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PHAY00011 > Inflammation I > Flashcards

Inflammation I Flashcards

Mechanism and anti-inflammatory drugs

1
Q

What are the five cardinal signs of inflammation?

A

Redness

Heat

Swelling

Pain

Alteration and loss of function

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2
Q

What are the 3 important enzyme systems in the inflammatory response?

A

Complement cascade (alternative pathways)

Coagulation and fibrinolytic cascade

Kinin-kallikrein system

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3
Q

What is the main product of the complement cascade that contribute significantly to the inflammatory response?

A

Anaphyloid toxins like C3a and C5a

Directly cause smooth muscle to spasms

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4
Q

What does kinin-kallikrein system generate?

A

Bradykinin

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5
Q

When did the kinin-kallikrein system activated?

A

Upon tissue injuries

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6
Q

Describe the events of the kinin-kallikrein system that produce bradykinin.

A

Injuries -> exposed negative surface

Activation of factor XII -> factor XIIa

Factor XIIa convert pre-kallikrein -> kallikrein (a serine proteases)

Kallikrein slip bradykinin out of HMW kininogen

Bradykinin - rapidly inactivated by ACE

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7
Q

How can bradykinin induce all 5 cardinal signs of inflammation?

A

Vasodilator: interact receptors on vascular -> NO production -> granulate cyclase production -> vasodilation on small vascular level -> increased RBC influx -> redness and heat

Vasodilation -> increased permeability -> fluid into extravascular environment -> swelling

Directly interact with pain receptors and sensory nerve fibre -> pain

Swelling pressing on fibre -> pain

Trigger eicosanoid production -> activation of inflammatory cells -> amplication of response + release granulated contents -> damage

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8
Q

What are the cells associated with the generation of inflammatory response?

A

Specialised inflammatory cells - present in tissues + recruited from blood.

Vascular endothelial cells

Structural cells

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9
Q

Name some inflammatory cells present in the tissues

A

Mase cells

Macrophages

Residue in tissue and ready to be inactivated

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10
Q

Name some inflammatory cells that can be recruited from the blood.

A

Neutrophils, eosinophils, monocytes, lymphocytes, basophils and platelets

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11
Q

What is the role of platelets in inflammatory response?

A

Involved in the coagulation and fibrinolytic system

Promote and facilitate the activity of blood leukocytes

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12
Q

How are vascular endothelial cells involved in the inflammatory response?

A

Determines how the inflammatory response progress

Able to produce many inflammatory mediators

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13
Q

What are the structural cells involved in the inflammatory response and how do they contribute?

A

Smooth muscle, epithelial cells and neurons - cells of the inflammed tissue

Rich source of locally active inflammatory mediators

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14
Q

What is eicosanoid?

A

Eicosanoids are any mediators derived from arachidonic acid (AA).

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15
Q

How are eicosanoids produced?

A

From arachidonic acid liberated from phospholipid - activity of phospholipase A2 (PLA2).

Through COX enzyme activation - 2-step process - 2 separate active sites

COX: AA -> PGG2 -> PGH2 -> 1 of 5 prostanoids (PGI2, PGF2-alpha, PGD2, PGE2 and TXA2 - dependent on cell types and synthase enzyme present

H2O2 produced, enhance activity of COX

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16
Q

How can the eicosanoids and prostanoids produced exert the inflammatory response?

A

Prostanoids: PGI2, PGF2-alpha, PGD2, PGE2 and TXA2

Act on G-coupled receptors: IP, FP, DP, EP and TP.

IP and some EP - Gs-coupled -> relaxation of smooth muscle.

FP and TP - Gq coupled -> increased intracellular Ca ions level

IP3 - Gi coupled -> regulatory receptor -> negative regulation of adenylate cyclase -> reduce cAMP level.

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17
Q

How is phospholipase A2 activated?

A

Increased intracellular calcium ions upon inflammatory cells activation.

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18
Q

Besides arachidonic acid, what is the other precursor of potent mediator liberated from phospholipid by PLA2?

A

Lyso-PAF -> platelet-activating factor (PAF) - NOT AN EICOSANOID.

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19
Q

Upon liberation, what metabolic pathway does AA go into?

A

Either COX pathway or LOX (lipoxygenase pathway)

Dependent on the cells and tissues.

