Pathophysiology of the cell
1. The role of lysosomes in the development of pathological processes.
All lysosomal enzyme are activated in case of inflammation. Sac-like structures that contain enzym
for digesting most cellular substances to their basic form, such as amino acids, fatty acids, an
carbohydrates (sugars). Cellular injury leads to release of lysosomal enzymes that cause cellular sel
destruction. A new function of lysosomes is signaling hubs of a sophisticated network for cellul
adaptation. Inside the cell, lysosomal enzymes process and digest material ingested by endocytosis.
These enzymes causes:
• Degranulation of smooth cells, activation of Hageman factor, activation of complement
• Release of histamine connection w/ gamma-globulin, lysis of cell’s membrane
• Formation of channels In endothelium
• Activation of Kallikereine G.d increase of vascular-tissue permeability
2. Lysosomal diseases. Pathogenesis, the main manifestations, diagnost
methods.
Disorders of lipid metabolism are termed lysosomal storage diseases because each disorder in this
group can be traced to a missing lysosomal enzyme. Lysosomal storage
disorders include more than 50 known genetic disorders. The incidence of lysosomal storage
disorders is approximately 1 in 5000 live births.These disorders cause an
excessive accumulation of a particular cell product, occurring in the brain, liver, spleen, bone, and
lung, and thus involving several organ systems. Generally these disorders are not included in
newborn screening. Some of these disorders may be treated with enzyme replacement therapy.
Main manifestations
• Aspartylglucosaminuria: Patients appear normal for several months after birth and then presen
with recurrent infections, diarrhea, and hernias. Later, there may be a gradual coarsening of facial
features, an enlarged tongue (macroglossia) and enlargement of the liver (hepatomegaly).
• Batten Disease: It is characterized by the accumulation of a fatty substance (lipopigment) in th
brain, as well as in tissue that does not contain nerve cells. Batten disease is marked by rapidly
progressive vision failure (optic atrophy) and neurological disturbances
• Cystinosis: The early signs of this disorder typically involve the kidneys and the eyes.
Excessive storage of the amino acid cystine in all cells of the b
• Fabry Disease: Early symptoms include episodes of severe burning pain in the hands and feet.
Other early signs may include a decrease in sweat production
,• Gaucher Disease Types I, II, and III. Neurological complications may include mental
deterioration, an inability to coordinate voluntary movements, and muscle spasms of the arms, legs,
or entire body.
• Glycogen Storage Disease II (Pompe Disease): The cardiac enlargement that is often present i
the infantile form is seldom seen in the childhood form.
Pathophysiology / etiology
• LSDs are caused by mutations in genes encoding soluble acidic hydrolases, activator proteins
transporter proteins, integral membrane proteins or nonlysosomal proteins that are necessary for
lysosomal function
• Main genes in LSDs: glucosylceramidase beta / GBA (Gaucher), galactosidase alpha / GLA
(Fabry), sphingomyelin phosphodiesterase 1 / SMPD1 (Niemann-Pick), hexosaminidase subunit
alpha / HEXA (Tay-Sachs), iduronate 2-sulfatase / IDS (Hunter), glucosidase alpha, acid / GAA
(Pompe), cystinosin, lysosomal cystine transporter / CTNS (cystinosis)
• As a result, metabolic machinery of the cell is impaired by defects in degradative and syntheti
enzymes, lysosomal membrane defects, disorders of lysosome biogenesis and endosome- lysosome
traffic
• Pathogenetic cascade leads to intralysosomal accumulation of undegraded substrates in
multiple tissues and organs
• Excessive storage of a substrate triggers cell damage via several mechanisms: activation of
apoptosis, alterations of plasma membrane lipid content (affect receptor responses and downstream
signaling), prolonged inflammation, calcium imbalance, dysregulation of autophagy, etc. (Nat Rev
Neurol 2013;9:583)
• All LSDs are inherited in an autosomal recessive manner, except X linked recessive Fabry,
Hunter and Danon diseases
Diagnosis and differential diagnosis
• Prenatal diagnosis is made by measuring alpha-glucosidase activity in cultures of amniotic
cells and samples of chorionic villus.
