Inflammation part 2 Flashcards
Activation of leukocytes and others
the responses of these leukocytes consist of recognition of the offending agents by TLRs and other recptors, described earlier, which deliver signals that activate the leukocytes to phagocytose and destroy the offending agents
recognition of microbes or dead cells induces several responses in leukocytes that are collectively called leukocyte activation
activation results from signaling pathways that are triggered in leukocytes resulting in increases in cytosolic CA and activation of enzymes such as protein kinase C and phospholipase A2. The functional responses that are most important for destruction of microbes and other offenders are phagocytosis and intracellular killing.
Phagocytosis
- recognition and opsonization of the particle to be ingested by the leukocyte; the efficiency of phagocytosis is greatly enhanced when microbes are opsonized by specific proteins (opsonins) for which the phagocytes express high affinity receptors. The major opsonins are IgG antibodies, the C3b breakdown product of complement, and certain plasma lectins, notably mannose binding lectin, all of which are recognized by specific receptors on leukocytes
- Engulfment with subsequent formation of a phagocytic vacuole. After a particle is bound to phagocyte receptors, extensions of the cytoplasm (pseudopods) flow around it, and the plasma membrane pinched off to form a vesicle (phagosome) that encloses the particle. The phagosome then fuses with a lysosomal granule, resulting in discharge of the granule’s content into the phaglysosome. During this process the phagocyte may also release granule contents into the extracellular space
killing or degradation of the ingested material
Oxygen dependent system:
ROS are produced by the rapid assembly and activation of a multicomponent oxidase, NADPH oxidase (also called phagocyte oxidase), which oxidizes NADPH and, in the process, reduces oxygen to superoxide anion. The ROS are produced within the lysosome and phagolysosme, where they can act on ingested particles without damaging the host cell is then converted into hydrogen peroxide (h2O2), mostly by spontaneous dismutaiton. H202 is not able to efficiently kill microbes by itself. However, the azurophilic granules of neutrophils contain the enzyme myeloperoxidase, which in the presence of a halide such as CL, converts to H2O2 to hypchlorite (the active ingredient in household bleach). The latter is a potent antimicrobal agent that destroys microbes by halogenation (in which the halide is bound covalently to cellular constituents) or by oxidation of protiens and lipds (lipid peroxidation). The H2O2-MPO halide system is the most eficient bactericidal system of neutrophils. Nevertheless inheritied deficiency of MPO by itself leads to minimal increase in susceptibility to infection, emphasizing the redundancy of microbicidal mechanisms in leukocytes. H2O2 is also converted to hydroxyl radical, another powerful destrctive agent. As disscued earlier these oxygen derived free radicles bind to and modify celllular lipds, proteins, and nucleic acids, and thus destroy cells such as microbes. Oxygen derived radicals may be relased extracellular from leukocytes after exposure to microbes, chemokines, and antigen antibody complexes, or following a phagocytic challenge. these ROS are implicated in tissue damage accompanying inflammation.
Nitric Oxide
NO has dual actions in inflammation: it relaxes vascular smooth muscle and promotes vasodilation, thus contributing to the vascular reaction, but it is also an inhibitor of the cellular component of inflammatory responses. NO reduces platelet aggregation and adhesion, inhibits several features of mast cell- induced inflammation, and inhibits leukocyte recruitment. Because of these inhibitory actions, production of NO is thought to be an endogenous mechanism for controlling inflammatory responses. NO is a soluble gas produced from arginine by the action of nitric oxide synthase (NOS), also participates in microbial killing. There are three different types of NOS: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). eNOS and nNOS are constitutively expressed at low levels and the NO they generate functions to maintain vascular tone and as a neurotransmitter respectively. iNOS, the type that is involved in microbial killing, is induced when macrophages and neutrophils are activated by cytokines (IFN gamma) or microbial products.
Oxygen independent systems
these include lysozyme, lactoferrin and major basic protein. major basic protein is especially important in eosinophilic toxicity to parasites. Lysosomes. Phagosomes merge with neutrophilic lysosomes to form phagolysosomes, allowing activated enzymes to biodegrade the bacteria
Chediak-hagashi disease
autosomal recessive
infants and children
netropenia with recurrent infections
oculocutaneous albinism
aberrant granules in neutrophils and other WBCs “giant” lysosomes
melanocytes: giant melanosomes
Chronic granulomatous disease of infancy
Basic defect is of NADPH oxidase resulting in a deficiency of oxygen dependent generation of H2O2 and microbial killing.
Reccurent infections especialy catalase producing microorganisms: Candida, S. Aureus, P Aeruginosa, Listera, Aspergillus, Serratia, E. Coli.
X linked recessive in most cases, therefore usually in males
variety of histopathologic patterns is seen, especially granulomas
Morphologic patters
acute inflammation is based on type of exudate
differences in the degree of vascular permeability
type of predominant leukocyte infiltrating tissues
type of predominant protein in the exudate
Serous inflammation
serous contains low MW proteins, especially albumin. Clear yellow fluid. No cells. The ksin blister resulting forma burn or viral infection is a good example of the accumulation of a serous effusion either within or immediately beneath the epidermis of the skin (fluid in a serous cavity is called an effusion. SEcond degree burn, common skin blister after reptitive trauma, skin blisters caused by varicella, herpes.
Fibrnous inflmmation
fibrinous contains large proteins esepcially fibirn. Often coats a surface. No cells. Fibrinous pneumonia in chlorine gas inhalation or viral infection (influenza). Fibrinous pericarditis in rheumatic carditis.
ulcer
local defect on the surface of an organ or tissue that is produced by necrosis of cells and sloughing of necrotic and inflammatory tissue. Ulcertaion can occur only when tissue necrosis and resultatant inflammation exist on or near a surface. ulcers are most commonly encountered in the mucosa of the mouth, stomach, intestines, or genitourinary tract and in the subcutaneous tissues of the lower extremities in older persons who have ciruclatory distburbances predisoposing affected tissue to extensive necrosis. Peptic ulcer of the stomach or duodenum, in which acute and chronic inflammation coexist.
Purulent (suppurative
in addition to albumin, fibrin and other proteins, the exudate contains neutrophils. A exudate composed of fluid, protein, and dead/dying neutrophils and other cells is pus. Pyo is the prefix which refers to pus. Examples: suppurative pneumonia or meningitis due to pyogenic microorganism, neisseria meningitiids, pyosalpinx (purulent infection of the fallopian tube due to neisseria gonorrhoeae.)
Eosinophilic
the eosinophil is prominennt or predominant in this type of exudate. it is characteriscally occurs in type 1 hypersensitivity (allergic) reactions and certain parasitic infections. Examples: Asthma, allergic rhinitis; nematode infection, ascariasis of small intestine.
hemorrhagic
damage to endothelial cells and vessel wall allow RBCs to leak into the surrounding tissue. rickettsia are especially prone to damaged endothelial cells. examples rocky mountain spotted fever.
cellulitis
a diffuse area of acute inflammation composed of edema fluid, bacteria, and neutrophils spread through tissue. Streptococcus pyogenes. Typically occurs in skin and subcutaneous tissues, so called flesh eating bacteria.
clincially characterized by a difuse area of swelling, redness, warmth and pain. Typically occurs in skin and subcutaneous tissues. Usually necrosis is not present but, in certain instances, it may be prominent features.
