BIOCHEMISTRY

YOUSIF ALI

INFLAMMATION
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INTRODUCTION
INFLAMMATION (which Stans for setting a fire in Latin) is nonspecific local defensive response
mechanism to infective organism by the innate immune system , it its classified depending on
the absence of the infective organism that triggers the inflammatory disease ( abnormal event
or chronic ) and thats because the inflammatory process will continue resulting in continuous
degranualation, respiratory burst activation of kin in and etc. Unlike normal or acute events
when there is an infectious organisms and in that case the inflammatory process is self-limiting
and consist of phagocytosis, degranulation, or respiratory burst and declines either naturally or
by antibiotics, it is involving leukocytes as the principal cellular mediators in the body’s defense
against pathogenic organisms. The 5 main signs of inflammation include Dalor (pain)Mediated
by bradykinin and prostaglandins, calor (heat), Rubor (redness),tumor (swelling) Mediated by
histamine and tissue damage , and functio laesa (loss of function). In addition IL-1 and TNF-𝛼
stimulates the secretion of PGE2 through the COX pathway from the HYPOTHALMUS, PGE2
resets the body temperature (raise the setpoint) and initiates fever

Inflammation

The process of acute inflammation is initiated by resident immune cells already present in the
involved tissue as a part of the innate immune system , mainly resident macrophages, dendritic
cells, histiocytes, Kupffer cells and mast cells. These cells have surface toll-like receptors (TLRs)
receptors known as pattern recognition receptors (PRRs), which recognize two subclasses of
molecules: pathogen-associated molecular patterns (PAMPs) and damage-associated molecular
patterns (DAMPs). PAMPs are compounds that are associated with various pathogens and
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examples of them include : Endotoxins , which is a type of liposaccharides ( LPS ),

peptidoglycans and flagellin. DAMPs are compounds that are associated with host-related injury
and cell damage.

At the onset of an infection, burn, or other injuries, these cells undergo activation (one of the
PRRs recognize a PAMP or DAMP) and release inflammatory mediators (histamine, leukotriene,
prostaglandins) responsible for the clinical signs of inflammation . Vasodilation or localized
hyperemia and its resulting increased blood flow causes the redness and increased heat
(mediated by histamine, which is released by mast cells after PRR and PAMP interaction).
Increased permeability of the blood vessels results in a leakage of plasma proteins and fluid into
the tissue (edema), which manifests itself as swelling (tumor) and that increase in the tissue
size will apply pressure on the Nociceptors and sensitize the nerve ending causing the painful
feeling . Some of the released mediators such as bradykinin which came from Kinenogen as a
feedback from blood clotting. The mediator molecules also alter the blood vessels to permit the
migration of leukocytes (rolling of the WBC because of the sugar molecules (integrins)
attaching to the P-selectins), mainly neutrophils. and macrophages (mature monocytes) , to
flow out of the blood vessels (extravasation>(fluid) - Diapedesis>(WBC)) through P-CAMS and
into the tissue. The neutrophils migrate along a chemotactic gradient created by the local cells
to reach the site of injury “positive Chemotaxis”. Finally, The loss of function is probably the
result of a neurological reflex in response to pain

The cellular component involves leukocytes (mostly neutrophils and monocytes), which
normally reside in blood and must move into the inflamed tissue to aid in inflammation. Some
act as phagocytes, ingesting bacteria, viruses, and cellular debris. Others release enzymatic
granules that damage pathogenic invaders. These cells move to the inflamed tissue by the
following process: 1- margination and endothelial adhesion: The white blood cells within the
vessels which are generally centrally located move peripherally towards the walls of the vessels.
Activated macrophages in the tissue release cytokines such as IL-1(interleukin1) and
TNFα(tumor necrotic factor) , which in turn leads to production of chemokines. Cytokines
released from injured cells induce the expression of E-selectin on endothelial cells later, which
functions similarly to P-selectin, but through I and V cams CAMs instead .

DEGRANULATION :
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Granulocytes (neutrophils, eosinophils, basophils) contain granules (packages) of chemicals:-

Enzymes that damage bacteria, histamine, cytokines, prostaglandins, leukotrienes and other
toxic chemicals - Granules are opened during phagocytosis due to PAMP/DAMP – PRR ligation -
Contents are released into extracellular environment = toxic environment for pathogen to live
in - Substances result in death of pathogen = damage body’s own tissue - CAUSES PAIN (Dolor)
and LOSS OF FUNCTION - Primary granules = hydrolytic and proteolytic enzymes - Proteolytic:
activate the kinin system which increases vascular permeability = allows entry of more
phagocytes to area - They activate complement and can also cause tissue damage

Eicosanoids:

- Leukotrienes, prostacyclin, prostaglandins and thromboxanes are known as eicosanoids

- 20 carbon atoms polyunsaturated fatty acids

Extravasated neutrophils engulf the pathogen, forming a phagosome. This phagosome fuses
with the lysosome, forming a phagolysosome.

