What is ischemia? What tissues are most vulnerable?
Inadequate blood perfusion of a tissue bed. Brain and heart are more vulnerable. E.g. acute myocardial infarction.
What is an infarction?
localized area of necrosis due to circulatory insufficiency
What are the principle events in ischemic cell injury?
1)compromised ATP Synthesis 2) cell swelling - Na+ enters the cell. -->hydropic change. and Blebbling 3) decreased pH in cell. Due to anaerobic glycolysis and build up of lactic acid. 4)organelle distortion. ER dilation, nuclear chromatin clumping, mitochondrial swelling. 5) mitichondrial injury due to rise of Ca2+ in cell.
What are two major changes thought to contribute significantly to irreversible cell injury?
1) mitochondrial can't generate ATP, can't regain oxidative phosphorylation 2)critical damage to membrane integrity
What morphological changes can you see of reversible cell injury by EM?
-membrane bleb -mitochondrial swelling with misaligned cristae -dilation of ER with ribosomal detachment -
What morphological changes can you see of reversible cell injury by LM?
What are endogenous sources of ROS?
1) ATP synthesis since O2 is final e- acceptor 2) rxns involving transition metals, e.g. Cu, Fe, Zn 3) NO 4) leukocytes, neutrophils and macrophages produce ROS to kill microbes
What are exogenous sources of ROS?
-radiation -pollutants -drugs -toxic substances
What are the mechanisms of free radical damage?
1)membrane lipid peroxidation-->increased membrane permeability 2)protein oxidation-->protein misfolding, degradation, damage to active sites of enzymes 3)DNA damage
How does our body defend against ROS?
-Detoxifying enzymes -antioxidants e.g. Vit E, A, C
What is reperfusion injury?
After cell injury due to ischemia, if blood flow is restored, can result in increased tissue damage b/c buildup of ROS from circulating leukocytes, a breakdown product of ATP, and incomplete oxygen reduction in damaged but viable mitochonrdia
What are some morphological changes from necrosis seen in the nucleus?
pyknosis-clumping, and shrinkage of nuclear chromatin karyorrhexis-nuclear fragmentation and irregular distribution karyolysis-nuclear dissolution
What are some cytoplasmic changes resulting from necrosis?
-increased eosinophilia (due to denatured protons and loss or RNA)
What are some morphological changes from coagulative necrosis?
1)grossly: necrotic are pale and dry 2)slide: no nuclei, cytoplasmic eosinophilia, preservation of architecture
What are some morphological changes from liquefactive necrosis?
1)from cerebral infarction a)grossly: softens, liquefies b) micro: dead parenchyma dissolution, debris, macrophages 2)from abscess a) grossly: pus filled pocket b)micro: clusters of PMN dead/dying, cellular debris, edema,
What are some morphological changes from dry gangrene?
grossly: black, dry, shriveled
What are some morphological changes from wet gangrene?
when bacterial infection is superimposed on necrosis. Secondary infection of dry gangrene. E.g. in GI tract. Usually fatal
What are some morphological changes from gas gangrene?
extensive necrosis and gas production. caused by clostridium species
What are some morphological changes from caseous necrosis?
grossly: soft, crumbly, looks cheesy micro: highly eosinophilic region, no recognizable parenchyma. can't say its caseous though.
What are some morphological changes from fat necrosis?
grossly: filmy patchy while chalky areas micro: white deposits with pale outlines of dead fat cells "ghost cells" filled with basophilic Ca deposits.
What is fibrinoid necrosis?
Vessel damaged caused by hypertension, vasculitis, autoimmune disease.
What is anatomical pathology?
study of gross and microscopic changes in cells and tissues caused by disease. Includes: surgical path, cytopath, hematopath, autopsy path
What does surgical pathology analyze?
biopsy and surgical specimens, e.g. diagnosis of malignancy
What does cytopathology look at? What is a sample you would send to such a lab?
analysis of exfoliated and aspirated cells. E.g. pap smear
What does hematopathology analyze?
Diagnosis of blood disorders
What does an autopsy pathologist look at?
Analyzes tissues removed after death
What does clinical pathology involve?
measurement and identificatino of substances, cells, and microorganisms in body fluids. Includes: hematology, urinalysis, chemistry, microbiology, immunology, transfusion medicine, molecular pathology
What staining method would you use for: glycogen, basement membrane, carbohydrate rich moeities, fungi?
Periodic acid-Schiff (PAS)
What is Gomori methenamine silver (GMS) staining used for?
basement membrane, fungi
What would you stain acid-fast bacilli (e.g. Mycobacterium tuberculosis) with?
What would you use Prussian blue to stain?
What would you use to stain amyloid?
What would you use Oil red O (or Sudan dye) to stain?
What is coagulative necrosis caused by?
ischemia, e.g. myocardial infarction
What is liquefactive necrosis caused by?
