Cellular adaptation,

Cell injury and

inflammation

Henock Solomon , MD, Pathology Resident

Outline
• Cellular adaptation
• Cell injury and cell death
• Inflammation
• Repair mechanisms

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1-Cellular adaptation and
cellular injury
1.1Cellular
adaptation
• An organ/cell is in homeostasis with the surrounding
physiological stress placed on it
• So, an increase, decrease or change in stress on an
organ leads to adaptation

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Homeostatic cell – metabolic change – adaptation/ injury
- injury could be reversible or
irreversible

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There are different mechanism of adaptations
• Hyperplasia
• Hypertrophy
• Atrophy
• Metaplasia

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A. Hyperplasia
• Defined as increase in number of cells
Physiologic hyperplasia:
- Occurs due to a normal stressor
- Increase in the size of the breasts during pregnancy
- Increase in thickness of endometrium during menstrual
cycle
- Liver growth after partial resection.

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Cont’d
Pathologic hyperplasia:
 Occurs due to an abnormal stressor
• Growth of adrenal glands due to production of
adrenocorticotropic hormone (ACTH) by a pituitary
adenoma
• Proliferation of endometrium due to prolonged estrogen
stimulus.

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B. Hypertrophy
• Increase in the size of the cell
Physiologic hypertrophy: Occurs due to a normal
stressor
• Enlargement of skeletal muscle with exercise
Pathologic hypertrophy: Occurs due to an abnormal
stressor
• Increase in the size of the heart due to aortic stenosis.
• Uterus during pregnancy

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Hypertrophy of LV

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C. Atrophy
• Decrease in the size of a cell that has at one time been
of normal size

Physiologic atrophy:
 Occurs due to a normal stressor
• Decrease in the size of the uterus after pregnancy
• Decrease in the size of the breast after lactation

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Metaplasia
• Change of epithelium at a site or location from one type
of epithelium to another type
• In metaplasia, the epithelium is normal in appearance
but in an abnormal location
• E.g. Barrett esophagus is due to reflux of gastric
contents into the esophagus, which causes the
epithelium type to convert from squamous to glandular

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Barrett's esophagus

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 1.2-Cell injury
Metabolic
homeostasis adaptation injury
change

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• Cell injury occurs when the cells cannot adapt to their new
environment
• Causes :- hypoxia
ischemia
physical and chemical agents
trauma
infectious agents
radiation
toxins
metabolic abnormalities (acquired or genetic)
aging , nutritional imbalances
immune dysfunction (hypersensitivity rxns, autoimmune
diseases
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Cell injury depends on

• The type and duration of an injury

• The severity/magnitude of the injury
• The type of cell injured

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Cont’d
• Four cellular systems are especially vulnerable to
cellular injury
1. DNA
2. Cell membranes
3. Protein generation
4. Adenosine triphosphate (ATP) production(aerobic
respiration)

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Mechanism of cell injury
1. Hypoxia
Decreased oxygen results in decreased production of
ATP.
• ATP is normally required by the Na/K pump and Ca2
pump.
• When ATP levels decrease, these pumps fail and sodium
(along with water, which follows sodium) enters the cell,
causing swelling.
• Also, calcium enters the cell, which activates
endonucleases, proteases, phospholipases, and DNases,
which damage the cell.
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Cells switch to anaerobic respiration to produce ATP,
which results in accumulation of lactic acid.
• The accumulation of lactic acid decreases the cellular
PH.
• Decreased pH causes disaggregation of ribosomes from
endoplasmic reticulum.

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Cont’d
2. Generation of oxygen-derived free radicals
(reactive oxygen species) by a stressing agent like super
oxide , hydroxyl ion

• A free radical is a molecule with an unpaired electron in

the outer orbit

• Free radicals are generated by normal physiologic

reduction-oxidation reactions, UV light, x-rays and
ionizing radiation,

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Cont’d
• Effects of free radicals
-Lipid peroxidation
- DNA fragmentation
- Protein cross-linking

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Protective factors against free radical damage
• Catalase - which degrades hydrogen peroxide.
• Superoxide dismutase - which converts superoxide to
hydrogen peroxide
• Glutathione - which catalyzes breakdown of hydroxyl
radicals.
• Vitamins A, C, and E - which have an antioxidant effect

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Cont’d
3. Chemical injury:
• Some chemicals are directly toxic to the cells and others
require conversion to a toxic metabolite
• E.g.
-Ethylene glycol (antifreeze) is not toxic, but its
metabolite,
oxalic acid is.
-In contrast, cyanide directly inactivates cytochrome
oxidase,
which impairs the formation of ATP.
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. Reversible cell injury
• Characterized by functional and structural alterations in
early stages or mild forms of injury, which are
correctable if the damaging stimulus is removed
• Microscopic features:-cellular swelling and fatty change.

