Transcript Pathology

L11
OXIDATIVE STRESS
Oxidative Stress
Oxidative stress – cell injury induced by free radicals (e.g.,
reactive oxygen species)
▫ Free radicals – chemical species that have a single unpaired electron
(which is highly reactive and possibly autocatalytic, converting other
molecules into free radicals to propagate a chain of damage)
Reactive oxygen species (ROS) – a type of oxygen-derived free
radical produced during normal cell activity in manageably low
concentrations and by activated leukocytes for the destruction of
microbes before being degraded and removed
▫ Increased production or decreased ROS scavenging  oxidative stress
Generation of Free Radicals
Oxidation-reduction reactions (occurring during normal metabolic
processes): reduction of O2 during respiration, generating two H2O
molecules
▫ Production of partially reduced intermediates after electrons transfer from O2):
superoxide anion (•O2- – one electron), hydrogen peroxide (H2O2 – two
electrons), and hydroxyl radical (•OH – three electrons)
Absorption of radiant energy: hydrolysis of H2O into •OH and •H by
ionizing radiation (e.g., UV light and x-rays)
Rapid bursts of ROS produced by activated leukocytes during
inflammation: precisely controlled oxidation-reduction reaction
catalyzed by NADPH oxidase
▫ Generation of •O2- by intracellular oxidases (e.g., xanthine oxidase)
Generation of Free Radicals
Enzymatic metabolism of exogenous chemicals and drugs:
generation of free radicals with similarities to ROS (e.g., CCl4 
•CCl3)
Transition metals (e.g., iron and copper): donate or accept free
electrons to catalyze free radical formation
▫ Fenton reaction (after enhanced reduction of ferric state by •O2-): H2O2 +
Fe2+ → Fe3+ + •OH + OH−
Nitric oxide (NO): chemical mediator that can act as a free radical
and be converted to peroxynitrite (ONOO-) as well as NO2, and
NO3-
Removal of Free Radicals
Free radicals are inherently unstable and decay spontaneously
▫ Dismutation of superoxide anion: •O2-  O2 + H2O2
Antioxidants – block free radical formation or inactivate free radicals (e.g.,
Vitamin A, Vitamin C, Vitamin E, glutathione)
Minimization of reactive iron and copper by binding to storage and
transport proteins (e.g., transferrin, ferritin, lactoferrin, ceruloplasmin),
preventing participation in ROS generation
Free radical-scavenging systems (located near the site of oxidative
generation):
▫ Catalase (in peroxisomes): 2 H2O2 → O2 + 2 H2O
▫ Superoxide dismutase (SODs): 2 •O2- + 2 •H → H2O2 + O2
▫ Glutathione peroxidase: H2O2 + 2 GSH → GSSG + 2 H2O / 2 •OH + 2 GSH → GSSG + 2
H2O
Pathological Effects
Lipid peroxidation in membranes: in the presence of O2, free radicals
can cause peroxidation of the lipids, leading to membrane damage
Oxidative modification of proteins: damages the active sites of
enzymes, disrupts the conformation of structural proteins, and
enhances proteasomal degradation of misfolded proteins (through
the oxidation of amino acid side chains, formation of covalent
protein-protein crosslinks, and oxidation of protein backbones)
Lesions in DNA: cause single- and double-strand breaks in DNA,
crosslinking of DNA strands, and the formation of DNA adducts
▫ Implicated in cell aging and the malignant transformation of cells (i.e.,
mutations)
Triggering of necrosis and apoptosis after cell injury and death
L12
CELLULAR ADAPTATIONS
Cellular Adaptations
Adaptations – reversible
changes in the size, number,
phenotype, metabolic activity,
or functions of cells in
response to changes in the
environment
Atrophy
Atrophy – a reduction in the size of an organ or tissue due to a decrease in
the cell size and number (from decreased protein synthesis or increased
protein degradation through the ubiquitin-proteasome pathway)
▫ Common during normal development:
▫ Embryonic notochord and thyroglossal duct in fetal development
▫ Decreased size of the uterus after parturition
▫ Accompanied by increased autophagy (i.e., “self-eating”) in which the starved cell eats
its own components in an attempt to reduce nutrient demand
▫ Marked by the appearance of autophagic vacuoles, persisting as residual bodies of cell debris that
resist digestion (e.g., lipofuscin granules) and impart a brown discoloration in the tissue
Pathological causes: decreased workload (or disuse), loss of innervation,
diminished blood supply (i.e., ischemia), inadequate nutrition (e.g.,
