Cell damage

Introduction

• Definition of pathology:
literally translated: study of suffering.
That branch of medicine treating of the essential
nature of disease, especially of the changes in the
body tissues and organs, which cause or are
caused by disease.
 ?What do we study in pathology
• Terminology of diseases
• Etiological factor(s): some diseases have a single
etiology others have multiple etiological factors
• Pathogenesis: mechanisms through which etiology
results in structural and functional changes in the cells,
tissues, organs leading to manifestations of the disease.
• Morphology: pathological gross and microscopic
changes in the cells and tissues induced by the disease
• Clinical symptoms and signs: the features that will
bring the patient to seek medical advice.
 ?What do we study in pathology
• Natural history:
Starting from the origin of the disease, into
the progression and outcome (prognosis).
• No investigations or treatment is included
in the pathology.
Divisions of pathology

General pathology
versus
Systemic pathology
 :General pathology
The basic ways in which cells and tissues
respond to stimuli
• Cell injury/adaptation
• Inflammation
• Repair
• Neoplasia
• Hemodynamic disorders
 systemic pathology

the particular responses of the specialized

organs:
• Infarction in heart
• Infarction in brain
• Infarction in intestine
 :Cell injury
Overview:
• Homeostasis: the cells survive, function and
interact within their immediate environment and
the intracellular milieu within a relatively narrow
range of physiological parameters.
• Adaptation: under a certain degree of stimuli
(physiological or pathological stress), the cells try
to achieve a new steady state and preserve
viability
 :Cell injury
• if the adaptive capability of the cells is
exceeded, or the injury was severe enough
from the start to overcome the adaptation
capacity, then cell injury will occur.
 :Cell injury
• Reversible: if the stimulus is removed, and under
certain limits, the injury can be reversed and the
cells can return back to their stable status.
• Irreversible: if the limits are exceeded (severe or
persistent stimuli), the cells will lose viability and
will die
 Necrosis: death of cells within viable
organs
 Apoptosis: programmed cell death.
 Causes of cell injury
1. Oxygen deprivation:
Hypoxia: oxygen deficiency; interferes
with the aerobic oxidative respiration. One of the
most common causes of cell injury
 Causes of hypoxia
• Ischemia: loss of blood supply in a tissue
due to impairment of the blood supply or
the venous drainage. The most common
cause of cell injury.
– The most common cause of hypoxia.
– The most common cause of cell injury.
– More injurious than hypoxia, because it impairs
the delivery of oxygen and glycolysis substrate
as well as the removal of waste.
 Causes of hypoxia
• Inadequate oxygenation of blood:
– Pneumonia.
– Carbon monoxide poisoning.
– Anaemia.
 Causes of cell injury
2. Chemicals:
whether known chemical injurious agents, or even
normal substrates in abnormal concentrations.
3. Infectious agents.
4. Immunological reactions: Antigen –antibody
reactions are meant to protect the host, but if
overridden or improperly operating will result in
diseases:
– hypersensitivity reaction pattern.
– autoimmune disorders
 Causes of cell injury
5. Genetic defects:
6. Nutritional imbalance:
Over or under nutrition. This includes vitamins
and minerals.
7. Physical agents:
Thermal, electrical, radiation, trauma.
8. Aging; “cellular senescence”:
Intrinsic aging of the cells, leading to alternations
in the replicative and the repair abilities.
 :Cellular adaptation
• Definition:
A new steady state which lies between
normal unstressed cell, and the injured
overstressed cell, in which the cell can
function and preserve viability.
 :Cellular adaptation
• Stresses can be
physiological, leading to physiological
adaptation, (hormones leading to
enlargement of the breast and the uterus
during pregnancy), or
pathological, leading to pathological
adaptation, (hormones produced by tumors
leading to endometrial hyperplasia).
 :Cellular adaptation
• The adaptive stimulus can act at any step
– Cell membrane/receptor binding.
– Signal transduction.
– Protein transcription, translation or export.
• All adaptive responses are reversible, if the
underlying cause is abolished.
 :Cellular adaptation
• Types of adaptive responses:
– Atrophy
– Hypertrophy
– Hyperplasia
– metaplasia
 Atrophy
• Definition:
Decrease in the size of the cell, due to the loss of the
cell substances, leading to diminished function of the
cell and a new equilibrium is reached.
• This is accompanied by decrease in the size of the
organ, if sufficient number of cells is involved.
• The cells are alive (not dead)
• Imbalance between protein synthesis and degradation
is the fundamental step, leading to reduction in
structural components.
 Causes of atrophy

