How and why Damage occurs in our Body
DNA damage
The
nuclear membrane is crossed by several factors which regulate the gene
expression and repair the DNA damage as soon as it occurs.
Mitochondrial damage
Mitochondrial damage-causing ATP
depletion.
Cell membrane damage disturbing the
metabolic and trans-membrane exchanges.
ATP Damage
Decreased
generation of cellular ATP: Damage by ischaemia versus hypoxia from other
causes. All living cells require continuous supply of oxygen to produce ATP
which is essentially required for a variety of cellular functions (e.g.
membrane transport, protein synthesis, lipid synthesis and phospholipid
metabolism).
Damage to membrane pumps
Damage to plasma membrane
pumps: Hydropic swelling and other membrane changes. Lack of ATP interferes in
generation of phospholipids from the cellular fatty acids which are required
for continuous repair of membranes. This results in damage to membrane pumps
operating for regulation of sodium and calcium.
Failure
of sodium-potassium pump. Normally, the energy (ATP)-dependent sodium pump
(Na+-K+ ATPase) operating at the plasma membrane allows active transport of
sodium out of the cell and diffusion of potassium into the cell.
cell Membrane damage
Failure of calcium pump: Membrane damage causes disturbance
in the calcium ion exchange across the cell membrane. Excess of calcium moves
into the cell (i.e. calcium influx), particularly in the mitochondria, causing
its swelling and deposition of phospholipid-rich amorphous densities. Ultra
structural evidence of reversible cell membrane damage is seen in the form of
loss of micro villi, Persistence of ischaemia or hypoxia results in
irreversible damage to the structure and function of the cell (cell death).
Mitochondrial damage
Calcium influx: Mitochondrial damage. As a result of
continued hypoxia, a large cytosolic influx of calcium ions occurs, especially
after reperfusion of irreversibly injured cell. Excess intracellular calcium
collects in the mitochondria disabling its function. Morphologically,
mitochondrial changes are vacuoles in the mitochondria and deposits of
amorphous calcium salts in the mitochondrial matrix.
Membrane damage
Activated phospholipases: Membrane damage. Damage to membrane
function in general, and plasma membrane in particular, is the most important
event in irreversible cell injury in ischaemia. As a result of sustained
ischaemia, there is increased cytosolic influx of calcium in the cell.
Increased calcium activates endogenous phospholipases.
Cytoskeleton damage
Intracellular proteases: Cytoskeleton damage. The normal
cytoskeleton of the cell (microfilaments, microtubules and intermediate filaments) which anchors
the cell membrane is damaged due to degradation by activated intracellular
proteases or by physical effect of cell swelling producing irreversible cell
membrane injury.
Nuclear damage
Activated
endonucleases: Nuclear damage. The nucleoproteins are damaged by the
activated lysosomal enzymes such as proteases and endonucleases. Irreversible
damage to the nucleus can be in three forms:
Pyknosis: Condensation and clumping of nucleus
which becomes dark basophilic.
Karyorrhexis: Nuclear fragmentation in to small bits
dispersed in the cytoplasm.
Karyolysis: Dissolution of the nucleus.
Lysosomal damage
Lysosomal hydrolytic enzymes: Lysosomal damage, cell death and phagocytosis. The lysosomal
membranes are damaged and result in
escape of lysosomal hydrolytic enzymes. These enzymes are activated due to lack
of oxygen in the cell and acidic pH. These hydrolytic enzymes include: hydrolase,
RNAase, DNAase, protease, glycosidase, phosphatase, lipase, amylase, cathepsin
etc) which on activation bring about enzymatic digestion of cellular components
and hence cell death. The dead cell is eventually replaced by masses of
phospholipids called myelin figures which are either phagocytosed by
macrophages or there may be formation of calcium soaps.
Membrane damage
CALCIUM OVERLOAD: Upon restoration of blood supply, the ischaemic cell is further
bathed by the blood fluid that has more calcium ions at a time when the ATP
stores of the cell are low. This results in further calcium overload on the
already injured cells, triggering lipid peroxidation of the membrane causing
further membrane damage. Free radicals(o, H, oH) may produce membrane damage
This
reaction is termed lipid peroxidation. The lipid peroxides are decomposed by
transition metals such as iron. Lipid peroxidation is propagated to other sites
causing widespread membrane damage and destruction of organelles
DNA damage
DNA damage. Free radicals
cause breaks in the single strands of the nuclear and mitochondrial DNA. This
results in cell injury; it may also cause malignant transformation of cells. Cytoskeleton
damage. Reactive oxygen species are also known to interact with cytoskeleton
elements and interfere in mitochondrial aerobic phosphorylation and thus cause
ATP depletion.
