Inflammatory Stress Flashcards

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1
Q

What is inflammation

A

A localized response to injury or infection that leads to the activation of immune-system cells and their recruitment to the affected sites

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2
Q

What are two main integral components of the host’s defense system

A

Innate immunity and adaptive immunity

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3
Q

What is inflammations associated with

A

The release of pro-inflammatory factors from immune cells

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4
Q

What are the signs of inflmations

A

Heat Redness swelling and pain

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5
Q

What is innate immunity

A

Nonspecific defense mechanisms that come into play immediately or within hours of a pathogen or damage apperance in the body

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6
Q

What do innate immune cells recognize

A

Pathogen invasion or cell damage with intracellular or surface receptors including Toll-like receptors

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7
Q

What are innate immune cells in tissues

A

Macrophages and dendtric cells

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8
Q

What are circulation innate immune cells

A

leukocytes monocytes and neutrophills

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9
Q

What do these receptors detect

A

Directly or indirectly pathogen associated molecular patterns (PAMPS)

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10
Q

What are PAMPs

A

microbial nucleic acids, lipoprotiens and carbodhydrates or damage associate molecular patterns (DAMPs)

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11
Q

What do these cells do

A

All these cells as well as fibroblasts and mast cells screte mutiple molecules (mediators) which mediate different aspects of the inflmmatory response

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12
Q

What do dendtric cells do

A

Recognize and ingest pathogens and coordiante the activity of many different types of immune cells by relasing pro-inflammatory cytokines and chemokines to recruit them to site of infection of immediate protection and by serving as antigen-presenting cells to adaptive immune cells

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13
Q

What do neutrophills and macrophages do

A

Recruited to sites of inflammation are directly involved in killing invading pathogens; accumulation of dead leucocytes including neutrophils eventually leads to the presence of pus at the site of the infection

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14
Q

What do the majority of innate immune cells express

A

Cell-surface receptors which recognize and are activated by broad classes of microbial molecules deemed PAMPS and TLR

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15
Q

What can we use to measure and detect inflmmation

A

Pro-inflammatory molecules

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16
Q

What are the 3 most common cytokines

A

Tumor necrosis factor TNF-a
interleukins IL-1B
IL-6
all markers of inflammatory stress

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17
Q

What plays an essential role in conjunction with most common pro-inflammatory cytokines

A

nuclear factor kB

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18
Q

What was discovered in the adult fly

A

Toll signaling induces the expression of several host-defense mechanisms including antimicrobial peptise which is critical for defense agianst gram positve bacteria and fungal pathogens

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19
Q

What are homologs of Toll where were they found and how many are there

A

Toll like receptors found in other animals associated with resistance to viral bacterial and fungal infection best characterized cell surface recports that interact with PAMP and DAMP 13 TLRs

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20
Q

What are the three domains of TLR

A

Extracellular domain- leucine rich repeats forms a sickled shaped and is involved in ligand recognition binds to microbial lipopolysaccharides, cell wall and nucleic acids
Cytoplasmic domain - contains specific subdomains TIRs which are responsible for the recuitment of six adapter protiens cytoplasmic tail binds MyD88- TIR TIR interacations
Transmembrane domain

21
Q

What is the second domain of MyD88

A

Death domain which is responsible for recruiting IRAK4 and IRAK 2 they also have DD domains these domains can bind to each other through DD interactations MyD88-DD/DD-IRAK
This occurs as a result of TLR activation this then phosphorylates downstream signalling molecules leading to release of active transcrpition factor NF-kb and trasncription of pro-inflammatory genes

22
Q

What are the two categories of microbial ligands

A

pathogen derived cell wall components (lipids, protiens, glycans) and pathogen derivednucleic acids

23
Q

What do the TLR 1, 2 ,4 ,5 ,6

A

Cell surface receptors and serve a sensors for microbed present and they recognize specefic components of pathogen eneveloope/cell wall

24
Q

What do TLR3,7,8,9,13 do

A

Located intracellulary in the membrane of endosomes they detect RNA and DNA components of degraded pathogens that have been taken into cells by phagocytosis

25
Q

What activates the dimers of TLRS

A

Various ligands, lipoteichoic acid and diacyl and triacyl lipoproteins

26
Q

Where is Nf-kB found

A

Promoter region of the inflammatory response genes: inflammatory cytokines, chemokines, COX-2, cytochrome p450 and HSP90, adhesion

