Adaptation Death Inflammation Repair

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ex of altered physiologic stimuli

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increased demand
increased trophic stimulation
decreased nutrients, stimulation
chronic irritation (chemical or physical)

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cellular adaptations

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hyperplasia
hypertrophy
atrophy
metaplasia

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reduced oxygen supply, chemical injury, microbial infection

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acute and self-limited
progressive and severe (includng DNA damage)

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cell injury

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acute reversible injury
irreversible injury --> cell death
-necrosis or apoptosis
subcellular alterations in various organelles

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metabolic alterations, genetic or acquired -->

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intracellular accumulations
calcifications

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prolonged life span with cumulative sublethal injury -->

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cellular aging

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source of injury: ischemia
first response -->

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adaptation
left: myocyte under hypertrophy (increase in cell size) to adapt the injury
i.e. after adaptation: myocyte-the thickness of ventricular wall > 2 cm

worse situation: cell death
if ischemia persists, cell death (ischemic necrosis) = MI

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metaplasia

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replacement of cells from one mature cell type to another

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mechanisms of hyperplasia

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increased growth factors/receptors of cells
activation of IC signaling pathways

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physiologic examples of hyperplasia

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Hormonal:
puberty
pregnancy
postmenstrual

compensatory: post hepatectomy, wound healing

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pathologic examples of hyperplasia

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hormonal: abnormal menstrual bleeding; benign prostate can allow cancerous proliferation to arise
viral infections: skin warts

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mechanism of adaptation -- atrophy

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increased protein degradation
accompanied by marked increase in number of autophagic vacuoles

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ex of atrophy

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decreased workload (disuse): atrophy of skeletal muscle fibers
loss of innervation (denervation atrophy): nerve damage: atrophy of muscle fibers
diminished blood supply: ischemia-atrophy of brain in later adult life
inadequate nutrition: protein-calorie malnutrition --> marasmus
loss of endocrine stimulation: loss of estrogen after menopause --> atrophy of endometrium and breast
aging (senile atrophy): lost of brain and heart cells
pressure: enlarged benign tumor: atrophy of surrounding compressed tissue

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mechanisms of metaplasia

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reprogramming of stem cells, undifferentiated mesenchymal cells
involved in tissue-specific and differentiation genes

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ex of metaplasia

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reprogramming of stem cells
undifferentiated mesenchymal cells
involved in tissue-specific and differentiation genes

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ex of metaplasia

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stones in excretory ducts of salivary glands, pancreases or bile ducts --> squamous metaplasia in epithelium
Vit A deficiency: squamous metaplasia in respiratory epithelium cancer in respiratory tract --> transformed normal cells

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myositis ossificans

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metaplasia of connective tissue after bone fracture

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sequential development of biochemical and morphologic changes in cell injury

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1. biochemical alterations --> cell death
2. ultrastructural
3. light microscopic changes
4. gross micoscopic changes --> can been seen via microscope (histology)

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hypoxia vs ischemia

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hypoxia: loss of oxygen of blood --> cells may adapt, be injured or die

ischemia: loss of blood supply in a tissue --> injures cells faster than hypoxia does

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physical agents of cell injury

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mechanical trauma
temperature radiation
atmospheric pressure
electric shock c

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chemical agents of cell injury

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glucose
salt
O2
As
Hg
cyanide
CO
air pollutants
insecticides

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infectious agents of cell injury

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viruses
bacteria
fungi

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genetic derangements

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Down syndrome
sickle cell anemia

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nutritional imbalances

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atherosclerosis
protein-calorie deficiency

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increased ROS -->

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damage to lipids, proteins, DNA

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entry of Ca2+ -->

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increased mitochondrial permeability
activation of multiple cellular enzymes

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membrane damage -->

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plasma membrane --> loss of cellular components

lysosomal membrane --> enzymatic digestion of cellular components

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protein misfolding, DNA damage -->

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activation of pro-apoptotic proteins

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cellular and biochemical mech of necrosis and apoptosis

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ATP depletion--> ischemic/toxic injury
membrane damage (defects in membrane permeability)
increased cytosolic Ca --> loss of calcium homeostasis (damage of cell membrane)
production of oxygen-related free radicals: oxidative stress

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ischemia can cause

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decreased oxidative phosphorylation in mitochondria --> decreased production of ATP -->
1. decreased Na+ pump -->influx of Ca2+, H2O, Na+ efflux of K+
2. anaerobic glycolysis --> decreased glycogen, increased lactic acid, decreased pH--> clumping of nuclear chromatin

detachment of ribosomes --> increased protein synthesis --> lipid deposition

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increased release of Ca from mitochondria and smooth ER due to injurious agent -->

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Increase in cytosolic Ca2+ will then activate cellular enzymes --> membrane damage/disruption of membrane/nuclear damage/increased ATP and increased mitochondrial permeability transition --> increased ATP
Increase in Ca2+-->Leaky membrane of mitochondria-->lost of cytochrome C, lose functions --> cell undergo apoptosis by activating caspase cascade

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what causes formation of superoxide?

