Pathology Flashcards
How is Factor XII (Hageman factor) activated?
i. Generated within plasma ii. Clotting Factor XII iii. Activated by exposure to negatively charged surfaces, such as basement membranes, proteolytic enzymes, bacterial lipopolysaccharide and foreign materials iv. Protein
What does activated Factor XII (Hageman factor) activate?
i. Conversion of plasminogen to plasmin→ plasmin induces fibrinolysis. Products of fibrin degradation (fibrin split products) augment vascular permeability in the skin and the lung. Plasmin also cleaves components of the complement system, generating biologically active products, including the anaphlatoxins C3a and C5a ii. Conversion of prekallikrein to kallikrein→ cleaves high MW kininogen, thereby producing several vasoactive low molecular weight peptides, collectively termed kinins iii. Activation of the alternative complement pathway iv. Activation of the coagulation system
What are kinins?
Kinins are potent inflammatory agents formed in plasma and tissue by the action of serine protease kallikreins on specific plasma glycoproteins termed kininogens
What are the functions of bradykinin?
i. Regulate multiple physiologic processes including BP, contraction and relaxation of smooth muscle, plasma extravasation, cell migration, inflammatory cell activation and inflammatory-mediated pain responses ii. Mediated by B1 receptors (induced by inflammatory mediators and are selectively activated by bradykinin metabolites) and B2 receptors (expressed constitutively and widely) iii. Rapidly inactivated by kininases iv. Can amplify inflammatory responses by stimulating local tissue cells and inflammatory cells to generate additional mediators, including prostanoids, cytokines, NO, and tachykinins
What are the clinical implications of inhibiting bradykinin degradation?
If the breakdown of bradykinin is inhibited, it could lead to pathologic edema
What does bradykinin do?
Bradykinin has hypotensive effects, acts as a vasodilator, increases membrane permeability causing a rapid accumulation of fluids
What are the functions of proinflammatory complement factors?
i. Anaphylatoxins (C3a, C4a, C5a) mediate smooth muscle contraction and increase vascular permeability ii. Proinflammatory molecules (MAC, C5a) chemotactic factors also activation leukocytes and tissue cells to generate oxidents and cytokines and induce degranulation of mast cells and basophils iii. Lysis (MAC): C5b binds C6 and C7, subsequently C8 to the target cell; C9 polymerization is catalyzed to lyse the cell membrane
What are the factors that regulate complement activation?
i. Spontaneous Decay: C4b2a and C3bBb and their cleavage products, C3b and C4b, decrease by decay ii. Proteolytic inactivation: Plasma inhibitors include factor 1 and serum carboxypeptidase N (SCPN). SCPN cleaves the carbosy-terminal arginine from anaphylatoxins C4a, C3a, and C5a. Removing the single amino acid markedly decreases the biological activity of each of these molecules iii. Binding of active components: C1 esterase inhibitors (C1 INA) binds C1r an C1s, forming an irreversibly inactive complex. Additional binding proteins in the plasma include factor H and C4b, respectively, enhancing their susceptibility to proteolytic cleavage by factor 1. iv. Cell membrane-associated mlecules: two proteins linked to the cell membrane by glycophosphoinositol (GPI) anchors are decay-accelerating factor (DAF) and protectin (CD59). DAF breaks down the alternative pathway C3 convertase; CD59 protectin binds membrane-associated C4b and C3b, promotes its inactivation by factor 1 and prevents formation of the MAC
What are the clinical manifestations associated with complement deficiencies?
i. Hereditary: 1. C3b, iC3b, C5, MBL→ pryogenic bacterial infections, membranoproliferative glomerulonephritis 2. C3, properdin, MAC proteins→ Neisserial infection 3. C1 inhibitor→ Hereditary angioedema 4. C1q, C1r, and C1s, C4, C2→ Systemic lupus erythematosus 5. Factor H and factor 1→ hemolytic-uremic syndrome, membranoproliferative glomerulonephritis ii. In general: when mechanisms regulating this balance do not function properly, or are deficient because of mutation resulting imbalances in complement activity can cause tissue injury. Uncontrolled systemic activation of complement may occur in sepsis, thereby playing a central role in the development of septic shock. iii. Chronic immune complex activation→ consumption of complement components and depletion of complement, may result in immune deposition and inflammation, which in turn may trigger autoimmunity iv. Infectious disease→ 1. Antibody production defects: increased susceptibility to pyogenic infection by infectious organisms 2. MAC formation deficiency: increased infections, particularly with meningococci 3. Complement MBL deficiency: recurrent infections in young children
List the mediators derived from membrane lipids
i. Arachidonic acid ii. Platelet activating factor
Which mediators cause vasodilatation?