energy-protein deficient marasmus with cachexia), loss of endocrine
stimulation (e.g., menopause), or pressure/compression (related to
ischemia)
Hypertrophy
Hypertrophy – an increase in the size of cells (subsequently increasing in
the size of the affected organ) due to the synthesis and assembly of
additional intracellular structural components (e.g., cellular proteins)
▫ Dividing cells: respond to stress by undergoing hypertrophy and hyperplasia
▫ Non-diving cells (e.g., myocardial tissues): respond to stress by solely undergoing
hypertrophy
Physiological causes: increased functional demand (e.g., muscle tissue
after working out) or stimulation by hormones and growth factors (e.g.,
estrogen-induced enlargement of the uterus during pregnancy)
Pathogenesis of cardiac hypertrophy:
▫ Integrated action of mechanical sensors (due to increased workload), growth factors
(e.g., TGF-β, IGF1, fibroblast GF), and vasoactive agents (e.g., α-adrenergic agonists,
endothelian-1, angiotensin II)  complex signal transduction pathways  activation
of transcription factors (e.g., GATA4, NFAT, MEF2)  increased synthesis of muscle
proteins
Hyperplasia
Hyperplasia – induced by hormones (e.g., proliferation of the
glandular epithelium of the female breast during puberty and
pregnancy) or growth factors (e.g., wart generation due to
papillomaviruses) when there is a need for increased functional
capacity of hormone-sensitive organs or a compensatory increase
after damage or resection
▫ Classic example: liver regeneration
Pathological causes: excessive or inappropriate actions of hormones
or growth factors on target cells (e.g., endometrial hyperplasia after
menstruation, resulting in absolute or relative increases in estrogen
concentrations)
Increases the risk for cancer development due to deregulated growth
control mechanisms, leading to unrestrained proliferation
Metaplasia
Metaplasia – the replacement of a differentiated cell type (e.g.,
epithelial or mesenchymal) with another cell type that is better
able to withstand the adverse environment
▫ Results from reprogramming of stem cells, differentiating along a new
pathway (through cytokine and growth factor signaling)—not a result
from a change in the phenotype of an already differentiated cell type
▫ Common: columnar  squamous (in the respiratory tract due to chronic
irritation)
Barrett’s esophagus: squamous  columnar (in the esophagus
due to refluxed gastric acid)
L13
ACUTE INFLAMMATION
Acute Inflammation
Acute inflammation:
▫ Dilation of small vessels, leading to an increase in
blood flow
▫ Increased vascular permeability of the
microvasculature, enabling plasma proteins and
leukocytes to leave the circulation
▫ Emigration of the leukocytes from the
microcirculation, accumulating at the site of the injury
before activating to eliminate the pathogen
▫ Phagocytes – recognize the pathogen and subsequently
release cytokines, lipid messengers, and mediators of
inflammation
Vascular reactions of acute inflammation:
changes in blood flow and permeability of the
vessels, maximizing the movement of plasma
proteins and leukocytes out of the circulation and
into the site of infection
Reactions of the Blood Vessels
Exudation – the escape of fluid, proteins, and blood cells from the
vascular system into the interstitial tissue or body cavities
▫ Exudate – an extravascular fluid that has a high protein concentration and
contains cellular debris (whose presence implies that there is an increase in
the permeability of small blood vessels triggered by an injury)
▫ Transudate – a fluid with low protein content (e.g., albumin) with minimal
cellular material and low specific gravity
▫ Essentially an ultrafiltrate of blood plasma as a result of osmotic or hydrostatic imbalance
without an increase in vascular permeability
Edema – an excess of fluid (exudate or transudate) in the interstitial
fluid or serous cavities
Pus – a purulent exudate rich in leukocytes (e.g., neutrophils), cellular
debris, and microbes
Reactions of the Blood Vessels
Changes in vascular flow and caliber:
▫ Vasodilation – early manifestation of acute inflammation induced by mediators
(e.g., histamine) on vascular smooth muscle, resulting in increased blood flow
and subsequent erythema
▫ The loss of fluid and increased vessel diameter lead to slower blood flow,
increased RBC concentrations in the small vessels, and increased viscosity of the
