PHYSIOLOGY

- - -GELLULAR
Phs1Jiolog1J & Pa -lhologlJ

Af,-o. To.fl9eeh.com
Table of Contents
Cellular Structure & Processes 1
Cellular Structure & Function 1
Cell Membrane 3
Selective Permeability
of the cell membrane 4
Extracellular Matrix 5
Cell-Cell Junctions 7
Endocytosis & Exocytosis 8
Osmosis 9
Resting Membrane Potential 10
Cell Signaling Pathways 11
Cytoskeleton & Intracellular
Motility 18
Nuclear Structure 20
Cellular Pathology 22
Necrosis & Apoptosis 22
Oncogenes & Tumor Suppressor Genes 25
Hyperplasia & Hypertrophy 26
Metaplasia & Dysplasia 27
Atrophy, Aplasia & Hypoplasia 27
Free Radicals & Cellular Injury 28
Ischemia 29
Inflammation 29
NOTES

CELLULAR STRUCTURE &

FUNCTION
osmsJl/ eellulo.T-s-lTue-luTe-o.nd-fune-lion
CELL STRUCTURE BASICS , Larger subunit: has ribozyme to catalyze
• Basic structural, biological, functional unit peptide bond formation (for bonds
that comprise organism between amino acids)
• Smallest self-replicating life-form
Endoplasmic reticulum
• Over 200 types in human body
• Membrane-enclosed organelle
• Cells - tissue - organ - organ systems • Appearance: stack of membranous,
- organism flattened disks (cisterns)
Basic constituents • Rough endoplasmic reticulum (RER)
• Plasma membrane , Contains bound ribosomes on surface
• Cytoplasm , Site of packaging, folding of proteins
° Fluid suspension
designated for secretion, lysosomal
degradation, plasma membrane
° Composition: cytosol, organelles
insertion; proteins packed into vesicles,
sent to Golgi apparatus for further
CYTOSOL modification
• Intracellular fluid , RER cisterna continuous with nuclear
° Composition: water; dissolved/ envelope
suspended organic, inorganic chemicals; • Smooth endoplasmic reticulum (SER)
macromolecules; pigments; organelles , No ribosomes
• Site of most cellular activity , Site of lipid, steroid synthesis, Ca2• ions
storage (muscles). glycogen metabolism.
ORGANELLES detoxification (liver)

• Specialized cellular subunits carry out Golgi apparatus (complex)

essential functions
Ribosomes
• Composition: rRNA. ribosomal proteins
• Can exist freely in cytoplasm/bound to
endoplasmic reticulum (forms rough
endoplasmic reticulum)
• Turns mRNA into protein via translation
• Organized into two subunits (40s, 60s)
O Small subunit: binding sites for mRNA,
tRNA
• Membrane-enclosed organelle
, Appearance: collection of fused,
flattened sacs (cisterns) with associated
vesicles. vacuoles
• Two sides
, Cis side: receives proteins from RER
(entry)
, Trans side: opposite side, releases
vesicles towards plasma membrane
(exit)

1
 afratafreeh.com exclusive
• Post-translational modification site (e.g. , In glucose absence, mitochondria can
phosphorylation, glycosylation, sulfonation) use fatty acids as fuel via beta oxidation
of proteins, lipids, hormones - sorted, (only medium sized fatty acids used;
packaged into secretory vesicles - longer ones chopped by peroxisome)
secreted out of cell/lysosomal fusion/plasma • Mitochondria number: correlates with cell
membrane insertion activity/energy requirements

Mitochondria Nucleus
• Double membrane-enclosed organelle; • Large, membrane-enclosed organelle
synthesizes ATP for cell via aerobic present in all cells except mature
respiration erythrocytes
O Outer smooth membrane: encloses • Contains genetic material (DNA, tightly
whole organelle packed into chromatin); coordinates cellular
O Inner membrane: forms folds, caverns activities
called cristae (contain proteins needed • Most cells contain one nucleus; some
for aerobic respiration); encloses cells have more (e.g. skeletal muscle cells,
mitochondrial matrix (contains osteoclasts, hepatocytes)
mitochondrial DNA, ribosomes) • Usually spherical, may take on other shapes
• lntermembrane space: space between , Lobulated (e.g. polymorphonuclear
inner, outer membrane leukocytes)
• In cytoplasm glucose undergoes glycolysis, , Elongated (e.g. columnar epithelium)
glucose cleaved into pyruvate
O Pyruvate enters mitochondria -
citric acid cycle (Krebs cycle), electron
transport chain (require oxygen)

C,£LL
~
GE.LL NUGLEUS E NDOPLASHIG
MEMIRANt~~~--- L GENETIC, MATERIAL RETIC.ULUH
L PHOSPHOLIPID 81LAVER L GENERATES
- PROT£1NS. LIPIDS.
~ STEROIDS

G'ITOSKELETON --c:r G'ITOSOL

L STRUCTURALSTABILITY L INTRACELLULARFLUID

CiiOL..Ciil APPARATUs--- MITOC.HONPIUA

L PAC,KAG£S PROTE.INS, L £NERG.'I
LIPIDS, i. HO~MON£S - AEROIIC:., 1£ TA
INTO VESIC,L£S R£'PIIATION
PE.ROXISOME .Jt
L C,I-IOPS LONG. FATTV AC.IDS
l,11rn1 :,l11c.os&, '•**:t
ac.icls
J,
ME:DIUM FATTV AC,IDS

Figure 23.1 Cellular structures and their functions.

2
 CELL MEMBRANE
osms.i"l/ eell-mem\>Te1ne

• Semipermeable membrane made from • Semipermeable

phospholipid bilayer; surrounds cell , Allows passage of certain molecules
cytoplasm through membrane (02, C02, etc.)
, Denies passage of others (large
Phospholipid bilayer
molecules such as proteins, glucose)
• Two-layered polar phospholipid molecules
• Certain molecule transportation (ions, H20)
comprising two parts
allowed through embedded membrane
O Negatively charged phosphate "head"
proteins (ion channels, pumps)
(hydrophilic; oriented outwards)
° Fatty acid "tail" (hydrophobic; oriented
inwards)
TRANSPORT PROTEINS

PHOSPHOLIPID
r +
CHANNELS CARRIERS ENZYMES
"'
_.,,,-HEAD:PHOSPHATE
- HYDROPHILIC.

~SKELETON:uLVCEROL

TAIL: FATTV ACIDS

- llPOPHILIC.
- IWDR0PH081C.
Figure 23.3 Transport proteins move
molecules that can't freely diffuse across
the cell membrane. Channels form a
tunnel through which water and ions flow.
WATER Carriers have a binding site for a specific
molecule and gates at both ends that open
sequentially. Enzymes, or ATPases, actively
pump ions in/out of the cell against their
concentration gradients.

~-~~-W_A-TE._R__.,J
\
81LAV€R
Figure 23.2 Phospholipid parts and their
arrangement in a cell membrane.