Both, platelet activating factor, arachidonic acid
Which mediators cause vasoconstriction?
Arachidonic acid
Which mediators cause smooth muscle contraction in the lungs?
Arachidonic acid
Describe the synthesis and functions of platelet activating factor (PAF) in inflammation.
1) Synthesis: synthesized by virtually all activated inflammatory cells, endothelial cells and injured tissue cells. PAF is derived from choline-containing glycerophospholipids in the cell membrane, initially by the catalytic reaction of PLA2, followed by acetylation by an acetyltransferase. Regulated by PAF-acetylhydrolase in plasma 2) Functions: Stimulates platelets, neutrophils, monocytes/macrophages, endothelial cells, and vascular smooth muscle cells. Induces platelet aggregation and degranulation at sites of tissue injury and enhances release of serotonin, thereby altering vascular permeability. Enhances functional response to a second stimulus and induces adhesion molecules expressions, specifically of integrins. Potent vasodilator. Induces intracellular signaling when P-selectin lightly teathers a leukocyte to an endothelial cell.
Compare and contrast the role of cytokines and chemokines in inflammation.
1) Cytokines produced at sites of tissue injury regulate inflammatory responses, ranging from initial changes in vascular permeability to resolution and restoration of tissue integrity. Have autocrine, paracrine, and endocrine functions. Through production of cytokines, macrophages are pivotal in orchestrating tissue inflammatory response. LPS stimulates TNFalpha and interleukins. Macrophage derived cytokines modulate endothelial cell leukocyte adhesion, leukocyte recruitment, acute phase response, and immune functions. 2) Chemokines direct cell migration. Accumulation of inflammatory cells at sites of tissue injury requires their migration from vascular spaces into extravascular tissue. During migration, cell extends a pseudopod toward increasing chemokine concentration. At the front of the pseudopod, marked changes in levels of intracellular calcium are associated with assembly and contraction of cytoskeleton proteins. i. Inflammatory chemokines ii. Homing chemokines iii. 70-130 aa
How does the synthesis and function of NO differ in endothelial cells as compared to macrophages?
i. Macrophages: help kill ii. L-arginine precursor (both) iii. Endothelial cells have eNOS enyme, macrophages have iNOS enzyme
Describe the mechanisms of action of histamine in inflammation
1) Histamine and serotonin are synthesized and stored in the electron dense granules of platelets. 2) Histamine is synthesized and stored in the granules of basophils and mast cells. 3) Their release from platelets occurs during aggregation. 4) Their release from mast cells and basophils is stimulated by trauma, binding of mast cell-bound IgE interacting with its antigen, or by the binding of C3a and C5a, substance P, IL-1 and IL-8 to their respective receptors on mast cells. Histamine induces transient increased vascular permeability by binding to H1 receptors on endothelial cell that leads to cell activation that includes contraction of myosin resulting in endothelial gaps. This initial and transient phase of increased vascular permeability lasts for up to 30 minutes.
What are the possible etiologies of increased generation of ROS?
i. Ionizing radiation, formation of mutations during chemical carcinogenesis, biological aging ii. Normal cell signaling—modulation of gene regulation, activation of mitogen activated protein (MAP) kinases, modifications, etc iii. Increased O2 concentration
What are the major forms of ROS?
i. O2- supraoxide anion ii. OH hydroxyl radical iii. Peroxynitrite (ONOO) iv. Lipid peroxide radials (RCOO) v. Hydrogen peroxide (H2O2) vi. Hydrochlorous acid (HOCl)
What is the normal physiologic source of superoxide in cells?
i. Leaks in mitochondrial electron transport, with an additional contribution from the mixed-function oxygenase (P450) system. ii. Sometimes leaks in response to inflammatory response
What is the mechanism by which superoxide and peroxynitrite are generated by macrophages and neutrophils during acute inflammation?
