Cell Adaptations, Cell injury and Death
A cell that cannot adapt can only go through hypertrophy. If a cell can no longer adapt, or it has reached the max of hypertrophy, it
will become injured, leading to reversible and irreversible injuries.
Hypertrophy: growth in size
Hyperplasia: Increase in number
Atrophy: shrinkage
Involution: loss in number of cells
Metaplasia: one adult cell type is replaced with another adult cell type
Neoplasia: Do not need trophic factor to grow
Cardiac Myocytes are in G1 and cannot divide
Physiological: Exercise
Pathological response: increase afterload, hypertension or aortic valvular disease
Mechanical: Stretch (adapts by increasing size)
Trophic: Sympathetic response, NE binding to Beta, Inc. HR; Stroke vol. Inc. in size
Triggered by increase in protein and organelle synthesis.
Uterine; Liver
Hormonal; Compensatory (when a portion of tissue is removed—Liver)
Pathological (XS hormonal or GF stimulation)
Limits in amount of tissue – frong-like projections
Liver hyperplasia is initiated by TNF and IL-6. Proliferation and differentiation is dependent on GF like HGF and EGF
Decrease in size of embryologically formed structures
Notochord- tells ectoderm to become neural plate; becomes part of nucleus pulposus
Thyroglossal duct
Certain large vessels of developing CV system
Decrease in Thymus size
Disuse atrophy
Denervation atrophy: diabetes
Ischemic atrophy: decrease in size/wt of brain in aging, plaques
Gradual reduction in blood flow to kidneys due to vessels disease may result in ischemic collapse and scarring of the
glomerulus and associated tubule.
Dry gangrene
Metaplasia: change in differentiation of cells
Stomach is simple columnar, esophagus is stat. squamous.
Reversible cell injury/Necrosis:
Membrane blebs are associated with both APOPTOSIS and NECROSIS
Swelling—No O2, Respiration stops, lowering ATP, Transporters cannot work to maintain ion gradients
Increase in intracellular Na+
Myelin figures: parts of membrane wrapped around.
ER: protein synthesis
Lysosomes: ROS; proteolytic enzymes may damage cell from within
NO inflammation
Signal transduction pathway
Cellular function may be lost before cell death occurs; will be lost even in reversible injury
Irreversible injury, typically associated with mitochondrial dysfunction; profound disturbances in membrane function -> Cell death
ETC final acceptor is O2 but e- may turn into ROS causing damage to lipids, proteins, DNA
Reversible injury:
-Cellular swelling
-Fatty change esp in liver; myocardial cells
-Ultrastructural changes
Membrane blebs
Amorphous densities
Dilation of ER causing detachment of ribosomes
Clumping of nuclear chromatin—apoptosis
Intracytoplasmic contents of necrotic cells may leak out
Troponin from muscle cells (cardiac specific forms)
Aspartate and Alanine transaminases from the liver
Morphological features:
Inc. eosinophilia (acidic)
Myeline figues—derived from cell membranes
Loss of nuclei
Karyolysis: Lysing of nucleus
Pyknosis: condensation of nucleus
Karyorrhexis: fragmentation of nucleus
Coagulative necrosis:
Loss of blood flow= loss of lysosomal enzyme function—cannot degrade area leading to gelatinous state.
Hemmorhagic necrosis:
A secondary artery will fill in necrotic area
Dry gangrene:
Requires amputation
Liquefactive necrosis:
Implies that it occurs in the CNS (form of coagulative)
When neutrophils build up, release “pus”
Casseous necrosis:
Associated with TB; cheese-like white, crumbly
May cause systemic infection
Fat necrosis:
Necrosis of pancreatic cells, which contain large amounts of hydrolytic enzymes.. digest Triglycerides to form FA.
FA will combine with Ca2+ to form soaps (saponification)
Fibrinoid necrosis:
Extreme hypertension or immune complex – leakage of fibrin and plasma proteins into vessel wall
Calcium is usually in the sarcoplasmic reticulum or outside a cell. Calcium will begin to rush into
Cytoplasm activating second messenger cascade.
ROS and Fe+ may cause Fentin RXN making Hydroxyl radicals attacking membranes creating lipidPeroxide (damaged membrane)
Decrease of ATP will decrease function of Na+ pumps, increase anaerobic glycolysis and detach Ribosomes
Damage to mitochondrial permeability transition pore
-leads to the loss of mitochondrial membrane potential and pH changes causing H+ to leak out of the membrane into INNER
membrane (ETC)
-failure of oxidative phosphorylation with decrease ATP
There is also leakage of cytochrome c and other pro-apoptotic proteins into cytoplasm
Sites of membrane damage:
-plasma membrane
-injury to lysosomal membranes
Reperfusion injury:
Metabolites enter the area
Cells in the area become accustomed to hypoxia; when O2 rushes into the area, the O2 is used to turn into ROS.. in turn, the ROS will
attack everything else
Chemical (toxic) injury:
Some chemicals may become toxic through cellular processes involving P450.