3
 SELECTIVE PERMEABILITY OF
THE CELL MEMBRANE
osms.i"l/ eell-mem\>Te1ne-selee-live-peTmee1\>ili-l14

• Cell membrane controls which molecules Channels

enter, leave • Non-specific; open to allow water, small
O Passive transport: no energy required polar molecules through (e.g. voltage-gated
O Active transport: energy required ----> calcium channel)
adenosine triphosphate (ATP)
Carrier proteins
• Very specific, only allow certain molecules
PASSIVE TRANSPORT to bind (e.g. glucose transporter protein
GLUT4)
Simple diffusion
• Random molecular motion
• Small, non polar molecules move from t ACTIVE TRANSPORT
concentration ----> I concentration
Primary
Fick's law • Uses ATP
• Three factors affect diffusive flux , Enzymes called ATPases use ATP as
• Concentration gradient fuel; (e.g. Na·-K· ATPase, Ca2- ATPase,
H--K· ATPase)
O Larger differences in solute
concentration on each side of , May create concentration/
mernbrane-» l driving torce-« j net electrochemical gradients
diffusion
Secondary
O Equal concentrations ----> no net diffusion
• Uses existing electrochemical gradients
(e.g.C02, 02 movement between alveoli,
, One solute, normally Na", moves
blood)
with concentration gradient through
• Membrane surface area
transporter=- supplies energy
O j surface area available for diffusion ----> l transporter needs to-» another solute
diffusion rate; vice versa (e.g. microvilli in against concentration gradient in same/
small intestines amplify surface area ----> opposite direction as Na· (e.g. sodium-
j nutrient, water absorption) glucose SGLTl transporter)
• Distance separating each side of
membrane (e.g. thickness) Bulk transport
O j distance molecules must travel-s ! • AKA vesicular transport
net diffusion; vice versa (e.g. pulmonary • Endocytosis
edema ----> j distance between , Cell membrane invaginates, pulling
cornpartments=- ! net diffusion) something in from outside (e.g.
pathogen phagocytosis)
Facilitated diffusion
• Exocytosis
• Uses transport proteins (e.g. channels,
, Vesicle inside cell pushes something out
carrier proteins)
(e.g. hormone secretion)
• Allows larger/polar molecules to move
across membrane

4
 afratafreeh.com exclusive
BULK TRANSPORT
~
MEMBRANE
ENDOCYTOSIS / INVAGINATES

EXOCYTOSIS

Illll11lllllllllllllllllllllllllll11Il11l
VESICLE- ~

Figure 23.4 Endocytosis and exocytosis.

EXTRACELLULAR MATRIX
osmsJl/ ex-lTo.eellulo.T-mo.-lTix
• Environment surrounding cells
• Varies between tissues (epithelial,
connective, muscular, and nervous)
THREE MAJ"OR MOLECULES
Adhesive proteins
• Adhere cells together (communication
extracellular fluid)
O E.g. integrins, cadherins
, Starts as procollaqen-» cleaved into
tropocollagen ----> arranged into collagen
fibrils
, Four types: type I (bone, skin, tendon).
type II (cartilage), type Ill (reticulin, blood
vessels), type IV (basement membrane)
• Elastin
with , Elastic, returns tissue to original shape
• Keratin
, Tough, found in hair, nails

Structural proteins Proteoglycans

• Give tissues tensile, compressive strength • Fill space between cells, hydrate, cushion
• Collagen cells
O Resists tension, can stretch , Consists of protein core with sugar
chains

5
 ADHESIVE
,...__,.._ PROT£1NS~ - STRUGTURAL/FIIROUS PROTtlNS

,,
"-"

COLLAGrE.N ELAS TIN KERATIN

J
fiYl'lllt.SSi s!rc.!c." it hAir &. 11Ails
rc.sis!cuic.c. rc.!Cli11 •"Ape.

Figure 23.6 The three kinds of structural

proteins in the extracellular matrix and their
functions.

Figure 23.5 Cadherins and integrins are both

adhesive proteins which hold cells together.

C.OttAGEN
~

COLLAGEN
PROCOLLAGEN PEPTIDEASES TROPOCOLLAGEN

W!il!!!!l!l!/!J!ililJ
l

COLLAGEN FIBER COLLAGEN FIBRIL

Figure 23.7 Collagen production steps.

PROT£06LVGANS
~

C..HAINS OF SU&AP.S
( GLVCOSAMINO&L'IC.ANS)
Figure 23.8 Structure of proteoglycans, which hydrate and cushion cells.
6
 CELL-CELL J"UNCTIONS
osms.i"l/eell-eell_june-lions
• Protein structures that physically connect
cells
• Improve cellular communication, tissue
structure; allow transport of some
substances between cells, create
impermeable barrier for others
• Only found between immobile cells;
abundant in epithelial tissue (e.g. in skin)
THREE J"UNCTION TYPES
Tight junctions
• E.g. in gastrointestinal tract/brain
• Seal adjacent-cell plasma membranes,
especially near apical surface; prevent
passage of water, small proteins, bacteria
° Formed by claudins, occludins
embedded in cellular plasma
membranes
O In "leaky" epithelia, tightjunctions may
allow certain molecules to pass (e.g. K+,
Na+, Cl in kidney's proximal tubules-
due to ion pores)
ceu.-ccu, 3'UNC.TIONS
CAO HEP.INS
PP.OTEIN}
PLAQUES FILAMENTS
Figure 23.9 The three types of cell junctions.
Adherens junctions
• E.g. in skin
• Anchor cells together, provide strength;
consist of three major components
, Actin filaments: provide cellular shape
, Protein plaques: anchor membrane,
bind to actin filaments
, Cadherins: attach to protein plaques,
connect to cadherins on other cells
Gap junctions
• E.g. in heart
• Connect adjacent cells, allow rapid
communication; formed by connexins --->
create tubular structure (allows charged
particles to pass)
, In cardiac myocytes: gap junctions
create coordinated heart contractions
, In infected cells: gap junctions send
cytokines to neighboring cells, triggering
apoptosis, preventing infectious spread
("bystander effect")
TIGHT J'Ul'IC,TIONS
'--e,LAUDINS
\.occLUDINS
\
ACTIN
7
 ENDOCYTOSIS & EXOCYTOSIS
osms.i"l/ e ndoe14-losis-o.nd-exoe14-losis
• Transports material in/out of cell • Edges of pit come together, clathrin
• Requires adenosine triphosphate (ATP) for proteins link up
energy • Vesicle pinches off; clathrin detaches,
returns to cell membrane

ENDOCYTOSIS • Vesicle merges with endosome to separate

receptors into second vesicle
• Cells engulf extracellular material

PHAGOCYTOSIS
• AKA cell eating PHAGOOiTOSIS
• Used by white blood cells (e.g.
macrophages, neutrophils)

