Causes of cell injury

Trauma, Loss of vascular supply, Infection, Toxins,Radiation,

Hypoxia
Relative loss of oxygen


Anoxia
Complete loss of oxygen


Most common cause of cell injury/death
Hypoxia or anoxia,(usually called by ischemia),


Ischemia
Failure of vascular supply (leads to lack of oxygen),


Intracellular Edema - histological appearance
-Hydropic change (clear, vacuolated cytoplasm from H2O
accumulation),-Edema in cytoplasm, mitochondria,
membranes,-cells all look swollen,


Cell death
1) Occurs when plasma membrane is disrupted (injury is no
longer reversible at this point 2) Disintegration of DNA, RNA,
phospholipid membranes 3) rupture of lysosomes into cytoplasm
4) massive influx of Ca++ to intracellular space


Eosinophilia
Histological sign of hypoxic cell death. Cytoplasm appears more
pink due to clumping of proteins. Loss of blue color due to loss
of DNA, RNA, and glycogen.


Karyolysis
Faded nucleus, histological appearance of cells in hypoxic cell
death,


Pyknosis
Shrunken nucleus, (morphology of hypoxic cell death),


Karyorrhexis
Fragmented nucleus, rhexis" = fragmented,morphology of
hypoxic cell death


Necrosis
Spectrum of morphologic change in cell death in living tissues,
a) progressive enzymatic cell degradation, b) invokes
inflammatory response, c) patterns: coagulative, liquefactive,
fat, caseous,


Tissue patterns of necrosis: Coagulative
Solid mass with "ghosted cell outlines" seen in solid organs


Tissue patterns of necrosis: liquefactive
Disintegrated necrotic tissue becomes liquid; seen in brain
& abscesses


Tissue patterns of necrosis: fat
Solid with ghosted fat cells and Ca deposits


Tissue patterns of necrosis: Caseous
Cottage cheese-like grossly.,
,Seen in some types of granuloma,


Tissue patterns of necrosis: Gangrenous
A type of coagulative necrosis in ischemia with black
"mummified" (dried out) tissue


Free radical induced cell injury
Definition: direct membrane attack leading to cell death,
,Sources: radiation, endogenous oxidative reactions, exogenous
chemicals, reperfusion,
,Endogenous sources: superoxide from mitochondria, p450
cytochromes, H2O2, peroxisomes, hydroxyl ions (from H20
ionization),
,Key damaging reactions:,>1) Lipid peroxidation of membranes,
2) oxidation of proteins,3) DNA single strand breaks,


Reperfusion injury
Hypoxic cells suffer additional damage from free radicals
delivered by fresh blood after a period of ischemia or lack of
oxygen.
Mechanism: white blood cells travel to the area of injury and
release inflammatory factors; including free radicals.
Restored blood flow also reintroduces oxygen within the cell
that can damage organelles.


Apoptosis
Greek: "falling off"
Definition: orchestrated sequential cell death.
Requires genetic activation - does NOT result in inflammatory
response.
Steps:
a) cell shrinkage
b) chromatin condenses with peripheral clumping
c) fragmentation into apoptotic bodies
d) ingested by macrophages
Histology: shrinkage of cell volume & shape, crosslinking of
cytoplasmic proteins (eosinophilia)


Apoptotic bodies
Apoptotic bodies, sometimes called also apobodies, are small
sealed membrane vesicles that are fragments of cells
undergoing apoptosis. The formation of apoptotic bodies
prevents leakage of potentially toxic/immunogenic cellular
contents of dying cells and prevents inflammation or
autoimmune reactions as well as tissue destruction.


Necrosis vs. apoptosis
Necrosis:
cell swelling
random nuclear fragments
inflammation
Apoptosis:
cell shrinkage
specific DNA fragmentation
no inflammation


Autophagy
-cell consumes its own contents
-a survival mechanism in the face of nutrient deprivation
Steps:
1) sequester portions of cytosol into autophagic vacuoles
2) fuse with lysosomes
3) autophagosome
Mech. of cell loss, possibly cell death in degenerative diseases
(parkinson's, alzheimers)


Fatty change
accumulation of lipids in cells - eg. in the liver as a result of
alcoholism
Histologically: Clear, sharp edged vacoles appear in cycoplasm
(eg. in liver)