-cerebreal infarction (ischemia causing brain injury) -abscess formation
What is caseous necrosis caused by?
frequently mycobacterium tuberculosis, also fungal infections
What are some causes of chronic fatty liver?
alcohol, obesity, diabetes, hypoxia, toxins, starvation and protein nutrition
What are some causes of acute fatty liver?
late pregnancy, therapeutic drugs, aspirin
Describe microscopic morphology of chronic fatty liver
-macrovesicular appearance. displaces nucleus to periphery. Is reversible
Describe microscopic morphology of acute fatty liver.
What are mallory bodies?
irregular, hyaline appearing inclusions in cytoplasm in hepatocytes that accumulate with chronic alcoholic liver disease
What are Lewy bodies?
hyaline inclusions that accumulate in damaged neurons in patients with parkinsons
What is hemosiderosis?
-When there is an increase in Fe uptake, iron is stored as hemosiderin. Leads to hemosiderosis. short term. E.g. bruise
How does hemochromatosis affect the body?
many organs are affected. Tissue destruction and scarring. lead to cirrhosis. destruction of islet cells in pancrease lead to diabetes.
What are the indications grossly and microscopically of hemochromatosis?
-grossly: brownish skin discoloration due to increased melanin -MA: hemosiderin appears yellow to golden brown. Prussian blue stain would visualize Fe
What is bilirubin?
-derived from hemoglobin porphyryn ring
What can an increased bilirubin amount result in?
jaundice, cirrhosis and liver failure if long term -in newborns: necrosis of neronal groups (kernicterus), can be fatal
What is lipofuscin and how does it look like microscopicaly?
-harmless, insoluble pigment of lipid-protein complex remnants -golden to dark brown cytoplasmic graunules around nucleus
What is Wilson disease and what is a symptom of it?
-defect in biliary excretion that leads to accumulation of copper, which causes cell damage and necrosis. Liver damage. Then brain injury. -Kayser-Flishcer ring is seen-greenish brown ring around periphery of iris
What is anthracosis?
Lungs and lymph nodes blackened over time due to carbon particulates
What does amyloidosis look like grossly and histologically?
-grossly: waxy, pale, rubbery appearance. -micro:affinity for congo red dye. apple-green
What is metastatic calcification?
-increased blood calcium levels lead to deposition of calcium in normal tissue
What is dystrophic calcification?
-deposition of calicum in injured or necrotic tissues
In chronic alcoholism, you might find what pathologically changes?
Chronic fatty liver-> macrovesicular fatty droplets and mallory bodies (alcoholic hyalin)
What does this liver display?
Hemochromatosis. red is due to Fe. nodules are indicative of cirrhosis.
This is a slide of the liver, what does this display?
Hemochromatosis from brownish color. Also shows diffuse fibrosis surrounded the nodule-->cirrhosis.
The discoloration in the basal ganglia of this cerebrum is caused by what disease? and the buildup of what?
Kernicterus in newborns due to high levels of unconjugated bilirubin in plasma.
What organ is this? What does its appearance indicate?
Kidney amyloidosis. Enlarged, firm, pale and waxy appearance.
This is a image of heart muscle. Normal heart also shown. What is the pathology here?
Amyloidosis. Amyloid deposited between muscle fibers.
Abnormal heart next to normal heart. What is pathology here?
Glycogen accumulation. Peri-nuclear.
What is pathology here?
Describe the hemodynamic events in acute inflammation.
tissue injury-->transient vasoconstriction (or not)-->vasodilation --> hyperemia (increase blood flow)-->change in capillary permeability-->exudation causing edema
What are the cardinal signs of inflammation?
5)loss of function
redness and heat together are called erythema
What are the different types of exudate?
serous- serum like
fibrinous- e.g. fibrous pericarditis
What is an example of when you would find serous exudate?
What is an example of when you would find purulent exudat?
Meningitis- in the brain
What is B an example of? A is normal lung.
Vascular congestion-packed RBC cells. Increased vascular permeability results in hemoconcentration (local increase in concentration of cells in blood) and a diminished rate of blood flow.
List the cellular events in inflammation.
margination (leukocyte rolling), pavementing (adherence and flattening of leukocytes), diapedesis (cross basement membrane to extravascular space), chemotaxis, phagocytosis
What are the mediators involved in transient vasocontriction?
thromboxane A2, leukotrienes.
What are the mediators involved in vasodilation?
histamine and serotonin (rapid response), prostacyclin, PAF (low concentration), Bradykinin, prostaglandin E, NO
What are the mediators involved in increase in permeability?
Initial: histamine and serotonin
Sustained:arachidonic acid metabolites, PAF (low concentration), VEGF, lysosomal constituents, ROS
general: neuropeptides (substance P), prostacyclin, leukotrienes
What do platelet activating factors do?
At low levels, as part of acute inflammation
Vasodilation and increased vascular permeability
At high levels, as part of pathogenesis of asthma
Vasoconstriction and bronchoconstriction
What is this heart showing? What do the arrows indicate?
Pericarditis. Fibrous exudate. shaggy appearance caused
by breaking of adhesions between
visceral and parietal pericardium
This is a picture of the lung. What is the pale are called?
area of consolidation. Means that the whole lobe is affected. This is lobar pneumonia.