Activation of a plasma membrane oxidase produces O2-, which is then converted to H2O2 and eventually to other ROS. These ROS have generally been viewed as the principle effectors of cellular oxidative defenses that destroy pathogens, fragments of necrotic cells or other phagocytosed material. Main role in cellular defenses may be as a signaling intermediate, to elicit release of proteolytic and other degradative enzymes
***How would a deficiency in NADPH generation impair killing of bacteria?
Phagocytosis activates a NADPH oxidase in PMN cell membranes. NADPH oxidase is a multicomponent electron transport complex that reduces molecular oxygen to O2-. Activation of this enzyme is enhanced by prior exposure of cells to a chemotactic stimulus or LPS. NADPH oxidase […]
What is the mechanism for generating hydrogen peroxide?
O2- anions are catabolized by superoxide dismutase (SOD) to produce H2O2. H2O2 is also produced directly by a number of oxidases in cytoplasmic peroxisomes. Alone, H2O2 is not particularly injurious, and it is largely metabolized to H2O by catalase. When produced in excess, it is converted to highly reactive hydroxyl radical.
What are the two mechanisms by which hydroxy radicals are formed?
i. Reaction of H2O2 with ferrous iron (Fe++) → Fenton reaction ii. Reaction of O2- with H2O2 → Haber-Weiss reaction
What is the biochemical mechanism involved in lipid peroxidation?
Peroxynitrite (ONOO-) is formed by the interaction of two free radicals, superoxide (O2-) and nitric oxide (NO)
What is the biochemical mechanism involved in the ROS mediated damage of cytoplasmic and membrane proteins?
i. Detoxifying enzymes such as SOD, catalase, and GPX ii. Scavengers of ROS such as vitamins E and C, retinoids, and NO radical
What is necrosis?
A morphologic expression of cell death resulting from different patterns of lysosomal enzyme degradation of cells and extracellular matrix, the type of necrotic debris, and by bacterial products when present.
Always pathologic.
What are some types of necrosis?
- Ischemic injury (most common)
- Cancer
- Chemical injury: unaltered chemicals, metabolites of P-450
- Infections: such as TB
What are the membrane changes in necrosis?
Influx of water causing the cell to swell, blebs
Cell injury–> influx of Ca++ which causes activation of enzymes, breakdown of membrane, release of cytosolic components to extracellular space
Myelin figures
Inflammation
Amorphous densities in mitochondria
Can use morphology to define the type of necrosis
MI–> inflammation response characterized by neutrophils which are then replaced by macrophages
What is indicated in the three panels of this image?
Heart muscle
Left: Normal myocardium, nuclei are in the center of the myocytes and there is not cytoplasmic alteration
Middle: Hydropic change, the nuclei are still in the middle of the myocytes, but now the myocytes are swollen and vacuolated due to intracellular accumulation of water, but they are not dead, reversible damage
Right: Necrotic myocardium, lack of nuclei, irreversible damage
What types of nuclear changes are noted in necrosis?
- Pykonsis: nuclear shrinkage with increased staining
- Karyolysis: fading of staining due to chromatin digestion
- Karyorrhexis: nuclear fragmentation of a pyknotic nucleus
- Total loss of nucleus
What is the most common morphologic change associated with cytoplasm during necrosis? (Demonstrated in attached image)
Coagulation– Proteolytic enzymes released from ruptured lysosomes and by calcium ion activation leads to similar protein denaturation
The dense pink of the necrotic myocardium indicates protein coagulation.
What type of necrosis is indicated in the image?
Coagulative Necrosis
Most common
Loss of nuclei (nuclei in image are from other cells in the tissue like neutrophils indicated by the black arrow coming to remove the dead cells in acute inflammatory response , not myocardium
Squiggly lines at yellow arrow is contraction band necrosis
What type of necrosis is indicated by the white arrow?
Coagulative necrosis of the heart caused by MI
Compare the dark brown area of the myocardium that is dead to that of the lighter colored uninvolved myocardium. This is due to ischemia secondary to atherosclerosis. Ischemic injury is a very common cause of coagulative necrosis. Drugs are another cause.
How do the type of WBCs change in an MI over time?
