Inflammation Drugs Flashcards
T or F. Nonsteroidal anti-inflammatory agents (NSAIDS) and corticosteroids both have nonspecific actions and are sometimes ineffective.
T. AND can have deleterious effects to other systems
What are the main mediators of vasodilation in inflammation?
PGI2, PGE1, PGE2, PGD2, NO
What are the main mediators of increased vascular permeability in inflammation?
Histamine, C3a, C5a,, Bradykinin, LTC4, LTD4, LTE4, PAF, substance P, calcitonin gene related pepide (CGRP)
What are the main mediators of chemotaxis and leukocyte activation in inflammation?
C5a, LTB4, LXA4, LXB4, bacterial products
What are the main mediators of tissue damage in inflammation?
neutrophil and macrophage lysosomal productsoxygen radicalsNO
What are the main mediators of fever in inflammation?
IL-1, IL-6, TNF-a, PGE2, PGI2, LBT4, LXA4, LXB4
What are the main mediators of pain in inflammation?
PGE2, PGI2, LTB4, Bradykinin, CGRP
Asthma, a bronchial condition, is characterized by two distinct phases:
bronchospastic (caused by histamine) and inflammatory (not caused by histamine).
What is the bronchospastic nature of asthma caused by?
due to the preformed mediator histamine that is ready and packaged in mast cells in the bronchial system. Histamine stimulates cholinergic receptors that result in smooth muscle contraction in the lungs
Release of histamine from mast cells in the bronchial system in relation to asthma causes what?
causes the initial bronchospasm and initiates the synthesis and release of a slew of inflammatory mediators, including. These include PGD2, LTC4, PAF (these are anti-inflammatory agents used to control this process and return cell physiology to normal as soon as possible), and ECP (eosinophil cationic protein), MBP (major basic protein) and proteases.
T or F. Whereas a series of anti-inflammatory drugs are appropriate for asthma, antihistamines are not. Why or why not?
T. Anti-histamines block the effects of histamine binding to H1 receptors, but currently no antihistamine has utility in preventing its release from mast cells.
Whereas corticosteroids were once the only anti-inflammatory drugs used for asthma, a number of other drugs are now used for specific patients who remain inadequately responsive to corticosteroids. Name them.
Leukotrience receptor blockers (Montelukast)Leukotriene synthesis inhibitors (Zileuton)IgE-antibody (Omalizumab)PDE4 Inhibitor (Roflumilast)
What is GATA-3?
a transcription factor that is specifically expressed in TH2 cells and plays a critical role in the differentiation of Th2 cells from uncommitted CD4+ lymphocytes.
What else does GATA-3 do?
In addition GATA-3 is essential for the gene expression of the cytokines IL-4, IL-5 and IL-13 that mediate allergic inflammation.
Where is GATA-3 present in the cell of a naive T lymphocyte?
In human T lymphocytes GATA-3 is normally localized to the cytoplasm,
What happens to GATA-3 when a T cell is activated?
GATA-3 is phosphorylated by p38 MAP kinase and translocates to the nucleus via the nuclear import protein importin-alpha.
How does Corticosteroids inhibit GATA-3 movement to the nucleus upon T cell activation?
Corticosteroids bound to glucocorticoid receptors inhibit GATA-3 function by competing for nuclear entry via importin-alpha and also by inhibiting p38 MAP kinase through the induction of MAP kinase phosphatase-1.So they are accidentally controlling T cell activation from preventing GATA-3 getting into the nucleus by competitive inhibition
GATA-3 is inhibited by the Th1 master regulatory transcription T-bet but in turn inhibits STAT-4 and thus T-bet so that Th2 polarization is maintained.
GATA-3 is inhibited by the Th1 master regulatory transcription T-bet but in turn inhibits STAT-4 and thus T-bet so that Th2 polarization is maintained.Since GATA-3 appears to be a critical transcription factor for allergic inflammation it is an obvious target for inhibition. However, direct inhibition by inhaled specific oligonucleotides or interference RNA is not yet possible. Corticosteroids act as indirect inhibitors and in patients with corticosteroid resistance p38 MAP kinase inhibitors may also prove to be useful in the future.
Describe the Ngb pathway.
There are two major signaling pathways that lead to upregulation of transcriptional activity that are mediated by inflammatory cytokines, this is one. Under resting conditions, NF-κB (a heterodimer of p50 and p65 subunits) is tightly bound to an inhibitor called IκB that sequesters NF-κB in the cytoplasm. Engagement of one of the TLRs or the signal transducing receptors for interleukin 1 (IL-1) or tumor necrosis factor (TNF) family members leads to induction of IκB kinase activity that phosphorylates IκB on critical serine residues. Phosphorylated IκB becomes a substrate for ubiquitination, which triggers degradation of IκB by the 26S proteasome. Loss of IκB results in release of NF-κB, which permits it to move to the nucleus and activate transcription of genes whose promoters contain κB recognition sites.
The second major transcription regulating pathway is the JAK/STAT pathway. Describe it.
Binding of human IFN-γ (a dimer) to its receptor brings about oligomerization of receptor complexes composed of α and β chains. The nonreceptor protein tyrosine kinases Jak1 and Jak2 are activated and phosphorylate critical tyrosine residues in the receptor such as the tyrosine at position 440 of the α chain (Y440). STAT1α molecules are recruited to the IFN-γ receptor based on the affinity of their Src homology 2 (SH2) domains for the phosphopeptide sequence around Y440. Receptor-associated STAT1α molecules then dimerize through reciprocal SH2-phosphotyrosine interactions. The resulting STAT1α dimers translocate to the nucleus and stimulate transcription of IFN-γ-regulated genes.