Conditions with free radical
injury. Currently, oxygen derived free radicals have been known to play an
important role in many forms of cell injury: i) Ischaemic reperfusion injury
ii) Ionizing radiation by causing radiolysis of water iii) Chemical toxicity
iv) Chemical carcinogenesis v) Hyperoxia (toxicity due to oxygen therapy) vi)
Cellular aging vii) Killing of microbial agents viii) Inflammatory damage ix)
Destruction of tumour cells x) Atherosclerosis.
Cytotoxic damage
DIRECT CYTOTOXIC EFFECTS: Some chemicals combine with
components of the cell and produce direct cytotoxicity without requiring
metabolic activation. The cytotoxic damage is usually greatest to cells which
are involved in the metabolism of such chemicals e.g. in mercuric chloride poisoning,
the greatest damage occurs to cells of the alimentary tract where it is
absorbed and kidney where it is excreted.
Cell membrane damage
Killing
of cells by ionizing radiation is the result of direct formation of hydroxyl
radicals from radiolysis of water. These hydroxyl radicals damage the cell
membrane as well as may interact with DNA of the target cell. Cell membrane
damage followed by cell death by necrosis (e.g. neurons).
Liver cell damage
Liver
cell damage, when fat cannot be metabolised in it. These causes are Conditions
with excess fat: i) Obesity ii) Diabetes mellitus iii) Congenital
hyperlipidaemia
Pancreatic damage
Excessive
intestinal absorption of iron: A form of haemosiderosis in which there is
excessive intestinal absorption of iron even when the intake is normal, is
known as idiopathic or hereditary haemochromatosis. It is an autosomal dominant
disease associated with much more deposits of iron than cases of acquired
haemosiderosis. It is characterised by triad of pigmentary liver cirrhosis,
pancreatic damage resulting in diabetes mellitus, and skin pigmentation. On the
basis of the last two features, the disease has come to be termed as bronze
diabetes.
Mitochondrial damage
Cell death by ATP depletion, membrane
damage, free radical injury Oxidative stress hypothesis (free radical-mediated
injury).Currently, it is believed that aging is partly caused by progressive
and reversible molecular oxidative damage due to persistent oxidative stress on
the human cells. In normal cells, very small amount (3%) of total oxygen
consumption by the cell is converted into reactive oxygen species.
With aging, there is low metabolic
rate with generation of toxic oxygen radicals, which fail to get eliminated
causing their accumulation and hence cell damage. The underlying mechanism
appears to be oxidative damage to mitochondria. The role of antioxidant in
retarding the oxidant damage has been reported in some studies.
tissue damage
The Ag-Ab reaction may cause tissue
damage. Endothelial cell injury due to cytotoxic damage to endothelium from
autoantibodies or antigen-antibody complexes.
Increased vascular permeability
(Irritant oedema). The vascular endothelium as well as the alveolar epithelial
cells (alveolo-capillary membrane) may be damaged causing increased vascular
permeability so that excessive fluid and plasma proteins leak out, initially
into the interstitium and subsequently into the alveoli.
Anoxic damage
Progressive vasodilatation. During
later stages of shock, anoxia damages the capillary and venular wall and
arteioles become unresponsive to vasoconstrictors listed above and begin to
dilate. Increased vascular permeability. Anoxic damage to tissues releases
inflammatory mediators which cause increased vascular permeability. This
results in escape of fluid from circulation into the interstitial tissues thus
deteriorating effective circulating blood volume.
Anoxic damage to heart, kidney,
brain. Progressive tissue anoxia causes severe metabolic acidosis due to
anaerobic glycolysis. There is release of inflammatory cytokines and other
inflammatory mediators and generation of free radicals.