Coagulative necrosis is characterized by an acute inflammatory response to cell death. The presence of neutrophils (aka polys, PMNs) define this as acute inflammation. Neutrophils are the first cells to arrive usually after 18 hours at the site of cell injury. The neutrophils begin the destruction of the dead cells. They live for approximately 24 hours and are replaced by macrophages. Destruction of the dead cells is accomplished cellular phagocytosis and intracellular digestion and by their release proteolytic enzymes, especially when the neutrophils die after 24 hours.
What type of necrosis is indicated in the image?
Liquefactive necrosis characterized by a lot of cell debris, distinct aggregates of bacteria, inflammatory cells releasing proteolytic enzymes
What is associated with liquefactive necrosis?
The etiology of liquefactive necrosis includes purulent (pus producing) bacterial and fungal infections, as well as ischemia injury of the brain.
Liquefactive necrosis is associated with rapid digestion of the stroma by lysosomal enzymes released from neutrophils. The released lysosomal enzymes digest (i.e. liquefy) the tissue beyond the ability for repair often leading to formation of an abscess.
The high magnification image on the right demonstrates the cellular debris and acute inflammatory cells that characterize these lesions.
What type of necrosis is indicated in the image?
Caseous Necrosis
What type of necrosis is indicated in the image?
Caseous Necrosis, indicated by the formation of distinct, well rounded, granulomas
What is associated with caseous necrosis?
Caseating necrosis is a form of coagulative that gets its name from the appearance of the gross specimen as seen in this lung with a large, cream colored, cottage cheese-like, apical mass.
Classically, caseating necrosis is associated with M. tuberculosis infections.
The microscopic appearance of caseating necrosis is that of destruction of tissue architecture combined with an irregular, round mass, whose center is an eosinophilic, amorphous, acellular debris surrounded by granulomatous inflammation with its multinucleated giant cell. The effect is that of an ovoid mass or masses.
What type of necrosis is indicated by the image?
Fat necrosis
What type of necrosis is indicated by this image?
Fat necrosis
This is a low magnification of pancreatitis inflammation of the pancreas. A refers to normal pancreas; B is an area of inflammation fibrosis and damaged pancreatic parenchyma, and C refers to fat necrosis.
What is associated with fat necrosis?
Fat necrosis is often associated with pancreatitis and can also be seen in direct trauma to adipose tissue. The gross appearance is that of chalky white-yellow plaques in the adipose tissue.
In fat necrosis the ruptured fat cells (dead adipocytes) release fatty acids that are degraded by lipases from the damaged pancreatic acinar cells. Deposition of calcium yields blue hued “soap bubble” appearance or saponification.
What are some of the consequences of necrosis?
Scarring and loss of organ function
Inflammation
Formation of ulcers and cavitary lesions
Calcification
Resolution
Autoimmune rsponse due to tissue destruction release of self-antigen
Describe the mechanisms of endothelial cells activation leading to vasodilation and increased vascular permeability
- Cells and endothelial cell membrane-bound mediators react first
- First activated by Histamine, Bradykinin, PAF, C3a, C5a, Leukotrienes
- Later activated by IL-1beta, TNFalpha - Upon endothelial activation, synthesis of NO and PGI2 to cause vasodilation
- Retraction of cytoskeletal proteins leads to opening of the intercellular gaps, which causes increased vascular permeability - Vasodilation = redness and warmth
What are some of the early activators of endothelial cell activation?
- histamine, bradykinin, platelet activating factor (PAF) and thrombin
- promote increased vasodilation and permeability.
What are the late activators of endothelial cell activation?
IL-1beta and TNFalpha
What factors will activated endothelial cells release?
Vasodilatation in the microvasculature due to the synthesis and release of NO and PGI2 and by the activated endothelial cells quickly reverses this process.
Transient vasoconstriction due to the synthesis of angiotensin II and endothelial-1 to balance activity of NO and PGI2.
Synthesis cytokines (e.g. IL-8) that help to promote PMN activation and emigration, as well as pro and anti-thrombotic factors, and extracellular matrix components.
Increased vascular permeability involve contraction cytoplasmic myosin mediated by histamine, bradykinin, and leukotrienes. A rearrangement of cytoskeletal elements, resulting in endothelial cell retraction, occurs late and is mediated by IL-1, TNF, and IFN-.