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O2
inflammation
radiation
chemicals
reperfusion injury

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superoxide --> hydrogen peroxide by

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SOD

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hydrogen peroxide --> hydroxyl radical by

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fenton reaction
+Fe2+

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pathologic effects of ROS: cell injury and death

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fatty acids -> oxidation --> generation of lipid peroxidases -->disruption of plasma membrane, organelles

proteins --> oxidation --> loss of enzymatic activity, abnormal folding

DNA --> oxidation --> mutations, breaks

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removal of free radicals

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SOD (in mitochondria)
converts superoxide to hydrogen peroxide
glutathione peroxidase in mitochondria converts hydroxyl --> hydrogen peroxide --> water and oxygen
catalase (in peroxisomes)
converts H2O2 --> H2O + O2

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mechanism of production of superoxide

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incomplete reduction of O2 during oxidative phosphorylation
phagocyte oxidase in leukocytes

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mechanism of H2O2 production

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generated by SOD from O2- and by oxidases in peroxisomes

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mechanism of hydroxyl radical production

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generated from water by hydrolysis
by radiation from hydrogen peroxide by fenton reaction

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ONOO- production

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superoxide + NO generate by NO synthase in many cell types

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increase cytosolic ca2+ activates what 2 enzymes

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phospholipase activation --> increased phospholipid degradation --> lipid breakdown products
protease activation --> cytoskeletal damage

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causes of necrosis

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1. enzymatic digestion
-autolysis: lysosomes from dead cells themselves
-heterolysis: lysosomes from leukocytes
2. protein denaturation:

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necrosis vs apoptosis

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cell size: enlarged (swelling) vs. reduced (shrinkage)

nucleus: pyknosis --> karyorrhexis --> karyolysis vs fragmentation into nucleosomes

PM: necrosis: disrupted
apoptosis: intact, altered structure esp orientation of lipids

cellular contents:
enzymatic digestion - may leak out of cell vs. intact: may be released in apoptotic bodies

inflammation:
frequent vs. no

invariably pathologic (culmination of irreversible cell injury) vs often physiologic--> eliminating unwatned cells, may be pathologic after some forms of cell injury esp DNA damage

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programmed destruction of cells during embryogenesis

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implantation
organogenesis
developmental involution

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hormone-dependent involution in adult:

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endometrial cell breakdown during menstrual cycle
ovarian follicular atresia in menopause
repression of lactating breast after weaning
prostatic atrophy after castration

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apoptosis-causes

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cell deletion in proliferating cell population: intestinal crypt epithelia
tumors
death of neutrophils
cytotoxic T cells
pathologic atrophy in parenchymal organs after duct obstruction: pancreas, parotid gland and kidney
cell injury in viral diseases: viral hepatitis
injurious stimuli: heat, radiation, drugs

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what inhibits apoptosis in the intrinsic pathway?

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Bcl-2 and Bcl-XL

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what promote apoptosis in intrinsic pathway?

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Bax and Bak

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what activates mitochondrial (intrinsic) pathway?

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growth factor withdrawal
DNA damage (by radiation, toxins, free radicals)
protein misfolding (ER stress)

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intrinsic pathway

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cell injury --> Bcl-2 family sensors --> Bcl-2 family effectors (bax and bak) --> mitochondria --> cytc c and other pro-apoptotic proteins--> initiator caspases --> executioner caspases --> endonuclease activation and breakdown of cytoskeleton --> DNA fragmentation, membrane bleb, apoptotic body

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extrinsic pathway = death receptor-initiated pathway

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Fas-Fas ligand-mediated apoptosis
TNF-induced apoptosis

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cytotoxic T-lymphocyte-stimulated apoptosis

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recognition of foreign antigen
secretion of perforin
Granzyme B

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viable cell in intrinsic pathway

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survival signal (gf) --> production of antiapoptotic proteins (Bcl-2 or Bcl-x) --> NO leakage of cytochrome c

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apoptosis in intrinsic pathway

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lack of survival signals/irradiation --> DNA damage --> activation of sensory (BH3-only proteins) --> antagonism of Bcl-2, acivation of Bax/Bak channel, leakage of cytc c other proteins --> activation of caspases --> apoptosis

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extrinsic (death receptor-initiated) pathway of apoptosis

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FasL + Fas --> procaspase-8 *autocatalytic caspase activation--> active caspase-8--> executioner caspases --> apoptosis

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dysregulated apoptosis

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inhibited apoptosis
increased cell survival: cancers, autoimmune disorders

increase apoptosis/excessive cell death: neurodegenerative diseases, ischemic injury, virus-induced lymphocyte depletion: AIDS

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cellular aging
factors that affect it:

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genetic
diet
social condition
age-related diseases
-atherosclerosis
-diabetes
-osteoarthritis
-osteoporosis

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mech of cellular aging

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telomere shortening
envionmental insults
DNA repair defects
abnormal growth factor signaling (insulin/IGF)

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biochemical events during cellular aging