Metabolism creates free radicals
-triglycerides accumulate in the liver causing fatty liver disease; if
concentration of toxin is very high—necrosis
Activated by a cascade of enzymes that lead to degredation of DNA, nuclear
and cytoplasmic proteins
Fragmentation of cells turn into apoptotic bodies which are phagocytosed.
Apoptosis of T-lymphocytes that are self-reactive as to not cause rheumatoid
Triggering by internal signals – the intrinsic or mitochondrial pathway
Triggering by external signals – the extrinsic or death receptor pathway
Cysteine proteases
Initiator: 2,8,9
Executioner: 3, 6, 7
Caspase activated DNAse results in DNA cleavage between nucleosomes (150-180bp)
BCL-2 is PROSURVIVAL and found in the outer membrane of the cell
Bax/Bak (proteins) are pro-apoptotic, and if there is a misfunction, there may be neoplasia
When bound, cytochrome C is released (first step in apoptosis)
P53 will upregulate Bax
Intrinsic pathway
Due to: cell/mitochondrial damage or hormone withdrawal
Results in BCL-2 release of Apaf-1 (apoptotic protease activating factor) into the
Apaf-1 allows the escape of cytochrome c form mitochondria
Apaf-1, cytochrome c, and procaspase 9 (initiator) polymerize into apoptosome
Caspase 9 is activated and that cleaves and activates other caspases in the
apoptotic cascade
Fas/Fas Ligand
Trimerized death domain that interacts with other intracellular death domains such as
FADD which leads to the activation of Caspase 8 (initiator) which will activate initiator
caspases and eventually apoptosis
Accumulation of protein
Protein resorption droplets in the renal tubular epithelial cells
A glomerular defect allows the protein to spill into the bowman’s space; the tubules try to resorb the protein but it cannot be
metabolized and exported quickly enough
Accumulation of metals
Small amounts of iron undergo autophagy, resulting in Hemosiderin (a brown pigment)
There is no physiological route for iron excretion so excess intracellular iron will cause injury due to free-radical formation and lipid
peroxidation resulting in DNA damage as well as collagen synthesis resulting in fibrosis
Inflammation and Repair
DOLOR: Bradykinin (potentiates prostaglandins),
substance P cause pain
TUMOR: swelling
CALOR: heat from increases blood flow
RUBOR: redness from inflammatory agents increasing
blood flow
Vasocontraction: Endothelin is released and binds to
vascular SM
(Gq receptor associated with DAG, IP3, Ca2+,
contraction) on ET1, ET2
Increases CA2+ and contraction
Vasodilation: more blood flow increasing inflammatory
markers, increase in vascular permeability, increasing protein increasing viscosity, decreasing velocity
PAMPS: Pathogen associated molecular pattern are recognized by toll-like receptors
Toll-like receptors will activate the transcription and production of
inflammatory mediators and cytokines
Inflammasome: group of proteins that come together to instill an
Inflammatory reaction by binding to caspase-1 and pro-inflammatory 1Beta
leading to acute inflammation
Stasis will increase chances of WBC to begin rolling and binding
TRANSCUDATE: Due to decrease in colloid osmotic pressure, only loss of
fluid, not protein
EXCUDATE: Due to inflammation, increase to vascular permeability, fluid and protein leakage (edema)
Pericyte: responsible for contraction of capillaries
Endothelial contraction:
Histamine, bradykinin, leukotrienes
Immediate transient response
If this is not controlled, junctional retraction occurs
Junctional retraction:
Caused by increased cytokines (IL-1, TNF) with onset of 4-6 hours
Leukocyte-dependent injury: free radicals and protease released from
leukocytes injure endothelial cells
Increased transcytosis: vascular endothelium derived GF (VEGF)
New blood vessel formation: tight junctions are not present yet and so there is increased vascular permeability
Selectins: cytokine activated (TNF, IL-1) from macrophage.