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20
Q

Name of compound activate the lipooxygeanse?

A

FLAP (five-lipoxygenase activating protein)

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21
Q

Through what pathway does leukotrienes produced from AA?

A

Lipoxygenase pathways

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22
Q

How is leukotrienes produced from AA?

A

LOX convert AA -> 5HPETE -> LTA4 (2 - step process)

Neutrophils - LTA4 hydrolases convert LTA4 - LTB4 -> amplification of neutrophil response.

Eosinophils and mast cells - LTC4 synthase convert LTA4 -> LTC4 (can be further -> LTD4 and LTE4) -> amplification of eosinophil response.

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23
Q

How many important co-factors is required for the activity of nitric oxide synthase (NOS) to work?

A

5 important co-factors

FMN, HAEM, FAD, BH4, Calmodulin

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24
Q

What enzyme produces nitric oxide?

A

Nitric oxide synthase (NOS).

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25
Q

Describe how NO is produced?

A

Activity of NOS

Through the conversion of L-Arg into L-CIT in the presence of O2.

At the same time NAPDH is converted into NADP+

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26
Q

How many isoforms of NOS are there?

A

3 isoforms:

NOS-1: neuronal NOS (nNOS)

NOS-2: inflammatory cells and vascular endothelial cells (iNOS)

NOS-3: endothelial NOS (eNOS)

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27
Q

What isoforms are constituitive and what isoforms are inducible?

A

NOS-1 and NOS-3 are constituitive - present all the time in neuron and endothelium

NOS-2 is inducible - only appeared during inflammation.

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28
Q

Why is it important for constituitive NOS to be constantly expressed?

A

Maintenance of vascular tones at acceptable level

Regulate activity of endothelium - preventing activation of platelets from being activated + stick to it

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29
Q

What are the main differences between constituitive NOS and inducible NOS?

A

Constituitive NOS are dependent on Ca ions and produce picomolar quantities of NO.

Inducible NOS are not dependent on Ca ions and produce nanomolar quantities of NO (much higher).

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30
Q

How are constituitive NOS activated?

A

Increased intracellular Ca ions

Calcium calmodulin interaction -> activate

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31
Q

How are inducible NOS activated?

A

Cytokines and bacterial toxins

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32
Q

Why is it beneficial for iNOS to produce 1000 times more NO than eNOS and nNOS?

A

Contribution towards host defence

Allow inflammatory cells are constantly activated.

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33
Q

Describe how NO is produced under physiological conditions

A

eNOS and nNOS produce NO - readily scavenged by Hb -> inactivated.

By product O2- (oxygen radicals) - toxic to tissue - controlled by superoxide dismutase and catalase.

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34
Q

What enzymes control the reactive oxygen species (the by-product of NO production) under control?

A

Superoxide dismutase -> convert O2- into H2O2.

Catalse -> convert H2O2 into O2 and H2O

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35
Q

How are the balance of NO and O2- impacted under pathophysiological conditions?

A

iNOS - excessive amount of NO

Phagocytic cells - oxidative burst killing mechanism - exessive amount of O2-

O2- and NO is cytotoxicity

O2- react with NO -> ONOO- (peroxynitrite) is also cytotoxicity

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36
Q

What is the main issues with this excessive production of NO and O2- during pathophysiological conditions?

A

Cytotoxicity

Can damage the activity of constituitive NOS.

Dysfunction of vascular endothelium -> risk of CVD.

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37
Q

What are the microvascular events happening in acute inflammatory response?

A

In arterial sites: Increased local blood flow.

In venous side: plasma leakage + cell extravasation

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38
Q

Explain the response of arteriole during acute inflammation.

A

Increase diamter -> increased blood flow.

Sensory nerve - peptide (CGRP, substance P) -> affect vascular tones

Vascular endothelial cells + inflammatory cells -> vasoactive mediators -> increased diameter of the vessels.

Vascular endothelial cells - NO through enOS + respond to inflammatory mediators (bradykinin, PAF, histamines) -> more NO through iNOS.

Inflammatory cells - NO through iNOS + prostanoids (eicosanoids)

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39
Q

Explain the response of post-capillary venule during acute inflammation.

A

Increased permeability -> plasma exudation into surrounding tissue

Mediators released from sensory nerve + vascular endothelial cells + inflammatory cells -> increased permeability.

