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* What are the biomarkers that are released from cardiac muscle when there is membrane damage?
* Cardiac specific isoform of _creatine kinase_ and _troponin_.
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* What are the biomarkers that are released from liver and bile duct epithelium when there is membrane damage?
* _Alkaline phosphatase_
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* What are the biomarkers that are released from hepatocytes when there is membrane damage?
* _Transaminases_
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What provides a means for the detection of tissue-specific cellular injury and necrosis using blood serum samples?
Leakage of intracellular proteins through the damaged cell membrane and ultimately into the circulation
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Accumulation of damage DNA and misfolded proteins triggers what kind of cell death?
Apoptosis
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* In ______ tissue damage, have a narrow window in until the irreversible phase
cardiac tissue
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* If having an MI, troponin IDd in blood w/in \_\_\_\_\_\_
2-4 hours
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* Pt presentation:
* Smoker, long hx of HTN
* Chest pain, radiation down L arm
* ST segment elevation
* Having an MI
* Cardiac cells deplete ATP quickly (bc mito damage) à lose contractility quickly
* In cardiac tissue damage, have a narrow window in until the irreversible phase
* If present w MI, cardiac biomarkers should be measured at presentation
* If having an MI, troponin IDd in blood w/in 2-4 hrs
After he dies, what do we see on autopsy?
cardiomegaly because of longstanding HTN
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* ATP depletion:
* mT damage:
* Influx if Ca2+
* Accumulation of ROS:
* Increased permeability of CM:
* Accumulation of damaged DNA:
* ATP depletion: failure of NRG dependent processes -\> reversible injury -\> eventually, necrosis
* mT damage: failure of NRG depent processes bc no ATP -\> ultimately necrosis; you can also have leakage of cytochrome C which can cause apoptosis
* Influx if Ca2+: active enzymes that damage cell and **damages mT by cauing pore to open**
* Accumulation of ROS: covalent modification of cell ptorins, lpipids and nucleic acids
* Increased permeability of membrane: affects plasma membrane, lysosome membrane and mT membrane =\> typically c**auses necrosis**
* Accumulation of damaged DNA and misfolded proteins =\> triggers apoptosis
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What happens in a pt having a MI?
MI=\> infarction =\> damage to mT =\> decrease in ATP and increase in ROS=\> contraciility decreases
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**most common type of cell injury in clinical medicine?**
What does it result from?
ISCHEMIA=\> decrease in blood flow =\> preventing blood from bring substrates, taking away waste products =\> decrease in O2 delivery to tissue =\> hypoxia.
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Ischemia is most often due to what?
**1. Mechanical _arterial obstruction_**
**2. _Reduced venous drainage_**
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* [Q:] How is ischemia different from hypoxia?
* Hypoxia NRG can be made by **anaerobic glycolysis,**
* In ischemia, no blood flow thus the substrates for glycolysis cannot be delivered**. Thus, aerobic AND anerobic metabolism cannot occur.**
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* ______ tends to cause more rapid and severe cell and tissue injury than does \_\_\_\_\_\_.
Fill in blank with: **ischemia** and **hypoxia in the absence of ischemia**
**Ischemia**: decrease in BF causes a decrease in arrival and leaving of dedation substances, which does not allow aerobic or anaerobic glycolysis.
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\<3 muscle ceases to contract within 60 seconds of coronary artery occulusion. Are the cells dead or alive?
ALIVE. loss of contraction does not mean they are dead
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* [Q:] What are the sequences of events that follow hypoxia or ischemia?
* 1. Low O2 in cell = no oxphos = decreased ATP
* 2. à No Na+ pump = K efflux, Na/H2O influx =swelling
* There is also an influx of Ca2+
* 3. **Loss of glycogen and decreased protein synthesis**
* 4. If ischemia persists: irreversible injury and necrosis begin: associated with:
* severe swelling of mT,
* Extensive damage to PMs (giving rise to **myelin figures)**
* Swelling of lysosomes.
* Large flocculent amorphous **densities develop in the mitochondrial matrix**
* These changes can be seen as early as **30-40 min in cardiac tissue after ischemia**
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Mammalian cells have developed protective responses to deal with hypoxic stress, the best defined is what TF and what does it do?
**- Hypoxia-inducible factor 1: a** transcription factor used for protection and helps to:
* **_BV formation_**
* **_Stimulates cell survival pathways_**
* **_Enhance anaerobic glycolysis_**
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Large, flocculent, amorphous densities develop in the mitochondrial matrix, what are these an indication of in myocardium and how quickly can they be seen?
- Indication of **irreversible injury**
- Seen as early as 30-40 mins. after ischemia
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What is the best known strategy for t**reating ischemia (and traumatic) brain and spinal cord injury?**
**Inducing hypothermia** (CBT \< 92 F)
* - Reduces metabolic demands of stressed cells,
* decreases cell swelling,
* suppresses formation of free radicals,
* inhibits the host inflammatory response
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What does restoration of blood flow do?