Process PINOOlTOSIS
• Cell extends arm-like projects (AKA
pseudopods) around target
• Cell membrane slowly engulfs target,
invaginates to form vesicle RECE.PTOR-MEDIATED
ENDOCYTOSIS
• Vesicle separates from cell membrane to
form phagosome
Figure 23.10 The three types of endocytosis.
• Phagosome fuses with lysosome, target is
digested
• Debris released by exocytosis EXOCYTOSIS
• Cells expel material into extracellular space
PINOCYTOSIS (e.g. neurotransmitters, hormones)
• AKA cell drinking • Last phagocytosis step
• Used by most cells to take in extracellular
fluid; non-specific Process
• Golgi apparatus creates vesicle from
Process various proteins, lipids, hormones
• Cell membrane invaginates around • Motor proteins use ATP to carry vesicle
extracellular fluid along cytoskeleton
• Edges of invagination come together to • Vesicle is pressed against cell membrane
form vesicle until rupture - spills contents into
• Motor proteins use ATP to carry vesicle into extracellular space
cytosol

RECEPTOR-MEDIATED
ENDOCYTOSIS
• Used by cells to take in specific molecules
(e.g. iron, cholesterol)

Process
• Clathrin-covered pits/coated pits with
Figure 23.11 Exocytosis: expulsion of
receptors bind certain molecules
material into extracellular space.
8
 OSMOSIS
osms.i"l/ osmosis
• Passive water-flow across selectively
permeable (semipermeable) cellular
membrane; primarily determined by
solute concentration differences (osmotic
pressure)
Factors affecting water movement across
membrane
• Molecules (e.g. water molecules, ions)
tend to move around (kinetic energy) +
movement is disordered, random (entropy)
- larger solutes tend to block openings in
semipermeable membrane
• If solute ions positively charged, they attract
slightly negatively charged oxygen atom in
water molecule; if solute ions are negatively
charged, they attract slightly positively
charged hydrogen atoms in water molecule
- water molecules partially attached to ion
- movement through membrane impeded
• Water molecules tend to move from
hypotonic side (more water/less solutes) to
hypertonic side (less water/more solutes)
SELECTIVELY-PERMEABLE
MEMBRANE
• Allows small molecules (e.g. water) across,
but not larger molecules/ions
Isotonic solution
• Side A = side B
• If solute concentration is same on each
side of membrane - net water movement
across membrane is zero (equilibrium)
Hypertonic/hypotonic solution
• Side A > side B or side B > side A
• If solute concentration is greater on one
side (hypertonic) - net water migration
across membrane is from hypotonic side
toward hypertonic side
CELLULAR EFFECT
• Red blood cell in hypertonic solution - net
movement of water molecules out of cell -
cell shrinks (crenation)
• Red blood cell in hypotonic solution - net
movement of water molecules into cell -
cell swells, may burst (lyses)

A """ 8 ""'" 1$0TONIG

[NAj
GA= GB
[er]
8
EQUILl8P.IUM:NET MOVEMENT of WATER
ACROSS the MEMBRANEis ZERO

H'i'PERTONIC ~ H'i'POTONIC, EQUALIZES

C,ONC,ENTI\ATIONS

PASSIVE. DIFFUSION
Figure 23.12 Net water molecule movement between isotonic, hyper/hypotonic solutions.
9
 afratafreeh.com exclusive

RESTING MEMBRANE POTENTIAL

osms.i"l/Tes-ling-mem\>To.ne-po-len-lio.l
• Electric potential across cell membrane
V =30.75xJog([ION]out)
O Given by weighted (based on m ~ [ION]
, Double charge: in
membrane permeability) sum of
equilibrium potentials for all ions = Value is flipped for negative ions
• High concentrations of Na-. Cl, Ca2• • Resting membrane potential is sum
outside cell; high concentrations of K+, A of equilibrium potentials of major ions
(various anions) inside cell ----> concentration multiplied by their membrane permeabilities
gradients are established
O Sodium-potassium pump uses ATP to _;
move two K ions into cell, three Na ions
out ELEG tll,oSTATlC.
O Potassium concentration= 150mMol/L C;ii'!AOI ~tJT (~iv,)
inside cell, 5mMol/L outside
• Concentration gradients establish
electrostatic gradients
° Concentration gradient pushes C.OIJU.tJffl.At\O~
potassium out through potassium leak C:i~~DIWT (~011--l)
channels, inward rectifier channels
O Anions remain in cell----> negative charge
builds up----> potassium is pulled back LN£(1.N5T)
into cell ~011--l = ~-iv, ~ fGl.llU6121U~
flOTEtJTIAL
• Equilibrium (Nernst) potential: electrostatic
gradient equal to concentration gradient Figure 23.13 Equilibrium potential = electric
(-92mV for potassium) potential for attracting K· back into the cell
• Nernst equation: equilibrium potential for that's needed to balance the concentration
anion gradient pushing K· out of the cell.

O Single charge: V =61.5xlog([ION]out)

m ~ [ION]m

% of IONS MOVING
ACROSS MEMBRANE EQUILIBRIUM POTENTIALS CONCENTRATION

IL... 9 -9l,,:v ( c:i')

i1 ...\J 1-111.,1-1--4•~ LovJ
+
(o.'H~ 12!1 '"" (.o i)= \ .H ...v Low 1-\1 GH
+
No.+~ ~'l v [» I)= o.~MI/ LO\)) --- HIGH

c.,-=9 ,i~ \I (.oi}=-~.u ...v LOW \-1\GH

Figure 23.14 The resting membrane potential is closest to the equilibrium potential of the most
permeable ion (K-J. Change in permeability----> change in resting membrane potential.
10
 CELL SIGNALING PATHWAYS
osms.i"l/eell-signo.ling-po.-lhwo.14s
INTRACELLULAR SIGNAL Cell signalling pathway stages
CLASSIFICATION l.Reception: ligand binds to receptor
• Classified according to distance between 2.Transduction: receptor changes activating
signaling, target cells intracellular molecules
O Autocrine: cell signals nearby cells 3.Response: signal triggers a response in the
of same type, including itself (e.g. target cell
monocytes secrete interleukin-1 ~)
O Paracrine: cell signals nearby cells of
different type (e.g. ECL cells secrete MAJ"OR TRANSMEMBRANE
histanune=-s signals D cells to secrete RECEPTOR CLASSES
somatostatin)
G protein-coupled receptors
O Endocrine: cell signals distant cells (e.g.
• Seven-pass transmembrane receptors
pituitary gland secretes TSH ----. signals
• Activate guanine nucleotide-binding (G)
thyroid gland)
proteins inside cell
• Signalling molecules (ligands) bind to
, G proteins have three subunits: alpha,
receptors; can be hydrophobic/hydrophilic
beta, gamma
O Hydrophobic: can't float in extracellular
, Alpha binds guanosine diphosphate
space----. brought to target cells
(GDP) when inactive
by hydrophilic carrier proteins; can
diffuse over cell mernbranes=- bind to , When ligand binds, alpha releases
receptors inside cell GDP, binds guanosine triphosphate
(GTP) instead ----. alpha separates from
O Hydrophilic: can float in extracellular
beta, gamma ----. alpha interacts with
space ----. reach target cells themselves;
proteins turning GTP back into GDP----.
can't diffuse over cell membranes=-
reattaches
bind to cell surface (transmembrane)
receptors

* AUTOCI\INE. Sl&NALS * PARAGRINE SIGNALS * ENDOCI\INE. SIGNALS

··~·
..•
L NE.ARSV C.E.LLS L DISTANT CELLS

..
L SAME. CE.LL

• •
•
•
ct··:.
OJ .\;)
,c:~·
~
•

* HVDROPH081C LIGANDS * HVDI\OPHILIC LIGANDS

. CK
-"O REC.E.PTOP.
PMTE.INS
~
~
TRANSME.M8RAN£.
RE.CE.PTORS

Figure 23.15 Autocrine. paracrine. and endocrine signals refer to signal distance from its target
cell. Hydrophobic and hydrophilic ligands refer to the affinity of the ligand for water.