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. Irreversible cell injury
• This type of injury occurs with damage to plasma or
lysosomal membranes, loss of DNA, or loss of
mitochondria.

• The two most important factors determining irreversible

damage are membrane disturbances and the inability
to
reverse mitochondrial dysfunction.

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• Microscopic feature: Hall mark of irreversible cell injury
is membrane damage
• Nuclear karyolysis (loss of basophilia), pyknosis
(shrinkage of nucleus), and karyorrhexis (fragmentation
of nucleus).

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Cont’d

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Cont’d

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1.3-Cell Death (Apoptosis and
Necrosis)
• Two forms of cell death
1. Apoptosis
2. Necrosis

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Apoptosis
• Programmed cell death

• During growth and development, some cells serve a

function
in the growth phase but need to be removed after their

purpose is fulfilled
Apoptosis does not generate an inflammatory reaction

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Causes of Apoptosis
Physiologic conditions
• The removal of supernumerary cells during
development
• Involution of hormone-dependent tissues on hormone
withdrawal
• Cell turnover in proliferating cell populations
• Elimination of potentially harmful self-reactive
lymphocytes
• Death of host cells that have served their useful
purpose. e.g. neutrophils in an acute inflammatory
response, and lymphocytes at the end of an immune
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Cont’d
Pathologic conditions
• DNA damage
• Accumulation of misfolded proteins
• Induced during certain infections particularly viral
infections, as a result of the virus itself (as in adenovirus
and HIV infections) or the host immune response (as in
viral hepatitis)

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 Apoptosis is mediated by caspases that activate
proteases and endonucleases.
1. Proteases break down the cytoskeleton.
2. Endonucleases break down DNA.
 Caspases are activated by multiple pathways.
1. Intrinsic mitochondrial pathway
2. Extrinsic receptor-ligand pathway
3. Cytotoxic CD8 + T cell-mediated pathway

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Removal of Dead cells
• The formation of apoptotic bodies breaks cells up into
"bite-sized” fragments that are edible for phagocytes.

• The process of apoptotic cell phagocytosis is called

efferocytosis

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Necrosis
• Uncontrolled death of cells due to one of the various
causes of cellular injury

• Characterized by denaturation of cellular proteins,

leakage of cellular contents through damaged
membranes, local inflammation, and enzymatic
digestion of the lethally injured cell.

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Patterns of necrosis
1. Coagulative Necrosis
• Coagulative necrosis is the type of necrosis in which
protein denaturation is more prominent than enzymatic
breakdown
• associated with preservation of the general cellular
architecture (the organ type is identifiable)
• Ischemia caused by obstruction in a vessel may lead to
coagulative necrosis of the supplied tissue in all organs
except the brain
• A localized area of coagulative necrosis is called an
infarct
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Cont’d

2. Liquefactive Necrosis
• Liquefactive necrosis occurs in situations in which
enzymatic breakdown is more prominent than protein
denaturation resulting in transformation of the tissue
into a viscous liquid
• is seen in focal bacterial or occasionally in fungal
infections,
• The necrotic material is frequently creamy yellow
because of the presence of leukocytes and is called pus
• Seen brain .pancreas

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hypoxic death of cells within the central nervous
system often manifests as liquefactive necrosis

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Cont’d
3. Caseous Necrosis
• Caseous necrosis is a “cheesy-looking” necrosis
associated with tuberculosis infections

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Cont’d
4. Fat Necrosis
• change in adipose tissue due to trauma or the release of
enzymes from adjacent organs (e.g., the pancreas)
• The trauma or enzymatic action causes a breakdown of
lipid and a release of fatty acids, which combine with
calcium to form chalky deposits

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Cont’d
Gangrenous necrosis
• commonly used in clinical practice.
• It is usually applied to a limb, generally the lower leg,
that has lost its blood supply and has undergone
necrosis (Dry gangrene typically coagulative necrosis)
• When bacterial infection - wet gangrene)
• Gas gangrene -Formed by gas forming bacteria (the
presence of gas in tissues) -Caused by clostridium
perfringens

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Dry gangrene

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Gas gangrene

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Cont’d
5. Fibrinoid Necrosis
• vascular damage usually seen in immune reactions
involving blood vessels

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Fibrinoid necrosis in an artery. The wall of the artery shows
a circumferential bright pink area of necrosis with inflammation

