Physio Flashcards
compensatory systems slowly falter and then fail.
➢ At the cellular level, this process is known as
senescence and apoptosis.
➢ At the organismal level, we know it as aging and death.
Gerontology:
is a relatively new discipline dealing with old issues (and issues encountered by older
adults).
Apoptosis
is a process whereby cells and their contents spontaneously fragment into membrane-
bound apoptotic bodies that are rapidly engulfed by phagocytes.
Apoptosis may be triggered by
intrinsic factors, including genetic programming and cell damage, and
by extracellular factors, such as toxins and growth factors.
What happened to arteries with getting old?
Arteries stiffen with age due to elastin cross-link breakage, increased collagen deposition, and
calcification, causing a compensatory increase in arterial blood pressure.
most diseases and failing organ systems is
O2 deprivation resulting from inadequacy of perfusion.
O2 restriction caused
interruption of local blood supply (ischemia) or
reduced arterial O2 levels (hypoxemia) initiates a sequence of
biochemical events known as an ischemic cascade.
ischemic cascade.
Significant events include switchover to anaerobic metabolism,
dissipation of ion gradients, Ca2+-induced toxicity, mitochondrial
breakdown, apoptosis, and necrosis.
Anaerobic metabolism:
O2 deprivation forces cells to convert from primarily aerobic to exclusively anaerobic metabolism to generate adenosine triphosphate (ATP).
The transition is the metabolic equivalent of switching over to an emergency gas-powered generator
during a domestic power outage.
Anaerobic “exhaust” comes in the form of lactic acid formation, which causes acidosis.
Lactic acid is produced even in healthy individuals during intense muscle activity, but local levels
remain relatively low because the circulation limits build up.
➢ If the biologic power outage reflects perfusion failure, however, lactic acid levels build rapidly, and
intracellular pH falls, which further compromises cell function.
➢ Necrosis
is pathologic cell or tissue death, culminating in lysis and release of cellular contents.
This contrasts with apoptosis, in which damaged and dying cells stimulate phagocytosis, and their
contents remain contained within membranes.
Cell death
2. Ion gradients:
Falling ATP levels limit the ability of ion pumps (e.g., Na-K ATPase and Ca
ATPase) to maintain transmembranous ion gradients (Figure 40.4).
➢ Membrane potential depolarizes, and intracellular Ca concentration rises as a
result.
➢ In excitable cells, depolarization triggers cationic influx via voltage-dependent Na
and Ca channels and K efflux via K channels, which effectively collapses the ion
gradients within seconds.
➢ These ion movements raise intracellular fluid osmolality, causing water to enter
by osmosis.
Cell death
3. Calcium toxicity:
Ca influx and release from intracellular stores activates a number
of signaling pathways that ultimately destroy the cell.
➢ These include ATPases, lipases, endonucleases, and Ca-
activated proteases such as calpains.
➢ Calpains are regulatory proteases under normal circumstances.
➢ When activated by ischemia-induced rises in intracellular Ca
concentration, calpains destroy the cytoskeleton and, with help
from Ca- dependent lipases, digest the plasma and intracellular
membranes ( Figure 40.5).
➢ The cell swells, lyses, and dies (necrosis).
Cell death
4. Excitotoxicity
Excitotoxicity is an aggressive positive feedback pathway that makes the brain highly vulnerable to O2
deprivation.
➢ Ischemia-induced increases in intracellular Ca concentration cause synaptic vesicles to fuse with the
synaptic membrane, releasing their contents into the synaptic cleft.
➢ These vesicles often contain glutamate, which is the brain’s principal excitatory neurotransmitter.
➢ Postsynaptic glutamate receptors (e.g., N-methyl, D-aspartate receptors) are Ca permeable, so
intracellular Ca levels rise even faster in neurons than they do in nonexcitable tissues.
➢ Thus, the ischemic cascade is accelerated in brain tissue.
Cell death
5. Mitochondrial breakdown:
Reduced O2 availability impairs mitochondrial function
and increases reactive oxygen species (ROS)
accumulation.
➢ ROS include the superoxide anion, hydrogen peroxide,
and the hydroxyl radical, all produced by the
mitochondrial electron transport chain (Figure 40.6).
ROS are extremely damaging to cells because they react with and break molecular bonds in lipids,
proteins, and DNA.
➢ Cells normally aggressively defend themselves against ROS using enzymes (e.g., superoxide
dismutase and peroxidase) and ROS scavengers (e.g., vitamins C and E).
➢ During ischemia, however, rising ROS levels increase mitochondrial membrane permeability, causing
organellar swelling and release of electron-chain constituents that initiate apoptosis.
➢ If cell necrosis does not occur within the first few minutes, apoptotic pathways impel cellular suicide
over a prolonged timescale, but the end result is the same nevertheless.