Hemosiderin accumulation
Hemoglobin derived golden yellow granules. A storage form of
iron.
Seen in overstorage of iron (in liver)
Causes: hemorrhage, hemolytic states such as blood transfusion
reactions, hemochromatosis
Histology staining techniques: Prussian blue is used to confirm
hemosiderin


Lipofuscin
Brown granules
Insoluble lipoprotein polymers that appear in cell as a byproduct
of lipid peroxidation
Part of normal wear and tear of cell
Non-toxic


Dystrophic calcification
White, gritty Ca++ granules deposits in dead, dying, neoplastic,
aging tissues


Metastatic calcification
Ca deposits in living cells and tissues, hypercalcemia


Hydropic change
Histological appearance of cells: clear, vacuolated cytoplasm
from water accumulation 


Steatosis
AKA fatty acid change - abnormal retention of lipids within a
cell


Inflammation
A normal bodily response to injury that only occurs in
vascularized, living tissue


Acute Inflammation (contrast with chronic inflammation)
Duration: minutes to days
Effector cell: neutrophil
Stereotypic
Vascular events:
1) immediate transient vasoconstriction (Arterioles, post
capillary venules)
2) followed by Vasodilation, stasis, hyperemia - Rubor and
Calor (redness, warmth)
3) Leakage of cells to interstitial space - tumor & dolor
(swelling, pain) due to endothelial cell contraction


Chronic inflammation
Duration: Days/years
Effector cell: macrophage, lymphocyte
Variable pattern
(eg. rheumatoid arthritis - leads to disfigurement)


Hyperemia
Increased localized blood flow


Margination
neutrophils adhere to blood vessel walls at the site of injury


Neutrophils
AKA polys, PMNs
Noted for its polymorphonuclear nucleus (has many shapes)
cytoplasmic granules
Granules released generate free radicals


Edema
Enlarged, swollen tissues, tense capsule; appear histologically as
clear spaces in ECM


Pus
aka neutrophil infiltrate
Pale, purulent exudate - neutrophils in the extracellular,
extravascular space


Fibrin
Clotting cascade final product is fibrin
Activation of coagulation cascade --> opaque, stringy surface
coating --> looks pink & stringy in extracellular space


Complications of acute inflammation: abscess
Localized collection of neutrophils w/
pseudocapsule&nbsp;<div>Liquefactive necrosis</
div><div>Follows acute inflammation</div><div>Usually
associated wtih staph</div>


Harmful effects of inflammation
-extracellular leakage of lysozomal enzymes during
phagocytosis<div>-free radicals</div><div>-tissue damage</
div><div><br /></div><div><br /></div>


Chronic inflammation - cellular events
Macrophage as key cell: recruits marcophages, lymphocytes,
plasma cells, neutrophils, eosinophils


Chronic inflammation - Clinical Manifestations
Low grade fever, night sweats
Weight loss
Chronic fatigue, cough
Recurrent pain
Progressive loss of function


Chronic inflammation - vascular and tissue events
Angiogenesis
Activation and proliferation of fibroblasts
Production of matrix & new collagen


Fibrosis
Collagen remodeling resulting in tissue destruction
Features:
Quiescent fibroblasts
Abundant collagen
Scant GAGs
Replacement of normal tissue


Angiogenesis
Growth of new blood vessels:
1) proteolysis of ECM
2) migration and chemotaxis
3) proliferation
4) lumen formation, maturation, inhibition of growth
5) increased permeability through gaps and transcytosis


Granulation tissue
Subtype of chronic inflammation
Features:
0.1-2mmnodular collections of modified macrophages
Variable lymphocytes, multinucleated giant cells, necrosis
Sequence:
-macrophage recruited to site of injury
-formation of giant cells
-tissue destruction, fibrosis
-can get necrosis in the center (eg. TB)
takes on cottage cheese appearance


Granulomatous inflammation
Subtype of chronic inflammation
Features:
0.1-2mm nodular collections of modified macrophages
Variable lymphocytes, multinucleated giant cells, necrosis
Sequence:
-macrophage recruited to site of injury
-formation of giant cells
-tissue destruction, fibrosis
-can get necrosis in the center (eg. TB)
takes on cottage cheese appearance


Giant cells
Formation of giant cells:
1) Macrophages are recruited to a site of injury.
2) Lose motility and forms clusters
3) Increases in cytoplasm and enlrgement
4) Fusion with other macros to form Giant Cells. Results in
tissue destruction & fibrosis.
"Foreign body giant cells" are giant cells that respond to a
foreign body.