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 2-Inflammation

 Definition: Inflammation is a local response (reaction)

of living vascularized tissues to endogenous and
exogenous stimuli.
 its fundamental to localize and eliminate the
causative agent and to limit tissue injury.
 Causes
 Physical agents - mechanical injuries, alteration in
temperatures and pressure, radiation injuries.
 Chemical agents- drugs and toxins.
 Biologic agents (infectious)- bacteria, viruses, fungi,
parasites
 Immunologic disorders- hypersensitivity reactions,
autoimmunity, immunodeficiency states etc.
 Genetic/metabolic disorders- example diabetes mellitus
etc.
 Nomenclature:
 The nomenclatures of inflammatory lesion are usually
indicated by the suffix 'itis'.
 Thus, inflammation of the appendix is called
appendicitis and that of meninges as meningitis, etc.…
 However, like any rule, it has its own exceptions
examples pneumonia, etc….
 Classification
 Inflammation is classified crudely based on duration of
the lesion and histologic appearances into acute and
chronic inflammation.
A. Acute inflammation
 Acute inflammation is an immediate and early response
to an injurious agent and it is relatively of short
duration, lasting for minutes, several hours or few days.
 It is characterized by exudation of fluids and plasma
proteins and the emigration of predominantly
neutrophilic leukocytes to the site of injury
 Cardinal signs of acute inflammation
 Redness (rubor): which is due to dilation of small blood vessels
 Heat (calor): which results from increased blood flow
(hyperemia) due to regional vascular dilation
 Swelling (tumor):which is due to accumulation of fluid in the
extravascular space which, in turn, is due to increased vascular
permeability.
 Pain (dolor): which partly results from the stretching &
destruction of tissues due to inflammatory edema and in part
from pus under pressure in as abscess cavity.
 Loss of function: The inflammed area is inhibited by pain
while severe swelling may also physically immobilize the tissue.
Redness
Swelling
Events of acute inflammation:
1. Vascular events
Transient vasoconstriction (lasting only for seconds)
Vasodilation .
 Increase vascular permeability leading to fluid leak and
formation of exudates ( exudates = fluid rich in protein
)
2. Cellular response
 The cellular response has the following stages:
Margination-Rolling-Adhesion-Transmigration-Chemotaxis
Then Phagocytosis

 Phagocytosis is the process of engulfment and internalization

by specialized cells of particulate material, which includes
invading microorganisms, damaged cells, and tissue debris.
 These phagocytic cells include polymorphonuclear leukocytes
(particularly neutrophils), monocytes and tissue macrophages.
 The ultimate step in phagocytosis of bacteria is killing and
degradation.

There are two forms of bacterial killing Oxygen-independent

mechanismb) Oxygen-dependent mechanism (More
effective compared to oxygen independent killing)
 Effects of acute inflammation
A. Beneficial effects
 Dilution of toxins
 Protective antibodies
 Fibrin formation
 Plasma mediator systems provisions
 Cell nutrition
 Promotion of immunity
B. Harmful effects
 Tissue destruction
 Swelling
 Inappropriate response
Four Outcomes of Acute Inflammation
 Complete resolution with regeneration
 Complete resolution with scarring
 Abscess formation
 Transition to chronic inflammation
2. CHRONIC INFLAMMATION
 Definition: Chronic inflammation can be defined as a
prolonged inflammatory process (weeks or months)
where an active inflammation, tissue destruction and
attempts at repair are proceeding simultaneously.
Causes of Chronic Inflammation
 Following bout of acute inflammation
 Persistent infections
 Infections with certain organisms, including viral
infections, mycobacteria, parasitic infections, and fungal
infections
 Autoimmune disease
 Response to foreign material
 Response to malignancy
Cells of chronic inflammation
 Monocytes and Macrophages-are scavenger cells of the
body
 Liver : Kupffer cell
 Reticuloendothelial system : sinus histiocytes
 CNS : microglial cells
 Skin : Langerhans cells
Other cells in chronic inflammation
 T-Lymphocytes
 B-lymphocytes and Plasma cells
 Mast cells and eosinophils
 Granulomatous Inflammation:
 Granulomatous inflammation is a distinctive pattern of
chronic inflammation characterized by aggregates of
activated macrophages that assume an epithelioid
appearance. (epithelioid cells and multinucleated
giant cells)
• esp seen in Mycobacterium tuberculosis and syphilis,
leprosy, fungal infections (e.g., coccidioidomycosis),
parasitic infections (e.g., schistosomiasis)......
Granuloma
Acute vs chronic inflammation
 3-Repair
Proliferation and the Cell Cycle
• Cell proliferation is fundamental to development, maintenance of
steady-state tissue homeostasis, and replacement of dead or
damaged cells
• The key elements of cellular proliferation are
1. Accurate DNA replication
2. Coordinated synthesis of all other cellular constituents,
3. Followed by equal apportionment of DNA and other
cellular constituents (e.g., organelles) to daughter cells
through mitosis and cytokinesis.
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 • The sequence of events that results in cell division is called the cell
cycle; it consists of G1 (presynthetic growth), S (DNA synthesis), G2
(premitotic growth), and M (mitotic) phases
Quiescent cells that are not actively cycling are said to be in the
G0 state.
When cells do detect DNA irregularities, checkpoint
activation delays cell cycle progression and
• Triggers DNA repair mechanisms.
• Cells will undergo apoptosis