Mediators -> expression of adhesing proteins on endothelial surface and leukocytes -> margination, firm adhesion and migration into tissues (neutrophil extravasation)

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40
Q

How can leukocyte interact with vascular endothelial cells?

A

Through adhesion molecules

Present on leukocyte surface + endothelial cell surface

41
Q

Are adhesion molecules always expressed?

A

Some are constituitively expressed

Some only expressed in response to inflammatory stimulus

Some constituitively expressed but require activation by inflammatory mediators.

42
Q

What are the adhesion molecules produced for the interactions between leukocytes and endothelial cells?

A

Selectin

Integrins

43
Q

How do selectins contribute to leukocyte-endothelial interactions?

A

Weak interaction -> loose tethering of the leukocytes to the endothelium

Explain the rolling along the endothelium

44
Q

How do integrins contribute to the leukocyte-endothelial interactions?

A

Strong interactions -> cells stop rolling

Firm adhesion to endothelium

Allow transendothelial migration

45
Q

What surface substances of endothelial cells that the integrins can interact?

A

ICAM-1 and VCAM-1

46
Q

What are the two types of selectin?

A

endothelial selectin (e-selectin) - bound to endothelial cell surface

platelet selectin (p-selectin) - rapidly mobilise

47
Q

What activates the expression of selectin and integrin?

A

Selectin - stimuli

Integrin - inflammatory mediators, cytokines from endothelial cells.

48
Q

Name the pleiotropic mediators that can direct inflammation

A

Peptides, proteins and glycoproteins

Pro-inflammatory and anti-inflammatory mediators

49
Q

Give examples of some inflammatory mediators.

A

IL-1 (pro-inflam), IL-4, IL-6 (pro-inflam), IL-10 (anti-inflam)

Chemokines like IL-8 and PF4

TNF-alpha (pro-inflam)

IFN-alpha, IFN-gama

G-CSF, GM-CSF (colony stimulating factor)

Growth factors (VEGF, FGF)

50
Q

What are the local mediators produced for inflammatory response?

A

Bradykinin - from the kinin-kallikrein system

Histamines - from mast cell degranulation

Eicosanoids - in response to inflammation from AA

PAF - in response to inflammation from AA

Neuropeptides - from sensory neurons

51
Q

What are the inflammatory proteins release for propagting and driving the immune response?

A

Cytokines

Adhesion molecules

Cell-derived enzymes like proteinases - to break down the cellular matrix structure

Inducible enzymes - COX-2 and NOS-2 (iNOS)

52
Q

What are the therapeutic properties of NSAIDs?

A

Anti-inflammatory

Analgesic - reduce pain

Antipyretic - reduce fever.

53
Q

What is the main mechanism of action of NSAIDs?

A

Inhibit the activity of cyclooxygenase (COX) enzymes (both steps) -> inhibit prostagladins production

Competitive and reversible (mostly)

54
Q

What is the only NSAID that is not a competitive and reversible inhibitor for COX?

A

Aspirin

55
Q

What is the important prostagladin that involved in the therapeutic properties of NSAIDs?

A

PGE2

56
Q

How can NSAIDs reduce the pain?

A

Prostagladins PGE2 sensitise sensory nerve fibre -> lower concentration of stimuli (bradykinin) can lead to same amout of pain

Inhibit prostagladin synthesis -> reduce pain sensation

57
Q

How can NSAIDs help to reduce overall body temperature?

A

PGE2 - hypothalamic set point raised during inflammation and infection

Inhibit synthesis -> reduce set point

58
Q

Different NSAID classes (6 classes)

A

Salicyclic acid derivatives - aspirin

Propionic acid derivatives - Ibuprofen, naproxen

Acetic acid derivatives - diclofenac, indometacin

Fenamates - mefenamic acid

Oxicams - piroxicam, meloxicam

Coxibs - celecoxib

59
Q

How is coxib like celecoxib different from other NSAIDs?

A

COX-2 selective

60
Q

How many distinct forms of COX exist?

A

2 forms:

COX-1 - constituitive expressed in kidney, vascularate, GI tract

COX-2 - induced in inflammation. But constitutively expressed in some organs.

61
Q

What organs are COX-2 expressed constitutively?

A

Brains

Kidney

Reproductive organs

62
Q

Why is it required to have COX-1 constitutively expressed in the body?