Ischemic damage
HYPOXIC
ENCEPHALOPATHY. Cerebral ischaemia in compensated shock may produce altered
state of consciousness. However, if the blood pressure falls below 50 mmHg as
occurs in systemic hypotension in prolonged shock and cardiac arrest, brain
suffers from serious ischemic damage with loss of cortical functions, coma, and
a vegetative state.
tubular damage
Kidney.
Renal fat embolism present in the glomerular capillaries, may cause decreased
glomerular filtration. Other effects include tubular damage and renal insufficiency.
Damage to tissue
Nitrogen
and other gases can produce bubbles within the circulation and obstruct the blood vessels causing damage to tissue. Inadequate
cardiac output resulting from heart block, ventricular arrest
and fibrillation from various causes may cause hypoxic injury to the brain. If
the arrest continues for 15 seconds, consciousness is lost. If the
condition lasts for more than 4 minutes, irreversible ischemic damage to the brain occurs. If it is prolonged for more
than 8 minutes, death is inevitable.
Damaged endothelial
cells
Process
of thrombosis is initiated at the site of damaged endothelial cells.An
important mechanism of microbicidal killing is by oxidative damage by the
production of reactive oxygen metabolites (O’2 H2O2, OH’, HOCl, HOI, HOBr).
Tissue damage
CHEMICAL
MEDIATORS OF INFLAMMATION also called as permeability factors or endogenous
mediators of increased vascular permeability, these are a large and increasing
number of endogenous compounds which can enhance vascular permeability.
However, currently many chemical mediators have been identified which partake
in other processes of acute inflammation as well e.g. vasodilatation,
chemotaxis, fever, pain and cause Tissue damage.
Cell damage
FREE
RADICALS: OXYGEN METABOLITES AND NITRIC OXIDE. Free radicals act as potent
mediator of inflammation: i) Oxygen-derived metabolites are released from
activated neutrophils and macrophages and include superoxide oxygen (O’2),
H2O2, OH’ and toxic NO products. These oxygen-derived free radicals have the
following action in inflammation: Endothelial cell damage and thereby increased
vascular permeability. Activation of protease and inactivation of antiprotease
causing tissue matrix damage. Damage to other cells.
Proteolytic damage
Acute
phase reactants. A variety of acute phase reactant (APR) proteins are released
in plasma in response to tissue trauma and infection. Their major role is to
protect the normal cells from harmful effects of toxic molecules generated in inflammation
and to clear away the waste material. APRs include the following: i) Certain
cellular protection factors (e.g. α1-antitrypsin, α1- chymotrypsin,
α2-antiplasmin, plasminogen activator inhibitor): They protect the tissues from
cytotoxic and proteolytic damage.
Tissue damage
If
the muscle sheath is damaged, it forms a disorganised multinucleate mass and
scar composed of fibrovascular tissue e.g. in Volkmann’s ischemic contracture. In
cancer, the transformed cells are produced by abnormal cell growth due to
genetic damage to these normal controlling genes. Other proposed mechanisms of
tissue injury in chronic alcoholism is free-radical mediated injury and genetic
susceptibility to alcohol-dependence and tissue damage. During radiotherapy,
some normal cells coming in the field of radiation are also damaged.
Organ Damage
Radiation-induced
tissue injury predominantly affects endothelial cells of small arteries and
arterioles, causing necrosis and ischaemia. Ionizing radiation causes damage to
the following major organs: 1. Skin: radiation dermatitis, cancer. 2. Lungs:
interstitial pulmonary fibrosis. 3. Heart: myocardial fibrosis, constrictive
pericarditis. 4. Kidney: radiation nephritis. 5. Gastrointestinal tract:
strictures of small bowel and esophagus. 6 Gonads: testicular atrophy in males
and destruction of ovaries. 7. Haematopoietic tissue: pancytopenia due to bone
marrow depression. 8. Eyes: cataract.
Platelet Damage
Drug-induced
Thrombocytopenia Many commonly used drugs cause thrombocytopenia
by depressing megakaryocyte production. In most cases, an immune mechanism by
formation of drug-antibody complexes is implicated in which the platelet is
damaged as an ‘innocent bystander’. Drug-induced thrombocytopenia is associated
with many commonly used drugs and includes: Chemotherapeutic agents (alkylating
agents, anthracyclines)
Muscle Damage
EXTERNAL
IMPACT. Direct external trauma to red blood cells when they pass through
microcirculation, especially over the bony prominences, may cause haemolysis
during various activities e.g. in prolonged marchers, joggers, karate players
etc. These patients develop haemoglobinaemia, haemoglobinuria (march
haemoglobinuria), and sometimes myoglobinuria as a result of damage to muscles.