What is in the light pink area of this lung?
Fibrin. Pink background often with chicken wire pattern.
What are the dark pink areas in the circle in these hepatocytes?
Mallory bodies. Commonly associated with alcoholic liver disease.
What are the causes of hemochromatosis?
Primary (hereditary) hemochromatosis
Increased intestinal iron absorption caused by autosomal recessive genetic defect
Multiple causes, especially iron overload from chronic blood transfusions
What is observed in this image?
Macrophages containing hemosiderin.
This is a prussian blue stain. What are the blue dots?
What is the inner circle and outer circle indicating?
Inner circle is a regeneration nodule. Outer circle is fibrosis. This is cirrhosis.
Edge of iris. What is this ring called?What is the disease?
Kayser-Fleisher ring. Wilson's disease. Copper accumulations
This apple-green birefringence is staining what? What stain is used?
Amyloid. Congo red when exposed to polarized light.
This is a pulmonary vessel showing?
How does chronic inflammation differ from acute inflammation?
-Absence of cardinal clinical signs
-Lack of uniformity in expression
Most acute - PMNs, a few macrophages
Some acute - lymphocytes (e.g. viral hepatitis)
Most chronic - mononuclear cells (lymphocytes, macrophages)
Some chronic - PMNs (e.g. osteomyelitis)
-Manifestation of a cell-mediated immune response
What are the cells predominant in acute inflammation?
What are the predominant cells in chronic inflammation?
mononuclear cells: lymphocytes, macrophages
How are macrophages recruited and activated in inflammation?
Non-immunologic stimuli (e.g., as endotoxin, fibronectin)
Cytokines from immune-activated T cells (particularly IFN-γ)
Cytokines from other cells (e.g., IL-4)
What are the cells within this granuloma?
What are giant cells?
-Giant cells in granulomas form by the fusion of epithelioid cells.
-Usually in the periphery of granulomas (but can be in the center).
-May attain diameters of 40 to 50 μm.
What type of cell is this?
Langhams type giant cell with horseshoe pattern
What type of cell is this?
Giant cell with Asteroid Body
What type of cell is this?
Schaumann Body within a Giant Cell
What are the morphological patterns of Non-Granulomatous Chronic Inflammation?
-Destruction of tissue
-deposition of collagen
-expansion of interstitium
What are granulomas?
-Small (0.5 – 2.0mm) collections of epithelioid cells, usually surrounded by a rim of lymphocytes
Sometimes plasma cells, fibroblasts, collagen and PMNs are present.
-Epithelioid cells are the defining cell
-Giant cells may be present.
How are granolomas initiated?
-relatively indigestible antigenic material-->type IV hypersensitivity reaction
-except: foreign bodies
Give an example of a non necrotizing and a necrotizing granuloma?
Non-necrotizing (e.g., sarcoidosis)
Necrotizing (e.g., tuberculosis)
What cytokine do granulomas need to form?
What is acute on chronic or subacute inflammation?
When acute inflammation changes to chronic, but before it is resolved, there is further acute inflammation. Eosinophils are present, as well as a mix of PMNs and mononuclear cells.
What cell type is always required fo rhte diganosis of a granulomatous inflammation?
What is happening in the cells the arrows are pointing to?
Apoptosis. Enlarged and pink cells. Loss of nuclei
What is this an example of?
Infarction. Wedge shaped. Localized area of necrosis.
Abscess or granuloma?
abscess. Filled with neutrophils.
What type of necrosis is this?
What are organisms coated with in opsonization to be recognized by PMNs and macrophages?
IgG or complement C3
What occurs in respiratory burst?
NADPH oxidase reduces O2-->dismutation to H2O2-->reacts with superoxide to form HO radical-->converted by myelperoxidase to HOCl or HOBr
How is NO produced?
By macrophages when NO synthase induced by cytokine stimulated cells.
What is leukotriene B4 invovled in?
What happens when NADPH oxidase is deficient?
Inability to have repiratory burst to generate H2O2
What does bradykinin do?
-producers of pain
-promote peripheral vasodilation through smooth muscle relaxation and contraction of endothelium
Restoration to pre-injury state
replacement of lost cells by cells of same type
The replacement of lost cells by connective tissue scar
Which of these may result in loss of some specialized function: resolution, regeneration, repair?
regeneration and repair
What are examples of labile cells?
surface epithelia, lining mucosa of all glands, hematopoietic cells
What are examples of stable cells?
fibroblasts and hepatocytes
What are examples of permanent cells?
neurons and cardiac muscle
Conversin of dead tissue or inert material into granulation tissue. Seen in fibrinous exudates, thrombi, infarcts, wound and fracture healing.
What is the microscopic pattern of granulation tissue?
fibroblast and nascent vessel proliferation, with some edema and extravasated RBC
What does regeneration depend on?
-removal of cause of injury
-regenerative capacity of the cells
-extent of the injury( basement membrane intact?)