blood, resulting in stasis
▫ Stasis – vascular congestion and localized redness of the tissue
Increased vascular permeability:
▫ Contraction of the endothelial cells (by histamine, bradykinin, leukotrienes) 
increased interendothelial spaces
▫ Endothelial injury  endothelial cell necrosis and detachment
▫ Transcytosis – increased transport of fluids and proteins through the
endothelial cell
Leukocyte Recruitment
Changes in blood flow and vascular permeability are quickly
followed by the influx of leukocytes into the tissue in order to
eliminate the offending agents
▫ Activated leukocytes may induce tissue damage due to the potency of
their immune products (as collateral damage)
Multistep process mediated and controlled by chemokines
(aiding in adhesion and signaling):
1. Margination, rolling, and adhesion to the endothelium
2. Migration across the endothelium and the vessel wall
3. Migration into the tissues toward a chemotactic stimulus
Leukocyte Recruitment
Leukocyte adhesion to the endothelium:
▫ Margination – process of leukocyte redistribution in which stasis allows WBCs
to move peripherally along the endothelial surface
▫ Subsequently, leukocytes adhere transiently to the endothelium, detach, and
bind again (during rolling) before coming to rest by adhering firmly
Mediated by complementary adhesion molecules (enhanced by
cytokines that are secreted by sentinel cells in response to
pathogens):
▫ Selectins – family of proteins that mediates the initial rolling interactions,
slowing down the leukocytes (e.g., P-selectin and E-selectin)
▫ Integrins – family of heterodynamic surface proteins that mediates firm
adhesion
Leukocyte Recruitment
Leukocyte migration through the endothelium:
▫ Diapedesis (or transmigration) – migration of the leukocytes through
the endothelium by chemokine stimulation, migrating toward the
chemical concentration gradient at the site of injury
▫ CD31 / PECAM-1 – platelet endothelial cell adhesion molecule
Chemotaxis of the leukocytes:
▫ Chemotaxis – movement of leukocytes into the tissue toward the site of
injury along an endogenous or exogenous chemical gradient
▫ Exogenous bacterial products: cytokines (e.g., chemokine IL-8), components of the
complement system (e.g., C5a), and arachidonic acid metabolites (e.g., leukotriene
LTB4)
Leukocyte Recruitment
Characterization of acute inflammation: presence of neutrophils
(6-24 hours) which are replaced by monocytes (24-48 hours)
Phagocytosis
Process:
▫ Recognition and attachment of
the particles to be ingested by
the leukocyte
▫ Engulfment (with the subsequent
formation of a phagocytic
vacuole)
▫ Killing (e.g., ROS and NO
derivatives) or degradation (e.g.,
lysozymes) of the ingested
material
L14
PAT TERNS OF ACUTE INFLAMMATION
Acute Inflammation
Morphological hallmarks: dilation
of the small blood vessels and
accumulation of leukocytes and
fluid in the extravascular tissue
▫ Special morphological patterns can be
superimposed depending on the
severity of the reaction, specific cause,
and the specific tissue and site involved
Serous Inflammation
Serous inflammation – marked by the
exudation of transudate (cell-poor fluid)
into the spaces created by cellular injury or
body cavities
▫ Effusion – accumulation of fluid derived from the
plasma (as a result of increased vascular
permeability) or mesothelial cell secretions (as a
result of local irritation)
Skin blister – accumulation of serous fluid
beneath the damaged epidermis of the skin,
resulting from a burn or viral infection
Fibrinous Inflammation
Fibrinous inflammation – passage of
fibrinogen out of the blood and deposition of
fibrin into the extracellular space after great
increases in vascular permeability or
procoagulant stimuli (e.g., cancer cells)
▫ Characteristic of inflammation in the lining of the
body cavities (e.g., meninges, pericardium, pleura),
appearing as an eosinophilic meshwork or
amorphous coagulum
Fibrinolysis – dissolution of fibrinous exudates
before clearance by MOs
▫ Without removal, stimulation and ingrowth of
fibroblasts and blood vessels can lead to scarring
through reorganization
Purulent (Suppurative) Inflammation
Purulent inflammation – characterized by the
production of pus, consisting of neutrophils,
liquefied cellular debris, and edema fluid
(commonly due to a pyogenic bacterial infection
that causes liquefactive tissue necrosis, such as
