Page 153 - Textbook of Pathology, 6th Edition

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CHAPTER 6

Figure 6.7 Chemical mediators of inflammation. Inflammation and Healing

The main actions of histamine are: vasodilatation, i) Metabolites via cyclo-oxygenase pathway: Prostaglan-
increased vascular (venular) permeability, itching and pain. dins, thromboxane A , prostacyclin. The name ‘prosta-
2
Stimulation of mast cells and basophils also releases products glandin’ was first given to a substance found in human
of arachidonic acid metabolism including the release of slow- seminal fluid but now the same substance has been isolated
reacting substances of anaphylaxis (SRS-As). The SRS-As consist from a number of other body cells. Prostaglandins and related
of various leukotrienes (LTC , LTD and LTE ). compounds are also called autocoids because these substances
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ii) 5-Hydroxytryptamine (5-HT or serotonin). It is present are mainly auto- and paracrine agents. The terminology used
in tissues like chromaffin cells of GIT, spleen, nervous tissue, for prostaglandins is abbreviation as PG followed by suffix
mast cells and platelets. The actions of 5-HT are similar to of an alphabet and a serial number e.g. PGG , PGE etc.
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histamine but it is a less potent mediator of increased vascular Cyclo-oxygenase (COX), a fatty acid enzyme present as
permeability and vasodilatation than histamine. It may be COX-1 and COX-2, acts on activated arachidonic acid to form
mentioned here that carcinoid tumour is a serotonin-secreting prostaglandin endoperoxide (PGG ). PGG is enzymatically
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tumour (Chapter 20). transformed into PGH with generation of free radical of
2
oxygen. PGH is further acted upon by enzymes and results
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iii) Neuropeptides. Another class of vasoactive amines is in formation of the following 3 metabolites (Fig. 6.8):
tachykinin neuropeptides, such as substance P, neurokinin a) Prostaglandins (PGD , PGE and PGF -α). PGD and PGE
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A, vasoactive intestinal polypeptide (VIP) and somatostatin. act on blood vessels to cause increased venular permeability, 2
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2
These small peptides are produced in the central and vasodilatation and bronchodilatation and inhibit
peripheral nervous systems. inflammatory cell function. PGF -α induces vasodilatation
The major proinflammatory actions of these neuropeptides 2
is as follows: and bronchoconstriction.
b) Thromboxane A (TXA ). Platelets contain the enzyme
a) Increased vascular permeability. thromboxane synthetase and hence the metabolite,
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b) Transmission of pain stimuli. thromboxane A , formed is active in platelet aggregation,
c) Mast cell degranulation. 2
besides its role as a vasoconstrictor and broncho-constrictor.
2. ARACHIDONIC ACID METABOLITES (EICO- c) Prostacyclin (PGI ). PGI induces vasodilatation, broncho-
2
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SANOIDS). Arachidonic acid metabolites or eicosanoids are dilatation and inhibits platelet aggregation.
the most potent mediators of inflammation, much more than d) Resolvins are a newly described derivative of COX
oxygen free radicals. pathway. These mediators act by inhibiting production of
Arachidonic acid is a fatty acid, eicosatetraenoic acid; pro-inflammatory cytokines. Thus, resolvins are actually
Greek word ‘eikosa’ means ‘twenty’ because of 20 carbon atom helpful—drugs such as aspirin act by inhibiting COX activity
composition of this fatty acid. Arachidonic acid is a and stimulating production of resolvins.
constituent of the phospholipid cell membrane, besides its It may be mentioned here that some of the major anti-
presence in some constituents of diet. Arachidonic acid is inflammatory drugs act by inhibiting activity of the enzyme
released from the cell membrane by phospholipases. It is then COX; e.g. non-steroidal anti-inflammatory drugs (NSAIDs),
activated to form arachidonic acid metabolites or eicosanoids COX-2 inhibitors.
by one of the following 2 pathways: via cyclo-oxygenase ii) Metabolites via lipo-oxygenase pathway: 5-HETE,
pathway and via lipo-oxygenase pathway: leukotrienes, lipoxins. The enzyme, lipo-oxygenase, a