• The differential diagnosis includes Duchenne muscular dystrophy, dystrophy of the limb girdl
dystrophy, and polymyositis.
3. The role of lysosomes in the development of inflammatory response.
The primary function of lysosomes is to degrade macromolecules through a series of enzymatic
reactions that are activated at acidic pH. This process is required to degrade molecules that are
internalized by cells (eg, by the process of endocytosis) or endogenous molecules that are
components of normal cell structures (eg, cell membranes, cytoskeleton, nucleic acids).
lysosomes play a diverse and important role in immunity and inflammation, in part through the
regulation of autophagy, control of inflammasome release of cytokines, and the regulation of
sphingolipid metabolism. In general, healthy lysosomes are required to exhibit a normal host
response to infection and to maintain a normal inflammatory response. Defective lysosomes lead to
abnormal autophagy, activation of inflammation, and reduced infection control.
,Lysosomes perform a range of functions, some of which, such as degradation, are common to all cel
types. Others, such as secretion or lysosomal exocytosis, are more specialised and tend to involve
fusion of this organelle with the cell surface to release its contents. This review describes lysosomal
regulation of the inflammatory glucocorticoid signaling pathways, and summarizes the roles of
lysosomes in negatively or positively modulating the production of inflammatory cytokines. We also
review the characteristic changes in lysosomal hydrolases and membrane proteins in common
autoimmune diseases.
4. Etiology, pathogenesis and prevention of accumulation diseases.
5. The role of disorders of the structure and function of cell membranes in th
development of pathological processes.
Cell membrane disorders result in damage to membrane pumps operating for regulation of sodium
and calcium and organelle failure as under;
i)Failure of sodium-potassium pump-Results in intracellular accumulation of sodium and diffusion o
potassium out of cell. The accumulation of sodium in the cell leads to increase in intracellular water
to maintain isosmotic conditions (i.e.hydropic swelling occurs)
ii)failure of calcium pump-Membrane damage causes disturbance in the calcium ion exchange acros
the cell membrane. Excess of calcium moves into the cell (i.e. Calcium influx) particularly in the
mitochondria,causing its swelling and deposition of phospholipid-rich amorphous denities.
iii)Organelle failure-due to uncontrolled iron influx.
6. Pathology of the cell nucleus.
The nucleus, which is surrounded by the cytoplasm and generally is located in the center of the cell,
is the largest membrane-bound organelle. Two pliable membranes compose the nuclear envelope.
The nuclear envelope is pockmarked with pits, called nuclear pores, which allow chemical messages
to exit and enter the nucleus). The outer membrane is continuous with membranes of the endoplasm
reticulum (The nucleus contains the nucleolus (a small dense structure composed largely of RNA),
most of the cellular DNA, and the DNA-binding proteins (i.e., the histones) that regulate its activity.
The DNA “chain” in eukaryotic cells is so long that it is easily broken. Therefore the histones that
bind to DNA cause DNA to fold into chromosomes which decreases the risk of breakage and is
essential for cell division in eukaryotes.
The primary functions of the nucleus are cell division and control of genetic information. Other
functions include the replication and repair of DNA and the transcription of the information stored in
DNA. Genetic information is transcribed into RNA, which can be processed into messenger,
transport, and ribosomal RNAs and introduced into the cytoplasm, where it directs cellular activities
Most of the processing of RNA occurs in the nucleolus.