A

Production of ‘housekeeping’ prostagladins like PGE2 and PGI2

63
Q

What is the role of the ‘housekeeping’ prostagladins?

A

Producing TXA2 in platelets

Producing prostacyclines in endothelial cells

Involved in renal blood flow and eGFR

Protection of gastric mucosa via synthesis of mucus and HCO3-

64
Q

Benefits of COX-2 in inflammation

A

Significantly amplified amount of PGE2 and other prostagladins

65
Q

What is the main side effects of NSAIDs?

A

GI side effects - higher risk in COX-1 selective

Inhibition of housekeeping PGs -> reduced mucus and HCO3- synthesis -> reduce mucosa protection

66
Q

Rank these drugs in the order of its pottential of causing GIT disturbance: aspirin, diclofenac, ibuprofen, indometacin, naproxen, piroxicam.

A

From lowest to highest:

Ibuprofen - diclofenac, naproxen, indometacin - piroxicam, aspirin

67
Q

Exploit the subtle differences between COX-1 and COX-2

A

Active site (hydrophobic channel) - wider in COX-2 - accommodate larger drugs

Arg120 - less important in COX-2

Amino acid 523 - Val in COX-2 and Ile in COX-1 - Ile is bigger than Val - steric hindrance for hydrophillic side pocket

Accessible side pocket in COX-2 - His and Arg residue - stabilise interaction

68
Q

What is the significance for the subtle differences between COX-1 and COX-2 structure and sequence?

A

Possible to design highly-selective COX-2 inhibitors.

69
Q

What NSAIDs are highly selective for COX-1?

A

Aspirin and piroxicam

70
Q

What NSAIDs can be classified as non-selective?

A

Ibuprofen and diclofenac

71
Q

What NSAIDs are highly selective for COX-2

A

Meloxicam and Celecoxib

72
Q

What are the roles of prostaglandins derived from COX-1 in the stomach at normal, inflammed and ulceration conditions?

A

Stimulate mucus and bicarbonate production in both normal and acute injury/inflammation condition

Roles unknown in ulceration

73
Q

What are the roles of prostagladins derived from COX-2 in stomach at normal, inflammaed and ulceration conditions?

A

Normal - unknown as COX-2 should not be expressed in this condition

Inflamed - cytoprotection

Ulceration - cellular repair

74
Q

Why are NSAIDs contraindicated in patients with known and suspect gastric ulcer?

A

Might interfere with cellular repair properties of COX-2. Inhibit production of mucus and bicarbonate -> reduced protection from gastric acid

Ulcers will never heal + get worse

75
Q

Is it appropriate to switch a patient from non-selective NSAIDs to COX-2 selective if they have GI side effects?

A

No as the recovery will be slowed down.

76
Q

Why did the elimination of COX-2 will affect the survival rate?

A

Removal of important component of immune system

Reduced level of prostagladins

77
Q

What prevents the spontaneous development of ulcers?

A

COX-1 constitutive expression and its housekeeping prostagladins

78
Q

Why are NSAIDs contra-indicated in patients with renal impairments?

A

Prostagladin derived from COX are involved in renal flow and GFR.

COX-2 constitutively expressed in macular denser cells of kidneys - release prostagladins - important for blood flow and filtration - esp when angiotensin level is high.

79
Q

How does the elimination of COX enzyme will affect the fertility of female?

A

PGs play vital role in parturition

COX-1 elimination -> delayed parturition

COX-2 elimination -> reduced ovulation, fertilisation and implantation (due to constitutive expression in female reproduction system)

80
Q

How is the risk of developing CVD in patients taking NSAIDs?

A

Diclofenac - high risk

Naproxen - safest, believed to be cardioprotection

Existing CVD or with established risk is at higher risk (esp with COX-2 selective)

81
Q

How do TXA2 and PGI2 maintain the balance in the blood vessels?

A

Both are produced from AA by COX enzymes. But - TXA2 only by COX-1, PGI2 from both COX-1 and COX-2

TXA2 produced from platelets. PGI2 from endothelial cells.

TXA2 increases platelet aggregation + vasocontriction

PGI2 reduces platelet aggregation + vasodilation

82
Q

What is the rate-limiting step of COX pathways?

A

Liberation of AA from the phospholipid

83
Q

How do the TXA2-PGI2 balance change when low-dose chronic aspirin is given?

