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CH 1 Baby Robbins Outline
CH 1 Baby Robbins Outline
1 Cellular Responses to Stress and Toxic Insults: Adaptation, Injury, and Death
(BABY ROBBINS OUTLINE w/ some big Robbins: page numbers and pictures reference big Robbins)
INTRODUCTION: (p.4)
PATHOLOGY: is the study of the structural and functional causes of human disease
o 4 aspects of a disease process that form the core of pathology are:
ETIOLOGY: cause of a disease
PATHOGENESIS: mechanism(s) of disease development
MORPHOLOGIC CHANGE: structural alteration induced in cells and tissues by
the disease (pathophysiology)
CLINICAL SIGNIFICANCE: functional consequences of the morphologic changes
(lesion)
Fig. 1-1
Stages of the cellular response to stress and
injurious stimuli
OVERVIEW: (p.5)
HOMEOSTASIS: a steady state
INJURY: More excessive stresses, or adverse pathology stimuli result in:
o 1) ADAPTATION
o 2) REVERSIBLE INJURY
o 3) IRREVERSIBLE INJURY and CELL DEATH [Table 1-1]
ADAPTATION: occurs when physiologic or pathologic stressors induce a new state that changes
the cell but otherwise preserves its viability in the face of the exogenous stimuli. These changes
include:
o HYPERTROPHY: increased cell mass (size)
o HYPERPLASIA: increased cell #
o ATROPHY: decreased cell mass
o METAPLASIA: change from 1 mature cell type to another mature cell type
REVERSIBLE INJURY: denotes pathologic cell changes that can be restored to normalcy in the
stimulus is removed or if the cause of injury is mild.
IRREVERSIBLE INJURY: occurs when stressors exceed the capacity of the cell to adapt (beyond a
“POINT OF NO RETURN”) and denotes permanent pathologic changes that cause cell death
(necrosis)
CELL DEATH: occurs primarily thru 2 morphologic and mechanistic patterns denoted NECROSIS
and APOPTOSIS (Table 1-2)
NECROSIS: the more common type of cell death involving:
o Severe cell swelling
o Denaturation and coagulation of proteins
o Breakdown of cellular organelles
o Cell rupture
o INFLAMMATION*
o Usually, a large number of cells in the adjoining tissue are affected
APOPTOSIS: occurs when a cell dies by activation of an internal “SUICIDE” PROGRAM, involving:
o An orchestrated disassembly of cellular components
o Minimal disruption of the surrounding tissue
o NO (or minimal) INFLAMMATION*
AUTOPHAGY: and adaptive response of cells to nutrient deprivation; a “self-cannibalization” to
maintain viablility
DEPLETION of ATP: decreased ATP synthesis and ATP depletion are common consequences of
both ischemic and toxic injury
o ATP is critical for membrane transport, maintenance of ionic gradients (Na+, K+, and
Ca2+) and protein synthesis
MITOCHONDRIAL DAMAGE: can occur directly due to hypoxia or toxins, or as a consequence of
increased cystolic Ca2+, oxidative stress, or phospholipid breakdown
o MITOCHONDRIAL PERMEABILITY TRANSITION PORE – a high-conductance channel that
leaks protons and dissipates the electromotive potential that drive oxidative
phosphorylation
o Also leak cytochrome c triggers apoptosis
INFLUX OF Ca2+ AND LOSS OF Ca2+ HOMEOSTASIS: cystolic Ca2+ is maintained at extremely low
levels by energy-dependent transport
o Ischemia and Toxins Ca2+ influx across the plasma membrane and release of Ca2+
from mitochrondria and ER
o Increased cystolic Ca2+ activates phospholipases that degrade membrane
phospholipids; proteases that breakdown membrane and cytoskeletal problems;
ATPases that hasten ATP depletion; and endonucleases that cause chromatin
fragmentation
ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS):
o FREE RADICALS - are stable, partially reduce molecules with unpaired electrons in outer