Karyolysis – “Nuclear fading” – Chromatin dissolution due to action of DNAses and RNAses Pyknos
– “Nuclear shrinkage” – DNA condenses into shrunken basophilic mass
, Karyorrhexis – “Nuclear fragmentation” – Pyknotic nuclei membrane ruptures and nucleus undergo
fragmentation
Then all undergo nuclear dissolution→Leading to an anuclear necrotic cell
7. Changes in mitochondria under physiological and pathological conditions
The mitochondria
Mitochondria contain metabolic machinery needed for cellular energy metabolism. Enzymes of
respiratory chain (electron-transport chain), found in inner membrane of mitochondria, generate mos
of cell's adenosine triphosphate (ATP) (oxidative phosphorylation). Have a role in osmotic
regulation, pH control, calcium homeostasis, and cell signalling. Oxidative phosphorylation occurs i
the mitochondria and is the mechanism by which the energy produced from carbohydrates, fats, and
proteins is transferred to ATP .
xPhysiological and pathological conditions
In normal cells mitochondria are dense , they have dark matrix and many crista.
• Enzymes are inside.
Typical response to functional overload of cells is mitochondrial
• swelling, which is due to decrease of ATP. Because if there is damage ,cell requires more
energy, so the intracellular level of ATP decreases
When the cell is overloaded its ATP is actively consumed which leads an increased in ADP In these
cases permeability of membrane increases, water .inter to the mitochondria and valum expands
considerably Mitochondria swelling is a protective response. because in this situation mitochondria
begins to produce more energy. it is explained by significant enlargement of the internal .membrane
area
mitochondrial swelling is a positive mechanism because it leads to increase in energy production if
some cells suffers of overload for long period of time, its ,mitchondria can be destroyed leading to
cell death There are 3 main stages of mitchondrial damage or destruction
• Swelling Vacculization (when matrix is lost in some spaces)becasue is matric there is enzyme
responsible petoduction ? of carbohydrates Absolute or complete lost of mitchondrial matrix ……
Pathological changes of mitochondria based on the morphological basis are classified into two
categories: simple swelling and the formation of megamitochondria (MG) (1, 2). Simple swelling
causes the enlargement of mitochondria at most 2-3 times larger in size. Further swelling of
mitochondria results in the rupture of the outer membrane, thus causing the loss of their contents. On
the other hand, one may call "MG” when they exceed those extents in diameters compared to contro
ones.
1. The role of lysosomes in the development of pathological processes.
All lysosomal enzyme are activated in case of inflammation. Sac-like structures that contain enzym
for digesting most cellular substances to their basic form, such as amino acids, fatty acids, an
carbohydrates (sugars). Cellular injury leads to release of lysosomal enzymes that cause cellular sel
destruction. A new function of lysosomes is signaling hubs of a sophisticated network for cellul
adaptation. Inside the cell, lysosomal enzymes process and digest material ingested by endocytosis.
These enzymes causes:
• Degranulation of smooth cells, activation of Hageman factor, activation of complement
• Release of histamine connection w/ gamma-globulin, lysis of cell’s membrane
• Formation of channels In endothelium
• Activation of Kallikereine G.d increase of vascular-tissue permeability
2. Lysosomal diseases. Pathogenesis, the main manifestations, diagnost
methods.
Disorders of lipid metabolism are termed lysosomal storage diseases because each disorder in this
group can be traced to a missing lysosomal enzyme. Lysosomal storage
disorders include more than 50 known genetic disorders. The incidence of lysosomal storage
disorders is approximately 1 in 5000 live births.These disorders cause an
excessive accumulation of a particular cell product, occurring in the brain, liver, spleen, bone, and
lung, and thus involving several organ systems. Generally these disorders are not included in
newborn screening. Some of these disorders may be treated with enzyme replacement therapy.
Main manifestations
• Aspartylglucosaminuria: Patients appear normal for several months after birth and then presen
with recurrent infections, diarrhea, and hernias. Later, there may be a gradual coarsening of facial
features, an enlarged tongue (macroglossia) and enlargement of the liver (hepatomegaly).
• Batten Disease: It is characterized by the accumulation of a fatty substance (lipopigment) in th
brain, as well as in tissue that does not contain nerve cells. Batten disease is marked by rapidly
progressive vision failure (optic atrophy) and neurological disturbances
• Cystinosis: The early signs of this disorder typically involve the kidneys and the eyes.
