Term
| what does acute inflammation generally consist of? |
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Definition
| blood vessels and accumulation of fluid and leukocytes in extravascular tissues |
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Term
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Definition
| all white cells, macrophages, PMNs |
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Term
| what processes is acute inflammation intertwined with? |
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Definition
| regeneration and scarring |
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Term
| what is acute inflammation fundamentally? what is it designed to do? can it be harmful? |
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Definition
| a protective response to rid the body of initial cause of injury and consequences of such. it can be potentially harmful if chronic. |
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Term
| are there any organs that inflammation should be prevented in? |
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Definition
| the eye, (scarring would contribute to blindness), and the reproductive tract, (risk of sterilization, limited cell replacement) |
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Term
| where does inflammation occur? what components of connective tissue are involved in this response? |
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Definition
| inflammation occurs in vascularized connective tissue. plasma, circulating cells, blood vessels, cellular and extracellular constituents of connective tissue are involved. |
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Term
| what should be the duration of acute inflammation? |
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Definition
| acute inflammation should have a short duration, (minutes to 3-5 days), and is associated with exudation of fluid and plasma proteins, (edema). it is also associated with emigration of leukocytes, neutrophils in particular, members of the innate immune response, (neutrophils/PMNs early, then macrophages). |
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Term
| what is chronic inflammation associated with in terms of the immune system's response? |
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Definition
| the presence of LYMPHOCYTES and macrophages, (also seen with primary infection), the proliferation of blood vessels, fibrosis and tissue necrosis, (collateral damage) |
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Term
| what are the four cardinal signs of inflammation? |
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Definition
| redness, (rubor), swelling,(tumor), head,(calor), pain,(dolor) |
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Term
| what are the three major components of acute inflammation? |
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Definition
| 1) alterations in vascular caliber leading to increased blood flow, (initial vasoconstriction of larger vessels/vasodilation of smaller vessels via histamine). 2) structural changes permitting plasma proteins and leukocytes to leave the circulation. 3)emigration of leukocytes from the circulation and accumulation at site of injury, (don't move via passive flow but by chemical gradient). |
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Term
| what is edema? what are it's two forms? |
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Definition
| swelling in tissue, either transudate or exudate |
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Term
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Definition
| edema of fluid containing a low amount of proteins, (primarily albumin), and a specific gravity <1.012. it is bascially an ultrafiltrate of blood plasma, resulting from hydrostatic imbalance across endothelia, the permeability of the endothelium is normal, (minimal changes to endothelium at acute inflammation onset). |
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Term
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Definition
| edema with inflammatory extravascular fluid containing a high protein level, cellular debris, and a specific gravity above 1.020. pus is an example, and its viscousity is a result of the nucelic acids released in cell death. |
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Term
| what changes occur to inflamed tissue? |
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Definition
| the higher volume of blood moving through slows down the speed of movement so the leukocytes stay and do their work in damaged, (not healthy tissue). changes on the endothelial cell surface, where the leukocytes are making contact and activation signals are released as a result, starting the process to allow fluid, plasma proteins and leukocytes into the tissue. |
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Term
| how are gaps in the vascular endothelial layer formed by contraction? where would you see this? |
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Definition
| they can be due to endothelial contraction, resulting from minor changes in infrastructure, (esp tight junctions), letting a lot of fluid and plasma proteins out into the tissue. this would be seen in venules, mediated by histamines/leukotrienes and is the most common and short lived change in vascular permeability, (minutes) |
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Term
| how are gaps in the vascular endothelial layer formed due to direct injury? why would you see this? |
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Definition
| if there are lacerations or bleeding for other reasons, coagulation occurs b/c the vascular network is ruptured. everything downstream is then ischemic, leading to possible necrosis/apoptosis and destroyed vascular network. |
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Term
| how are gaps in the vascular endothelial layer formed due to leukocytes? when would you see this? |
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Definition