Selectins will appear on endothelium, bind to sialyated
groups on antigens on leukocytes
Immunoglobulin-like: on endothelial and will bind to the
integrin on the leukocyte
PECAM-1: allow the cell to slip through the
Integrins: bind to the immunoglobulin like ligands on the
endothelial cells. Transform into high affinity state after
chemokine (proteoglycan) activation of leukocytes
Leukotriene B4 is a major chemotaxis substance, product
of COX
Within neutrophil: Myeloperoxidase and Chloride and take
hydrogen peroxide and make a OCL* free radical lipid peroxide which will lyse bacteria within the phagocyte
Types of Inflammation:
Serous: very mild inflammation due to increased plasma protein due to increased vascular permeability
Suppurative (Purulent) Inflammation and Abscess formation
Mediators of inflammation:
Cell derived:
Granules: mast cells, basophils, platelets have histamine
Histamine binds to H1 receptors causing
constriction of large arteries but dilation of
arterioles as well an increased venular
permeability via endothelial cell contraction
Serotonin is found in dense granules in platelets causing
aggregation and coagulation
Plasma derived:
Liver makes acute phase coagulating factors
Kinin- factor 12
Platelet activating factor increases aggregation of platelets by bringing
Main pyrogen: TNF works on hypothalamus increasing basal body
Acute phase protein: CRP, coagulative factors, complements
• Synthesized by the liver, these proteins are
secreted in response to stimulation by
circulating IL-6
– C-reactive protein - opsonin
– Fibrinogen
– Serum AA protein – opsonin
Expressed, and presumably Secreted:
– eotaxin
– platelet factor 4
– monocyte chemoattractant protein-1 (MCP-1)
– RANTES: “Regulated upon Activation, Normal T-cell
IL-8 – polypeptide chemokine produced by
activated macrophages
– potent chemoattractant and activator of neutrophils
Oxygen Derived Free Radicals: from neutrophils and macrophages
Free radicals have the potential of damaging endothelial cells. They will also creat chemotactic lipids, inactivate A1AT, produced by
the NADPH oxidative reaction in leukocytes.
Alpha-1-antitrypsin deficiency: buildup of abnormally
folded A1AT and can cause liver damage, inactivates
WBC enzymes
Genetic disorder
Abscense of the protein systemically results in lung
damage since there is no inactivation of WBC
iNOS: opposing to eNOS; found in macrophages and
monocytes, activated by TNF and IL-1. Microbiocidal
and works with ROS
• C3a and C5a are anaphylatoxins, causing
histamine release and thus ↑ vascular
permeability and vasodilation
• C3b and C3bi are opsonins
• C5b-C9 form the membrane attack complex and
cause lysis of bacteria and cells
• C5a is also associated with:
– leukocyte activation – adhesion – chemotaxis
Plasma proteinases: Kinin system
Activated by Factor 12 (Hageman) to convert prekallikrein to kallikrein, then HMWK to Bradykinin
Bradykinin will increase vascular permeability, induce SM contraction, arteriolar dilation, and most importantly PAIN
When fibrin is formed, fibrinopeptides are split which also increase vascular permeability and act as chemotactic for leukocytes
Plasmin converts C3 to C3a (inflammation reaction)
Chronic inflammation characteristics: often caused by persistent infections and the
body’s inability to kill; persistent autoimmune response
Tissue destruction and fibrosis formation
Infiltration of monocytes
Macrophage activation
Classical Activation
Activated by interferon gamma
from T-cells
Produce lysosomal enzymes, NO,
and ROS to kill bacteria
Secrete inflammation inducing
cytokines (TNF, IL-1)
Host defense
Alternative activation
Associated with lymphocyte IL-4 and
Involved in tissue repair
Promote angiogenesis, fibroblasts,
collagen formation, and
antinflammation through TGF-Beta
Acute Phase Reaction: Systemic effects associated with inflammation
IL-1, IL-6, TNF (which are produced by leukocytes in response to
bacterial LPS)
Pyrogens may be endogenous/exogenous (bacterial LPS—stimulate IL-1/TNF)
These increase COX in hypothalamus which increases prostaglandins
Leukocytosis: associated with bacterial infections when TNF and IL-1 release cells from bone marrow (prolonged release is
dependent on colony stimulating factor)
Because cells are being released so rapidly, there may be an increased ratio of immature granulocytes.
Tissue repair
Regeneration is possible with an intact basement membrane; once it is destroyed by severe injury, it causes a more vigorous
inflammatory response causing increased accumulation of fibroblasts and collagen resulting in a scar.