Foreign body granuloma
Granuloma re: a foreign body, eg. leaking silicon from breast
implant or sutures.<div><br /></div>


Hyperemia
active vascular dilatation (eg. acute inflmamation)
aka active congestion


Congestion
Passive vascular dilation from reduced outflow/blockage.
&nbsp;Increased RBCs w/in blood vessels&nbsp;


Hemorrhage
Leakage of red cells into tissue


Hemostasis
Process of blood clot formation
1) Endothelial cell injury
2) Vasoconstriction
3) Platelet activation
4) Coagulation cascade
5) Formation of thrombus (clot)


Thrombosis
Abnormal thrombus formation
Three primary factors:
1) Endothelial injury
2) Abnormal blood flow (stasis or turbulent)
3) Hypercoagulability
"Virchow's Triad"


Thrombi
Appearance: Intralumenal mass w/ mix of RBCs, platelets, and
fibrin which form Lines of Zahn
Can develop anywhere in CV system; size&shape vary w/ site
of origin
-Arterial/cardiac thrombi: due to turbulence or endothelial
cell injury
-Venous thrombi: due to stasis


Mural thrombus
In the wall of the heart


Lines of Zahn
Lines that appear in a thrombus because components of
thrombus (RBCs, platelets, fibrin) separate into areas by
molecular which appear alternating light and dark


Fates of thrombus
a) propagate: inlarge & extend w/ in vascular system
b) dissolve - fibrinolytic system
c) Organize and recanulize: smooth muscle ingrowth and
angiogenesis resulting in new lumen & flow
d) embolize: detach and travel to distant site


Thrombus - organization w/ recanulization
Occurs in large thrombi
After 5-7 days: migration of fibroblasts & onset of
angiogenesis w/in the thrombus
Fibroblasts organize the clot into granulation tissue.
10-14 days: "recannulization" - angiogenesis results in new
vessels w/in thrombus


Embolism
Detached solid, liquid, or gaseous mass carried by blood to
distant site from origin<div><br /></div>


Common types of embolisms
Thromboembolism, bone marrow embolism, air embolism


Pulmonary embolism
Thrombus in iliac vein that has detached from origin &
traveled through heart into pulmonary artery
lodges in narrowest site of bifucation resulting in occlusion of
blood flow
May result in sudden death


Infarction
Ischemic area caused by occlusion of blood supply


Red infarction
Only occurs where there is dual blood supply (eg. lungs)
(infarct areas with only one blood supply appear white)


White infarct
occurs where there is a single blood supply
eg. spleen


Atherosclerosis
"Gruel hardening"
Disorder reuslting in arterial lesions called atheroma or
atheromatous plaques. Raised lesions in the intima protrude
into the lumen resulting in turbulent blood flow
causes 50% of deaths in the developed world
Etiology unclear - chronic inflammation/healing response?


Formation of atheromatous plaque
1) endothelial cell injury
2) incraesed permeability, inflammatory cell adhesion, and
migration
3) smooth muscle recruitment to intima
4) Macrophage & smooth muscle cells engulf lipid
5) smoth muscle proliferation, collagen deposition, extracellular
lipid


Fatty streak
Area of lipid filled macrophages w/in intima; Lesion that
starts early in life towards formation of atheromatous plaque


Atherosclerotic plaque
Complex, raised lesion w/ smooth muscle cells, macrophages, T
cells, collagen, lipid
A fibrous cap forms over the plaque (which we want so the
plaque doesn't rupture); plaque may have necrotic center


Aneurysm
Localized abnormal dilation of a blood vessel or the heart
"true" aneurysm: thinned wall typically from MI,
aterosclerosis, congenital, HTN
"false" pseudoaneurysm: defect leading to extravasation and
hematoma


Hypertrophy
Increased size of cells


hyperplasia
increased number of cells


atrophy
decreased size and/or number of cells<div>
decreased size and/or number of cells
usually due to compromised blood flow


metaplasia
replacement of one mature cell type for another
occurs only in epithelial cells - eg. in smokers, respiratory epi
changes from columnar to squamous cells
Occurs re: chronic stress in that epithelium