11
 I. &-PROTEIN C,OUPLED RECEPTORS
INAGTIVE
G-PltOTEIN-{ Q Q ?$
SUBUNITS I-:'
\
t SUBUNITS
GOME TOGETHER
* Prot6i11is t11rn6d.off
Figure 23.16 Mechanism of action of G-protein coupled receptors.
• Three types of G protein with different
pathways
o G q : activates phospholipase C in cell
membrane - phospholipase C cleaves
phosphatidylinositol 4,5-bisphosphate
into inositol trisphosphate, diacylglycerol
- inositol trisphosphate opens calcium
channels in endoplasmic reticulum
(calcium flows to cytoplasm, changing
electrical charge distribution in cell
- cell depolarization); diacylglycerol
binds to protein kinase C which
phosphorylates target proteins
O Gs: stimulates adenylate cyclase -
adenylate cyclase removes phosphate
from adenosine triphosphate
(ATP) creating cyclic adenosine
monophosphate (cAMP) - cAMP binds
to regulatory subunit of protein kinase A
- catalytic subunit of protein kinase A
phosphorylates target proteins
O G.: inhibits adenylate cyclase - negative
f~edback on Gs
Enzyme-coupled receptors
• Single-pass transmembrane receptors
• Trigger enzymatic activity inside cell when
specific ligands bind
AGTIVE
* GTP l,i11cls to * AlPHA SUBUNIT
5-prote.i11 sapa1'atas
• Composition: extracellular, ligand-binding
domain; intracellular, enzymatic domain
• Three main enzyme-coupled receptor types
, Receptor tyrosine kinases: when ligand
binds, these phosphorylate their own
tyrosine residues - conformational
change creates binding site for other
signalling proteins
, Tyrosine kinase associated receptors:
when ligand binds, these phosphorylate
various proteins to relay signal to
tyrosine kinases inside cell
, Receptor serine/threonine kinases:
when ligand binds, type II receptors of
this kind phosphorylate type I receptors,
which in turn phosphorylate various
proteins to relay signal to serine/
threonine kinase domain inside cell
Ion channel receptors
• Ion channels which open when specific
ligands bind
• Allow ions (e.g. chloride, calcium, sodium,
potassium) to flow through
• Resulting shift in electric charge distribution
triggers response
12
 PHOSPHOIWL
(;,ROUP

ENDOPLASMIC.
RETICULUM

Figure 23.17 Gq pathway.

•PROTEIN*

G ~ S
ADENVLATe:
GVGLASE

LJJ o(--LJ
/" PP.OTEIN

~. ll TRIG.GEP,S
C.ELLULAP,
RESPONSE

Figure 23.18 Gs pathway.

• filE6"TIVt
Fttl>IAC.K

Figure 23.19 G; pathway.

13
 II. £NZVM£-COUPLED RE.C,E.PTORS
1. RECEPTOR TVROSI NE Kl NASE. J.•" M£SSENG£RS
" '"" ~. phtsphtrtl•t•'
L actl"u•'

4 LIC:iANDS BIND * DIM£RIZE * GROSS- * TRIG.Gi£RS SIGNALING.

PHOSPHOIWLATION PATHWAV

2. TVROSINE IC.INASE ASSOGIATE.D RECEPTORS

~ RECEPTORS
BIND LIC:aAND

C.VTOPLASMIG
TVROSINE KINASE

0 ......_,;:, ,,. ill PHOSPHORVLATES TARGET PROTEINS

3. RECEPTOR SE.RINE/THREONINE Kl NASE

('--'1"'SJ ') P.£GRUITS anil

~"' PHOSPHORVLATES
TARGET PI\OTEINS
TVP£ II REC.EPTOI\
PHOSPHORVLATES ancl
AC.TIVATES TVPE 11\EC,EPTOI\

Figure 23.20 Types of enzyme-coupled receptors and their pathways.

111. ION C,HANN£L R£CEPTO~S l> IONS FLOW

{> DOWN GiRADIENT
~ ~ <1

ill CHANNEL
CLOSED

Figure 23.21 Mechanism of action for ion channel receptors.