27
Q

What is COX-2

A

Inflammatory response gene thought to be responsible for much of the increased prostaglandind production at inflammatory sites target of many anti-inflammatory drugs

28
Q

What is prostaglandins

A

Hormone like compounds which have important effects on local blood flow and perception of pain ADVIL inhibits COX enzymes

29
Q

What is the COX-2 gene highly dependent on

A

NG-Kb activation

30
Q

What are three famileies that central for NF-kb signaling

A
  1. Nf-kb/Rel family of transcription factors 2. IkB inhibitor protiens
  2. I-kB protein kinases (IKK)
31
Q

what is NF-kb REL family composed of

A

Five related transcription factors RElA/p65 RElB c-rel NFkb1 p50/p105 and NF-kB2 p52/p100

32
Q

What are the similarties of the transcription factors in the NF-kb/Rel family

A

Share a N terminal DNA binding domain and the dimerization domain RHD can form homodimers and hetrodimers that regulate the expression of genese influencing a broad range of biological processes

33
Q

What can NF-kB dimers bind to

A

Variety of releated target DNA sequences called kB sites to modulate gene expression

34
Q

What do RelB c-REL and p65 contain

A

C-terminal transcription activation domainds TAD which enable co-activator recruitment and target gene expression

35
Q

What do p50 p52 lack

A

TAD and only activate transcription by forming heterodimers with p65 c-REl or RelB or by recruiting other TAD contaning protiens

36
Q

What can p50, p52 do

A

Repress transcription on binding to DNA

37
Q

What is the inihibtiory ikB family composed of

A

8 protiens two of them are non processed

38
Q

What does the IKK complex family connsist of

A

conssit of two catalyticallly active kinases IKK1 and IKK2 and NEMO

39
Q

What are the components of Canonical NF-kB components

A
  1. Transcription factor which is a hetro dimer RELA(p65)/p50 (NF-kB1)
  2. Sensor which is IKbA an inhibitor of NF-kB
  3. Transducer which trimeric IKK complex composed of two catalytic subunits and one regulatory subunit
40
Q

What is the canonical NF-kb signaling pathway in resting cells

A

NF-kb is inactive in complex with I-KB and the acatviation

41
Q

What are the 6 steps of canonical NF-kB signaling pathway

A
  1. Many agents can stimulate trimeric I-kB kinase activation by phospphoylation IKKb subunit. The phosphorylation of IKB is driven by protien kinase TAK1
  2. The I-kb kinase B subunit phosphorylates the inhibitos 1-kBa, which then binds an E3 ubiquitin ligase
  3. E3 ubiqutin ligase induces polyubiquitination of I-kbA
    4.Uqbiunitated I-kbA degraded
  4. Removal of I-kBa unmasks nuclear loclaization signals in both subunits of NF-kB causing them to translocate into the nucleus
  5. NF-kb acitvates transcption of numerous target genes including genes encoding various inflammatory cytokines and the gene encoding I-kBa which acts to terminate signaling
42
Q

How can you measure NF-kB activation

A

Western blotting and immunofluroescene for detecting p65

43
Q

What was pulmonary arterty endothelial cells treated with

A

lipopolysaccharide which is a cell wal component of Gram negative bacteria

44
Q

What were the results of spatio temporal changes

A

There is a time dependent movement of p65 from cytoplasm to nucleus over 2h
second fluorscence immunostaning shows taht p65 from cytoplasm to nucleus over 1h however over 4-24 hours the staning returns back to the cytoplasm

45
Q

What does the stain returning back to the cytoplasm mean

A

The negative feedback is working due to acummulation of newly synthesized I-kBA which is required to maintain the balance and avoid overactivation of NF-kb

46
Q

What are the noncanonical components of NF-kb

A
  1. transcrption factor hetrodimer RELB/p52
  2. Sensor which is NF-kb2 p100
    Transducer which is IKKa kinase and one catlytic subunit
47
Q

What is the difference between the non canonical and the canonical pathway

A

Non canonlical pathway relies on phospholatyion of induced p100 processing into p52 triggered by TNFR
Dependent on NIK kinase and IKKA but not on the trimeric IKK complex and TGF-b acitvated kinase 1 TAK!
Slow and persistent

48
Q

What does NF-kb non-canonical releate to

A

Lymphoid oragnogensis, -cell survival and maturation, dendtric cell activation and bone metabolism

49
Q

What does deregulated non-canonical NF-kb signaling associated with

A

Lymphoid maliganices