Pathology 3 Flashcards
What is inflammation?
A nonspecific host response to something injurious
What are the main causes of inflammation (6)?
- Infection
- Tissue necrosis
- Immune reaction
- Trauma
- Foreign bodies
- Physical and chemical agents
What are the four signs and symptoms of acute inflammation?
- Redness
- Swelling
- Heat
- Pain
* Sometimes loss of function is added to this list
T or F: Acute inflammation has a rapid onset and a short duration.
T
What are the five forms of inflammation?
- Purulent
- Abscessing
- Fibrinous
- Serous
- Granulomatous
What are the three components of inflammation?
- Vascular response
- Leukocyte (WBC) response
- Systemic response
What happens in the vascular response of inflammation?
Dilation and increased permeability, which permits an outpouring of fluid, plasma proteins, and leukocytes from the blood into the extracellular space
What is serum and why is it thin?
Serum is the liquid portion of blood that has clotted and been centrifuged to separate the clotted cells and proteins. It’s thin because it has a low protein content and no cells.
What is plasma?
The liquid portion of blood that has been anti coagulated and centrifuged, leaving a protein-rich liquid portion including the blood clotting factors
What is serous inflammation?
A form of usually acute inflammation marked by an outpouring of think fluid from blood vessels or mesothelium or a skin blister
What is fibrinous inflammation?
A form of usually acute inflammation characterized by deposition of fibrin-rich exudate on pleura, pericardium, peritoneum, or meninges
Exudate
An inflammatory ECF with high protein content, cells, cellular debris, and specific gravity > 1.020.
Transudate
Thin serous acellular fluid
What is purulent (aka supparative) inflammation?
Usually acute inflammation featuring production of abundant pus. It’s commonly caused by infection with pyogenic bacteria.
What is pus?
Purulent exudate rich in neutrophils, cellular debris, and commonly microbes. It’s thick, opaque, and variably colored.
What are some causes of congenital leukocyte defects?
Leukocyte adhesion deficiency 1 and 2, chronic granulomatous disease, myeloperoxidase deficiency, chediak-higashi syndome, and cryopyrin-associated periodic fever syndromes
What are some causes of acquired leukocyte defects?
Diabetes mellitus, hemodialysis, malnutrition, and leukemia
What are the four most important systemic effects of acute inflammation?
- Fever or hypothermia
- Tachychardia
- Hyperventilation
- Leukocytosis (more WBC in circulation in blood)
Acute inflammatory response is largely mediated by _________.
Cytokines, especially IL-1, TNF, and IL-6
Acute inflammation results in an increase in what?
CRP, Amyloid-A, Fibrinogen, Epinephrine, Norepinephrine, Glucagon, WBC and platelet counts
Acute inflammation results in a decrease in what?
Albumin, Serum iron and zinc, RBC production, Skeletal muscle
What is neutrophilia and what is it associated with?
More neutrophils in circulation in the blood; associated with bacterial infections
What are the types of leukocytosis?
- Neutrophilia
- Lymphocytosis
- Eosinophilia
What is lymphocytosis and what is it associated with?
Leukocytosis consisting of lymphocytes; associated with viral infections
What is eosinophilia and what is it associated with?
Leukocytosis consisting of eosinophils; associated with allergies and parasites
Severe acute inflammation can cause neutrophils to have _______ and _____.
Dohle bodies and toxic granulations
What are Dohle bodies and what do they look like?
Patches of dilated endoplasmic reticulum that appear as “sky-blue peripheral cytoplasmic puddles”
What do toxic granulations look like?
They’re dark blue or purple granules that are bigger and coarser than the small, faintly stained neutral granules in segmented neutrophils
Toxic granulations are more common in (immature/mature) neutrophils.
Immature
Acute phase reactants include ________.
Fibrinogen Complement proteins Amyloid-A CRP Alpha-1-antitrypsin Hepcidin Ferritin
What does amyloid A do?
Plays a role in recycling and reusing cholesterol from destroyed and damaged cells. It replaces apolipoprotein A in HDL and targets delivery of HDL to macrophages, suppressing ACAT and enhancing neutral cholesterol esterase and ABC transporters in macrophages.