Staphylococci)
▫ E.g., acute appendicitis
Abscesses – localized collections of purulent
inflammatory tissue (after seeding of pyogenic
bacteria into the tissue) with a central mass of
necrotic leukocytes and tissue cells surrounded by
preserved neutrophils
▫ May become walled off and ultimately replaced by
connective tissue
Ulcers
Ulcer – local excavation of the surface of an
organ or tissue produced by the sloughing of
inflamed necrotic tissue (after tissue necrosis and
resultant inflammation)
▫ The mucosa of the mouth, stomach, intestines, or
genitourinary tract
▫ The skin and subcutaneous tissues of the lower
extremities of individuals with circulatory disturbances
Peptic ulcers – coexistence of acute and chronic
inflammation in the stomach or duodenum
▫ Acute stage: intense neutrophilic infiltration and
vascular dilation
▫ Chronic stage: fibroblastic proliferation, scarring, and
accumulation of lymphocytes, MOs, and plasma cells
Outcomes of Acute Inflammation
Complete resolution: restoration of the site of acute inflammation
to normal after successful elimination of the pathogen, involving
removal of cellular debris and microbes by MOs and resorption of
edema fluid into the lymphatics
Healing by connective tissue replacement (e.g., scarring or fibrosis):
after substantial tissue destruction or abundant fibrin exudation,
connective tissue grows into the area of damage, converting it into a
mass of fibrous tissue through reorganization
Progression to chronic inflammation: when the acute inflammatory
response cannot be cleared due to persistent pathogens or
interference with the normal healing process
L15
CHRONIC INFLAMMATION
Chronic Inflammation
Chronic inflammation – prolonged response in which
inflammation, tissue injury, and attempts at repair coexist
Causes:
▫ Unresolved acute inflammation (e.g., acute bacterial infection of the
lung  chronic lung abscess)
▫ Persistent infections that are difficult to resolve (e.g., Mycobacterium
and viruses), often evoking a delayed-type hypersensitivity reaction or
granulomatous reaction
Chronic Inflammation
▫ Hypersensitivity diseases caused by excessive and inappropriate
activation of the immune system
▫ Autoimmune disease – immune reactions developed against auto-antigens (e.g.,
rheumatoid arthritis and multiple sclerosis)
▫ Unregulated immune responses against microbes (e.g., IBS)
▫ Allergic disease – immune response against common environmental substances (e.g.,
bronchial asthma)
▫ Prolonged exposure to potentially toxic agents:
▫ Exogenous: particulate silica – a nondegradable inanimate material that, when
inhaled, results in silicosis (an inflammatory lung disease)
▫ Endogenous: atherosclerosis – induction of the arterial wall by excessive production
and tissue deposition of cholesterol and other lipids
Morphological Features
Result of the local activation of specific
cells and produced mediators:
▫ Infiltration with mononuclear cells (e.g.,
MOs, lymphocytes, plasma cells)
▫ Tissue destruction induced by persistent
pathogens or inflammatory cells
▫ Attempts at healing by connective tissue
replacement of damaged tissues through
angiogenesis and fibrosis
Cell Mediators
Macrophages (MOs) – dominant phagocytic cells which secrete cytokines and growth
factors, destroying pathogens and tissues and activating other cells (e.g., T cells)
▫ Act as filters for particulate matter, microbes, and senescent cells to effectively eliminate
microbes in cellular and humoral immune responses
▫ Monocytes – circulating precursors of MOs derived from hematopoietic stem cells of the bone
marrow and fetal progenitors during early development
▫ Normally diffusely scattered in the connective tissues, comprising the mononuclear phagocytic
system (or reticuloendothelial system): Kupffer cells of the liver, sinus histiocytes of the spleen
and lymph nodes, microglial cells of the CNS, and alveolar MOs of the lungs
Classical activation: induced by microbial products (e.g., endotoxin), T cell-derived
signals (e.g., INF-γ), foreign substances (e.g., crystals or particulates) to generate M1
MOs  produce NO and ROS derivatives and upregulate lysozymes in order to
enhance the killing of pathogens and stimulate inflammation
Alternate activation: induced by other cytokines (e.g., IL-4 and IL-13) to act as M2
MOs in tissue repair, secreting growth factors to promote angiogenesis, activate