14
HORMONAL MECHANISMS
• All cells receive, process outside signals via
specific proteins (receptors)
O Ligand (signalling molecule-e.g.
hormone) binds to receptor -
physiological response
• Target tissue sensitivity to hormone effect
controlled by receptor quantity/affinity
O t receptor quantity - t maximal
response
O t receptor affinity - t response
likelihood
HORMONE RECEPTOR
UPREGULATION/DOWNREGULATION
Down regulation
• External stimulus - cell ! hormonal
receptor quantity/affinity
° Chronic exposure to excessive signalling
molecules (e.g. neurotransmitters/
drugs - ligand-induced target receptor
desensitization/internalization)
O Hormones may alter other hormonal
receptor sensitivity (e.g. in uterus-
progesterone downregulates its own
receptor, estrogen receptor)
O Mechanisms: ! new receptor synthesis,
t existing receptor degradation.
inactivating receptors
Upregulation
• External stimulus - cell t hormonal
receptor quantity/affinity
O Repeated exposure to receptor
antagonists/prolonged ligand absence
- upregulation
O Hormone may upregulate receptors for
other hormones (e.g. in uterus estrogen
upregulates its own receptor. also
luteinizing hormone (LH) receptors in
ovaries)
O Mechanisms: j new receptor synthesis.
! existing receptor degradation.
activating receptors
SECOND MESSENGER SYSTEMS
• Primary extracellular signalling molecules
often hydrophilic - cannot cross cell
membrane - second messenger system
carries. amplifies signal across cell
membrane
• Second messengers: intracellular signalling
molecules released by cells - triggers
physiological changes in response to
hormone/ligand-receptor interaction
, Include: cyclic AMP (cAMP), cyclic GMP
(cGMP). inositol trisphosphate (IP3),
diacylglycerol (DAG). Ca2-
, Involved in cellular processes:
proliferation, differentiation, migration,
survival, apoptosis
G PROTEINS
• Membrane-bound proteins: act as
molecular switches, couple hormone
receptors to effector enzymes
• Heterotrimeric proteins - three subunits -
alpha (a). beta (~). gamma (y)
• Can be stimulatory (Gs)/inhibitory (Gi)
, Activity determined by a subunit (as/ai),
that contains GTPase activity
Binding
• a subunit binds guanosine diphosphate
(GDP)/triphosphate (GTP)
, GDP binding - inactive state
, GTP binding - active state - coupling
, Guanosine nucleotide-releasing factors
(GRFs) facilitate GDP dissociation
, GTPase-activating factors (GAPs)
facilitate GTP hydrolysis
• GRFs. GAPs relative activity
' i G protein activation rate
• Final signal transduction occurs via cyclic
adenosine monophosphate (cAMP) signal
pathway/phosphatidylinositol signal
pathway
ADENYLYL CYCLASE MECHANISM
• Hormones acting via cAMP mechanism:
adrenocorticotropic hormone, luteinizing
hormone, follicle-stimulating hormone,
thyroid-stimulating hormone. antidiuretic
hormone (V2 receptor), human chorionic
gonadotropin, melanocyte-stimulating
hormone. corticotropin-releasing hormone,
calcitonin, parathyroid hormone, glucagon
• Hormone binds to receptor coupled to Gs/
Gi protein - adenylyl cyclase activation/
inhibition - intracellular cAMP ti!
• Stimulatory receptor events
, Hormone binds to receptor -
15
 conformational change in as subunit -
as subunit releases GDP - replacement
by GTP - as subunit detaches from Gs
protein
Oas subunit-GTP complex migrates
within cellular membrane - binds -
activates adenylyl cyclase
O Activated adenylyl cyclase catalyzes
adenosine triphosphate (ATP) - l
cAMP (second messenger)
O Intrinsic GTPase activity in G protein
- GTP converts - GDP - as subunit
inactive again
• cAMP acts as second messenger -
hormonal signal amplification - final
physiological reaction
• Intracellular cAMP - protein kinase
A activation - intracellular protein
phosphorylation - physiological response
• Phosphodiesterase degrades intracellular
cAMP - 5' adenosine monophosphate
(inactive metabolite) - hormonal response
cessation
PHOSPHOUPASE C MECHANISM
• Hormones acting via phospholipase
C mechanism: gonadotropin-releasing
hormone, thyrotropin-releasing hormone,
growth hormone-releasing hormone,
angiotensin II, antidiuretic hormone (Vl
receptor), oxytocin
• Receptor Gq phospho/ipase C complex:
embedded in cell membrane
• In neutral state (no bound hormone) aq
subunit binds GDP - inactive Gq protein
• Hormone binding - GDP release from
aq subunit - GTP binding - aq subunit
detaches from Gq protein
O aq-GTP complex migrates within cell
membrane - activates phospholipase
C - DAG, IP3 released from
phosphatidylinositol 4,5-diphosphate
(PIP2)
O IP3 - Ca2- intracellular stores released
(from endoplasmic/sarcoplasmic
reticulum)
O
DAG. IP3 - activate protein kinase C -
protein phosphorylation - physiological
response
STEROID HORMONE MECHANISM
• Hormones acting via steroid hormone
mechanism: glucocorticoids, estrogens,
progesterone, testosterone, aldosterone,
1,25-dihydroxycholecalciferol, thyroid
hormone
• No cell membrane-mediated transduction
step
, Steroid hormone diffuses across cell
membrane - binds to cytosolic (or
nuclear) receptor proteins (monomeric
phosphoproteins) - DNA transcription,
protein synthesis initiated
• Receptor proteins
, Part of intracellular receptor gene
superfamily
, Each receptor protein has six domains
(A-F)
, Steroid hormone binds E domain near
C terminus (central C domain binds to
DNA via zinc fingers)
• Steroid-receptor protein complex -
conformational change in receptor protein
- activation - enters nucleus
• Hormone-receptor complex combines
with similar hormone-receptor complex
(dimerization)
• New complex binds at C-domain via zinc
fingers to specific DNA sequences (steroid-
responsive elements), located in target
genes' 5' region
• DNA-bound active hormone-receptor
complex acts as transcription factor for
specific genes - messenger RNA (mRNA)
transcription
• mRNA leaves nucleus - translated into
new protein with physiological action
specific to original hormone
TYROSINE l(INASE MECHANISM
• Hormones acting via tyrosine kinase
mechanism: insulin, insulin-like growth
factor 1, growth hormone, prolactin
• Primary mechanism: tyrosine kinases
phosphorylates protein tyrosine residues
• Two main categories
, Receptor tyrosine kinases - intrinsic
kinase activity within receptor
16
 O
Tyrosine kinase-associated receptors -
no intrinsic kinase activity, associated
noncovalently with proteins without
kinase activity
Receptor tyrosine kinases (RTKs)
• Three structural domains
O Extracellular binding domain: binds
hormone
O Hydrophobic transmembrane domain:
membrane anchor
O Intracellular domain: tyrosine kinase
activity
• Hormone binding - activation
O Activation - phosphorylates itself,
other proteins
• Monomer-type RTKs
O E.g. epidermal growth factor receptors,
nerve growth factor
O Hormone binding to extracellular
domain - receptor dimerization -
intrinsic tyrosine kinase activation -
tyrosine moieties phosphorylation of
itself, other proteins - physiological
response
• Dimer-type RTKs
O E.g. insulin, insulin-like growth factor
receptors
O Hormone binding - intrinsic tyrosine
kinase activation - tyrosine moieties
phosphorylation of itself, other proteins
- physiological response
Tyrosine kinase-associated receptors
• E.g. growth hormone
• Three structural domains
O Extracellular binding domain: binds
hormone
O Hydrophobic transmembrane domain:
membrane anchor
O Intracellular domain: no tyrosine kinase
activity; non-covalently associated with
tyrosine kinase (e.g. Janus kinase family)
O Hormone binds to extracellular domain
- receptor dimerization - associated
protein's tyrosine kinase activated -
tyrosine moieties phosphorylation of
associated protein, hormone receptor,
other proteins
GUANYLYL CYCLASE MECHANISM
• Hormones acting via guanylyl cyclase
mechanism include: atrial natriuretic
peptide, nitric oxide (NO)
• Extracellular receptor domain binds ligand;
intracellular domain has guanylyl cyclase
activity
• Ligand binding - guanylyl cyclase
activation - GTP to cGMP conversion
• cGMP activates cGMP-dependent kinase
- protein phosphorylation (proteins
responsible for physiological response)
Intracellular forms (e.g. NO receptor)
• Cytosolic guanylyl cyclase mediates signal
conversion
• NO synthase cleaves arginine (in vascular
endothelial cells) - citrulline, NO
• NO diffuses from endothelial cells into
adjacent vascular smooth muscle - binds,
activates soluble (cytosolic) guanylyl
cyclase - GTP conversion - cGMP-
smooth muscle relaxation
SERINE/THREONINE l(INASE
MECHANISM
• Involved in cell proliferation regulation,
apoptosis, cell differentiation, embryonic
development
• G protein-linked receptors - adenylyl
cyclase, phospholipase C-linked
mechanism
• Hormone binding - protein kinase
activation - serine, threonine moieties
phosphorylation - physiological response
, Ca2+-calmodulin-dependent protein
kinase (CaMK), mitogen-activated
protein kinases (MAPKs) phosphorylate
serine, threonine in subsequent reaction
cascade
17
 CYTOSl(ELETON &
INTRACELLULAR MOTILITY
osms.i"l/e14-loskele-lon-o.nd-i n-lro.eellulo.r-mo-lili-l:14
• Non-membrane-bound organelles Microtubules
comprising complex protein filament • Approx. 25nm
network • Dynamic structures made of alternating
• Provide structural stability, shape, proteins
organization, intracytoplasmic motility, cell , a- and13-tubulins; polymerize to form
motility microtubules
• Stretch across cell
TYPES • Functions
, Intracellular transport (e.g. vesicle
Microfilaments
movement, melanin transport within
• Actin filaments: approx. 7nm
pigmented cells)
• Dynamic structures made of actin
, Structural integrity
monomers
, Cell division (form mitotic spindle)
O Arranged in long twisting chain
, Cilia, flagella structural components
• Form network just below cell membrane
• Functions Intermediate filaments
O Muscle contraction: slide closer • Approx. 8-lOnm
together, further apart • Static structures made of various fibrous
O Diapedesis: create pseudopodia for proteins (e.g. keratin, desmin, vimentin)
white blood cells (like neutrophils) depending on cell type
° Cell division: allows cell to pinch-off, • Rope-like structure; forms branching
divide into two cells during mitosis network
O Microvilli function • Functions
O Mechanical cell membrane support , Organelle, cell-cell anchoring
, Play key role in providing structural
integrity, cell shape