| leukocyte activation occurs with their endothelial cell association, but if their exit is delayed and they enter the phagocytic phase while still in the vascular network, they will release damaging factors to break through the endothelium |
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Term
| how are gaps in the vascular endothelial layer formed due to trancytosis? when would you see this? |
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Definition
| fluids can be moved from one side to the other of a vascular endothelial cell via vesicles, (just fluid and plasma proteins) |
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Term
| how are gaps in the vascular endothelial layer formed due to angiogenesis? when would you see this? |
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Definition
| if you don't have an intact blood vessel system, it will remain leaky until a new network is re-established |
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Term
| how does leukocyte extravasation occur? what first has to happen with the blood? how does the leukocyte initially attact to the endothelial cell? how does the leukocyte more permanently attach to the endothelial cell? how does the leukocyte actually enter the cell? |
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Definition
| the vessel, (post capillary venule), goes from smaller to larger diameter, which causes the blood flow to slow, and leukocytes make contact with the endothelial cells. then selectins are upregulated, (very rapidly -w/in 2 hrs), in response to pro-inflammatory stimuli from vesicles. the leukocytes roll along these selectins, (low affinity) and stop when they hit integrins, (higher affinity). the leukocyte flattens out, (due to net flow, requires cytoskeletal activation) and is activated. to enter the cells, the leukocyte looks for gaps and squeeezes between the endothelial cells and releases factors that allow it to cut its way through the basement membrane. |
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Term
what does the leukocyte do once it has entered the cell? what are the first cells to enter? second? |
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Definition
it follows the chemokines to the point of injury, (some of the earlier ones just respond to chemicals released by the microorganisms, b/c no chemokines have been released yet). they phagocytize pathogens/destroy tissue damage or pathogens.
they then may release chemokines such as TNF, IL-1, IL-6 to draw in a second wave of cells. polymorphonuclear cells are usually the first to enter, followed by macrophages. |
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Term
| if macrophages are still present at 5-7 days w/in cells, what might they do? |
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Definition
| release chemokines to call in other leukocytes |
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Term
| do leukocytes enter cells by diffusion? |
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Definition
| no, it is energy-requiring, (need up-regulation, cytoskeletal changes, movement, etc) |
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Term
| what do P+E selectins on the endothelial cell interact with on the leukocyte surface? |
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Definition
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Term
| what do the integrins on leukocytes interact with on the endothelial molecules? |
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Definition
CD11/CD18, (integrins), and LFA-1, Mac-1 bind to ICAM-1 on endothelial cells
alpha4beta1, (VLA4), (integrins), and alpha4beta7, (LPAM-1) bind to VCAM-1 on endothelial cells |
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Term
| what are the pre-formed vesicles of P-selectin in endothelial cells called? what stimulates their release? why are they held in this manner rather than created on demand? |
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Definition
| weibel-palade bodies, which are stimulated by histamine thrombin. creating new proteins could take several hours, while up-regulating these vesicles only takes 15-30 min. though the nucleus is also stimulated so that new proteins will be made once up-regulation has started. |
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Term
| can resident macrophages induce adhesion molecules on their endothelial cells? how? |
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Definition
| yes, the macrophages can release TNF and IL-1 and be expressing the appropriate ligand for the receptor. |
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Term
| what is avidity? affinity? what is the intended result of both? |
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Definition
| avidity is how long the macrophage and endothelial cell will associate, (find molecule of interest and hand onto it longer), while affinity is how often they will find each other, (find it w/more frequency due to higher number of receptors). these both should result in higher levels of association of leukocyte and macrophage |
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Term
| what is the sequence of events following acute injury? |
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Definition
| edema, neutrophils, and then monocyte/macrophages |
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Term
| what is the edema portion of acute injury characterized by? |
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Definition
| fluid flowing to the area, (via tiny vesicles or simply due to direct injury), and minimal cytoskeletal reorganization |
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Term
| what are the earliest cells that respond to acute injury? |
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Definition
| neutrophils or polymorphonuclear cells which respond to bacterial products and damaged tissue/extracellular matrix components. these respond within 48 hrs, and once they have established themselves, and if necessary/or massive stimulus, they call in monocytes which then differentiate into macrophages |
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Term
| what are some biochemical events within the leukocytes during inflammation? in terms of surface changes? mobility? secretory granules? Ca++ release? |