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 General Concepts of Repair
Repair and healing of damaged cells and tissues start almost as
soon as the inflammatory process begins.
• Tissue repair involves 5 overlapping processes:
Hemostasis (coagulation, platelets)
Inflammation (neutrophils, macrophages, lymphocytes, mast cells)
Regeneration (stem cells and differentiated cells)
 Fibrosis (macrophages, granulation tissue [fibroblasts,
angiogenesis], type III collagen)
Remodeling (macrophages, fibroblasts, converting collagen III to I)

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 1. Regeneration
Vs
2. Fibrosis

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1.Repair by Tissue Regeneration
• Replacement of damaged tissue with native tissue; dependent on
regenerative capacity of tissue
• Different tissues have different regenerative capacities.
Labile tissues possess stem cells that continuously cycle
to regenerate the tissue.
1. Small and large bowel (stem cells in mucosal crypts)
2. Skin (stem cells in basal layer,)
3. Bone marrow (hematopoietic stem cells)

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 Stable cells
• Cells of these tissues are quiescent (in the G0 stage of the cell
cycle) and have only minimal proliferative activity in their normal
state, but are capable of dividing in response to injury or loss of
tissue mass.
• Stable cells constitute the parenchyma of most solid tissues, such
as liver, kidney, and pancreas, fibroblasts, and smooth muscle cells
• With the exception of liver, stable tissues have a limited capacity to
regenerate after injury

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• Permanent cells (few stem cells and/or differentiated cells with the
capacity to replicate) have a very low level of replicative capacity.
• Examples include neurons, skeletal muscle cells and cardiac muscle

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 2. REPAIR BY FIBROSIS
• Replacement of damaged tissue with fibrous scar
• Occurs when regenerative stem cells are lost (e.g., deep skin cut)
or when a tissue lacks regenerative capacity (e.g., healing after a
myocardial infarction)
• Granulation tissue formation is the initial phase of repair .
-Consists of fibroblasts (deposit type III collagen),
capillaries (provide nutrients),and myofibroblasts
(contract wound)
• Eventually results in scar formation, in which type III collagen is
replaced with type I collagen
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1. Type III collagen is pliable and present in granulation
tissue, embryonic tissue, uterus, and keloids.
2. Type I collagen has high tensile strength and is present in
skin, bone, tendons, and most organs.
3. Collagenase removes type III collagen and requires zinc
as a cofactor

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Types of Wound Healing (Skin)
 Primary union (healing by first intention) occurs when wounds are
closed physically with sutures, metal staples, dermal adhesive, etc.
 N.B Leads to minimal scar formation
Secondary union (healing by secondary intention) occurs when
wounds are allowed to heal by wound contraction and is mediated by
myofibroblasts at the edge of the wound
• E.g. When cell or tissue loss is more extensive, such as in large
wounds, abscesses, ulceration, and ischemic necrosis (infarction) in
parenchymal organs

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Aberrations or complications in Wound Healing
Delayed wound healing may be seen in wounds complicated by foreign
bodies, infection, ischemia, diabetes, malnutrition, scurvy, etc.
 Hypertrophic scar results in a prominent scar that is localized to the
wound, due to excess production of granulation tissue and
predominantly type 3 collagen which is arranged in parallel pattern to the
epidermis. . It is common in burn patients
Keloid formation is a genetic predisposition that is common in African
Americans.
It tends to affect the earlobes, face, neck, sternum, and forearms, and it
may produce large tumor-like scars extending beyond the injury site.
There is excess production of collagen that is predominantly contain
type 1 collagen arranged haphazardly
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01/24/2025 Dr. Birhanu Kassie, resident Physician of Pathology
 Thank you!

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References
• Robbins and cotrans pathologic basics of disease, 10th
edition

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