What does fibrinogen do?
It causes sticky erythrocytes and an increased ESR
What influences the erythrocyte sedimentation rate (ESR)?
Inflammation, age, size/shape/concentration of erythrocytes
What does CRP do?
It binds to phosphocholine residues that are unique to bacteria, and once bound it becomes a ligand for complement C1 binding, initiating the classical complement cascade.
What cytokine induces CRP synthesis?
IL-6
T or F: Bacterial and viral infections raise the CRP level.
F: CRP goes up with bacterial but not viral infection
What characterizes systemic inflammatory response syndrome (SIRS)?
2 or more of the following:
- Temperature >100.4 or 90/minute
- Respiratory rate >20/minute or PCO2 12000 or 10% bands
The majority of patients with sepsis have (positive/negative) blood cultures.
Negative
What are acute phase reactants?
Proteins produced in abundance with inflammation
What are the 5 big signs of the flu?
- Fever
- Malaise
- Myalgia
- Nasal congestion
- Sore throat
Which cell type predominantly defines acute inflammation?
Neutrophil
Which cell type predominantly defines chronic inflammation?
Mononuclear cells like lymphocytes and monocytes
Fever seen in acute infections and acute inflammatory responses is due primarily to ____ and ___.
IL-1 and TNF
What does the ESR measure and what does it tell you?
ESR = erythrocyte sedimentation rate. It is a test for inflammatory response. When acute phase reactant proteins are present, RBCs stick together and act as larger profile bodies and they sediment in the serum more quickly than individual red cells.
What is the Hof in a plasma cell?
Clearing in the cytoplasm where the Golgi apparatus resides
Emigration of ______ from the microcirculation into the site of injury is the characteristic event occurring early in the acute response to injury.
Leukocytes
What is responsible for the redness and warmth that you see in an inflamed area?
Vascular dilation
What is the VERY first thing that happens in the vascular response to inflammation?
Vasoconstriction until ATP runs out and vessels relax, letting blood flow
The result of transudation and exudation is ______.
Edema
When a vessel leaks, generally you see (exudate/transudate) first.
Transudate
What is the most characteristic cause of increased vascular permeability? Where is this seen?
The creation of gaps between endothelial cells by contraction of those cells
Seen in post capillary venules
Endothelial cell retraction occurs under the effect of ___________ (3).
IL-1, TNF, and hypoxia
What is the immediate sustained response?
Vessel are injured by effects such as burns, toxins, or certain chemicals, and the endothelial cells die. They undergo necrosis, cell death, and detachment and leave large gaps and holes.
T or F: Endothelial cell retraction is reversible.
T
What is leukocyte dependent injury?
As leukocytes travel carrying chemicals, their cargo is occasionally leaked or spilled into the endothelium.
What is transcytosis? What mediates it?
Mechanism by which materials can pass through the endothelial cell without damaging or injuring it. Mediated by VEGF.
What are the steps of how leukocytes respond to the process of phagocytosis?
- Neutrophil engulfs bacteria into a phagosome
- Phagosome is attached to a primary granule
- Secondary granule comes in, and ROS are formed in an oxidative burst
- Dead bacteria fragments undergo exocytosis into tissues and circulation
What modulates leukocyte rolling and adhesion?
Selectins
What modulates leukocyte adhesion and transmigration?
Integrins
What is margination?
Leukocyte accumulation at the periphery of blood vessels
What is rolling?
Leukocytes are pushed out of the central axial column by flowing blood
What is pavementing?
Leukocytes line up along the blood vessel wall
Where do you find E-selectin, P-selectin, and L-selectin.
E-selectin: endothelium
P-selectin: endothelium and platelets
L-selectin: most leukocytes
What is diapedesis?
Leukocytes move between endothelial cells and through the basement membrane into the extravascular spaces
What modulates diapedesis?
Molecules of the immunoglobulin superfamily on endothelial cells that interact with integrins on leukocyte cell surfaces
What are the endothelial adhesion molecules?
ICAM-1 and VCAM-1
What are examples of integrins?