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Definition
| leukocytes need to make surface changes to associated with endothelial cells. they need to turn on phagocytic machinery/reorganize cytoskeleton. they have to send out a pseudopod and translocate into the EC environment, pulling themselves along the chemical gradient. through receptor-ligand interactions involving protein phosphorylation, secretory granules are released that cut through the basement membrane and destroy the microorganism, (oxidative burst). they also release Ca++ from the ER which starts arachidonic acid formation, increases adhesion molecule affinity, and helps change the cytoskeleton. |
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Term
| what are some signals that activate leukocytes? what are the results? |
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Definition
| mainly microbial products at first, then N-formyl-methionyl peptides, and some lipid mediators. these stimulate secondary chemokines to be released from the first wave of leukocytes, ROS production, cytoskeletal changes, chemotaxis, and phagocytosis |
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Term
| what things might be commonly found on the surface of a pathogen that a phagocyte would respond to? what happens to pathogens engulfed by phagocytes? |
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Definition
| the Fc, (constant) region of an antibody or C3b of the complement cascade would activate a phagocyte to engulf a pathogen. once engulfed, the pathogen will be fused with a lysosome, where ROS will be released, (such as the NADPH oxidase system generating O2 radicals) |
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Term
| how specific are phagocytic cells in choosing the cells they engulf? what can they recognize? how can this be problematic? |
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Definition
| not very specific, they do however have Fc receptors, so they can recognize microbes with antibodies on them. they can also recognize C3b of the complement system. this can be problematic in chronic inflammation due to a lot of collateral damage. |
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Term
| what does the phagocyte have in its lysozomes that helps break down engulfed microbes? how does this occur? |
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Definition
| NADPH oxidase creates superoxide, 02*, hydrogen peroxide and hypochlorous solution. phagocytes also have INOS, inducible nitric oxide synthase which turns arginine into NO. all of these transfer free e- against the microbe, imparting damage to the DNA, EC molecules, inducing breaks and instability. |
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Term
| can leukocyte defects be genetic or aquired? |
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Definition
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Term
| how might leukocyte defects be aquired? what problems might occur with: thermal injury, diabetes, hemodialysis, leukemia, LAD, neutrophil-specific granule deficiency, myeloperoxidase deficiency? |
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Definition
| thermal injury or diabetes can cause changes in chemotaxis. hemodialysis and diabetes can cause changes in adhesion. leukemia can cause changes in phagocytosis and microbial activity. LAD1, (lack of B chain of integrin on leukocyte), causes problems with selectin association, inhibiting the rolling process. neutrophil-specific granule deficiency keeps neutrophils from cutting through the basment membrane. myeloperoxidase deficiency causes problems with leukocytes' ability to kill microorganisms, b/c O2 radicals might not be enough |
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Term
| where are pre-formed mediators of inflammation? what do they help do? where do they come from? |
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Definition
| they are produced in the liver and some are held in weibel-palade bodies. others in circulation include CRP and complement. histamine, (from mast cells), serotonin, lysosomal enzymes, (from leukocytes). these help w/things like exiting the vascular network, things like lysosomal enzymes are crucial for destroying things like parasytic worms that are too big to be phagocytized. |
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Term
| what are some mediators of inflammation that are newly synthesized locally in response to stimuli? who makes them? |
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Definition
| IL-1 and TNF are produced by resident macrophages, some endothelial cells. prostaglandins, leukotrienes, NO, cytokines are also examples |
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Term
| why are clotting factors released? |
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Definition
| clotting factors are released to avoid excess blood loss from damage, creating ischemia downstream that has to be bypassed using other parts of the vascular network. |
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Term
| what part does complement play in acute inflammation? |
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Definition
| complement plays a large role in acute inflammation, it is one of the earliest mediators present. complement has direct anti-microbial and some chemotaxic properties |
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Term
| how does the C3 from he alternative and classical complement pathway affect microorganisms? |
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Definition
| the these complement pathways involve direct binding on the pathogen surface, where C3b stays associated to the surface and C3a splites and dissociates as a chemical mediator |
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Term
| what happens when there are defects affecting C2, C4 of the classical pathway? |
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Definition
| higher incidence of autoimmune disorders, esp lupus and erythematosus |
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Term