18
 GY TOSkE LE TON
AGTIN FILAMENTS
MUSC.LE GONTRAC.TION GELL DIVISION GE.LL MOVE.M£NT

U_.~
~~ @
INT£AM£1>1AT£ FILAMENTS
-~--- ---- STR£NuTH io CE.LL STRUCTURE.

FASTEN ANCHOR C.ELLS ANCHOR C.ELLS

OP-6.ANE.LLE.S io CELLS io £NVIRONl'\E.NT

• •

MIGAOTUSUL£$
OVERALL SHAPE.
cx-TUBULIN~ PROTOFI LAMENTS MIC.ROTU8ULE
P-TUBULIN~
~ x13-

TRANSPORTATION C£NTP.IOL£S
of VESICLES

____ _ )._
~
___ l. CILIA
_
r ~
NON-MOTIL£/ MOTIL£/
PRIMAP.'i CILIA S£C,ONDARI{ CILIA

CE:LLS th<>! LINE.

PHOTORE.CE:PTOR CE.LL FALLOPIAN TUBe:S

Figure 23.22 Cytoskeleton components and their functions.

19
 afratafreeh.com exclusive

NUCLEAR STRUCTURE
osmsJl/ nueleo:r-s-l:Tue-l:uTe
NUCLEAR ENVELOPE NUCLEOLUS
• Encloses, separates nucleus from • Dense non-membrane-bound structure;
cytoplasm some cells have more than one nucleolus
• Composed of selectively permeable • Contains rDNA----> transcribed into rRNA
membrane phospholipid bilayer • Assembles ribosomal subunits

Nuclear pores
• Form where membranes fuse together at NUCLEOPLASM
various intervals • Protoplasmic material
• Each pore lined with nuclear pore complex , Composed of complex water, molecule,
(nucleoporin) to facilitate communication ion mixture
between nucleus, cytoplasm • Contains nucleolus, chromatin
• Allow bidirectional macromolecule
movement
CHROMATIN
Outer membrane • Helical fiber
• Anchoring proteins that hold nucleus in , Composed of 46 DNA molecules
place within cytoplasm wrapped around proteins (histones)
• Continuous with RER • Histones help regulate DNA, gene
expression
Inner membrane • Chromosomes become visible as chromatin
• Covered by nuclear lamina fibers become tightly coiled during cellular
• Thin filamentous protein network, creates division
web within nucleus; provide support for
chromatin

NUGLEAR £NVELOP£
PHOSPHOLIPID
BILA'iEP.S
~'IX,-l,v'l.),U-.,1
ANC.HORIN(;aPP.OTEINS
1.-1-f.~ ........--. NUC.LE.OPORINS
OUTER

I
NUC.LE.AR
COMPLEX CHROMATIN

Figure 23.23 Nuclear envelope components.

20
Nucleosome
NUCLEUS
• Eight histones packed together in four
stacks of two; DNA wraps around them
twice
• Strung on strand of DNA-like "beads on
string"

Two chromatin types

• Euchromatin: loosely packed DNA. actively
being transcribed into RNA
• Heterochromatin: densely packed DNA. Figure 23.24 The nucleoplasm contains the
inactive (not being transcribed) nucleolus and chromatin.

CHROMATIN

GHROMOSOM£

LOOPV. C.ONTINUOUS
FIBEP.
Tl6HT HELIC.AL FIBE.R
~ NUCLE.OSOME

HISTONE.S

Figure 23.25 In the nucleus, DNA wraps around collections of histone proteins to form
nucleosomes.

GHROMOSOM£

GHROMOSOM£ i
"111110.r alw u.11
.livlslon ,livi.lr.s )

CE:NTROMEP.E

GHROMOSOM£
j
GHROMOSOM£

Figure 23.26 During cell division, chromosomes make an exact copy of themselves. The two
are connected at the centromere. Each copy is called a sister chromatid. During cell division, the
sister chromatids separate so that there is one copy of their genetic material in each daughter
cell.
21
 NOTES

NECROSIS & APOPTOSIS

osmsJl/neeY-osis-o.nd-o.pop-losis
• Two main ways by which cells die Fibrinoid necrosis
• Occurs in malignant hypertension/vasculitis
NECROSIS • Fibrin/inflammation damages blood vessel
• Cell death by injury/disease walls
O External triggers (e.g. infection, Also includes oncosis
temperature)
• Toxins/ischemia damage mitochondria
O Internal triggers (e.g. ischemia)
• ATP can no longer be synthesized (e.g.
Coagulative necrosis ionic pumps)

• Occurs in hypoxic tissue • Sodium, water flow into cell ----> swelling

• Structural proteins bend out of shape • Cell bursts, triggers inflammatory process