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reduced oxidative phosphorylation by mitochondria
decreased capacity for uptake of nutrients of cells
decreased capacity for repair of chromosomal damage
metabolic events
oxidative stress-induced damage: increased cell aging
higher rate of mitochondrial generation of superoxide anion radical --> increased cell aging
over-expression of antioxidant enzymes SOD and catalase --> decreased cell aging

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protective response of progressive damage in cell aging process:

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-recognition and repair of un-repaired damage DNA by endogenous DNA repair enzymes
antioxidants

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mech of inactivation superoxide

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conversion to hydrogen peroxide and oxygen by SOD

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mech of inactivation of hydrogen peroxide

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conversion to H2O and O2 by catalase
GPS

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hydroxyl radicals

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conversion to water by GPS

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ONOO-

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conversion to HNO2 by peroxiredoxins

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regeneration

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growth of cells and tissues to replace lost structures
REQUIRES an intact connective tissue scaffold

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healing (regeneration and scar formation)

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scar formation occurs if the ECM framework is damaged
causing alterations of the tissue architecture

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ex of regeneration

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organs (compensatory growth): partial hepatotectomy
unilateral nephrectomy
acute chemical injury to liver

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healing (regeneration and scar formation)

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atherosclerosis
scar formation in myocardium after infarction
chronic chemical injury to liver

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regenerative capacity depends on

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capacity of quiescent cells to reenter cell cycle
efficient differentiation of stem cells in area of injury

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regeneration in mammalian organs

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compensatory growth process (hypertrophy and hyperplasi) --> restore function capacity of an organ w/o necessarily reconstituting its original anatomy

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inadequacy of regeneration

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rapid fibroproliferative response and scar formation after wounding

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normal cell proliferation and growth -players in regeneration and repair

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cell cycle and landmarks
stem cells
growth factors
signaling mech for activation of transcription

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players in healing and repair - ECM

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collagens
elastin
cell adhesins
proteoglycans

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fibroproliferative response - limited damage

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ECM deposition normla
scar formation

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fibroproliferative response - ongoing damage

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chronic inflammation
ECM deposition abnormal
fibrosis

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angiogenesis -neovascularization

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recruitment of endothelial precursor cells
-Nitric oxide, VEGF, metalloproteinases
-endothelial cell proliferation and migration
-recruitment of periendothelial cells

branching of preexisting vessels
growth factors involved

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angiogenesis from pre-existing vessels

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1-vasodilation in response to NO, VEGF-induced increased permeability of pre-existing vessel
2-proteolytic degradation of BM
3-migration of EC toward angiogenic stimulus
4- proliferation of EC
5-maturation of EC
6-recruitment of periendothelial cells to support endothelial tubes and form mature vessel

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angiogenesis by mobilization of EPCs from bone marrow

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1-EPCs are mobilized from bone marrow and migrate to a site of injury or tumor growth
-EPCs express hematopoetic stem cells markers, endothelial specific markers
2-EPCs differentiate and form a mature network by linking w/ preexisting vessels
-EPCs participate in replacement of lost EC, reendothelization of vascular implants, neovascularization of ischemic organs, cutaneous wounds, tumors

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scar formation within granulation tissue

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fibroblast migration and proliferation in site of injury
ECM deposition by fibroblasts
tissue remodeling by MMPs, TIMPs

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sequence of healing

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1. induction of inflammatory process in response to initial injury w/ removal of damaged dead tissue
2. proliferation and migration of parenchymal and connective tissue cells
3. formation of new blood vessels (angiogenesis) and granulation tissue
4. synthesis of ECM proteins and collagen deposition
5. tissue remodeling
6. wound contraction
7. acquisition of wound strength

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deficient scar

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dehiscence (bursting or splitting open of a wound)
ulceration

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excessive repair

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exuberant granulation blocks reepithelialization
-hypertrophic scar (raised above wound)
-keloid (extends beyong original injury)

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contractures

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wound deformity
-claw hand
-loss of mobility

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persistent stimulus (chronic inflammation) leads to activation of macs and lymphocytes:

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1. growth factors: PDGF, FGF, TGFbeta
2. cytokines: TNF, IL-1, IL-4, IL-13
3.decreased metalloproteinases

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what increases collagen synthesis?

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1. proliferation of fibroblasts, endothelial cells, specialized fibrogenic cells
2. cytokines

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fibrosis

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increased collagen synthesis
decreased collagen degradation (due to decreased metalloproteinase activity)

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chronic inflammation lead to joint destruction

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rheumatoid arthritis

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chronic alcoholism of infection with hep B or C viruses

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liver cirrhosis

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repeated bouts of acute pancreative inflammation leads to loss of pancreativ acinar cells and replacement of fibrous tissue

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chronic pancreatitis

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repeated inhalation of mineral dusts

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lung fibrosis

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what are examples of fibrosis?

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rheumatoid arthritis
liver cirrhosis
chronic pancreatitis
lung fibrosis

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restitution of normal structure

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regeneration
ex:
liver regeneration after partila hepatectomy
superficial skin wounds
resorption of exudate in lobar pneumonia

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scar formation

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repair
deep excisional wounds
myocardial infarction

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tissue scar

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fibrosis
chronic inflammatory diseases