| what is the most severe possible defect in complement? |
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Definition
| a defect in C3, which ties all the pathways together. without therapy, (prophylatic antibiotics, serum replacement), this will result in a shorter life-span |
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Term
| what does the fibrinolytic system do? |
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Definition
| maintains balance between excessive clot and clotting disorder |
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Term
| upon activation what are some arachidonic acid products produced by up-regulation of phospholipases? |
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Definition
| leukotrienes, prostaglandins, (big ones). also, prostacyclin, thromboxane, and lipoxin. |
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Term
| what arachidonic acid products are produced by endothelial cells? |
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Definition
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Term
| what arachidonic acid products are produced by platelets? |
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Definition
| leukotrienes and thromboxane |
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Term
| what are platelets generating thromboxane doing? |
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Definition
| causing vasoconstriction and platelet aggregation, (COX path) |
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Term
| what are platelets generating lipoxin doing? |
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Definition
| inducing vasodilation, (5-LOX path) |
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Term
| why would platelets induce vasoconstriction and vasodilation? |
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Definition
| the 5-LOX pathway uses leukotriene E4, which is something that neutrophils in close association with platelets can provide. thus if there are neutrophils around, platelets will induce more vasodilation. in the absence of neutrophils, platelets are shifted towards the COX pathway, leading to vasoconstriction |
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Term
| beyond vasodilation, what are other effects of products from the LOX-5 pathway? |
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Definition
| lipid soluble, chemotactic factors that act over a short distance. leukotrienes and lipoxins can also be produced. |
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Term
| what is a major product of the COX pathway? |
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Definition
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Term
| what is the enzyme that steroids inhibit that creates arachidonic acid from cell membrane phospholipids? when would you want to use steroids? |
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Definition
| phospholipase. steroids are applicable in autoimmune disorders, this will block all pro-inflammatory stimuli, and neither the COX or 5-LOX pathway will be induced. |
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Term
| what is prostaglandin made into in endothelial cells vs platelets? what are the effects of these products? what does prostaglandin do on its own? |
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Definition
| in endothelial cells, prostaglandin is made into prostacyclin, which causes vasodilation. in platelets, prostaglandin is made into thromboxane which causes vasoconstriction. on its own prostaglandin causes vasodilation and potentiates edema |
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Term
| when do you want to intervene in terms of inflammation? |
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Definition
| intervention is helpful when chronic inflammation results in pathology |
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Term
| what is the difference between COX-1&2 in terms of where and when they are expressed? what medications block these, are there considerations for which rx to pick? |
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Definition
| COX-1 is constitutively expressed in many tissues, most of which are in the GI tract. COX-2 is more related to inflammation, though it is likely expressed on a low level at other times. aspirin inhibits both, and b/c it affects COX-1, it can have bad GI effects longterm. other NSAIDs that only affect COX-2 have less side effects. |
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Term
| are there inhibitors for 12-LOX or 5-LOX? |
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Definition
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|
Term
| why not prescribe steroids to reduce acute inflamation? |
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Definition
| b/c it induces an immune compromised state, which is good in the short term for autoimmune conditions, but it leaves the pt susceptible to other infections |
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Term
| what are the eicosanoids? |
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Definition
| thromboxane A2, leukotrienes, prostaglandins, and lipoxins |
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Term
| what are the actions of the following eicosanoids thromboxane A2, leukotrienes, prostaglandins, and lipoxins? |
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Definition
| thromboxane A2, leukotrienes C,D,E: vasoconstriction. prostaglandins: vasodialation. leukotrienes C,D,E: increased vascular permeability. lipoxins, leukotriene B: chemotaxis, leukocyte adhesion. |
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Term
| can you get the generation of lipoxin in a neutrophil? |
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Definition
| no, but neutrophils do produce some of it's intermediates |
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Term
| what are some sources for platelet activating factor, (PAF)? |
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Definition
| endothelium, platelets, monocytes, and macrophages, (including resident macrophages and mast cells) |
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Term