1. Promote recovery in cells that have been reversibly injured
2. Promote damage to cells that have been IRREVERSIBLY injured
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What are the 4 mechanisms that contribute to **ischemia-reperfusion injuries?**
1) **Oxidative stress** :reoxygenation may increase ROS's and reactive nitrogen species; also a decrease in activity of antioxidants
2**) Intracellular Ca2+ overload:**
* Increase in Ca2+ Begins during *acute* ischemia.
* Continues to get worse when the reperfusion happens and the blood brings lots more Ca to the cell and the membrane is damaged and unable to keep it out.
* Remember that Ca causes the pores to open in the mito that makes shit go down in the cell. (depletes ATP à further injury)
3) **Inflammation**: surrounding cells are dying from necrosis and releasing factors that attract immune cells. neutrophils brought to site of inflammation by reperfusion and exacerbate initial insult
4) C**omplement system activation**: some IgM antibodies have propensity to deposit in ischemic tissues, and when blood flow resumes, complement proteins bind the Ab's and cause more cell injury and inflammation
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* __________ == #1 contributor to cell death
* D**epletion of ATP** == #1 contributor to cell death
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* **Chemical injury** is a frequent problem in clinical medicine and is a major limitation to drug therapy. The liver metabolizes many drugs, making it a frequent target of drug toxicity. Actually, toxic liver injury is the MOST COMMON reason for ending use/development of a drug.
* Chemicals induce cell injury by 1 of 2 mechanisms: wjat are they
* 1. Direct toxicity to cells
* 2. Indirect: conversion from inactive toxic chemical =\> reactive toxic metabolic
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What is the most frequent reason for terminating the therapeutic use or development of a drug?
Toxic liver injury
\*Many drugs are metabolized in liver
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What 2 chemical can cause direct toxicity to cells?
and how?
* **1. Mercury (mercuric chloride)**
* Binds to sulfhydryl groups of the cell membrane proteins =\> increases membrane permeability and inhibition of ion transport.
* Greatest damage occurs to cells that concentrate, absorb, or excrete the chemicals like the _GI and kidne_y.
* **2, Cyanide**
* Cyanide poisons _cytochrome oxidase and inhibits oxphos._
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Which drugs therapeutic drugs i**nduce cell damage by direct cytotoxic effects?**
Many **antineoplastic chemotherapy agents** and **antibiotics**
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[SUMMARY Q:] What events occur in mild ischemia vs **severe and prolonged ischemia?**
* **Mild (reversible):** Decreased oxphos =\> decrease ATP production =\> breaks Na/K ATPase =\> _swelling_.
* **Severe/prolonged ischemia (irreversible)**: severe swelling of mT =\> Ca2+ influx inside the mT and into the cell with rupture of lysosomes and plasma membrane =\> release of cytochrome C from mT =\> necrosis or apoptosis =\> DEATH.
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how do we get rid of cells undergoing **apoptosis**?
* 1. They break up into apop bodies, which contains portions of cytoplasm and nucleus. However, PM remains intact.
* 2. PM becomes a target for phagocytes, which devour it berore contents leak out so there is NO inflammation.
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Apoptosis can be physiological or pathological.
when does physiological apoptosis occur?
1. **Embryogenesis** (destruction of cells during implantation, organogenesis, dev involution, and metamorphosis)
2. **Shrinkage of hormone sensitive dependent organs with hormone withdrawal**.
1. Exs. Endometrial shedding during menstration, ovarian follicle atresia in menopause, regression of lactating breast after weaning, and prostatic atrophy after castration
3. **Cell loss in proliferating populations**
* Ex. immature lymphocytes in bone marrow, thymus/B lymphocytes in germinal centers w/o useful Ag receptors, and epitlelial cells in intestinal crypts
4. **Elim of harmful, self-reacting lymphocytes**
* Either before or after they have matured.
5. **Death of host cells that have served their purpose: n**eutrophils in a acute inflammatory response and lymphocutes at the end of a immune response
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Apoptosis can be physiological or pathological.
when does p**hysiological apoptosis** occur?
1. DNA damage
2. Acummulation of misfolded proteins
3. Virus-induced cell death via virus itself or the host immune response (T-cells)
4. Pathological atrophy in parenchymal organs after duct obstruction.
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* Apoptosis morphology
* 1. **Cell shrinkage;** **Dense cytoplasm with tightly packed organelles.**
* NO cell swelling.
* 2. **Chromatin condensation into oddly shaped masses in the periphery and then even the nucleus may fragment into pieces.**
* 3. Formation of **cytoplasmic blebs and apoptotic blebs**
* First shows surface blebbing, then fragments into compact membrane bound **apoptotic bodies** (w organelles, and w or wo nuclear fragments
* 4 The apoptotic cells or cell bodies are then **eaten by Mfs then degraded by lysosomal enzs**
* 5. Apoptotic cells/bodies are **very eosinophilic** (and see dense chromatin)
* 6. Bc shrinkage and quickly phagocytized and **no inflamm**, may not see on mico
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What is the most characteristic feature of **apoptosis** seen with electron microscope?