fibroblasts, and stimulate collagen synthesis
Cell Mediators
Lymphocytes – T and B cells which mediate adaptive immunity, leading to persistent and
severe inflammation (and cluster with APCs to generate tertiary lymphoid tissue)
▫ Effector and memory lymphocytes are Ag-stimulated using adhesion molecule pairs (e.g., selectins and
integrins) and chemokines to migrate to inflammatory sites after activated MO cytokine-induced (e.g.,
TNF and IL-1) recruitment
CD4+ T cells – secrete inflammatory cytokines
▫ TH1 cells – produce INF-γ  classical M1 MO activation
▫ TH2 cells – produce IL-4, IL-5, and IL-13  recruit and activate eosinophils and alternatively activate M2
MOs
▫ TH17 cells – produce IL-17  recruit neutrophils and monocytes
Bidirectional interaction with MOs  propagate chronic inflammation: MO display of Ag to T
cells through costimulators on the membrane and cytokine production (e.g., IL-12) and T celldirected cytokine production of MO activators for further Ag presentation and cytokine
secretion
Activated B cells and antibody-producing plasma cells: specific for persistent foreign Ags, selfAgs, or altered tissue components
Cell Mediators
Eosinophils – granulocyte abundant in IgE-mediated immune reactions
and parasitic infections
▫ Major basic protein – highly cationic protein that is toxic to parasites and lyses
mammalian epithelial cells
Mast cells – widely distributed in connective tissue to participate in
acute and chronic inflammation, expressing FcεRI receptors for IgE to
stimulate degranulation of histamine and prostaglandins (can lead to
anaphylactic shock after allergic reactions)
Neutrophils – characteristic of acute inflammation but can be induced
by persistent microbes or mediators from MOs and T cells (e.g.,
osteomyelitis) during chronic inflammation
Granulomatous Inflammation
Granulomatous inflammation – form of chronic inflammation characterized
by collections of activated MOs and T cells (often during central necrosis) in
a cellular attempt to contain an offending agent that is difficult to eradicate
▫ Epithelioid cells – activated MOs that develop abundant cytoplasm and resemble
epithelial cells (and are surrounded by a collar of lymphocytes)
▫ Langerhans giant cells – multinucleated giant cells frequently found in granulomas
after the fusion of multiple activated MOs
Foreign body granulomas – incited by relatively inert foreign bodies (e.g.,
talc or sutures) that are large enough to prevent macrocytic phagocytosis in
the absence of T cell-mediated responses
Immune granulomas – caused by persistent T cell-mediated responses
when the inciting agent is difficult to clear so that activated T cells produce
cytokines (e.g., IL-2 and INF-γ) to perpetuate the subsequent T cell and
macrocytic response
L16
WOUND HEALING
Tissue Repair
Repair – the restoration of the tissue architecture and
function after an injury that is critical to survival
▫ Regeneration by proliferation of residual (uninjured) cells and
maturation of the tissue stem cells, replacing the damaged
components in order to return to a normal state (e.g., skin and
intestinal epithelium)
▫ Scar formation through the deposition of connective (fibrous)
tissue when an injured tissue is incapable of complete
regeneration or the supporting structures are severely damaged
Both regeneration and scar formation can contribute in
varying degrees to repair the tissues
Fibrosis – the extensive deposition of collagen in the
lungs, liver, and kidneys after chronic inflammation
▫ Organization – when fibrosis develops in a tissue space
occupied by inflammatory exudate
Connective Tissue Deposition
Angiogenesis – the formation of new blood vessels, supplying nutrients and oxygen
to support the repair process
Formation of granulation tissue – migration and proliferation of
fibroblasts and deposition of loose connective tissue (with vessels
and interspersed leukocytes) and deposition of ECM proteins
produced by fibroblasts, generating a pink and soft, granular
appearance, by locally produced cytokines and growth factors
(e.g., TGF-β)
Remodeling of connective tissue – decrease in the number of proliferating
fibroblasts and new vessels with an increase in ECM deposition, evolving into a scar
composed of largely inactive, spindle-shaped fibroblasts, dense collagen, fragments
of elastic tissue, and other ECM components
▫ Collagen synthesis – critical to the development of strength in healing