| what are the major inflamatory actions of PAF? |
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Definition
| leukocyte aggregation+adhesion, priming for chemotaxis, platelet activation, stimulation of other mediators, (oxygen radicals, LTs) |
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Term
| what would a low dose of PAF induce? what about a high dose? |
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Definition
| a low dose induces vasodialation and increased vascular permeability. a high dose would induce vasoconstriction and bronchoconstriction. |
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Term
| how do histamine and PAF compare? |
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Definition
| PAF is more potent, histamine's effect is almost instantaneous, but rapidly depleted. histamine is an initiator of the inflamatory process, and PAF steps in 24-48 hrs later to maintain the process |
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Term
| what are the earliest mediators of inflamation? why are they produced and where do they come from? |
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Definition
| Il-1 and TNF are produced by macrophages and other cells after being stimulated by bacterial products, immune complexes, toxins, physical injury, and other cytokines |
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Term
| what acute phase reactions do IL-1 and TNF bring about? |
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Definition
| decreased appetite, APP response, (some go up, some do down) |
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Term
| what systemic hemodynamic effects of IL-1 and TNF can be problematic if distributed systemically? |
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Definition
| increased vascular caliber, blood loiters, some leaks, BP plummets, some vessels collapse, hypotension that can lead to shock |
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Term
| what are endothelial effects of Il-1 and TNF? |
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Definition
| increased leukocyte adherence, prostaglandin synthesis, pro-coaguant activity increased in the short term, anti-coagulant activity increased in the long term. production of IL-1, IL-8, IL-6 |
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Term
| what are the fibroblastic effects of IL-1 and TNF? when do they occur? |
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Definition
| increased proliferation of fibroblasts, collagen synthesis, collagenase, protease. under normal conditions these happen during the resolution phase and can lead to wound healing. |
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Term
| what are the effects on leukocytes by TNF and IL-1? |
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Definition
| increased cytokine secretion |
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Term
| what is the progression in terms of cellular immune system components and their interaction via cytokines/signaling molecules? |
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Definition
| neutrophils respond to bacterial products, and to a limited degree 1st chemokines and produce factors resulting in up-regulation of monocytes. these monocytes then produce certain factors that stimulate lymphoid cells entering the microenvironment |
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Term
| what are signals targeted at neutrophils? |
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Definition
| IL-8, (a prototypic chemokine), bacterial products, and others |
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Term
| what are signals targeted at monocytes? where do they come from? |
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Definition
| MIP-1, alpha and beta, all produced by monocytes and resident cells and eosinophils/basophils |
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|
Term
| what are signals targeted at lymphocytes? where do they come from? |
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Definition
| lymphotaxin, RANTES, produced by resident cells, macrophages, and eosinophils/basophils |
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Term
| under normal, (not acute inflammation), conditions what role does NO play in the body? |
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Definition
| eNOS, (NO synthase), in endothelial cells produces NO constitutively at a low level, which increased slightly with inflamation. ENOS has local and short term down regulatory effect on non-specific leukocyte adhesion. it causes vasodilation, relaxes smooth muscle, maintains normal architecture and decreases platlet aggregation. essentially keeps normal balance. |
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Term
| during acute inflammation, how is NO used? |
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Definition
| macrophages are stimulated to activate iNOS which gives a massive NO increase, an RNS that can affect pathogens as well as play a compensatory function that reduces inflammation |
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Term
| what are the 2 kinds of granules that neutrophils have? |
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Definition
| specific and azurophil granules |
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Term
| what do specific granules do? |
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Definition
| they are the granules that help neutrophils leave vascular network, (as they are the first to do so), they contain lactoferitin, lysozyme, alkaline phosphatase, type IV collagenase, etc |
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|
Term
| what do azurophil granules do? |
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Definition
| these are for killing pathogens. they contain myeloperoxidase, lysozyme, cationic proteins, acid hydrolases, all molecules w/many anti-microbial properties that would be damaging if released into the EC, and endothelial cells if released too soon. these factors can degrade cells down to pus. |
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