Enzymes in the lysosome and reactive oxygen species ( free radicals) kill the pathogen. The
formation of these free radicals is through respiratory burst pathways and will result in the
neutrophils sacrificing themselves and also possibly damaging the nearby body tissue :

- H2 and ca+2 ion influx into the phagosome depolarises the plasma membrane

- ( NADPH oxidase ) converts molecular oxygen into the superoxide free Radical (toxic anion)
using NADPH as electron donor

- Superoxide dismutase (SOD) converts superoxide into hydrogen peroxide (toxic)

- Myeloperoxidase(MPO) converts hydrogen peroxide into hypochlorous acid (HOCL) , which is

toxic also.
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Superoxide leaks out and damages the surrounding tissue

Then, degranulation happens, thats by having neutrophils, basophils and eosinophils releasing
their granular compounds which damages bacteria, histamine and all other toxic substances

Macrophage phase is next and it includes the mature monocyte or the oncs that left the
bloodstream (macrophages) engulfing the pathogens and breaking it into smaller fragments this
step is regulated by MCP-1/CC=12/CC-15 ( double check them !!!!)

Calcium influx also serves to stimulate the release of phospholipase A2. This serves to activate
the membrane bound arachidonic acid. Free arachidonic acid can enter either the lipoxygenase
pathway (LOX) or the cyclooxygenase pathway (COX). The lipoxygenase pathway leads to the
production of leukotrienes, HETE and HPETE ( will convert to LTA 4 ,and all cause
bronchoconstriction and increase in the permeability of the blood vessels. Cyclooxygenase
pathway leads into the production of prostaglandins (PGG2) and by raising the cAMP. which
play a role in increase of pain, fever, vasodilation, vasoconstriction and platelet aggregation . If
we manage to block specific aspects of each of the pathways, we are effectively able to decrease
the inflammatory response by inhibiting the production of such mediators.

40% of people will develop an inflammatory disease at some point in their lives, Although
infections are known to be treated by antibiotics. But, As the diagram shows, glucocorticoids
and corticosteroids can prevent the production of prostaglandins and by binding to specific
regions of DNA called glucocorticoid response elements (GREs). significantly reducing the
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inflammatory response and inhibiting the PLA-2 and COS-2 pathways . In addition, NSAIDs
such as aspirin and ibuprofen can be used to block the cyclooxygenase pathway independently
and H2 histamine receptor antagonists can prevent the production of leukotrienes and
histamine and are commonly used to treat peptic ulcers.

Fact: rheumatoid arthritis > immune system inflaming and attacking the joints and their synoial
memberane

Possible things to add : hyperpolarization + H2O2 degradation +

degranulation (role of calcium) + phagocyte ratio + granule enzymes +
opsonization

1. Psoriasis
Inflammatory autoimmune disease affects the skin by abnormal differentiation and
maturation
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Plaque + guttate + pustular + nails + psoriatic Arthropathy + erythrodermic

Idiopathic but is thought to be

● genetic
● PPT factors (infection, trauma, drugs and stress),
● loss or a deficiency of glycocalyx It
● Low cAMP:cGMP ratio
● Low ATPase
● High carbohydrate metabolic rate

causes leukocyte recruitment to the dermis and epidermis which results in psoriatic plaques
specifically neutrophils to the stratum corneum , and also neutrophils have a direct effect on
the epidermal cell proliferation rate which causes an increase in the phospholipase A2 in
comparison to normal inflammatory response .

The epidermis is infiltrated by a large number of activated T cells which can induce
keratinocyte proliferation. An increased, dysregulated inflammatory process occurs with
uncontrolled production of various cytokines such as tumor necrosis factor-α (TNF-α),
interferon-γ and interleukin-12.

Vascular engorgement occurs due to superficial blood vessel dilation

Epidermal hyperplasia causes an accelerated cell turnover rate decreasing from about 23
days to 3-5 days. The abnormal cell maturation causes poorly adherent stratum corneum
which results in flaky, scaly silver lesions on top of salmon-colored psoriatic skin .

systemic treatment and antibiotics should be avoided. Medicated corticosteroid creams

combined with phototherapy (exposure to sunlight).

psoriatic lesions can be treated by peritoneal or haemodialysis

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2. Peptic ulcers
Human stomach thought not to have

resident bacteria due to the strength of HCL Acid but H.Pyloripylori present on

gastric mucosa and becomes more common with aging, associated with other type of
ulcers and less likely to occur again after being treated with antibiotics

H.Pylori is thought to cause ulceration for two reasons firstly due to ammonia produced
by urease causes ionic changes to the mucosa and and H+ back diffusion,

And secondly due to the mucosa degrading protease which is produced by H.pylori

Prostaglandins play an important defensive role when it comes to ulcers and thats by
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Stimulating the GI tract lining to form mucus

And to inhibit the acid secretion directly

Treatment :

Cimetidine and Ranitidine ( H2 receptor antagonists ) Cause inhibition of acid secretion

in stomach

Study by Gas chromatography was done and Results suggest diversion of arachidonic
acid towards PGE2 production due to inhibition of lipoxygenase pathway.

TREATMENT
Modulate degranulation process e.g.

• Drugs that raise cAMP inhibit microtubule assembly and degradation.

Drugs that inhibit cAMP breakdown phosphodiesterase inhibitors e.g. methylxanthines,

theophylline

STEROIDS AND NSAID but there are unwanted side effects

NSAID reduce prostaglandin production

Talk about the two pathway inhibition

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DOUBLEN CHECK

AA METABOLISM

BIOSYNTHESIS OF PROSTAGLANDINS

BIOSYNTHESIS OF LEUKOTRIENES BY 5- LIPOXYGENASE PATHWAY