Excessive storage of the amino acid cystine in all cells of the b
• Fabry Disease: Early symptoms include episodes of severe burning pain in the hands and feet.
Other early signs may include a decrease in sweat production
,• Gaucher Disease Types I, II, and III. Neurological complications may include mental
deterioration, an inability to coordinate voluntary movements, and muscle spasms of the arms, legs,
or entire body.
• Glycogen Storage Disease II (Pompe Disease): The cardiac enlargement that is often present i
the infantile form is seldom seen in the childhood form.
Pathophysiology / etiology
• LSDs are caused by mutations in genes encoding soluble acidic hydrolases, activator proteins
transporter proteins, integral membrane proteins or nonlysosomal proteins that are necessary for
lysosomal function
• Main genes in LSDs: glucosylceramidase beta / GBA (Gaucher), galactosidase alpha / GLA
(Fabry), sphingomyelin phosphodiesterase 1 / SMPD1 (Niemann-Pick), hexosaminidase subunit
alpha / HEXA (Tay-Sachs), iduronate 2-sulfatase / IDS (Hunter), glucosidase alpha, acid / GAA
(Pompe), cystinosin, lysosomal cystine transporter / CTNS (cystinosis)
• As a result, metabolic machinery of the cell is impaired by defects in degradative and syntheti
enzymes, lysosomal membrane defects, disorders of lysosome biogenesis and endosome- lysosome
traffic
• Pathogenetic cascade leads to intralysosomal accumulation of undegraded substrates in
multiple tissues and organs
• Excessive storage of a substrate triggers cell damage via several mechanisms: activation of
apoptosis, alterations of plasma membrane lipid content (affect receptor responses and downstream
signaling), prolonged inflammation, calcium imbalance, dysregulation of autophagy, etc. (Nat Rev
Neurol 2013;9:583)
• All LSDs are inherited in an autosomal recessive manner, except X linked recessive Fabry,
Hunter and Danon diseases
Diagnosis and differential diagnosis
• Prenatal diagnosis is made by measuring alpha-glucosidase activity in cultures of amniotic
cells and samples of chorionic villus.
• The differential diagnosis includes Duchenne muscular dystrophy, dystrophy of the limb girdl
dystrophy, and polymyositis.
3. The role of lysosomes in the development of inflammatory response.
The primary function of lysosomes is to degrade macromolecules through a series of enzymatic
reactions that are activated at acidic pH. This process is required to degrade molecules that are
internalized by cells (eg, by the process of endocytosis) or endogenous molecules that are
components of normal cell structures (eg, cell membranes, cytoskeleton, nucleic acids).
lysosomes play a diverse and important role in immunity and inflammation, in part through the
regulation of autophagy, control of inflammasome release of cytokines, and the regulation of
sphingolipid metabolism. In general, healthy lysosomes are required to exhibit a normal host
response to infection and to maintain a normal inflammatory response. Defective lysosomes lead to
abnormal autophagy, activation of inflammation, and reduced infection control.
,Lysosomes perform a range of functions, some of which, such as degradation, are common to all cel
types. Others, such as secretion or lysosomal exocytosis, are more specialised and tend to involve
fusion of this organelle with the cell surface to release its contents. This review describes lysosomal
regulation of the inflammatory glucocorticoid signaling pathways, and summarizes the roles of
lysosomes in negatively or positively modulating the production of inflammatory cytokines. We also
review the characteristic changes in lysosomal hydrolases and membrane proteins in common
autoimmune diseases.
4. Etiology, pathogenesis and prevention of accumulation diseases.
5. The role of disorders of the structure and function of cell membranes in th
development of pathological processes.