LDA-1 and Mac-1: bind to ICAM-1
VLA-1: binds to VCAM-1
The adhesion molecules that cause the leukocytes to firmly adhere to the endothelial surface are ______.
Integrins
T or F: Transmigration through the endothelial and basement membrane is a passive process.
F
Transmigration through the endothelial and basement membrane is modulated by ________.
PCAM-1
What is the order of cellular events in acute inflammation?
- Margination and rolling
- Adhesion and transmigration
- Chemotaxis and cell activation
- Phagocytosis and degranulation
What is chemotaxis?
Movement of cells or organisms in response to chemicals
What can produce the chemical gradient needed for leukocyte chemotaxis?
Soluble bacterial products, complement (C5a), LTB4, and cytokines such as the chemokine family including IL-8
What are pseudopods?
Formations by which cells travel along a chemical gradient
In chemotaxis, there is G protein-mediated activation of _______.
Phospholipase C
In leukocyte activation, activation of protein kinase C results in __________.
Degranulation and secretion of lysosomal enzymes and the generation of the oxidative burst
What are the 3 steps of phagocytosis?
- Recognition and attachment
- Engulfment
- Killing and degradation
During phagocytosis, engulfment is triggered by ______.
The binding of opsonized particles
What are azurophilic granules?
Granules located in the cytoplasm of granulocytes that are responsible for the production of perchlorate
Dead microorganisms are degraded by _______.
Lysosomal acid hydrolases
T or F: Pro-inflammatory cytokines upregulate the expression of endothelial cell adhesion molecules that bind leukocytes, directing them to the site of infection.
T
What are the main cytokines involved in the acute phase response?
IL-6, IL-1, TNF-alpha, IFN-gamma, and TGF-beta
What is the main stimulator for the increased production of most acute phase reactant proteins?
IL-6
Which cytokines stimulate hepatic Kupffer cells, thereby amplifying the cytokine response.
IL-6, TNF, and IL-1
How does the central nervous system participate in acute phase response?
By mediating fever and by secreting ACTH
Hickam’s dictum
A patient can have as many diseases as he darn well pleases
T or F: The older the patient, the less likely Occam’s razor will be correct and the more likely that Hickam’s dictum will apply.
T
Chronic inflammation consists of what three simultaneous processes?
- Active inflammation
- Tissue destruction
- Attempted repair
What are the 4 main causes of chronic inflammation?
- Persistent infections
- Prolonged toxin exposure
- Autoimmunity
- Conditions of unknown etiology
What are the key cellular players in most chronic inflammation?
Macrophages
What are macrophages activated by?
- Secretion of acid and neutral proteases
- Plasminogen activator
- Complement components
- Coagulation factors
- Arachindonic acid metabolites
- ROS
- NO
- IL-1 and TNF
Macrophages are drawn to sites of inflammation by chemotaxis by _______.
MCP-1, C5a, PDGF, TGF-alpha, fibrinonectin, and fibrinopeptide fragments
Macrophage proliferation and immobilization are important in maintaining chronic inflammation, especially in _____.
Atherosclerosis
Activated T cells secrete _______, which activates macrophages.
IFN-gamma
What are some examples of macrophage predominant diseases?
Atherosclerosis, subacute phase pneumonia, Gaucher disease, gout and usual interstitial pneumonia
What are some examples of lymphocyte predominant diseases?
Thyroiditis, rheumatoid arthritis, and myocarditis
What is a granuloma?
An aggregate of activated macrophages working together
What are some examples of granulomatous diseases?
TB, leprosy, syphilis, cat-scratch disease, and sarcoidosis
What do cat-scratch disease granulomas look like?
They tend to be rounded or stellate with central necrotic granular debris and neutrophils
What do sarcoidosis granulomas look like?
The tend to have non-necrotizing tight naked granulomas without a rim of lymphocytes
What are lymphatics lined by?
Endothelium with scant basement membrane
Inflammation of lymphatic channels is known as ________.
Lymphangitis
Inflammation of lymph nodes is known as ________.
Lymphadenitis
Enlargement of lymph nodes is known as _______.
Lymphadenopathy
Why do chronic infections tend to go to lymph nodes?