orbitals that make them particularly reactive with other molecules; also called reactive
oxygen species (ROS)
Most common and biological systems
Major forms:
Superoxide anion (O2, 1 extra e-)
Hydrogen peroxide (H2O2, 2 extra e-)
Hydroxyl ions (OH, 3 extra e-)
Peroxynitrate ion (ONOO-; [NO] and O2)
Free Radical generation occurs by:
Normal metabolic processes such as the reduction of O2 H2O during
respiration
Absorption of radiant energy
Production by leukocytes during inflammation to sterilize sites of
infection
Enzymatic metabolism of exogenous chemicals or drugs
TRANSITION METALS can catalyze free radical formation
NO, an important chemical mediator can act directly as a free radical
or be converted to other highly reactive forms
Free Radicals inherently unstable and generally DECAY SPONTANEOUSLY
Systems that contribute to Free Radical inactivation:
ANTIOXIDANTS (vit. E & A, ascorbic acid, and glutathione)
Levels of TRANSITION METALS binding to storage and transport
proteins
Free Radical scavenging ENZYME systems catabolize H2O2 and O2
DEFECTS IN MEMBRANE PERMEABILITY: membranes can be damaged directly or indirectly
o Increased plasma membrane permeability affects intracellular osmolarity as well as
enzymatic activity
DAMAGE TO DNA AND PROTEINS: damage to DNA that exceeds normal repair capacity leads to
activation of apoptosis
o W/in limits, all the changes of cell injury described previously = REVERSIBLE INJURY
o However, persistent or excessive injury causes cells to pass a threshold into
IRREVERSIBLE INJURY associated w/:
Extensive cell membrane damage
Lysosomal swelling
Mitochondrial vacuolization w/ deficient ATP synthesis
o REVERSIBLE IRREVERSIBLE = 2 phenomena consistently characterize IRREVERSIBILITY
1) Inability to reverse mitochondrial dysfunction (lack of ATP generation) even
after resolution of the original injury
2) Development of profound disturbances in membrane function
EXAMPLES OF CELL INJURY AND NECROSIS: (p.23)
ISCHEMIC AND HYPOXIC INJURY:
o Most common forms of cell injury in clinical medicine = ISCHEMIA and HYPOXIA
HYPOXIA – is reduced O2-carrying capacity
HYPOXIA leads to loss of ATP generation by mitochondria; ATP
depletion has multiple, initially reversible effects
o OSMOTIC LOAD CELL SWELLING
o CELLULAR ENERGY METABOLISM is altered
Hypoxia ANAEROBIC GLYCOLYSIS -> GLYCOGEN
STORES ARE RAPIDLY DEPLETED and REDUCED
INTRACELLULAR pH
o Reduced protein synthesis
ISCHEMIA – (causes hypoxia*) is due to reduced blood flow
o ALL the aforementioned changes are reversible and oxygenation is restored
o If ISCHEMIA persists IRREVERSIBLE INJURY, a transition largely dependent upon the
extent of ATP DEPLETION and MEMBRANE DYSFUNCTION
ATP depletion induces the pore transition change in the mitochondrial
membrane diffusion of solutes
ATP depletion also RELEASES CYTOCHROME C, a soluble component of the ETC
that is a key regulator in driving apoptosis
Increased cytosolic calcium activates membrane phopholipases, leading to
progressive loss of phospholipids and membrane damage; decreased ATP also
leads to diminished phospholipid synthesis
Increased cytosolic calcium ACTIVATES INTRACELLULAR PROTEASES causing
degradation of intermediate cytoskeletal elements cell swelling Cell
membrane stretching and rupture
FFAs and lysophospholipids accumulate in ischemic cells as a result of
phospholipid degradation = directly toxic to membranes
ISCHEMIA-REPERFUSION INJURY:
o REPERFUSION INJURY = Depending on the intensity and duration of the ischemic insult,
additional cells may die AFTER blood flow resumes, involving either necrosis or
apoptosis
Clinically important in MI, acute renal failure, and stroke