Cell proliferation is controlled via growth factors; dependent on
cell type
There are two SNA damage check points in the cell cycle
@ G1/S and G2/M
Stem Cells
-self-renewal: allows maintenance of functional population of
- asymmetric replication: stem cell divides, one daughter enters a
differentiation pathway while the other remains undifferentiated
Cells may be cultured by adding certain growth factors such as c-Myc (which when mutated in cancer cells results in a loss of
proliferation control)
Growth factors: proteins that
stimulate the survival and
proliferation of particular cells. They
promote migration, differentiation
and other cellular responses.
They typically bind to tyrosine-kinase
GPCRs are important for binding
chemokines and mediating chemotaxis of WBC
JAK/STAT receptors can have signalling molecules bind directly to DNA
Extracellular matrix: network of protein that sequester H2O and supplies turgor to tissue, gives rigidity to bone, supplies a substrate
for cell migration and adhesion, as well as a reservoir for growth factors.
Interstitial matrix
found between cells in connective tissue, and between epithelium and supportive vascular and smooth muscle structures; made
mostly of mesenchymal fibroblast
fibrillar/non-fibrillar collagen
fibronectin; elastin
Basement Membrane
Forms plate-like mesh between epithelium and mesenchyme
Nonfibrillar type iv collagen
Laminin I (Integrins on epithelial cells bind to laminin on BM)
Collagens and elastins: Fibrous structural proteins which confer tensile strength and recoil
Collagen: 3 polypeptide chains in triple helix
Fibrillar: 1, 2, 3, 5 cross-link laterally due to lysyl-oxidase, Vit C requiring enzyme
Found in scar tissue
Nonfibrillar: 4 found in BM
Elastin: Gives ability to recoil and return to baseline structure
Large blood vessels, uterus, skin, ligaments
Proteoglycans and Hyaluronan: Water-hydrated gels which permit resilience and lubrication
Proteoglycans: highly hydrated gel-like compressible for joints
Serves as a reservoir for growth factors
Made up of long protein backbone with glycoaminoglycans like heparan sulfate
Hyaluronan: large mucopolysaccharide without a protein core that forms a viscous gel-like matrix
Laminin, fibronectin, integrins: Adhesive glycoproteins that connect matrix elements to one another and to cells
Laminin: most abundant in BM, connects cells to underlying ECM components such as type 4 collagen and heparan sulfate;
helps modulate cell proliferation
Fibronectin: disulfide linked heterodimer binds to large number of ECM components including collagen and proteoglycans,
binds fibrin
Integrins: transmembrane heterodimeric glycoprotein chains, important for leukocyte adherence to endothelium, main
receptor for laminins and fibronectin. Seen in membrane of all cells except for RBC
Steps in Angiogenesis
• Vasodilation in response to NO and increased vascular permeable in response to VEGF
• Separation of pericytes from the outside
• Migration of endothelial cells toward the area of tissue injury
• Proliferation of endothelial cells just behind the leading front of migrating cells
• Remodeling into capillary tubes
• Recruitment of peri-endothelial cells to form mature blood vessel (Ang)
• Suppression of endothelial proliferation and migration, and deposition of basement membrane
Growth factors involved in angiogenesis: VEGF (VEGF-A), Ang1, Ang2 which stabilize blood vessels, and FGF
Major inducer of angiogenesis following injury, expressed in most tissues (especially in the epithelium)
Binds to tyrosine-kinase receptors
Induced by hypoxia, TGF-beta, TBF-alpha, PDGF
Stimulates proliferation and migration of endothelial cells, initiating sprouting of capillaries from existing vessels
Fibroblast Growth Factors (FGF)
Bind to tyrosine kinase receptors, heparan sulfate on proteoglycan of CT
Stimulates proliferation of endothelial cells
Migration of macrophages and fibroblasts to injured area
Angiopoetins 1 & 2 Ang1, Ang2
Stabilization of new vessels
Recruitment of new pericytes, smooth muscle and surrounding ECM
Transforming growth factor Beta
Binds to serine-therosine kinase
Stimulates production of collagen, fibronectin, and proteoglycans, and inhibits collagen degradation by decreasing MMPs and
increasing the activity of tissue inhibitors of metalloproteinases (TIMPS)
TGF- b suppresses endothelial proliferation and migration, and enhances the production of ECM proteins
Platelet derived growth factor (PDGF)
Proliferation and migration of smooth muscle and fibroblasts
Matrix metalloproteinases (MMPs)
Zinc containing enzymes that can cleave a Large number of different ECM components, including fibrillar and nonfibrillar collagen,
fibronectin, proteoglycans, and laminin.
Produced by wide variety of cells, especially fibroblasts, macrophages and neutrophils, but under regulation of growth factors and
Action opposed by TIMPs produced by most mesenchymal cells.