Patho infl. and recovery Flashcards
What 3 factors induce ROS production and lead to mitochondria damage?
Radiation, toxins, reperfusion
Where originates oxygen used to form ROS in reperfusion?
Restoration of arterial blood flow to an affected limb floods ischemic tissue with oxygen. This molecular oxygen reacts with enzymes (…) to form ROS.
Molecular oxygen reacts with …………. (3) to form ROS.
xantine oxidase, NADPH oxidaze, NO synthase
What 3 types of ROS are formed after molecular oxygen reacts with some enzymes?
superoxide, hydroxyl radicals, singlet oxygen
How ROS disrupt cellular functions? (3)
DNA mutations, protein synthesis disruption/protein damage, membrane lipis peroxidation
What are antioxidant enzymes that convert ROS to oxygen and water?
superoxide dismutase, glutathione peroxidase, calatase
What reaction is catalyzed by catalase/glutathione peroxidase?
hydrogen peroxide (H2O2) –> H2O (it is called detoxification)
When are neutralized ROS generated during cellular respiration?
Before it causes damage
What are the result molecules in detoxification?
Oxygen and water
Why there is ROS damage to cell after reperfusion if normally cells are capable to neutralize it?
Because in postischemic damage, the production of ROS exceeds the neutralizing capabilities of antioxidant enzymes (high oxidative stress) –> cell injury and death
What is high oxidative stress?
ROS exceeds the neutralizing capabilites of antioxidant enzymes
Eg there is prostata cancer with radiation treatment. What condition may develop?
acute radiation enteritis
What are 2 mechanisms that cause cell damage when used ionizing radiation?
DNA double-stranded breakage and generation of ROS
DNA double-strand breakage in ionizing radiation?
Breakage of both strands is required. Single-strand breaks can be repaired by polymerase
What is used to form ROS (tipo unstable molecules) by ionization?
WATER. Unstable molecules formed by the ionization of water.
Radiation-induced DNA damage impairs ………. and initiates ………….. of susceptible cells.
Mitosis; apoptosis
What are susceptible cells for radiation?
Intestinal crypt stem cells and other highly proliferative cells (eg, cancer cells, hematogenous precursors)
What immune response is innitiated by cellular damage due to radiation?
induced immune response –> increased proinflammatory cytokines + migration of leukocytes (eg neutrophils) –> Inflammation –> production of additional ROS that leads to contribution of radiation-induced tissue damage
What proinflammatory cytokines participate in radiation-induced cell damage?
IL-1, IL-6, TNF-alpha
What is the result of GI mucosal denudation due to radiation therapy?
decreased absorptive area –> diarrhea
What causes diarrhea in radiation therapy?
GI mucosal denudation –> decreased absorptive area –> diarrhea
What are late GI complications due to radiation therapy?
Intestinal fibrosis = strictures, adhesions, bowel obstruction
As an antioxidant, ………………….. neutralizes ROS, preventing …………..
superoxide dismutase; preventing cell injury.
Cytochrome P450 enzymes metabolize ……………. and ………..
endogenous toxins as well as drugs.
How can cytochrome P450 enzymes can lead to hepatotoxicity?
Cytochrome P450 enzymes metabolize endogenous toxins as well as drugs. They are capable of producing ROS, which can contribute to the hepatotoxicity seen with certain drugs.
What enzyme is bactericidal, but also causes oxidative damage to host cells?
myeloperoxidase
NADPH oxidase catalyzes the reduction of …………… to ………….., aiding in bacterial destruction by phagocytic cells.
molecular oxygen to superoxide free radicals
What reaction catalyzes NADPH oxidase?
reduction; molecular oxygen to superoxide free radicals
What is the effect on bacterias y superoxide free radicals that are produces by NADPH oxidase?
It aids bacterial destruction by phagocytic cells
Proteasome activity normally increases in …………………………..
response to oxidative stress
the ubiquitin-proteosome system is inhibited by ……………..
ionizing radiation
radiation-induced tissue damage occurs primarily through the ……………..
Generation of free radicals
Ionizing radiation causes …………… and ……………damage
cellular and DNA
What triggers progressive inflammation and tissue damage in radiation therapy?