Cell membrane disorders result in damage to membrane pumps operating for regulation of sodium
and calcium and organelle failure as under;
i)Failure of sodium-potassium pump-Results in intracellular accumulation of sodium and diffusion o
potassium out of cell. The accumulation of sodium in the cell leads to increase in intracellular water
to maintain isosmotic conditions (i.e.hydropic swelling occurs)
ii)failure of calcium pump-Membrane damage causes disturbance in the calcium ion exchange acros
the cell membrane. Excess of calcium moves into the cell (i.e. Calcium influx) particularly in the
mitochondria,causing its swelling and deposition of phospholipid-rich amorphous denities.
iii)Organelle failure-due to uncontrolled iron influx.
6. Pathology of the cell nucleus.
The nucleus, which is surrounded by the cytoplasm and generally is located in the center of the cell,
is the largest membrane-bound organelle. Two pliable membranes compose the nuclear envelope.
The nuclear envelope is pockmarked with pits, called nuclear pores, which allow chemical messages
to exit and enter the nucleus). The outer membrane is continuous with membranes of the endoplasm
reticulum (The nucleus contains the nucleolus (a small dense structure composed largely of RNA),
most of the cellular DNA, and the DNA-binding proteins (i.e., the histones) that regulate its activity.
The DNA “chain” in eukaryotic cells is so long that it is easily broken. Therefore the histones that
bind to DNA cause DNA to fold into chromosomes which decreases the risk of breakage and is
essential for cell division in eukaryotes.
The primary functions of the nucleus are cell division and control of genetic information. Other
functions include the replication and repair of DNA and the transcription of the information stored in
DNA. Genetic information is transcribed into RNA, which can be processed into messenger,
transport, and ribosomal RNAs and introduced into the cytoplasm, where it directs cellular activities
Most of the processing of RNA occurs in the nucleolus.
Karyolysis – “Nuclear fading” – Chromatin dissolution due to action of DNAses and RNAses Pyknos
– “Nuclear shrinkage” – DNA condenses into shrunken basophilic mass
, Karyorrhexis – “Nuclear fragmentation” – Pyknotic nuclei membrane ruptures and nucleus undergo
fragmentation
Then all undergo nuclear dissolution→Leading to an anuclear necrotic cell
7. Changes in mitochondria under physiological and pathological conditions
The mitochondria
Mitochondria contain metabolic machinery needed for cellular energy metabolism. Enzymes of
respiratory chain (electron-transport chain), found in inner membrane of mitochondria, generate mos
of cell's adenosine triphosphate (ATP) (oxidative phosphorylation). Have a role in osmotic
regulation, pH control, calcium homeostasis, and cell signalling. Oxidative phosphorylation occurs i
the mitochondria and is the mechanism by which the energy produced from carbohydrates, fats, and
proteins is transferred to ATP .
xPhysiological and pathological conditions
In normal cells mitochondria are dense , they have dark matrix and many crista.
• Enzymes are inside.
Typical response to functional overload of cells is mitochondrial
• swelling, which is due to decrease of ATP. Because if there is damage ,cell requires more
energy, so the intracellular level of ATP decreases
When the cell is overloaded its ATP is actively consumed which leads an increased in ADP In these
cases permeability of membrane increases, water .inter to the mitochondria and valum expands
considerably Mitochondria swelling is a protective response. because in this situation mitochondria
begins to produce more energy. it is explained by significant enlargement of the internal .membrane
area
mitochondrial swelling is a positive mechanism because it leads to increase in energy production if
some cells suffers of overload for long period of time, its ,mitchondria can be destroyed leading to
cell death There are 3 main stages of mitchondrial damage or destruction
• Swelling Vacculization (when matrix is lost in some spaces)becasue is matric there is enzyme
responsible petoduction ? of carbohydrates Absolute or complete lost of mitchondrial matrix ……
Pathological changes of mitochondria based on the morphological basis are classified into two
categories: simple swelling and the formation of megamitochondria (MG) (1, 2). Simple swelling
causes the enlargement of mitochondria at most 2-3 times larger in size. Further swelling of
mitochondria results in the rupture of the outer membrane, thus causing the loss of their contents. On
the other hand, one may call "MG” when they exceed those extents in diameters compared to contro
ones.