Because they are the processing centers of the immune system in the lymphatic sewer system of the body
T or F: Chronic inflammation can increase the ESR.
T
Which typically elevates the ESR more: acute or chronic inflammation?
Acute inflammation
Fever as a component of the systemic inflammatory response is due to _______.
The release of pyrogens from the mononuclear phagocyte system
What are the main endogenous pyrogens?
IL-1 and TNF-alpha
What are the main causes of fever?
Infection, infarction, tumors, non-infectious inflammation, hemorrhage, brain damage, drug reactions, and heatstroke
Which hormone can raise body temperature?
Progesterone
In regard to body temperature, fully anesthetized patient is __________.
Poikilothermic – has ambient temperature
What is the general basis of anemia of chronic disease?
The body acts as if all chronic inflammation is due to infection with microbes competing for our iron and hides it from them.
If a chronically ill patient has a hemoglobin of less than 10 g/dl, what should you look for?
Something besides anemia of chronic disease, like bleeding
What down-regulates the expression of ferroportin?
IFN, LPS, TNF-alpha
What is ferroportin?
The only iron export protein in iron-transporting cells
_______ binds to ferroportin and leads to its degradation.
Hepcidin
What stimulates the production of hepcidin, and what does hepcidin do?
IL-6 and LPS stimulate hepcidin production, and hepcidin inhibits the duodenal absorption of iron and macrophage iron recycling
Which cytokine upregulates transferrin receptor expression and increases transferrin-receptor-mediated uptake of transferrin bound iron into monocytes?
IL-10
Chronic excess stimulation of TNF release in advanced cancer results in _______.
Cachexia (wasting syndrome)
Chronically elevated serum amyloid A can result in ________ in some patients.
Secondary amyloidosis
Lipooxygenases convert arachidonic acid into ___________.
Leukotrienes and lipoxins
Cyclooxygenase converts arachidonic acid into ________.
Prostaglandins
How do corticosteroids work?
They block the production of arachidonic acid and all the metabolites made from it
How do NSAIDs work?
They block prostaglandin production
T or F: NSAIDs block cyclooxygenase reversibly.
Most do, except aspirin, which prevents platelets from making thromboxane for the rest of their lives
Cyclooxygenase (1/2) is constitutively expressed and cyclooxygenase (1/2) is inducible.
1: constitutively expressed
2: inducible
_______ might have all the anti-inflammatory effects of other NSAIDs with less gastric bleeing (but more heart attacks)
Rofecoxib – a COX-2 inhibitor
Cyclooxygenase in ________ makes prostacyclin.
Endothelium
Cyclooxygenase in _______ makes thromboxane.
Platelets
What are release triggers of histamine?
- Physical injury
- Binding of IgE to Fc receptors on mast cells
- C3a and C5a anaphylatoxins
- Leukocyte-derive histamine releasing proteins
- Supstance P
- Certain cytokines
- IL-8
T or F: Effects of serotonin are similar to histamine.
T
Serotonin is present in ________ and released during ________.
Present in platelet dense body granules and is released during platelet aggregation
What are neuropeptides important for?
Their ability to transmit pain signals
One of the most important neuropeptides is ________.
Substance P
Nerve fibers that secrete neuropeptides are prominent in ___________.
The lung and GI tract
The kinin system, clotting system, and complement system are linked by _______.
Hageman factor (factor XII) – synthesized by the liver and activated by collagen, basement membrane, or platelets
________ sits at the top of the kinin cascade and the clotting cascade, both of which are important in inflammation.
Activated Hageman Factor (XIIa)
How does the kinin cascade influence the fibrinolytic system?
Through kallikrein activation of plasminogen to plasmin
How is plasmin related to the complement cascade?
Plasmin affects the activation of complement C3 to C3a
Activation of the kinin system leads to formation of ______ from _____.
Formation of bradykinin from high MW kininogen
Physiologically, activation of the kinin system leads to _________.
Increased vascular permeability, arteriolar dilation, and bronchial smooth muscle contraction
Pain is a feature of injection of ______ and ______ into skin.