▫ Scar maturation leads to a regression of vascularization, transforming the
granulation tissue into a pale, largely avascular scar
Healing by First Intention
Healing by first intention (or primary union) – the
principal mechanism of repair when the injury involves
only the epithelial layer, consisting of inflammation,
proliferation of the epithelial and other cells, and
maturation of the connective tissue scar
▫ Clean, uninfected surgical incision by surgical sutures: the
incision causes only focal disruption of the epithelial basement
membrane continuity (and death of a minimal amount of
epithelial and connective tissue cells
Wounding causes the rapid activation of coagulation
pathways, forming a blood clot on the wound surface
that serves to stop bleeding and act as a scaffold for
migrating cells
▫ As dehydration occurs at the external surface of the clot, a scab
forms to cover the wound
Healing by First Intention
24 hours: neutrophils migrate toward the fibrin clot, releasing proteolytic enzymes in order
to begin clearing debris, while basal cells at the edge of the cut epidermis show increased
mitotic activity
24-48 hours: migration and proliferation of epithelial cells from both edges in order to
deposit basement membrane components, and those cells that meet in the midline
beneath the scab create a thin but continuous epithelial layer to close the wound
Day 3: replacement of neutrophils by MOs while granulation tissue progressively invades
the incision space
Day 5: neovascularization reaches its peak as granulation tissue fills the incisional space
Week 2: continued collagen accumulation and fibroblast proliferation while the infiltration
of leukocytes, edema, and vascularization are significantly decreased
▫ Blanching begins through increased collagen deposition within the incisional scar and regression of
vascular channels
Month 1: the scar is comprised of cellular connective tissue largely devoid of inflammatory
cells and is covered by a normal epidermis
Healing by Second Intention
Healing by second intention (or secondary union) – the
mechanism of tissue repair involving a combination of
regeneration and scarring when the cell or tissue loss is more
extensive (e.g., abscesses, ulcerations, ischemic necrosis)
▫ More intense inflammatory reaction alongside the development of
abundant granulation tissue, the accumulation of ECM that forms a
large scar, and wound contraction by myofibroblasts
Large tissue deficits generates a larger fibrin clot with more
exudate and necrotic debris in the wounded area accompanied
by more intense inflammation, leading to a greater potential
for secondary, inflammation-mediated injury
Large amounts of granulation tissue are formed resulting in a
greater mass of scar tissue
Healing by Second Intention
Formation of a provisional matrix containing fibrin, plasma
fibronection, and type III collagen which is replaced by a matric
composed primarily of type I collagen within 2 weeks
▫ The epidermis resumes its normal thickness and architecture
Month 1: the scar is composed of acellular connective tissue devoid
of inflammatory infiltrate and is covered by an intact epidermis
Wound contraction – closes large surface wounds by decreasing the
gap between the dermal edges and by reducing the wound surface
area (after the formation of a network of myofibroblasts that exhibit
the ultrastructural and functional features of contractile smooth
muscle cells)
▫ Large skin defects can be reduced to 5-10% of their original size by week 6
Abnormalities
Inadequate granulation tissue or scar formation:
▫ Dehiscence (or wound rupture) – occurs frequently after abdominal surgery due to an increase in
abdominal pressure
▫ Ulceration – due to inadequate vascularization during healing
Excessive formation of repair components:
▫ Hypertrophic scars – accumulation of excessive amounts of collagen, leading to a raised scar
▫ Keloids – when scar tissue grows beyond the original wound boundaries and does not regress
Exuberant granulation – the formation of excessive amounts of granulation tissue which
protrudes above the level of the surrounding skin and blocks reepithelialization (during proud
flesh)
Desmoids (or aggressive fibromatoses) – when incisional scars or traumatic injuries are
followed by exuberant proliferation of fibroblasts or other connective tissue elements after