A

More PGI2, less TXA2

TXA2 produced from platelet - no nucleus - no enzyme regenerated.

PGI2 from endothelial cells - enzyme can be regenerated.

Aspirin irreversible inhibitor of COX-1 -> no TXA2 produced until new platelet form

Endothelial cells regenerate COX-1 + induce COX-2 -> more PGI2

84
Q

How do the TXA2-PGI2 balance change when COX-2 selective NSAIDs is given?

A

More TXA2 than PGI2

85
Q

How do the TXA2-PGI2 balance change when non-selective NSAIDs is given?

A

Dependent on the agent and the patient

86
Q

Explain how glucocorticoidsteroids can exert its anti-inflammatory properties.

A

Act in the cell nucleus

Alter transcription of mRNA for specific proteins

Increase the synthesis of anti-inflammatory mediators - like Annexin-1 and cytokines (transactivation)

Reduce the synthesis of inflammatory mediators and cell adhesion molecules + inducible enzymes (transrepression)

87
Q

Describe how glucocorticoids reach the nucleus upon administration.

A

Lipophillic drugs (structure based on cholesterol)

Equilibrium of unbound and bound steroids (to albumin and corticosteroid-binding globulin)

Unbound - diffuse across membrane -> interact with glucocorticoid receptors -> conformational changes -> expossure of DNA binding site.

Complex bind to DNA - alter transcription

Then unbound -> degraded in cytosol

88
Q

What does the steroid-receptor complex do in transactivation mechanism?

A

homodimerise with second complex

translocate to nucleus

interact with promoter region encoding for anti-inflammatory mediators

Induce production

89
Q

What does the steroid-receptor complex do in transrepression mechanism?

A

Interfere interaction between transcription factor with DNA

Transcription factor involved in generation of pro-inflammatory mediators

Inhibit

90
Q

The outcomes of transactivation and transrepression of corticosteroids.

A

Produce annexin-1 -> inhibit PLA2 -> no AA and PAF produced

Inhibit synthesis of prostanoids, leukotrienes and PAF (via indirectly inhibit of PLA2 activity)

Suppress iNOS and COX-2 production

91
Q

Name 2 transcription factor systems affected by glucocorticosteroids.

A

Nuclear factor Kappa-B (NFKB) - inhibitory protein (IKB) system

AP-1 system.

92
Q

Describe how glucocorticoids impact the NFKB-IKB system.

A

Nuclear factor Kappa-B is involved in the production of manu cytokines and adhesion molecules and inducible enzymes

Normally inactivated by inhibitory proteins (IkB).

IkB removed -> allow NFkB translocate into nucleus.

Glucocorticoids promote IkB production through transactivation process -> inactivate more NFkB

93
Q

Give some examples of corticosteroids.

A

Hydrocortisone, Cortisone, Prednisolone, Dexamethasone, Betamethasone

94
Q

Why are all corticosteroids compared to hydrocortisone?

A

Hydrocortisone is identical to cortisol, a body stress hormone.

Allow direct comparison

95
Q

Rank the potency of these corticosteroids: betamethasone, dexamethasone, cortisone and prednisolone.

A

From lowest to highest:

cortisone -> prednisolone -> dexamethasone, betamethasone

96
Q

Rank the duration of action of these corticosteroids: betamethasone, dexamethasone, cortisone and prednisolone.

A

From lowest to highest:

cortisone (8-12) -> prednisolone (12-36) -> dexamethasone, betamethasone (36-72)

97
Q

What are the potential side effects of glucocorticoids?

A

Adrenal insufficiency

Cushing’s syndrome - increased cortisol level, atrophy of adrenal gland due to adrenal insufficiency

Insulin resistance

Neuropsychiatric effects

Glaucoma

Skin thinning, capillary weaker -> bruising

Osteoporosis

Oral candidiasis - esp with inhaled - suppress immune response

Muscle wasting

Susceptible to infection - suppress immune response

98
Q

Why does long-term use of corticosteroid can cause adrenal insufficiency?

A

Through the hypothalamic pituitary (HPA) axis suppression due to feedback mechanism

Reduce cortisol production

99
Q

How can steroid side effects be reduced in asthma?

A

locally and topically

reduce dose

PHAY00011 (9 decks)

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