Bradykinin and Kininogen
____________ amplifies the whole set of plasma proteases in the clotting system.
Kallikrein
________ forms insoluble clots and enhances leukocyte adhesion to endothelial cells.
Thrombin
What do fibrinopeptides do?
They’re a part of the clotting system and they increase vascular permeability and play a role in chemotaxis
What would happen if we didn’t have the fibrinolytic system?
There would be continuous and irreversible clotting
How does the fibrinolytic system counter-regulate clotting?
By cleaving fibrin, which lyses clots.
What is the central role of the Hageman factor?
It activates the kinin, clotting, fibrinolytic, and complement systems
Which plasma proteases contribute to vascular permeability?
Bradykinin, C3a, C5a
Which plasma protease is important in chemotaxis?
C5a
What functions is the lipooxygenase pathway responsible for?
Vasoconstriction, bronchospasm, and increased vessel permeability
What functions is the cycloocygenase pathway responsible for?
Prostacyclin: vasodilation, inhibition of platelet aggregation
Thromboxane: vasoconstriction, platelet aggregation
_________(3) potentiate edema through vasodilation.
PGD2, PGE2, and PGF2
5-HETE and Leukotriene B4 are involved in _______.
Chemotaxis
Which arachidonic acid metabolites mediate vasoconstriction?
TXA2 and LT C4, D4, and E4
Which arachidonic acid metabolites mediate vasodilation?
Prostacyclin, PGE1, PGE2, PGD1, Lipoxins
Which arachidonic acid metabolites are involved in increased vascular permeability?
LTC4, D4, and E4
Which arachidonic acid metabolites are involved in chemotaxis and leukocyte adhesion?
LTB4, Lipoxins
What does platelet-activating factor do?
It can aggregate platelets and cause degranulation and it is 100x more potent than histamine in inducing vasodilation and increased vascular permeability
-But it scan also cause vasoconstriction and bronchoconstriction
Autocrine cytokines
Act on the same cell that produces it
Paracrine cytokines
Act on cells in the immediate vicinity
Endocrine cytokines
Act systemically (enter bloodstream to act on cells that are far, far away)
Secretion of IL-1 and TNF is stimulated by _______.
Endotoxin, antigen-antibody complexes, toxins, physical injury, and other inflammatory mediators
______ causes aggregation and activation of neutrophils and causes hypotension in septic shock.
TNF
T or F: IL-1 and TNF induce systemic acute phase responses.
T
What are the major groups of chemokines?
- CXC (alpha chemokines): attract neutrophils
- CC (beta chemokines): attract monocytes, macrophages, and eosinophils
What role does nitric oxide play in inflammatory response?
- It is used by macrophages to kill microbes and to kill tumor cells that the macrophages have engulfed
- It relaxes smooth muscles and blood vessels and antagonizes all stages of platelet activation
NO is synthesized from _________ by _______.
L-arginine, molecular oxygen, NADPH, and other cofactors by NOS (nitric oxide synthase)
How can free radicals amplify inflammation?
- By increased chemokines, cytokines, and adhesion molecule expression
- Initiate thrombosis and increased permeability in direct cell injury
What are the antioxidant protective systems?
Catalase, superoxide dismutase, glutathione
Where are acid proteases active?
Usually only in the phagolysosome
Neutral proteases can be found in the ECM in the form of _________(3).
Elastase, collagenase, and cathepsin
What do antiproteases do and what are examples of these?
They check and help reverse the action of neutral proteases
-Examples: alpha-2-macroglobulin in the serum and alpha-1 antitrypsin in tissue
_______ is the most important of the peroxidases.
Myeloperoxidase
Peroxidase negative granules contain substances such as ______ and ______.
Lactoferrin and lysozyme
What are characteristics of hypersensitivity granulomas?
Multinucleated giant cells that are aggregates of activated macrophages (epitheloid macrophage)
-Associated with T cell responses to certain microbes
What are characteristics of foreign body granulomas?
No epitheloid macrophages
Have multinucleated giant cells
What is an empyema?
Collection of pus in a cavity
What is a sinus and what is a sinus tract?
Sinus: cavity formed by a draining abscess
Sinus tract: pathway of a draining sinus to skin of body cavity