excision (as rare neoplasms lying in in the interface between benign and malignant tumors
Contracture – an exaggeration of contraction, resulting in deformities of the wound and
surrounding tissues (e.g., palms of the hands and soles of the feet after serious burns)
L17
INTRACELLULAR ADAPTATIONS
Intracellular Accumulations
Metabolic derangements in cells  intracellular
accumulation of abnormal amounts of various substances
(which may be harmless or associated with varying degrees
of injury)
Pathways:
▫ Inadequate removal of normal substances due to defects in
packaging and transport mechanisms (e.g., steatosis in the liver)
▫ Accumulation of an abnormal endogenous substance due to genetic
or acquired defects in folding, packaging, transport, or secretion
(e.g., α1-antitrypsin)
▫ Failure to degrade a metabolite due to genetic enzyme deficiencies
(called storage diseases)
▫ Deposition and accumulation of an abnormal exogenous substance
due to a lack of enzymatic machinery for degradation or the inability
to transport it to other sites (e.g., carbon or silica particles)
Lipids
Steatosis (or fatty change) – abnormal
accumulation of triglycerides within
parenchymal cells (usually in the liver)
due to toxins, protein malnutrition,
diabetes mellitus, obesity, and anoxia
▫ Developed nations: commonly caused by
alcohol abuse and nonalcoholic fatty
liver disease associated with diabetes and
obesity
Cholesterol and Cholesterol Esters
Atherosclerosis – accumulation of atherosclerotic plaques (lipid
vacuoles consisting of cholesterol and cholesterol esters) in
smooth muscle cells and MOs within the aorta and large
arteries, creating a foamy appearance and producing a yellow
cholesterol-laden atheromas
Xanthomas – intracellular accumulation of cholesterol-laden
MOs, creating clusters of foamy cells in the subepithelial
connective tissues of the skin and tendons to produce tumorous
masses
Cholesterolosis – focal accumulation of cholesterol-laden MOs in
the lamina propria of the gallbladder
Niemann-Pick Disease (Type C) – lysosomal storage disease
caused by an enzyme mutation involved in cholesterol trafficking
in multiple organs
Proteins
Intracellular accumulations of proteins appear as rounded eosinophilic
droplets, vacuoles, or aggregates in the cytoplasm, appearing as
amorphous, fibrillar, or crystalline under the microscope
Amyloidosis – protein deposits in the extracellular spaces
Proteinuria – appearance of reabsorption droplets in the
proximal renal tubules due to reversible heavy leakage
across the glomerular filter, resulting in the appearance
of pink hyaline droplets within the cytoplasm of the
tubular cells
▫ The endoplasmic reticulum greatly distends, producing large,
homogeneous eosinophilic inclusions (called Russell bodies)
Emphysema – α1-antitrypsin deficiency caused by mutations that
significantly slow protein folding, leading to the buildup of partially folded
intermediates that aggregate in the ER of the liver
Proteins
Types of cytoskeletal proteins: microtubules (20-25 nm), thin actin
filaments (6-8 nm), thick myosin filaments (15 nm), and intermediate
filaments (10 nm)
▫ Intermediate filaments – provide flexible intracellular scaffold that organizes the
cytoplasm and resists the forces applied to the cells
▫ Keratin filaments (epithelial cells), neurofilaments (neurons), desmin filaments (muscle cells),
vimentin filaments (connective tissue cells), glial filaments (astrocytes)
Alcoholic hyaline – eosinophilic cytoplasmic inclusion in liver
cells characteristic of alcohol liver disease that is
predominately composed of keratin intermediate filaments
▫ Hyaline – alteration of the cells or extracellular spaces that gives a
homogeneous, glassy, pink appearance after hematoxylin and eosin
staining
Neurofibrillary tangle – neurofilaments and other proteins
found in the brain during Alzheimer’s disease
Glycogen
Glycogen – readily available energy
source stored in the cytoplasm of
healthy cells
▫ Glycogenoses – glycogen storage disease
that leads to excessive intracellular
deposits of glycogen, appearing as clear
vacuoles that dissolve in aqueous fixatives
▫ Usually fixed in absolute alcohol and stained with
Best’s carmine or PAS to impart a rose or violet
color)
Pigments
Pigments – colored substances that can be exogenous (coming from
outside the body) or endogenous (synthesized within the body)