Cell membrane Damage
Reversible-irreversible sickling: The
oxygen-dependent sickling process is usually reversible. However, damage to red
cell membrane leads to formation of irreversibly sickled red cells even after
they are exposed to normal oxygen tension. Iron overload due to repeated blood
transfusions causes damage to the endocrine organs resulting in slow rate of
growth and development, delayed puberty, diabetes mellitus and damage to the
liver and heart.
There are 2 main features of DIC—bleeding as the most common manifestation and organ damage due to ischaemia caused
by the effect of widespread intravascular thrombosis such as in the kidney and brain.
Less common manifestations include: microangiopathichaemolytic anaemia and
thrombosis in larger arteries andveins.
Transfusion haemosiderosis. Post-transfusion iron overload with deposition of iron in
the tissues of the body occurs after repeated transfusions in the absence of
any blood loss e.g. in thalassaemia major and in severe chronic refractory
anaemias. The body has no other means of gettingrid of extra iron except iron
excretion at the rate of 1 mg perday. A unit of whole blood (400 ml) contains
about 250 mgof iron. After approximately 100 units, the liver, myocardium and
endocrine glands are all damaged.
The HDN due to Rh-D incompatibility in its severest form may result in
intrauterine death from hydropsfoetalis.
Moderate disease produces a baby born withsevere anaemia and jaundice
due to unconjugate dhyper bilirubinaemia.
When the level of unconjugatedbilirubin exceeds 20 mg/dl,
it may result in deposition ofbilepigment in the basal ganglia of the CNS
called kernicterusand result in
permanent brain damage. Mild disease, however,
causes only severe anaemia with or without jaundice.
Damage due to radiation exposurehas been linked to
development of leukaemias and lymphomas. Genetic damage to single clone of
target cells. Leukaemias and lymphomas arise following malignant
transformation of a single clone of cells belonging to myeloid or
lymphoidseries, followed by proliferation of the transformed clone. Basic
mechanism of malignant transformation is genetic damage to the DNA of the
target white cells followed by proliferation, disrupting normal growth and differentiation.
The pathogenesis of hyperplasic intimal thickening is unclear. Probably, the
changes result following endothelial injury from systemic hypertension, hypoxia
orimmunologic damage leading to increased permeability. Ahealing reaction
occurs in the form of proliferation of smooth muscle cells with fibrosis. Brain—Chronic ischemic brain damage, cerebral
infarction.
Aortic aneurysm may result from damage to the aortic wallIn majority of
cases, coronary atherosclerosis causes progressive ischemic myocardial damage
and replacement by myocardial fibrosis. The damage to the myocardium is caused
either by direct viral cytotoxicityor by cell-mediated immune reaction. Atelectasis
of the lungs results in hypoventilation, pulmonary hypoperfusion and ischaemic
damage to capillary endothelium. Free
radicals which are reactive oxygen species which damage the lung
parenchyma.
Glaucoma is a group of ocular disorders that have in
common increased intraocular pressure. Glaucomais one of the leading causes of
blindness because of theocular tissue damage produced by raised intraocular
pressure. In all types of glaucoma, degenerative changes appear after some
duration and eventually damage to the optic nerveand retina occurs.
Acute sinusitis may become chronic due to incomplete
resolution of acute inflammation and from damage to the mucous membrane.N
SAIDs-induced mucosal injury. Non-steroidal anti-inflammatory drugs are most
commonly used medications in the developed countries and are responsible for
direct toxicity, endothelial damage and epithelial injury to both gastricas
well as duodenal mucosa. Mucosal damage e.g. in tuberculosis, Crohn’s
disease, lymphoma, amyloidosis, radiation injury, systemic sclerosis. However, following hypotheses are significant in causing
mucosal cell damage:
1. Hypersensitivity
reaction as seen by gluten-stimulated antibodies.