What are the normal fluid dynamics in capillaries?
Hydrostatic pressure from blood pumping through the vessels pushes fluid into the interstitial space (~14mL/min). Oncotic pressure from the increased solute concentration in the capillary pulls fluid from the insterstitial space back to the capillary (~12mL/min). A difference of ~2mL/min is sent to the lymphatics.
What are some differences in direct and leukocyte depended cell injury?
Direct injury:
Location: Arterioles, capillaries, and venules
Caused by: toxins, burns, chemicals
Reaction: Fast and may be long lived (hours to days)
Leukocyte dependent injury:
Location: Mostly venules, pulmonary capillaries
Reaction: Late response, may be long lived (hours)
What type of inflammation is indicated by the image?
Suppurative inflammation
Left: “Chicken wire” appearance of the normal lung with that of the acute pneumonia.
Right: Airway filled with purulent material. The alveoli of the lungs, where gases are exchanged, is filled with purulent material in the acute bronchopneumonia as compared to the normal lung.
What is indicated by the image?
Left: Normal prostate
Right: Chronic inflammation from chronic prostatitis
Nonspecific chronic inflammation with lymphocytes and macrophages– lots of WBCs
What is indicated by the image? What type of inflammation?
Chronic inflammation in viral pneumonia
The alveolar wall is thickened by edema and mononuclear cells. The death of epithelial cells lining the alveoli results in a cell poor exudate that “coagulates” into a thick pink-staining hyaline membrane that lies on the surface of the alveoli. This yields a ground-glass like lungs on chest radiographs, and respiratory failure.
Covering up the surface, unable to exchange gas through hyaline membrane
The mechanism of damage is a “cytokine storm” – overwhelming stimulation of the immune response leading to excess release of cytokines. This is the mechanism behind the deaths associated with “bird flu”.
What type of inflammation is indicated by the image?
Granulomatous inflammation
Caseating granulomas are indicative of infections by M. tuberculosis and Bartonella henselae (cat-scratch fever).
What is depicted in the image?
Cirrhotic liver
Smooth normal architecture of liver is replaced by nodular appearing shrunken liver, increases hydrostatic pressure 2-3x in portal vein which is transported back into the microvascular within the abdominal cavity, increases hydrostatic pressure in arterial end
What is depicted in the image?
Top: Normal lung
Bottom: Pulmonary edema refers to fluid accumulation in the alveoli. It can be a transudate or an exudate.
Pulmonary edema is caused by left heart failure; the inability of the left heart to pump out an appropriate volume of blood with each contraction. The underlying etiology may include disease of the aortic or mitral valves, or damage to the cardiac muscle fibers by an infarction (ischemic injury) or an infection (myocarditis) that weakens the heart.
The end result is that blood backs up in the pulmonary veins of the lung increasing the hydrostatic pressure within the pulmonary capillaries the form the thin walls of the alveoli.
What are the causes of these lymphedemas?
These are three classic examples of lymphedema
The left image demonstrates marked edema in the lower limb secondary to surgical trauma as noted by the scars above the ankle, but what we don’t see is the destruction of the inguinal lymph nodes.
The middle image is that of upper limb edema following an axillary lymph node dissection, most likely due to breast cancer.
The image of the right is classic for lymphatic filariasis (e.g., Wuchereria bancrofti ) or elephantiasis involving the scrotum and lower limb.
What is pulmonary edema caused by?
Seen on the X-ray as a cloudiness, resulting from left heart failure.
These patients manifest respiratory difficulties due to related to the pulmonary edema that accompanies left heart failure and congestion. These patient are short of breath (dyspnea), can not lie flat in bed (orthopnea).
What happens in right sided heart failure?
Enlarged right ventricle (looks like a tennis shoe).
Physical exam demonstrates cyanosis, distention of the jugular vein (arrow), an enlarged liver (hepatomegaly) and spleen (splenomegaly), there may be a fluid wave indicative of ascites, and pitting edema in the lower limbs.
The venous blood pressure is often elevated.
What is hepatic congestion?
The classic appearance of a congested liver is similar to that of a nutmeg; thus a nutmeg liver.
The brown color seen in the fixed section of liver, represents blood expanding the hepatic sinuses.
This is better seen at the microscopic level as in the image on the right.