Exogenous pigment: carbon (coal dust) – air pollutant in urban areas
that is phagocytosed by MOs within the alveoli before being
transported to the tracheobronchial lymph nodes
▫ Anthracosis – accumulations of carbon that blackens the tissues of the lungs
and associated lymph nodes
Endogenous pigments:
▫ Lipofuscin – insoluble brown pigment (known as the
“wear-and-tear” pigment) composed of polymers of lipids
and phospholipids complexed with proteins, acting as a
sign of free radical injury and lipid peroxidation
▫ Prominent in the liver and heart of aging patients or individuals with severe malnutrition and
cancer cachexia
Pigments
▫ Melanin – endogenous, brown-black pigment formed
after tyrosinase catalysis of tyrosine to dihydrophenylalanine in melanocytes
▫ Hemosiderin – hemoglobin-derived golden
yellow-brown, granular, or crystalline pigment, acting
as a major storage form of iron after a local (due to
hemorrhages) or systemic (leading to an overload)
excess of iron
▫ Ferritin – typical storage form of iron in association with apoferritin in the cells
▫ Hemosiderosis – deposition of iron in organs and tissues due hemochromatosis (a
metabolic error that causes an increased absorption of dietary iron), hemolytic
anemia (causing the premature lysis of RBCs), and repeated blood transfusions
Pathologic Calcification
Pathologic calcification – abnormal tissue deposition of calcium
salts with smaller amounts of iron, magnesium, and other salts
(stained with hemotoxylin and eosin to give a basophilic and
amorphous granular appearance)
▫ Dystrophic calcification – when deposition occurs locally in necrotic
tissues (despite normal serum levels of calcium), appearing as fine, white
granules or clumps
▫ Common: atheromas of advanced atherosclerosis and aging or damaged heart valves
▫ Psammoma bodies – lamellated configurations from the
progressive acquisition of outer layers of encrusted mineral
deposits (e.g., thyroid cancer) stemmed from necrotic seed crystals
Pathologic Calcification
▫ Metastatic calcification – when deposition occurs in normal tissues
(due to hypercalcemia), appearing as fine, white granules or clumps
▫ Causes: increased secretion of parathyroid hormone (PTH), resorption of bone
tissue, vitamin D-related disorders, or renal failure
▫ Common: interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries,
and pulmonary veins (which all excrete acid and possess an internal alkaline
compartment that predisposes them to metastatic calcification)
L18
CHRONIC GRANULOMATOUS DISEASE
Genetic defects in the early innate immune response typically
affect leukocyte functions or the complement system 
increased vulnerability to bacterial infections
▫ Leukocyte adhesion deficiency type 1 – defects in the biosynthesis of the
β2 chain shared by the LFA-1 and Mac-1 integrins
▫ Leukocyte adhesion deficiency type 2 – the absence of sialyl-Lewis X
(fucose-containing ligand for E- and P-selectins) as a result of a defect in
fucosyl transferase (enzyme that attaches fucose moieties to protein
backbones)
Defects in Leukocyte Function
Genetic defects in phagolysosome function:
▫ Chédiak-Higashi syndrome – autosomal recessive
mutation in LYST (regulates lysosomal trafficking) that
leads to the defective fusion of phagosomes and
lysosomes, resulting in defective phagocyte function and
susceptibility to infections
▫ Associated defects in melanocytes (leading to albinism), cells of the
nervous system associated with nerve defects, and platelets
(causing bleeding disorders)
▫ Abnormalities: neutropenia, defective degranulation, and
delayed microbial killing
▫ Generates the appearance of giant granules within
leukocytes resulting from aberrant phagolysosome fusion
Defects in Leukocyte Function
Genetic defects in microbicidal activity:
▫ Chronic granulomatous disease – congenital disorders
characterized by defects in bacterial killing due to
abnormal phagocyte oxidase (phagolysosomal enzyme
that generates superoxide), leading to a susceptibility to
recurrent bacterial infections
▫ Causes: X-linked defect in gp91phox (membrane bound
component) or autosomal recessive defect in p47phox and
p67phox (cytoplasmic components of phagocyte oxidase)
▫ Generates a MO-rich chronic inflammatory reaction,
attempting to control an infection (when neutrophil
defenses are inadequate)  collections of activated MOs
that wall off the pathogens in granulomas