Neoplasia
New growth


Dysplasia
Abnormal growth
Malignant changes within epithelial cells but have not become
invasive (still confined by basement membrane)
(malignant changes include: hyperchromatic nuclei, enlarged
nucli, mitotic figures)


Tumor
"swelling" - refers to a growth


Benign neoplasm
Characteristics:
Local expansion only
Fibrous capsule
Slow, expansile growth
no invasion of adjacent tissue
Histology: resembles the tissue it originated in
*contrast with malignant


Malignant neoplasm
invasive, capable of spread to distant sites
Not encapsulated
Variable, rapid, infiltrative growth
Variable resemblence to normal tissue
invasion of adjacent tissue
potential to metastasize


cancer
malignant neoplasm


Parenchyma
Proliferating neoplastic cells<div>(tumor cells)</div>


Stroma
Connective tissue, often resembles granulation tissue with
angiogenesis, activated fibroblasts, inflammatory cells.
&nbsp;Provides nutrients and blood supply to tumor cells


Neoplasm prefixes: Adeno
Gland forming
*prefixes describe pattern of growth and/or type of cell


Neoplasm prefixes: Squam-
Squamous cell
*prefixes describe pattern of growth and/or type of cell


Neoplasm prefixes: Leio-
Smooth muscle
*prefixes describe pattern of growth and/or type of cell


Neoplasm suffixes: -Oma
benign (with exceptions - lymphoma &amp; melanoma)


Neoplasm suffixes: carcinoma
epithelial differentiation; malignant<div><br /></
div><div>Most common, epithelial; lung, breast, colon</div>


Neoplasm suffixes: Sarcoma
Mesenchymal differentiation - malignant<div><br /></
div><div>rare except in children (10%)</div>


Neoplasm suffixes: blastoma
embryonic tissue - malignant, mostly in children, tissue looks
like embryonic tissue


Malignant changes in the epithelial layer (histologic
appearance)
Hyperchromatic nuclei (dark nuclei due to increase in DNA)
Pleomorphic & enlarged nuclei with increased nucleus to
cytoplasm ratio
Mitotic figures
Process confined to basement membrane


Carcinoma in situ
Severe dysplasia - the whole layer of cells has undergone
malignant changes
Not invasive but has potential to become invasive


Teratoma
Germ cell tumors, embryologic


Lymphoma
Malignancy of lymphoid cells


Melanoma
Malignancy of melanocytes


Cancer Progression
TGIM
Transform
Grow
Invade
Metastasize


Cancer growth
Cancer cells have increased growth and decreased apoptosis
independent of normal cell cycle regulation


Cancer stem cells
cacner cells w/ limitless capacity for proliferation; cells w/in
tumor w/ capacity to initiate and sustain the tumor


Metastasis
Tumor implant discontinuous with the primary tumor
lymphatic pread - regional lymph nodes
hematogenous spread - first capillary bed


Cancer staging TNM - T
T: extent of primary tumor
T0: no evidence of primary tumor
Tis: carcinoma in situ
T1: confined to mucosa
T2: invades into muscularis
T3: invades through to serosa
T4: estends to adjacent organs


Cancer staging TNM - N
N: extent of regional lymph node involvement
N0: no regional lymph node metastases
N1: 1-3 pericolonic lymph nodes
N2: 4 or more lymph nodes


Cancer staging TNM - M
M: distant metastases
M0: no distant metastases
M1: distant present


Cancer stage
refers to how much cancer is in the patient; most important
factor in prognosis of a tumor type
determined by pathology, imaging, clinical features
(not the same as cancer grade - determined by pathologist)


Tumor grading
Assigned by pathologist, grade reflects the differentiation of
the cancer
(Well, moderate, or poorly differentiated)
independent predictor of prognosis
*not the same as staging


Transudate
An abnormal fluid accumulation w/ no cells in it<div><br /></
div><div><font color="#5aa146">exudate</font> has cells</
div>


Nutmeg liver
Blood accumulation in the liver; has the appearance of a sliced
nutmeg...<div><br /></div><div>Consequence of right heart
failure and hydrostatic pressure increases</div>


Edema
Abnormal fluid accumulation
may be due to increased blood volume (leading ot increased
hydrostatic pressure and fluid leakage into interstitial space)
or low plasma abumin


Congestive heart failure
Can lead to chronic edema due to increased capillary
hydrostatic pressure and decreased renal blood flow&nbsp;