Ionizing radiation causes cellular and DNA damage primarily through generation of reactive oxygen species, which can trigger progressive inflammation and tissue damage.
What breakdowns proteins?
Ubiquitin protease pathway
Viral infection. Need to activated cellular immune. What is needed for activation and what system participates?
Need viral protein presentation to effector immune cells (eg CD8 lymph). These proteins are broken down by ubiquitin protease pathway and hydrolyzed peptides are presented to effector cells.
What proteins are broken down by ubiquitin-proteasome pathway?
native and foreign intracellular (eg viral) proteins
What initiates UPP?
Ubiquitin ligase
What does ubiquitin ligase?
It recognizes proteins and catalyzes the attachement of ubiquitin
What specific feature have proteins that participate in UPP and eventually are broken down?
Those proteins are tagged with ubiquitin. Then they are broken down by proteosome to peptide fragments –> recycled to amino acids
What catalyzes breakdown of proteins in UPP?
proteasome; proteins to peptide fragments
What is presented to MHC class I in viral infection?
PEPTIDE FRAGMENTS!!!!!
The are got after proteins are broken down by proteasome
What cell process if initiated by cytotoxic CD8 when eg viral peptides are presented?
apoptosis
What process happens when apoptosis is initiated by cytotoxic CD8?
activation of caspase cascade through the release perforin and granzyme
What is activated by perforins and granzymes?
caspase cascade
What state is cachexia?
hypermetabolic
What drives cachexia?
elevated proinfalmmatory cytokines (eg TNF-alpha, IL-6)
What is stimulated by TNF-alpha and IL-6 in cachexia?
UPP, therefore there is the degradation of muscle proteins (actin, myosin)
In cancer-related cachexia, high levels of pro-inflammatory cytokines lead to increased ……………………….. of ……………….. proteins, which in turn leads to extensive skeletal muscle loss
ubiquitination of sarcomeric muscle proteins -_> extensive skeletal muscle loss
How is called the destruction of targeted proteins?
selective proteolysis
Oligopeptides formed within within proteasomes further degraded by …………………………. into ………..
cytosolic peptidase into individual amino acids
Necrosis is characterized by ……………………… and …………………………due to external factors such as infection, toxin, or trauma.
cellular injury and premature death
What are the reasons of necrosis?
external factors such as infections, toxins, trauma
Main change in necrotic cell?
irreparable damage to the cellular membrane with subsequent leakage of cellular contents
Duchenne and Becker muscular dystrophies are caused by X-linked mutations to the ……………….
dystrophin gene
Function of dystrophin?
Dystrophin provides mechanical stability to muscle cells during contraction.
Pathophysiology when dystrophin gene mutations?
Mutations are associated with membrane tears that allow calcium to enter the cell and cause myofiber damage
What happens to the cell when telomers shorten beyond a certain point?
the cell undergoes apoptosis or senescence
Reprogramming of undifferentiated mesenchymal cells (eg, connective tissue) is a form of ……………………
Metaplasia
………………………………….(eg, connective tissue) is a form of metaplasia
Reprogramming of undifferentiated mesenchymal cells
Acid phosphatase is found in the …………………………
lysosomes
What does acid phosphatase?
hydrolyzes organic phosphates
guanylate cyclase plays important role in …………………….. and ……………………… of ………………. (eg ……….. and ………………..)
activation and regulation of diverse physiologic processes (eg smooth muscle relaxation, retinal phototransduction)
What secondary signal is in smooth muscle relaxation and retinal phototransduction?
guanylate cyclase
Apoptosis is a means of carefully regulated cell death in which the cell activates …………………..
enzymes to degrade its own nuclear DNA and proteins
What is the membrane condition in apoptosis?
it is intact
Why there are no inflammation in apoptosis?
because no cell contents are leaked into the surrounding tissue
What are the apoptosis phases? (2)
initiation and execution
What happens in initiation phase in apoptosis?
protein-hydrolyzing caspases are activated
What happens in execution phase in apoptosis?
caspases bring about the cell death by cleaving cellular proteins and activating DNAses
protein-hydrolyzing caspases are activated in ………… phase
initiation
caspases bring about the cell death by cleaving cellular proteins and activating DNAses in ………….. phase
execution
The initiation of apoptosis occurs via signals from …………………………….