• Lysosomal proteins become ineffective at

removing affected proteins
• Cell dies, some structure remains
Gangrenous necrosis
• Also occurs in hypoxic tissue
• Dry gangrene: tissue dries up
• Wet gangrene: if infection, liquefactive
necrosis also occurs
Liquefactive necrosis
• Hydrolytic enzymes digest dead cells into
creamy substance
Caseous necrosis
• Occurs in fungal/mycobacterial infections
• Cell disintegrate (not fully) ----> cottage
cheese consistency
Fat necrosis
• Occurs in response to fatty organ trauma
• Adipose cell membranes ruptured
• Fatty acids combine with calcium,
dystrophic calcifications
• Can occur in pancreas as result of
inflammation (AKA pancreatitis)
APOPTOSIS
• Programmed cell death
• Based on caspase cascade
, Pro-caspases cleaved into caspases,
activating caspase 3
, Caspase 3 causes activation of cascade
of caspase proteins
, Cleaves various integral proteins,
degrading cellular components (e.g.
nucleus, organelles, cytoskeleton)
, Cell loses structure, resulting in blebs,
which break off, undergo phagocytosis
Intrinsic
/mitochondrial pathway
• Induced by stress (e.g. radiation)
• Process
, Intracellular proteins BAX, BAK pierce
mitochondrial membrane
, This allows SMACS, cytochrome C to
flow out of mitochondria
causing , SMACS binds to proteins that otherwise
inhibit apoptosis
, Cytochrome C binds to ATP, APAF-1,
forming apoptosome
, Pro-caspase 9 cleaves into caspase 9,
activating caspase 3
22
 0/TOSOL

BAX BAK 0
0 0 0 0 O O
--Q q O
~ 0 ;JS;~~~~~
0
MITOC.HONDRIA 0

)
PRO-C,ASPAS£,

APOPTOSOME *
C.ASPASE,

* 3
CASPAS£

*
OTHER CASPASES

*
APOPTOSIS

Figure 24.1 The intrinsidmitochondrial apoptosis pathway.

23
Extrinsic/death receptor pathway cell (AKA death domain)
• Process O Death domain changes shape, binds
O External cell initiates apoptosis by various proteins to form internal
releasing various signaling proteins signalling complex
O Signaling proteins bind to death O Pro-caspase 8 cleaves into caspase 8,
receptors on cell membrane activating caspase 3
° Cytosolic end of protein dives deep into

EXAMPLE 1 EXAMPLE a
MACROPHAGE

CYTOTOXIC T CELL

D£ATH 1'£CEPTORS
) \
----TUMOR NECROSIS f AS RECEPTO~
FAC.TO~ REC.EPTOR t

I
•

DEATH-INDUCING
SIGNALING COMPLEX - FADD
(DISC)

'' i
P~O\GASPASE-8
', .i.
C,ASPASE-S ...±+ GASPASE-3
40TH£~S

~GASPASE
CASCADE
~APOPTOSIS
Figure 24.2 Two examples of the extrinsiddeath receptor pathway. In example 1, a macrophage
recognizes an old cell, a pathogenic cell, or a cell that has completed its task. It releases TNF-a,
which binds to the death receptor tumor necrosis factor receptor 1. In example 2, when a
cytotoxic T cell detects that a cell is expressing foreign antigens, the T cell expresses FAS ligand
on its membrane. FAS ligand binds to the death receptor called FAS receptor. In both cases, the
death domain binds other proteins to form DISC and the caspase cascade leads to apoptosis.
24
 ONCOGENES & TUMOR
SUPPRESSOR GENES
osms.tl/ oncoge nes--lumol"-suppl"essol"-ge nes

• Code for proteins involved in progression of

cell cycle
O Positive regulation: oncogenes stimulate
cell growth, division
O Negative regulation: tumor suppressor
genes stop cell cycle progression,
-1,H
promote apoptosis \) PROPo\OT£R
8 1ij
Proto-oncogenes
CHROMOSOME:
• Code for growth factors, growth factor
receptors (e.g. receptor tyrosine kinase) Figure 24.3 Burkitt lymphoma can occur
• Signal transduction proteins (e.g. RAS due to translocation between portions
GTPase), transcription factors (e.g. MYC), of chromosomes 8 and 14, resulting in
apoptosis inhibitors (e.g. BCL-2) overexpression of proto-oncogene MYC.
• Active when cell needs to grow, divide
• Translocations, amplifications, point
mutations turn proto-oncogenes into PHILADELPHIA CHROMOSOME
oncogenes PHILADELPHIA
C.HROMOSOI-\£
O Overexpression
O E.g. in Burkitt lymphoma, MYC {
moved from chromosome 8 to near CHROMOSOMAL
lgH promoter on chromosome 14 TRANS LOCATION
- overexpression of cyclins, cyclin- )
_...gc.R
dependent kinases 'A8L
O E.g. in chronic myeloid leukemia with
Philadelphia chromosome 1 22

Tumor suppressor genes Figure 24.4 When a translocation occurs

between the long arms of chromosomes
• Code for various tumor suppressors, other
9 and 22, the resulting chromosome 22
protein inhibitors
with part of chromosome 9 is called the
• Active throughout cell cycle
Philadelphia chromosome. It contains fusion
• Various mutations cause uncontrolled cell gene BCR-ABL, whose protein BCR-ABL has
growth, division tyrosine kinase activity (on/off switch for cell
division). Since it's always on, myeloid cells
keep dividing - leukemia.

25
 HYPERPLASIA & HYPERTROPHY

• Two ways by which cells adapt to stress • Pathological processes: e.g. excessive
• Often happen together in tissues with stem hormonal stimulation ----> excessive
cells endometrial growth
• Sometimes associated with cancer: cells
mutate-« dysplasia
HYPERPLASIA
• Organ/tissue cells l in number
• Only happens in organs with stem cells that HYPERTROPHY
can differentiate, mature • Organ/tissue cells l in size

Types Causes
• Compensatory hyperplasia: in organs that • Physiological processes: e.g. I functional
regenerate (e.g. skin) demand ----> muscle cells produce more
• Hormonal hyperplasia: in organs regulated myofilaments
by hormones (e.g. endocrine) • Pathological processes: e.g. hypertension
----> cardiac myocytes produce more
Causes myofilaments
• Physiological processes: e.g. pregnancy ---->
enlargement of breast

DEMAND PLAC.ED is MORE

THAN C.AN .,~ HANDLED
= STRiss

H'/P£RPLASIA HVPE.RTROPH
* CELLS i11 a11 ORGAN er TISSUE * CELLS in can ORGAN
tin NUMIER er TISSUE f 111 SIZ£

Figure 24.5 An analogy to describe the difference between hyperplasia and hypertrophy.
When the workload is bigger than one lumberjack can handle, she gets stressed. Hyperplasia is
like hiring more lumberjacks to help; hypertrophy is like the one lumberjack getting bigger and
tougher so she can cut down more trees on her own.

26
 METAPLASIA & DYSPLASIA
osms.i-1:/me-lo.plo.sio.-o.nd-d14splo.sio.
METAPLAS1A METAPLASIA
~
• Mature differentiated cell transforms into
new mature cell type
• Often caused by environmental stressor
O E.g. tobacco smoke: pseudostratified
columnar epithelial cells in airways----.
stratified squamous epithelium
• Reversible if stimulus reverted
=
DYSPLASIA
• Tissue develops large number of immature MATUP.£ GOl.Ut'\IIAR EPITHELIAL CELLS
cells
• Precancerous state ( IRRIT"NT
• Four pathological changes to cell
O Anisocytosis (AKA unequal cells) ~
O Poikilocytosis (AKA abnormally-shaped
cells)
O Hyperchromatism (AKA excessive
pigmentation)
O Increases number of mitotic figures
(AKA more mitosis)

Figure 24.6 Example of metaplasia caused

by exposure to tobacco smoke.