• Physiological:
– thymic involution, aging.
• Pathological:
– decrease work load (disuse atrophy)
– loss of innervation (Denervation atrophy)
– diminished blood supply (ischemic atrophy)
– inadequate nutrition
– loss of hormonal stimuli
 :Mechanisms of atrophy
Identical in physiological and pathological causes.
Imbalance between the protein synthesis and
degradation, with degradation playing a major
role.
 Autophagy and cell atrophy
• lysosomes:
act on exogenous proteins engulfed by endocytosis or
subcellular components leading to the formation of
autophagic vacuoles, which are increased in atrophy.
 :Mechanisms of atrophy
• ubiquitin-proteasome pathway:
– acts on cytosolic and nuclear proteins.
– The protein/ubiquitin complex are engulfed by the
cytoplasmic proteasome
 Mechanisms of atrophy
• Sometimes the number of cells can be
reduced by the process apoptosis of, which
is under the same influences as the atrophy.
 :Hypertrophy

• Definition:
Increase in the size of cells by an increase
in the number and density of the cellular
substances, leading to an over all increase
in the size and the function of the organ,
and a new equilibrium is reached.
 :Hypertrophy
• Mainly occurs in organs composed of cells that
can’t divide (cardiac muscles).
• This is not accompanied by an increase in the
number of the cells.
• Causes:
Physiological or pathological:
– Increase in the work load (body building, hypertension).
– Increase in hormonal stimulation. This involves both
hypertrophy and hyperplasia.
 :Hypertrophy
Mechanisms:
• Increase in the synthesis of structural
proteins/cell, leading to an overall increase
in the workload of the organ.
Cardiac muscle hypertrophy in
hypertension
skeletal muscle hypertrophy in body
:building
 :Hyperplasia

• Definition: an increase in the size of the

organ due to increase in the number of the
cells in the organ, leading to increase in the
function.
• This is seen in cells that can divide.
:Hyperplasia
• In many instances,
hyperplasia and
hypertrophy occur at
the same time. Uterus
during pregnancy is a
good example.
 :Hyperplasia
Causes:
• Physiological:
– hormonal hyperplasia.
– compensatory hyperplasia: which is under the
influence of growth factors, liver resection.
• Pathological:
– Under the effect of hormones or growth factors.
Endometrial hyperplasia is an example.
 :Hyperplasia
• Both hypertrophy and hyperplasia are
reversible, if the stimulus is removed.
• Persistence of the stimulus any change the
process into neoplasia “cancer”
Hypertrophy and hyperplasia
 :Metaplasia

• Definition: replacement of one type of adult

cell, whether epithelial or mesenchymal, by
another type of adult cell, aiming at
replacing cells that are sensitive to certain
stimuli by a more resistant cell type.
• This happens through reprogramming of
stem cells or undifferentiated mesenchymal
cells.
Examples of Metaplasia
 :Subcellular responses to injury
• lysosomal catabolism:
– Primary lysosomes: membrane bound
intracellular organelles containing a variety of
hydrolytic enzymes
– Secondary lysosomes, “phagolysosome” : when
the 1ry lysosomes fuse with vacuoles
containing material for digestion.
 :Type of phagocytosis

• Autophagy:
– When intracellular organelles are sequestered
from the cytoplasm in an autophagic vacuole.
This combines with 1ry lysosome to form
autophagolysosome.
– This is seen especially with atrophy, aging,
development and remodeling.
 :Type of phagocytosis
• Heterophagy:
– Inflammatory cells engulf and destroy foreign bodies
e.g. microorganisms or foreign material by the process
of endocytosis:
• Pinocytosis: is engulfment of soluble material.
• Phagocytosis: engulfment of large material.
– Endocytic vacuoles combine with 1ry lysosomes to
form heterophagic phagolysosomes
• If carbohydrate, completely digested.
• If lipid, residual bodies, lipofuscin pigment.
• Some foreign material can stay within cells like carbon
particles.
lipofuscin
 :Mitochondrial alternations

• increase number in hypertrophy, decrease in

atrophy
• increase in the size in alcoholic liver
(megamitochondria)
 Heat shock proteins; HSP
Synonymous: stress proteins, molecular
chaperones
• Cytoplasmic proteins that are involved in
protein kinesis and repair, like protein
folding, translocation and disaggregation.
• Important adaptive response found in all
species
 Heat shock proteins; HSP
• 2 families:
– Produced always at low levels; HSP60, 90
– Produce under stress; HSP 70
• HSP induced after injurious stimuli leads to
refolding denatured proteins before causing death.
If not responding, the protein is directed to bind
with ubiquitin-proteasome pathway, leading to
degradation.
• Lewy bodies and Mallory bodies are examples.
Heat Shock Proteins; HSP