Describe it
- **Chromatin condensation**
- Chromatin aggregates peripherally, under the nuclear membrane, into dense masses and then may fragment
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What happens to the size of the cell in necrosis vs. apoptosis?
Necrosis the cell swells
Apoptosis the cell shrink
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Whhat are the 2 stages of apoptosis?
What are they guided by?
* **Guided by caspases**
* 1. Initiation phase: caspases are enzymatically activated
* 2. Execution phase: other caspases trigger degradation of cellular components.
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Which pathway is the major mechanism of apoptosis in all mammalian cells?
**Intrinsic Mitochondrial pathway; however, malignant cells have learned to avoid it**
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* What are the _anti-apoptotic proteins_ in the that prevent activation of **intrinsic mT pathway?**
* What domains do they contain?
* What do they prevent?
- BCL2, BCL-XL, MCL1
- BH1-4 (four BH domains)
- Cytochrome c leakage
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What are the **pro-apoptotic protein**s in the intrinsic mT pathway?
What domains do they have?
What do they promote?
- BAX and BAK
- BH1-4
- Promote mitochondrial outer membrane permeability, allows leakage of Cytochrome C
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What are the major **sensors** of apoptosis in the i**ntrinsic mT pathway.**
Domains?
Function?
- BAD, BIM, BID, Puma, Noxa
- BH3 ONLY
- Sensors of cellular stress and damage, regulate the balancebetween the anti-apoptotic and pro-apoptotic proteins
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Describe the intrinsic mT pathway.
* 1. Cell viability is maintained when surviving signals (growth factors_)_ produce _anti-apoptotic proteins_ like BCL2, BCL-XL and MCL-1, which make outer mT membrane impermeable and prevent leakage of cytochrome C.
* Have 4 BH domains
* Found in the _outer mT membrane,_ _cytosol_ and _ER membrane_
* 2. Loss of survival signals, DNA damage and other insults =\> activate _sensors_ (BH3-only proteins like BAD, BIM, Puma and Noxa), which balance the activity of the pro and anti-apoptotic proteins and detect damage=\>
* Sensors have only 1 BH domain
* 3. Sensors block anti-apoptotic protein and activate _pro-apoptotic proteins_ BAX and BAK, which form pores in mT membrane.
* 4. Cytochrome C and other mT proteins leak
* 5. Cytochrome C binds to APAF-1, forming an apoptosome
* 6. Apoptosome binds c**aspase-9, the critical initiator caspase**
* 7. Caspase-9 cleaves adjacent caspase molecules, creating an a**uto-amplification process which activates the executioner caspases (caspase-3/6).**
* 8. ALSO _Smac/Diablo (mito proteins)_ enter the cytoplasm and neutralize proteins (IAPs) that inhibit apoptosis.
* IAPs usu block caspase activation to keep the cell alive
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Whatis another name for the extinsic pathway of apoptosis?
Death-receptor initated apoptotic pathway
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What are the BEST KNOWN death receptors of the extrinsic pathway of apoptosis?
**- Fas (CD95)**
**- TNFR1**
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What is the adaptor protein that begins the pathway of apoptosis once Fas binds FasL?
FADD
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* Extrinsic (death-receptor initiated) apoptotic pathway
* What is it?
*
* 1. Fas ligand (FasL), located on T cells that kill self-Ag and cytotoxic T cells that kill virus infected tumors, binds to Fas receptor, located on ALL cells.
* Fas is located on all cells
* 2. =\> 3+ Fas proteins come together and create a binding site for FADD (Fas-associated death domain), adaptor protein that initiates pathway.
* 3. FADD then binds inactive caspase 8 (caspase 10 in humans) =\> activates, which will activate executioner caspases 3 and 6
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What protein is capable of i**nhibiting the death receptor pathway of apoptosis**?
How?
What contains this protein?
**FLIP**
- Binds pro-caspase-8, but cannot cleave and activate because it lacks protease domain. "locks it"
**- Viruses and normal cells** use this inhibitor to protect themselves from Fas-mediated apoptosis
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How are the extrinsic and intrinsic pathways of apoptosis interconnected in tissues like **_hepatocytes_ and _pancreatic_ β cells?**
* In hepatocytes and pancreatic-B-cells, caspase 8 activated the BH3 protein -\> feeding into the mito pathway
* Activation of both pathways delivers a fatal blow to the cells
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What are the proteins in the execution phase of apoptosis (both pathways)?
**- Caspase 3 and 6** are the executioner caspases
- Cleave an inhibitor of _cytoplasmic DNase, chops up DNA_
- _Degrade the nuclear matrix_
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What are the most prominent ("eat me") signals for apoptotic cells ready to be engulfed by phagocytes?
**- Phosphatidlyserine(**ligand for _macrophage_ receptor)
**- Thrombospondin** (_adhesive glycoprotein_ recognized by phagocytes)
- **C1q** (antibody of the complement system, recognized by _phagocytes_)
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