two separate pathways
What are 2 pathways that initiate apoptosis?
intrinsic (mitochondrial) and extrinsic (dead receptor)
In the intrinsic pathway, the mitochondria become more ………………….. and it leads to release of ………………………. into………………..
permeable; pro-apoptotic substances; into cytoplasm
Release of pro-apoptotic substances in intrinsic pathway in apoptosis happens in response to ………………………………… (2)
in response to stress or the cessation of survival signal
Where reside anti-apoptotic proteins?
in mitochondrial membranes and cytoplasm
What are anti-apoptotic proteins?
Bcl-2 and Bcl-x
When anti-apoptotic proteins are replaced by pro-apoptotic proteins?
When cell is exposed to stress or the cessation of survival signals
What are pro-apoptotic proteins?
Bak, Bax, Bim
What cause pro-apoptotic proteins?
The pro-apoptotic proteins allow for the increased permeability of the mitochondria, which results in the release of caspase-activating substances like cytochrome c.
What is released when pro-apoptotic proteins replace anti-apoptotic proteins?
due to incr. mitochondria permeability - release of caspase-activating substances
What is the key enzyme in apoptosis?
caspases
What can activate caspases?
cytochrome c
Where occur death receptors in apoptosis?
in the cell surface
To what family belongs death receptors?
tumor necrosis factor receptor family
What are 2 best known death receptors?
type 1 TNF receptor (TNFR1) and Fas (CD95)
What is FADD?
death-domain containing adapter protein
What happens when Fas cross-links with its ligands?
multiple molecules of Fas come together to form a binding site for FADD
What happens when FADD binds Fas formed binding site?
FADD then binds an inactive form of a caspase, again bringing multiple caspase proteins together that through a cascade effect eventually induce caspase activation.
Hemosiderin accumulation is common in patients who have ………………… or …………………….
hemolytic anemia or who undergo frequent blood transfusions
Chronic inflammatory conditions are characterized by the persistent stimulation of …………………………………. (2)
Neutrophils and macrophages
Persistent stimulation of neutrophils and macrophages in chronic inflammation leads to increase of ………….. (4)
Inflammatory cytokines such IL-1, IL-6, TNF and INF-gamma
What are 2 important acute phase reactants?
fibrinogen and globulins (CRP)
What influence has acute phase reactants on RBCs?
they cause RBCs to overcome their zeta potential (negative potential that separates them) –> rouleaux formation –> it is heavier than separate RBCs –> settle to the bottom of tube more quickly
Etiology of fibrinoid necrosis?
Malignant hypertension, vasculitis
Etiology of fat necrosis?
Acute pancreatitis, trauma (subcutaneous adipose tissue)
Etiology of liquefactive necrosis?
CNS infarcts, severe bacterial infection (eg gangrene)
Etiology of caseous necrosis?
Mycobacterial infection Fungal infections (histoplasma, cryptococcus, coccidioides)
Etiology of coagulative necrosis?
irreversible ischemic damage outside CNS
Difference between apoptosis and necrosis?
apoptosis - no membrane damage.
necrosis - loss of membrane integrity –> proinflammatory intracellular material leaks –> injury of surrounding tissue
Necrosis is an uncontrolled process of cell death that results in …………………… of cellular proteins and ……………………. of cellular components
denaturation;
enzymatic digestion
In most organs, irreversible ischemic injury typically results in ………………………… (what necrosis?)
coagulative necrosis
Why in coagulative necrosis is maintained cellular architecture?
digestive enzymes denaturate before they destroyed cellular architecture, but nuclei are absent.