2. Toxic effect of gluten due to inherited enzyme deficiency in the mucosal cells Liver cells
synthesise albumin, fibrinogen, prothrombin, alpha-1-antitrypsin, haptoglobin,
ceruloplasmin, transferrin, alpha fetoproteins and acute phase reactant
proteins. The blood levels of these plasma proteins are decreased in extensive
liver damage. Jaundice usually reflects the severity of liver cell damage since
it occurs due to failure of liver cells to metabolise bilirubin.
In acute failure such as in viral hepatitis, jaundice
nearly parallels the extent of liver cell damage, while in chronic failure such
as in cirrhosis jaundice appears late and is usually of mild degree. The
genesis of CNS manifestations in liver disease is by toxic products not
metabolised by the diseased liver. The toxic products may be ammonia and other
nitrogenous substances from intestinal bacteria which reach the systemic
circulation without detoxification in the damaged liver and thus damage the
brain. Acetaldehyde is toxic and may cause membrane damage and cell necrosis.
RISK FACTORS FOR ALCOHOLIC LIVER DISEASE. All those who indulge in alcohol abuse do not develop
liver damage. Hepatotoxicity by ethanol metabolites. The major
hepatotoxic effects of ethanol are exerted by its metabolites, chiefly
acetaldehyde. Acetaldehyde levels in blood are elevated in chronic alcoholics.
Acetaldehyde produces hepatotoxicity by production of two adducts:
Haemochromatosis is an iron-storage disorder in which
there is excessive accumulation of iron in parenchymal cells witheventual
tissue damage and functional insufficiency of organs such as the liver,
pancreas, heart and pituitary gland. However, the magnitude of the iron excess
in secondary haemochromatosis is generally insufficient to cause tissue
damage..
Proteases such as trypsin and chymotrypsin play the most important
role in causing proteolysis. Trypsin also activates the kinin system by
converting prekallikrein to kallikrein, and thereby the clotting and complement
systems are activated. This results in inflammation, thrombosis, tissue damage
and haemorrhages found in acute haemorrhagic pancreatitis. Acinic cell damage caused by the
etiologic factors such as alcohol, viruses, drugs, ischaemia and trauma result
in release of intracellular enzymes.
Chronic pancreatitis due to chronic alcoholism accompanied by a high-protein diet results in
increase in protein Concentration in the pancreatic juice which obstructs the
ducts and causes damage. It is important to note that ARF originating in pre-
and post-renal disease, such as by renal ischaemia or renal infection,
eventually leads to intra-renal disease. Thus, fullblown ARF reflects some
degree of nephron damage.
The ARF occurring secondary to disorders in which neither
the glomerulus nor the tubules are damaged, results in pre-renal syndrome.
Chronic Renal Failure
(CRF):
Chronic renal failure is a syndrome
characterised by progressive and irreversible deterioration of renal function
due to slow destruction of renal parenchyma, eventually terminating in death
when sufficient number of nephrons have been damaged. Acidosis is the major
problem in CRF with development of biochemical azotaemia and clinical
uraemia syndrome.
Infectious causes: A good example of chronic renal infection causing CRF is
chronic pyelonephritis. The chronicity of process results in progressive damage
to increasing number of nephrons leading to CRF. Obstructive causes: Chronic obstruction in the urinary tract
leads to progressive damage to the nephron due to fluid backpressure. The
examples of this type of chronic injury are stones, blood clots, tumours,
strictures and enlarged prostate. Polyuria and nocturia occur due to
tubulointerstitial damage.
Circulating immune complex deposits. This mechanism used to be considered very important for
glomerular injury but now it is believed that circulating immune complexes
cause glomerular damage under certain circumstances only. Tubular damage in ischaemic ATN is
initiated by arteriolar vasoconstriction induced by renin-angiotensin system,
while in toxic ATN by direct damage to tubules by the agent.
These events cause increased
intratubular pressure resulting in damage to tubular basement membrane.
Due to increased intratubular pressure, there is tubular rupture. Damage
to tubules is accompanied with leakage of fluid into the interstitium causing interstitial oedema.
Ischaemic ATN: Ischaemic ATN, also called tubulorrhectic ATN, lower
(distal) nephron nephrosis, anoxic nephrosis, or shock kidney, occurs due to
hypoperfusion of the kidneys resulting in focal damage to the distal parts of
the convoluted tubules.