o Several mechanisms potentially underlie reperfusion injury:
New damage may occur during reoxygenation by increased generation of ROS
INCREASED local inflammatory cell infiltration
COMPLEMENT activation cell injury and inflammation
CHEMICAL (TOXIC) INJURY:
o Occurs by 2 general pathways:
1) DIRECTLY
2) INDIRECTLY
APOPTOSIS: (p.25)
APOPTOSIS = PROGRAMMED CELL DEATH – occurs when a cell dies thru activation of a tightly
regulated internal SUICIDE program
FUNCTION OF APOPTOSIS – is to eliminated unwanted cells selectively, with minimal disturbance
to surrounding cells and the host
DOES NOT elicit an INFLAMMATORY REACTION** – dead cell is rapidly cleared before its
contents have leaked out
o Therefore, FUNDAMENTALLY DIFFERENT FROM NECROSIS, which is characterized by loss
of membrane integrity, enzymatic digestion of cells, and frequently a host reaction
LIPIDS:
Tryglycerides (most common),
Cholesterol and cholesterol esters, &
Phospholipids can accumulate in cells
PATHOLOGIC CALCIFICATION:
PATHOLOGIC CALCIFICATION – the abnormal tissue deposition of calcium salts --- occurs in 2
forms:
o DYSTROPHIC CALCIFICATION – arises in nonviable tissues in the presence of normal
calcium serum levels
o METASTATIC CALCIFICATION – happens in viable tissues in the setting of hypercalcemia
DYSTROPHIC CALCIFICATION:
o Occurs arteries in atherosclerosis, and damaged heart valves, and in areas of necrosis
o Calcium can be intracellular and extracellular
o INITIATION (NUCLEATION):
EXTRACELLULAR initiation – occurs on membranes-bound vesicles from dead or
dying cells that concentrate calcium due to their content of charged
phospholipids
INTRACELLULAR initiation – calcification occurs in mitochondria dead or dying
cells
o PROPAGATION of crystal formation depends on:
The concentration of calcium and phosphates
The presence of inhibitors, and
Structural components of the extracellular matrix
METASTATIC CALCIFICATION:
o Results from hypercalcemia, which has four principal causes:
1) ELEVATED PARATHYROID HORMONE
2) BONE DESTRUCTION, as in primary marrow malignancies or by diffuse
skeletal metastasis, by accelerated bone turnover (Paget’s disease), or
immobilization
3) VITAMIN D-RELATED DISORDERS, including vitamin D intoxication and
systemic sarcoidosis
4) RENAL FAILURE, causing secondary hyperparathyroidism due to phosphate
retention and the resulting hypocalcemia
CELLULAR AGING:
With increasing age, degenerative changes impact the structure and physiologic function of all
organs systems
The tempo and severity of such changes in any given individual are influenced by genetic factors,
diet, social conditions, and the impact of other comorbidities, such as atherosclerosis, diabetes,
and osteoarthritis
CELLULAR AGING – reflecting the progressive accumulation of sublethal cellular and molecular
damage due to both genetic and exogenous influences --- leads to cell death and diminished
capacity to respond to injury
AGING – appears to be a regulated process influenced by a limited number of genes; this, in turn,
implies that aging can potentially be parsed into definable mechanistic alterations:
o CELLULAR SENESCENCE (esp TELOMERE SHORTENING)
o ACCUMULATED METABOLIC AND GENETIC DAMAGE
Increased ROS production
The recognition and repair of damaged DNA is also a critical counterbalance
o In patients with Werner syndrome, there is a premature aging due to defective DNA
helicase with accelerated accumulation of chromosomal damage
Genetic instability is also characteristic of other disorders associated with premature aging (e.g.,
ATAXIATELANGIECTASIA)
THE MOST EFFECTIVE WAY TO PROLONG THE LIFESPAN IS CALORIC RESTRICTION