How differs liquefactive necrosis and coagulative?
in coagulative - maintaines cellular architecture;
in CNS liquefactive - digestion of cellular constitutienst and liquefaction of necrotic tissue
In what areas occurs fat necrosis?
in tissues with high numbers of adipocytes (pancreas, breast, subcutaneous fat)
in fat necrosis: TG –> free fatty acids. What 2 factors cause this reactions?
active enzymes (eg lipases) or mechanical damage
From where occurs enzymes in fat necrosis?
enzymes are released from damaged cells
What combines with free fatty acids in fat necrosis?
it combines with calcium = saponification (calky-white deposits)
What is seen under microscopy in fat necrosis?
anucleated adipocytes with calcium deposits
what cells surround in caseous necrosis?
epithelioid macrophages and giant cells
How is described material in the centre of granuloma? it is made of ……….
white, friable, cheese-like material. it is made up of CELL FRAGMENTS AND AMORPHOUS PROTEINACEOUS DEBRIS
Why tissue architecture is preserved in coagulative necrosis?
Due to early denaturation of lytic enzymes
2 microscopic changes in coagulative necrosis?
Cells are nucleated with eosinophilic cytoplasm.
Leukocytes eventually infitlrate and digest necrotic tissue
What immune cells digest necrotic tissue in coagulative necrosis?
Leukocytes
Fibrinoid necrosis results from ………………… (2)
Immune complex and/or plasma proteins (eg fibrin) that leak through the damaged intima and depositing within the vessel wall.
How appear deposits in fibrinoid necrosis in histology?
circumferential ring of pink, amorphous material surrounding the vascular lumen. (proteinaceous material - nes leakina baltymai eg fibrin)
How looks liquefactive necrosis?
infected abscess fluid is creamy yeallow due to dead leukocytes (pus)
why abscess is yellow in liquefactive necrosis?
due to dead leukocytes (pus)
How resolves brain infarcts?
it resolves into CSF-filled space
Why occurs dystrophic calcification?
Dystrophic calcification occurs in areas of tissue injury or necrosis that escape removal by phagocytes
What binds calcium in dystrophic calcification?
Phosphate ions bins calcium –> salts, which appear as white granules.
How microscopically occurs dystrophic calcification?
amorphous, basophilic material on H&E stain
How long it takes for dystrophic calcification to develop?
slowly - months and years following injury
What type of necrosis in in kidney and heart?
coagulative
Why there is not maintained cell architecture in brains in ischemia?
because there is lack of supporting architecture.
How long it takes to manifest for liquefactive necrosis in brains?
it occurs within 10 days oof infarction
What cells digest infarcted CNS tissue?
microglia (CNS macrophages)
What replaces digested CNS tissue?
cystic space surrounded by astroglial scar (gliosis)
How long it takes to form a cystic space + gliosis in CNS infarction?
months to years
Fibrinoid necrosis. What material accumulates?
Accumulation of fibrin-like material in the walls of blood vessels
fibrinoid necrosis in cerebral arteries can predispose a …………………….
hemorrhagic stroke
What immune cells can be seen in fibrinoid necrosis?
neutrophilic infiltrates
tuberculosis infection in CNS. Acute or chronic?
Chronic
fat necrosis. What cells engulf what?
foamy macrophages contains engulfed lipids debris + release free fatty acids that combine with calcium.
free fatty acids combine with calcium and form deposits. They are eosinophilic or basophilic?
basophilic
Coagulative necrosis occurs following ………………
hypoxic cell death
Wound healing process needed to …. (2)
restore continuity and tensile strength.
4 stages of wound healing.
4 sequential (but overlapping) phases: hemostasis, inflammation, proliferation, and maturation.
What phase occurs immediately after tissue injury?
hemostasis
What is involved in hemostasis? (3)
small vessel constriction;
platelet aggregation;
clotting cascade activation;
Result of hemostasis? (3)
platelet plugging, fibrin clot formation, and cessation of bleeding
For relatively minor injuries, hemostasis is often accomplished within …………….
minutes
The fibrin clot that is formed during hemostasis provides a ………………
scaffold for subsequent wound healing
inflammation after wound injury usually starts within ……………………
hours of injury
What cells primary participate in inflammation phase?
mast cells –> degranulate –> vascular permeability + CELLULAR INFILTRATION (neutrophil, monocytes)
Function of neutrophils in inflammation phase?
digest bacteria, necrotic tissue and foreign debris
Function of monocytes in inflammation phase?
secrete growth factors (TGF-beta, VEGF, IL-1, TNF-alpha) –> promote next phase of healing
what 2 factors released from platelets in hemostasis phase?
