Cell derived inflammatory mediators

Platelet aggregation REF: Robbin’s pathology 7^th edition page 63

Preformed histamine is present in mast cell granules and is released by mast cell degranulation in response to variety of stimuli. In humans histamine causes:

1. Arteriolar dilatation
2. Increased permeability of venules (however constricts large arteries)
3. Via binding to H1 receptor on endothelial cells

Vasodilation is the most important vascular effect of histamine in humans.

It involves both H1 and H2 receptors distributed throughout the resistance vessels in most vascular beds.

Histamine’s effect on small vessels results in efflux of plasma protein and fluid into the extracellular spaces and an increase lymph flow, causing edema.

The gaps between endothelial cells also may permit passage of circulating cells recruited to tissues during the mast cell response.

In the epidermis, it causes itch; in the dermis, it evokes pain, sometimes accompanied by itching.

• A localized red spot within a few seconds and reaches a maximum in 1 minute.               
• A brighter red flush, or “flare,” extending around 1 cm developing more slowly.             
• A wheal that is discernible in 1-2 minutes.

The initial red spot results from the direct vasodilating effect of histamine (H1 receptor–mediated NO production).
The flare is due to histamine-induced stimulation of axon reflexes that cause vasodilation indirectly.
The wheal reflects histamine’s capacity to increase capillary permeability (edema formation).

A i.e. Endothelium

Nitric oxide is synthesized from arginine by the enzyme NO synthetase (NOS) in endothelial cellsQ. It causes vasodilation.

Ans. is ‘a’ i.e., Mast cells

Mast cells and basophils

• Mast cells and basophils are important inflammatory cells.
• They precipitate in both acute & chronic inflammation.
• Basophils circulate in the blood, whereas mast cells reside and mature in tissues.
• They are the most important cells in immediate hypersensitivity and are also the most important source of histamine.
• Other secretions are : Serine proteases, Carboxypeptidases, Glycosidoses, Proteoglycans, Sulfatases.

Ans. is ‘a’ i.e., Angiotensin

Ans. is ‘c’ i.e., Myeloperoxidase

• Myeloperoxidase is not an inflammatory mediator. It is an enzyme of neutrophil which catalyzes the conversion of Ct, Br-, and and SCN- to the corresponding acids (HOC1, HOBr etc.). These acids are potent oxidants and help in destroying the invading organisms.

Ans. is d  i.e., Arachidonic acid metabolites

Lipoxins

• Lipoxins are a recent addition to the family of bioactive products generated from arachidonic acid.
• The principal actions of lipoxins are to inhibit leukocyte recruitment and the cellular components of inflammation.
• There is an inverse relationship between the amount of lipoxin and leukotrienes formed, suggesting that the lipixins may be the endogenous negative regulators of leukotrienes action and may play a role in the resolution of inflammation.
• Lipoxins are generated by three pathway : –

i) 5-LOX iniatiated pathway/the LTA4 route

• This pathway involves peripheral blood platelet leukocyte interactions –> Human platelet becomes the major source of lipoxins when platelet – polymorphonuclear leukocyte (PMN adhesion occurs).
• The leukocyte 5-LOX converts arachidonic acid to LTA₄ which is then released and further transformed by adherent platelets to lipoxin A₄ via the lipoxin synthase activity of LOX.

ii) 15-LOX initiated pathway

• It is initiated at mucosal surface by 15-LOX, that coverts arachidonic acid to 15-HETE which is taken up by PMNs and is converted to lipoxin via 5-LOX.

iii) Aspirin-triggered 15-epilipoxin circuit

• Aspirin inhibits COX-1 and COX-2 by acetylation and the inhibition is irreversible.

o Acetylated form of COX-1 is inactive; whereas, acetylated form of COX-2 remains active. However, activity of aspirin acetylated COX-2 switches from generating a prastaglandin intermediate to producing 15-R HETE, the precursor of 15-epi-lipoxins.

o Aspirin acetylated COX-2 enzyme can convert arachidonic acid to 15-R HETE. Which is then transformed to 15-epi-lipoxins (l 5-epi-LXA₄ or 15-epi-LXB₄) in leukocytes. These are called aspirin triggered lipoxins.

Endogenous pathways for lipoxin generation Aspirin triggered lipoxin generation

Leukocyte                                Platelet                                     Aspirin acetylated               leukocyte

5-LOX                                       12-LOX                                             COX-2                          5-LOX

AA______ > 5HPETE_ —> LTA₄___ > Lipoxins     AA            > 15-R-HETE______________ ->15 epi­lipoxins 5-LOX initiated pathway

Mucosal                       Leukocyte

15-LOX                        5-LOX

—> 15 S – HETE_____ Lipoxins 15-LOX initiated pathway

Also know

• A new class of arachidonic acid-derived mediators is resolvin that inhibit leukocyte migration and activation -> Antiinflammatory activity of aspirin may be due to inhibition of cycloxygenase and increased production of resolvin.

Ans. is ‘b’ i.e., Interleukin IL-8

Ans. is ‘a’ i.e., Vasoconstriction

Functions of platelet activating factor are :

o It causes platelets to aggregate and blood vessels to dilate. Thus, it is important to the process of hemostasis. At a concentration of 10-¹² mol/L, PAF causes life threatening inflammation of the airways to induce asthma like symptoms

o PAF is used to transmit signals between neighboring cells and acts as a hormone, cytokines, and other signaling molecules.

o The PAF signaling system can trigger inflammatory and thrombotic cascades.

o Unregulated PAF signaling can cause pathological inflammation and has been found to be a cause in sepsis, shock, and traumatic injury.

o PAF initiates an inflammatory response in allergic reactions.

o PAF also induces apoptosis in a different way that is independent of the PAF receptor.

o It is an important mediator of bronchoconstriction.

Ans. is ‘b’ i.e., Thromboxane A2

Ans ‘D’ Arginine.

NITRIC OXIDE (NO)/ENDOTHELIUM DERIVED RELAXING FACTOR (EDRF)

• Nitric oxide, a vasodilator is formed by the action of nitric oxide synthase on Arginine. 
• Synthesis: NO is formed by the action of Cytosolic enzyme NO synthase in endothelial & neuronal cells.
• Substrate: Arginine, O2, NADPH
• Coenzyme: NADPH, FAD, FMN, Heme, tetrahydrobiopterin
• Product: Citrulline, NO

Functions

• Relaxes smooth muscles
•  Prevents platelet aggregation
• Functions as a neurotransmitter in the brain
• Mediates tumoricidal, bactericidal actions of macrophages
• Involved in penile erection

Ans. is ‘a’ i.e., Decrease leucocyte migration, adhesion, chemotaxis

Effects of lipoxins (LXA₄, LXB₄ ) are :‑

• Inhibit neutrophil chemotaxis and leukocyte recruitment (major action).
• Vasodilatation
• Promote moncytic phagocytosis of apoptotic neutrophils.

Ans. is ‘c’ i.e., Histamine