ATROPHY, APLASIA, & HYPOPLASIA

osms.i-1:/o.-lroph14-o.plo.sio.-h14poplo.sio.
• Three ways by which cellular, bodily • May be associated with ! cell number (e.g.
growth fails/reverts apoptosis)
, E.g. orthopedic casting of an extremity
ATROPHY • May be associated with ! cell size
• Cell/organ/tissue size reduction , Loss of nerve/hormonal supply
• Causes include disuse, denervation, , Ubiquitin proteasome pathway:
ischemia, nutrient starvation, interruption of proteasome destroys polyubiquitinated
endocrine signals filaments/vacuoles destroy ubiquitin-

27
 tagged organelles (e.g. muscle atrophy) HYPOPLASIA
• Reduced size/abnormal shape of organ/
tissue
APLASIA
• Growth fails during embryogenesis in some
• Failure of organ/tissue to form properly
precursor cells
• Growth fails during embryogenesis with no
precursor cells

FREE RADICALS & CELLULAR

INJ"URY
osmsJl/f,-ee-,-adicals-and-cellula,--inju,-14

FREE RADICAL DEFENSE AGAINST FREE

• Chemical species with unpaired electron in RADICALS
outer orbit
Antioxidants
O Physiologic causes: e.g. oxidative
• E.g. vitamins A, C, E
phosphorylation, enzyme activity
• Eliminate free radicals by donating
O Pathologic causes: e.g. ionizing
electrons
radiation, inflammation, metal
interactions, drugs/chemicals) Metal carrier proteins
• May result in cellular injury • E.g. transferrin for iron, ceruloplasmin for
copper
FREE RADICAL CELLULAR INJ"URY • Bind, carry metals to prevent free radical
MECHANISMS production

Lipid peroxidation Enzymes

• Free radicals "steal" electron from lipids on • Eliminate various free radical species
cell membrane , Superoxide dismutase----> superoxide
• Damages cell membrane, entire cell , Catalase ----> hydrogen peroxide
, Glutathione peroxidase----> hydroxyl
Protein oxidation
radical
• Free radicals oxidize proteins, including
DNA, inside cell
O DNA oxidation ----> mutations e- cancer

__.
+te·
H:tO
SupeToxio.e H140.To9en H140. Tox14I -te ·
o.nion peToxio.e Tao.ical ~ Radta\t~

Figure 24.7 Oxygen is an example of a molecule that can become a free radical.

28
 ISCHEMIA
osms.i"l/isehe mio.
• Reduction in blood flow to organ/tissue ---->
oxygen shortage
° Caused by blockage/compression of
blood vessel
Arterial ischemia
• ! arterial blood flow----> I oxygen received
• E.g. atherosclerosis: plaque blocks arteries
to heert -e ischemic heart disease
Venous ischemia
• ! venous blood ftow -» ! drainage----> !
blood flow ----> ! oxygen received
• E.g. Budd-Chiari syndrome: clot blocks
hepatic vein ----> liver ischemia ----> edema/
hepatomegaly
Outcomes
• Sometimes, congestion ----> ii pressure ---->
fluid forced out/edema
• ll oxygen ----> cell death (e.g. tissue necrosis,
infarction)
, lschemic penumbra: ischemic but still
viable tissue
, Collateralization: growth of collateral
vessels to serve ischemic tissue
• Time to reperfusion: time taken to re-
establish perfusion before cells die
, Short----> cells survive-» reversible
, Long ----> cells die ----> irreversible

INFLAMMATION
osms.tl/inflo.mmo.-1:ion
• Immune response described by four key cells
signs: • Activate cells, sparking inflammatory
° Calor: heat response
O Dolor: pain • Mast cells contain granules with
O Rubor: redness inflammatory mediators
O Tumor: swelling , E.g. histamine, serotonin, cytokines, and
• May also involve "functio laesa" (AKA loss eicosanoids
of function) • ----> separate endothelial cells on nearby
• Triggered by external, internal factors capillaries

• External • Macrophages eat any invading pathogens

O Non-microbial: allergens, irritants, toxic • Cytokines cause capillaries to enlarge, j
compounds vascular permeability
O Microbial: virulence factors, pathogen • Endothelial cells release nitric oxide for
associated molecular patterns (PAMPs) vasodilation, j vascular permeability

• Internal • Leukocytes, especially neutrophils,

attracted through capillaries by
O Damage associated molecular patterns
chemokines, microbial products; squeeze
(DAMPs)
through membrane
Example process , AKA extravasation
• PAMPs, DAMPs recognized by pattern • Leukocyte follows gradient of inflammatory
recognition receptors (PRRs) on immune mediators
29
• Neutrophils phagocytose pathogens • Dendritic cells phagocytose pathogens,
immediately before destroying themselves present antigens to T lymphocytes,
• Antibodies bound to pathogens activate activating adaptive immune system
complement system • Ends with tissue repair
O Aids in opsonization, kills pathogens by
lysis

1. 0 , v· a, ,
~-

~-· p
D~Mi .' ;" P~MP, "( ~.
·- ,· .' ' ~

O_.,.. ... ([)

GJ WI'

MAC.~OPHAC:AE
MAST CELL EATS
PATHOGENS
INFLAMMATORY
MEDIATORS
.J, ~ c:::::z::> ~
~· ....... :.:::::;::=:::, ~~---,-.
---,. t VASCULAR
PERMEA81UT'/

Figure 24.8 1: DAMPs and PAMPs activate immune cells. 2: Macrophages phagocytose
pathogens at the site of inflammation. Mast cells release inflammatory mediators that widen
the distance between adjacent endothelial cells. 3: Endothelial cells release nitric oxide c- j
vasodilation, vascular permeability.

1.MIC.ROBIAL ',
PRODUC.TS •

\
v· .._
:

r;;CWJNES
GOMPL£MENT SYSTEM
l
* ATTRAC,TLEUl(.OC.VTES
• HELP w/ OPSONIZATION
®~
p~~ ~
,..· \-ADHESION
··............ PROTEIN • KILL PATHOC,£NS

Figure 24.9 1: Neutrophils are the first leukocytes recruited during the acute inflammatory
process. They squeeze through the gap between endothelial cells (extravasation) and follow
the gradient of inflammatory mediators to the site of inflammation. 2: Neutrophils quickly
phagocytose pathogens. While this is happening, complement proteins are activated by the
presence of pathogens and help with opsonization (they bind to microbes so leukocytes can
more easily eat them). Some can also kill pathogens by forming a channel in their membranes.

30