PDGF, TGF-beta
PDGF from hemostasis phase induces …….. in inflammation phase.
macrophages
What factor from hemostasis activates macrophages in inflammation phase?
PDGF
TGF-beta from inflammation phase induces …….. in proliferation phase.
fibroblasts
What factor from inflammation activates macrophages in proliferation phase?
TGF-beta
Proliferation, which begins during the ……….phase and continues for ………..afterward
inflammatory phase and continues for weeks afterwar
3 processes that happens in proliferation phase?
epithelization, fibroplasia, angiogenesis
What happens in epithelization?
Basal keratinocyte proliferation and migration of new epithelial cells form a new superficial epithelial layer that acts as a barrier to bacteria.
what happens in fibroplasia?
Fibroblasts proliferate and synthesize ground substance and collagen, forming a matrix into which capillaries can grow
What process during fibroplasia help to decrease wound size?
Simultaneous contraction of myofibroblasts (ie, differentiated fibroblasts that produce contractile proteins) helps decrease the wound size.
What important proteins produce fibroblasts during fibroplasia?
differentiated fibroblasts that produce contractile proteins
What happens in angiogenesis?
Proliferation and migration of endothelial cells from nearby blood vessels lead to ingrowth of new capillaries into the collagen matrix.
Proliferate and migration of what cells happens in angiogenesis in proliferation phase? From where those cells migrate?
Endothelial cells;
nearby blood vessels
Matrix in fibroplasia is formed from ………….
collagen (collagen matrix - here can grow new capillaries)
The last phase of wound healing?
maturation
What happens in maturation phase?
collagen remodeling and cross-linking
the primary mechanisms by which the tensile strength of the wound increases?
collagen remodeling and cross-linking
duration of hemostasis?
0 hours-1 day
duration of inflammation?
3 hours- 5 days
duration of proliferation?
3 days - 5 weeks
duration of remodeling?
3 weeks - 2 years
What factors are produced by fibroblasts in proliferation phase?
FGF, VEGF, extracellular matrix
What enzymes plays a role in remodeling?
matrix metalloproteinases
What types of collagen in remodeling?
type III –> type I
hemostasis. 2 results?
vasoconstriction;
fibrin clot formation
Inflammation. 3 results?
vasodilation;
incr. permeability;
inflmmatory cells chemotaxis
Recurrent respiratory infections + dextrocardia –?
Kartagner syndrome
Kartagner syndrome is a form of ………………
primary ciliaryy dyskinesia (PCD)
Inheritance of Kartagner syndrome?
autosomal recessive
Eukaryotic flagella and cilia are composed of …………
central core known as the axoneme
the axoneme is anchored to the cell by a ………………..
basal body
The axoneme of flagella and motile cilia consists of a …………
a circular array of microtubule doublets surrounding 2 central microtubules (9+2 arrangement
Each doublet in cilia has an ………….. and ………..subunits which are connected to ………………..
Each doublet has an A and B subunit and is connected to the adjacent doublet via dynein arms.
These dynein arms contain an …………. that generates energy to slide the microtubules past each other, producing ciliary movement
ATPase
how happens ciliary movement?
These dynein arms contain an ATPase that generates energy to slide the microtubules past each other, producing ciliary movement.
Primary ciliary dyskinesia can result from failure of the …………….. to develop normally.
dynein arms
Why patients with PCD experience recurrent respiratory infections?
due to impaired mucociliary clearance
What cardio pathology seen on xray in kartagner syndrome (PCD)?
dextrocardia
impaired ciliary movement during embryogenesis can cause …………….
situs inversus (reversed right/left positioning of internal organs).
genital manifestation in PCD in women and men?
Infertility in men (impaired sperm motility) and women (immobility of fallopian tube cilia)
Deficiency of the C1 complement component causes increased susceptibility to ………………. bacteria and also predisposes to developing ………………………
encapsulated bacteria (eg, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis); SLE
Same manifestation in PCD and cystic fibrosis?
recurrent respiratory infections, infertility;
in PCD - sinus inversus (in cystic is not seen)
Epithelial cell chloride channels are defective in ……………….
cystic fibrosis