Toxic ATN: Toxic ATN, also called nephrotoxic ATN or toxic
nephrosisor upper (proximal) nephron nephrosis, occurs as a result of direct
damage to tubules, more marked in proximal portions, by ingestion, injection or
inhalation of a number of toxic agents. Prognosis
of toxic ATN is good if there is no serious damage to other organs such as
heart and liver. Efflux of sterile urine can also cause renal damage.
Obstructive pyelonephritis. Obstruction to the outflow of urine at different levels
predisposes the kidney to infection recurrent episodes of such obstruction and
nfection result in renal damage and scarring. Rarely, recurrent attacks of
acute pyelonephritis may cause renal damage and scarring.
Other risk factors. Other factors which alter the prognosis in hypertension
include: smoking, excess of alcohol intake, diabetes mellitus, persistently
high diastolic pressure above normal and evidence of end-organ damage (i.e.
heart, eyes, kidney and nervous system). Irradiation damage resulting in
permanent germ cell destruction.
XERODERMA PIGMENTOSUM.
This is an autosomal recessive disorder in which sun-exposed skin is more
vulnerable to damage. The condition results from decreased ability to repair
the sunlight-induced damage to DNA.
Intracellular accumulation of sorbitol and fructose so produced results
in entry of water inside the cell and consequent cellular swelling and cell
damage. Also, intracellular accumulation of sorbitol causes intracellular
deficiency of myoinositol which promotes injury to Schwann cells and retinal
pericytes. These polyols result in disturbed processing of normal intermediary
metabolites leading to complications of diabetes.
Excessive oxygen
free radicals. In hyperglycaemia, there is increased
production of reactive oxygen free radicals from mitochondrial oxidative
phosphorylation which may damage various target cells in diabetes.
Hypoglycemia:
Hypoglycemic episode may develop in patients of type 1 DM. It may result from
excessive administration of insulin, missing a meal, or due to stress. Hypoglycemic
episodes are harmful as they produce permanent brain damage, or may result in
worsening of diabetic control and rebound hyperglycaemia, so called Somogyi’s effect.
Diabetic neuropathy:
Diabetic neuropathy may affect all parts of the nervous system but symmetric peripheral
neuropathy is most characteristic. The basic pathologic changes are segmental
demyelination, Schwann cell injuryand axonal damage. The pathogenesis of
neuropathy is not clear but it may be related to diffuse microangiopathy as
already explained, or may be due toaccumulation of sorbitol and fructose as a
result of hyperglycaemia, leading to deficiency of myoinositol.
IgG and IgM immune complexes trigger inflammatory damage to the synovium,
small blood vessels and collagen. Activation of macrophages releases more
cytokines which cause damage to joint tissues and vascularisation of cartilage
termed pannus formation. Ventually
damage and destruction of bone and cartilage are followed by fibrosis and ankylosis producing joint deformities
Myasthenia gravis (MG) is a neuromuscular disorder of
autoimmune origin in which the acetylcholine receptors (AChR) in the motor
end-plates of the muscles are damaged.
NEURONS:
The neurons are highly specialised
cells of the body which are unable of dividing after the first few weeks of
birth. Thus, brain damage involving the neurons is permanent.
In response to injury or damage, however, these cells have
capability to enlarge in size, proliferate and develop elongated nuclei, so
called rod cells. Microglial
cells may actually assume the shape and phagocytic function of macrophages and
form gitter cells. The foci of
necrosis and areas of selective hypoxic damage to the neurons are surrounded by
microglial cells which perform phagocytosis of damaged and necrosed cells; this
is known as neuronophagia.
Ischaemic brain damage:
Generalised reduction in blood flow resulting in global hypoxic-ischaemic encephalopathy
ISCHAEMIC BRAIN
DAMAGE:
Ischaemic necrosis in the brain
results from ischaemia caused by considerable reduction or complete
interruption of blood supply to neural tissue which is insufficient to meet its
metabolic needs. The brain requires sufficient quantities of oxygen and glucose
so as to sustain its aerobic metabolism, mainly by citric acid (Krebs’) cycle
which requires oxygen. Moreover, neural tissue has limited stores of energy
reserves so that cessation of continuous supply of oxygen and glucose for more
than 3-4 minutes results in permanent damage to neurons and neuroglial cells.
Selective neuronal damage: Neurons are most vulnerable to damaging effect of
ischaemia-hypoxia and irreversible injury
Post a Comment